Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Ulcerative colitis-associated neoplasia (UCAN) harbors unique genetic alterations and mutational tendencies. The clinical application of gene panel testing enables precision medicine by tailoring treatment to individual gene alterations. We hypothesized that gene panel testing may detect clinically important genetic alterations in UCAN, with potential usefulness for the diagnosis and treatment of UCAN. In the present study, gene panel testing was used to identify genetic alterations in UCAN, and the possibility of clinical utility of gene panel testing in UCAN was investigated. The present study included 15 patients with UCAN, and gene panel testing was performed to identify genetic alterations associated with diagnosis and treatment. Genetic alterations of UCAN were compared with those of 203 patients with sporadic colorectal cancer (CRC). APC and PTEN mutations were less frequent, while RNF43 frameshift or nonsense mutations were more frequent in UCAN compared with sporadic CRC. TP53 mutations were identified in 13/15 patients (87%) with UCAN. Notably, 4/15 patients (27%) with UCAN had no genetic alterations other than TP53 mutation, while this occurred in 1/203 patients (0.5%) with sporadic CRC (P<0.001). Microsatellite instability-high was identified in 2/15 patients (13%) with UCAN. Mutational signature 3, which is associated with homologous recombination deficiency, was detected in 14/15 patients (93%) with UCAN, and enriched in UCAN compared with sporadic CRC (P=0.030). In conclusion, gene panel testing can detect important genetic alterations that can be useful for diagnosis and treatment in UCAN, and may provide clinicians with important information for tailored treatment strategies.

DOI： 10.3892/ol.2022.13562

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Gastric cancer is a Lynch syndrome (LS)-associated tumor, with the cumulative lifetime risk in LS patients estimated to be 5.8-13%. Hence, surveillance for gastric cancer is important for LS patients, especially in those with a family history of gastric cancer or of Asian descent. We report a very rare case of a LS patient who showed gastric metastasis from jejunal adenocarcinoma curatively resected 8 years prior. A 79-year-old female was diagnosed with a synchronous gastric submucosal tumor (SMT) and right-sided colon cancer. She was referred to our hospital as she and her family had histories of LS-associated tumors. She underwent curative intent surgery for the tumors. Postoperative histopathological examination revealed the gastric SMT was an adenocarcinoma completely covered by non-neoplastic gastric mucosa. Immunohistochemical analyses showed the gastric SMT had the same expression pattern for CDX2, cytokeratins 7 and 20 as the jejunal adenocarcinoma. Thirty-four months after surgery the patient is alive without recurrence or any other LS-associated tumors. To the best of our knowledge, this is the first report of gastric metastasis from small bowel adenocarcinoma in a LS patient. Awareness of this case may be important for gastric cancer surveillance in LS patients.

DOI： 10.1007/s12328-022-01625-5

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media {LLC}  

Neuroendocrine neoplasms of the colon and rectum are colorectal epithelial neoplasms with neuroendocrine differentiation. A platinum regimen used for small cell lung cancer is the currently recommended chemotherapy for gastroenteropancreatic neuroendocrine carcinomas (GEP-NECs), regardless of the organ. The BRAF V600E mutation has been recently reported as a druggable driver mutation in colorectal NECs. In BRAF V600E mutant colorectal cancer, a combination of BRAF inhibitor and anti-epidermal growth factor receptor (EGFR) antibody, with or without a MEK inhibitor, is recommended. Here, we report the case of 77-year-old man who had lymph node recurrence after surgery for primary ascending colonic NEC. Two cytotoxic regimens, cisplatin plus irinotecan and modified FOLFOX6, were administered as first- and second-line chemotherapies with no remarkable response observed. At this point, genetic analysis confirmed the tumor harbored a BRAF V600E mutation. Thus, a regimen of BRAF inhibitor plus anti-EGFR antibody was administered. After commencing this regimen, carcinoembryonic antigen levels decreased within normal range, and there was dramatic shrinkage of the lymph node metastases observed by chest and abdominal computed tomography scans. To our knowledge, this is the first reported case of a colorectal NEC responding to a BRAF inhibitor and anti-EGFR antibody.

DOI： 10.1007/s12328-022-01599-4

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media {LLC}  

BACKGROUND: Mesenteric lymph node (MLN) involvement is often observed in ovarian cancer (OC) with rectosigmoid invasion. This study aimed to investigate the clinical significance of MLN involvement in the pattern of liver metastasis in patients with OC. METHODS: We included 85 stage II-IV OC patients who underwent primary or interval debulking surgery. Twenty-seven patients underwent rectosigmoid resection, whose status of MLN involvement was judged from hematoxylin and eosin (H&E) staining of resected specimens. The prognostic significance of clinicopathological characteristics, including MLN involvement, was evaluated using univariate and multivariate analyses. RESULTS: MLN involvement was detected in 14/85 patients with stage II-IV OC. Residual tumor status, cytology of ascites, and MLN involvement were independent prognostic factors for progression-free survival (PFS; p = 0.033, p = 0.014, and p = 0.008, respectively). When patients were classified into three groups (no MLN, one MLN, two or more MLNs), the number of MLNs involved corresponded to three distinct groups in PFS (p = 0.001). The 3-year cumulative incidence of liver metastasis of patients with MLN involvement was significantly higher than that of patients without MLN involvement (61.1% vs. 8.9%, p < 0.001). MLN involvement was significantly associated with liver metastasis of hematogenous origin (p < 0.001) compared with peritoneal disseminated origin. CONCLUSION: MLN involvement is an important prognostic factor in OC, predicting poor prognosis and liver metastasis of hematogenous origin.

DOI： 10.1245/s10434-021-09899-8

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Tumor mutational burden-high (TMB-H), which is detected with gene panel testing, is a promising biomarker for immune checkpoint inhibitors (ICIs) in colorectal cancer (CRC). However, in clinical practice, not every patient is tested for TMB-H using gene panel testing. We aimed to identify the histopathological characteristics of TMB-H CRC for efficient selection of patients who should undergo gene panel testing. Moreover, we attempted to develop a convolutional neural network (CNN)-based algorithm to predict TMB-H CRC directly from hematoxylin and eosin (H&E) slides. METHODS: We used two CRC cohorts tested for TMB-H, and whole-slide H&E digital images were obtained from the cohorts. The Japanese CRC (JP-CRC) cohort (N = 201) was evaluated to detect the histopathological characteristics of TMB-H using H&E slides. The JP-CRC cohort and The Cancer Genome Atlas (TCGA) CRC cohort (N = 77) were used to develop a CNN-based TMB-H prediction model from the H&E digital images. RESULTS: Tumor-infiltrating lymphocytes (TILs) were significantly associated with TMB-H CRC (P < 0.001). The area under the curve (AUC) for predicting TMB-H CRC was 0.910. We developed a CNN-based TMB-H prediction model. Validation tests were conducted 10 times using randomly selected slides, and the average AUC for predicting TMB-H slides was 0.934. CONCLUSIONS: TILs, a histopathological characteristic detected with H&E slides, are associated with TMB-H CRC. Our CNN-based model has the potential to predict TMB-H CRC directly from H&E slides, thereby reducing the burden on pathologists. These approaches will provide clinicians with important information about the applications of ICIs at low cost.

DOI： 10.1007/s00535-021-01789-w

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1245/s10434-021-09919-7

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Other Link： http://link.springer.com/article/10.1245/s10434-021-09919-7/fulltext.html

Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE: Clinical calculators and nomograms have been endorsed by the American Joint Committee on Cancer (AJCC), as they provide the most individualized and accurate estimate of patient outcome. Using molecular and clinicopathologic variables, a third-generation clinical calculator was built to predict recurrence following resection of stage I-III colon cancer. METHODS: Prospectively collected data from 1,095 patients who underwent colectomy between 2007 and 2014 at Memorial Sloan Kettering Cancer Center were used to develop a clinical calculator. Discrimination was measured with concordance index, and variability in individual predictions was assessed with calibration curves. The clinical calculator was externally validated with a patient cohort from Washington University's Siteman Cancer Center in St Louis. RESULTS: The clinical calculator incorporated six variables: microsatellite genomic phenotype; AJCC T category; number of tumor-involved lymph nodes; presence of high-risk pathologic features such as venous, lymphatic, or perineural invasion; presence of tumor-infiltrating lymphocytes; and use of adjuvant chemotherapy. The concordance index was 0.792 (95% CI, 0.749 to 0.837) for the clinical calculator, compared with 0.708 (95% CI, 0.671 to 0.745) and 0.757 (0.715 to 0.799) for the staging schemes of the AJCC manual's 5th and 8th editions, respectively. External validation confirmed robust performance, with a concordance index of 0.738 (95% CI, 0.703 to 0.811) and calibration plots of predicted probability and observed events approaching a 45° diagonal. CONCLUSION: This third-generation clinical calculator for predicting cancer recurrence following curative colectomy successfully incorporates microsatellite genomic phenotype and the presence of tumor-infiltrating lymphocytes, resulting in improved discrimination and predictive accuracy. This exemplifies an evolution of a clinical calculator to maintain relevance by incorporating emerging variables as they become validated and accepted in the oncologic community.

DOI： 10.1200/JCO.20.02553

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

Some bacteria are symbiotic in tumor tissues, and metabolites of several bacterial species have been found to cause DNA damage. However, to date, the association between bacteria and host genetic alterations in colorectal cancer (CRC) has not been fully investigated. We evaluated the association between the intra-tumor microbiome and host genetic alterations in 29 Japanese CRC patients. The tumor and non-tumor tissues were extracted from the patients, and 16S rRNA genes were sequenced for each sample. We identified enriched bacteria in tumor and non-tumor tissues. Some bacteria, such as Fusobacterium, which is already known to be enriched in CRC, were found to be enriched in tumor tissues. Interestingly, Bacteroides, which is also known to be enriched in CRC, was enriched in non-tumor tissues. Furthermore, it was shown that certain bacteria that often coexist within tumor tissue were enriched in the presence of a mutated gene or signal pathway with mutated genes in the host cells. Fusobacterium was associated with many mutated genes, as well as cell cycle-related pathways including mutated genes. In addition, the patients with a high abundance of Campylobacter were suggested to be associated with mutational signature 3 indicating failure of double-strand DNA break repairs. These results suggest that CRC development may be partly caused by DNA damage caused by substances released by bacterial infection. Taken together, the identification of distinct gut microbiome patterns and their host specific genetic alterations might facilitate targeted interventions, such as modulation of the microbiome in addition to anticancer agents or immunotherapy.

DOI： 10.1016/j.csbj.2021.05.049

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE: The 9th Japanese Classification of Colorectal Cancer (9th JSCCR) has two main differences from the TNM classification (8th AJCC): first, main or lateral lymph node metastasis is classified as jN3; second, tumor nodules (ND) are treated as lymph node metastasis. In this study, we verified the 9th JSCCR for rectal cancer, focusing on the differences with the 8th AJCC. METHODS: This retrospective analysis involved 212 patients with stage I-III rectal cancer. ND was evaluated using whole-mount sections. We evaluated the relapse-free survival of each staging system, and compared the prognostic significance of the different staging systems using the Akaike information criterion (AIC) and Harrell's concordance index (c-index). RESULTS: Main or lateral lymph node metastasis was detected in nine of 212 (4%) patients. ND was detected in 79 of 212 (37%) patients. The best risk stratification power was observed in the 9th JSCCR (AIC, 759; c-index, 0.708) compared with the 7th JSCCR (AIC, 771; c-index, 0.681), 8th JSCCR (AIC, 768; c-index, 0.696), and the 8th AJCC (AIC, 766; c-index, 0.691). CONCLUSIONS: The 9th JSCCR, which includes the concepts of jN3 and ND, is useful for the risk stratification of rectal cancer, and the contributes to precise decision-making for follow-up management and adjuvant therapy.

DOI： 10.1007/s00595-020-02024-4

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Right-sided colorectal cancer (RCRC) demonstrates worse survival outcome compared with left-sided CRC (LCRC). Recently, the importance of RNF43 mutation and BRAF V600E mutation has been reported in the serrated neoplasia pathway, which is one of the precancerous lesions in RCRC. It was hypothesized that the clinical significance of RNF43 mutation differs according to primary tumor sidedness. To test this hypothesis, the clinicopathological characteristics and survival outcome of patients with RNF43 mutation in RCRC and LCRC were investigated. Stage I-IV CRC patients (n=201) were analyzed. Genetic alterations including RNF43 using a 415-gene panel were investigated. Clinicopathological characteristics between RNF43 wild-type and RNF43 mutant-type were analyzed. Moreover, RNF43 mutant-type was classified according to primary tumor sidedness, i.e., right-sided RNF43 mutant-type or left-sided RNF43 mutant-type, and the clinicopathological characteristics between the two groups were compared. RNF43 mutational prevalence, spectrum and frequency between our cohort and TCGA samples were compared. RNF43 mutation was observed in 27 out of 201 patients (13%). Multivariate analysis revealed that age (≥65), absence of venous invasion, and BRAF V600E mutation were independently associated with RNF43 mutation. Among the 27 patients with RNF43 mutation, 12 patients were right-sided RNF43 mutant-type and 15 left-sided RNF43 mutant-type. Right-sided RNF43 mutant-type was significantly associated with histopathological grade 3, presence of lymphatic invasion, APC wild, BRAF V600E mutation, microsatellite instability-high (MSI-H), and RNF43 nonsense/frameshift mutation compared with left-sided RNF43 mutant-type. Similarly, RNF43 nonsense/frameshift mutations were more frequently observed in RCRC compared with LCRC in the TCGA cohort (P=0.042). Right-sided RNF43 mutant-type exhibited significantly worse overall survival than RNF43 wild-type and left-sided RNF43 mutant-type (P=0.001 and P=0.023, respectively) in stage IV disease. RNF43 mutation may be a distinct molecular subtype which is associated with aggressive tumor biology along with BRAF V600E mutation in RCRC.

DOI： 10.3892/or.2020.7561

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE: Treatment strategies of rectal cancer differ between tumors located above (RS/Ra) and below (Rb) the peritoneal reflection. Based on the extent of distal spread (DS), the Japanese Society for Cancer of Colon and Rectum proposed an optimal distal margin in RS/Ra and Rb tumors. In this study, we investigated the clinical significance of DS between RS/Ra and Rb tumors. METHODS: We analyzed 287 stage I-III rectal cancer patients who underwent curative intent resection without preoperative therapy. DS and other pathological factors were evaluated using whole-mount sections. To investigate the clinical significance of DS in RS/Ra and Rb tumors, clinicopathological variables, including DS, were analyzed for the survival outcome according to the tumor group. RESULTS: DS was detected in 20 out of 185 (11%) patients with RS/Ra tumors and 8 out of 102 (8%) patients with Rb tumors. DS was not significantly associated with the overall survival (OS) or relapse-free survival (RFS) in RS/Ra tumors, but was an independent prognostic factor for the OS and RFS in Rb tumors (P = 0.002 and 0.007, respectively). CONCLUSIONS: The clinical significance of DS differs between RS/Ra and Rb tumors. DS is associated with a worse survival in Rb tumors, but not in RS/Ra tumors.

DOI： 10.1007/s00595-019-01882-x

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

AIMS: SMAD4 acts as a tumour suppressor, and the loss of SMAD4 is associated with poor prognosis in colorectal cancer (CRC) patients. Although next-generation sequencing (NGS) enabled us to detect numerous genetic alterations in a single assay, the clinical significance of SMAD4 alteration detected with NGS has not been fully investigated. The aim of this study was to evaluate the clinicopathological characteristics and clinical significance of SMAD4 alteration detected with NGS in CRC. METHODS AND RESULTS: We retrospectively investigated 201 patients with stage I-IV CRC, by using a 415-gene panel. To analyse the relationship between SMAD4 alteration and other clinicopathological characteristics, we evaluated clinicopathological variables, including invasive-front pathological markers: tumour budding, poorly differentiated cluster, and Crohn-like lymphoid reaction. Fifty-six patients (28%) had SMAD4 alteration: 24 and 32 patients had SMAD4 mutation and deletion, respectively. SMAD4 alteration was significantly associated with T category (P = 0.027), N category (P = 0.037), M category (P = 0.028), and invasive-front pathological markers, such as poorly differentiated cluster grade 3 (P = 0.020) and absence of Crohn-like lymphoid reaction (P = 0.004). Immunohistochemistry revealed that SMAD4 alteration was significantly associated with loss of SMAD4 (P = 0.023). In 90 patients with stage I-III disease, SMAD4 alteration was significantly associated with poor prognosis for relapse-free and overall survival (P = 0.047; P = 0.022, respectively). Conversely, in 111 patients with stage IV disease, SMAD4 alteration was not significantly associated with overall survival. CONCLUSION: SMAD4 alteration is associated with invasive-front pathological markers and poor prognosis in stage I-III CRC patients.

DOI： 10.1111/his.13805

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Comprehensive genomic sequencing (CGS) enables us to detect numerous genetic alterations in a single assay. We aimed to identify molecular markers for predicting prognosis and conversion surgery in Stage IV colorectal cancer (CRC) using CGS. One-hundred eleven patients with Stage IV CRC who underwent primary tumor resection were analyzed. We retrospectively investigated genetic alterations using CGS of a 415-gene panel. Clinicopathological variables and genetic alterations were analyzed to identify independent prognostic factors of overall survival (OS). Forty-five of 111 patients had R0 resection; of these, 11 patients underwent conversion surgery. Univariate and multivariate analyses identified histopathological grade 3, R0 resection, BRAF V600E mutation, and SRC mutation as independent prognostic factors for OS (P = 0.041, P = 0.013, P = 0.005, and P = 0.023, respectively). BRAF V600E and SRC mutations were mutually exclusive, and SRC mutation was significantly associated with left-sided tumor and liver metastasis compared to BRAF V600E mutation (P = 0.016 and P = 0.025, respectively). Eleven of the 74 initially unresectable patients underwent conversion surgery for R0 resection, yet none harbored BRAF V600E or SRC mutations. BRAF V600E and SRC mutations are important molecular markers which can predict prognosis and conversion surgery in Stage IV CRC.

DOI： 10.1038/s41598-019-39328-6

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND/OBJECTIVE: Restorative proctocolectomy (RP) may improve quality of life in patients with ulcerative colitis (UC)-associated lower rectal cancer to a greater extent than total proctocolectomy. However, patients with UC-associated cancer often have flat mucosal lesions that make it extremely difficult to endoscopically delineate the tumor margins. Therefore, there is a potential risk of residual tumor and local recurrence after RP in patients with UC-associated lower rectal cancer. The aim of this study was to assess the feasibility of RP in patients with UC-associated cancer of the lower rectum. METHODS: We retrospectively identified nine patients who had undergone RP for UC-associated lower rectal cancer at the Niigata University Medical and Dental Hospital between January 2000 and December 2016. The incidence of flat mucosal cancer, distal margin status, and oncologic outcomes were evaluated in the nine patients. RESULTS: Eight (89%) of the nine patients had flat mucosal cancer in the lower rectum. The median length of the distal margin was 22 mm (range 0-55 mm). No patient developed local or distant recurrence during follow-up. One patient had a positive distal margin. This patient underwent annual pouchoscopy, but had no local recurrence and died of pancreatic cancer 81 months after RP. The remaining eight patients were alive at the final observation. Five-year and 10-year overall survival rates in the nine patients were 100% and 66.7%, respectively. CONCLUSION: Patients with UC-associated lower rectal cancer often have lesions of the flat mucosal type. However, RP is feasible and not necessarily contraindicated in such patients.

DOI： 10.1016/j.asjsur.2018.01.003

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier {BV}  

BACKGROUND: Recent advances in next-generation sequencing have enabled the detection of BRAF V600E mutations as well as BRAF non-V600E mutations in a single assay. The present work aimed to describe the clinicopathological characteristics and clinical outcome of the BRAF non-V600E mutant-type in colorectal cancer (CRC). PATIENTS AND METHODS: CRC samples from 111 Stage IV patients were analyzed for somatic mutations using a 415-gene comprehensive genomic sequencing panel. Patients were classified according to BRAF status as wild-type, V600E mutant-type, or non-V600E mutant-type. Differences between clinicopathological characteristics and genetic alterations were analyzed among the three groups. Overall survival (OS) and the response to anti-EGFR therapy were also analyzed. RESULTS: Comprehensive genomic sequencing revealed that 98 patients (88%), 7 patients (6%), and 6 patients (6%) were wild-type, V600E mutant-type, and non-V600E mutant-type, respectively. Non-V600E mutant-type tumors were frequently left-sided (83%), while V600E mutant-type tumors were frequently right-sided (86%; P = 0.025). Non-V600E mutant-type showed better OS than V600E mutant-type (P = 0.038), with no significant difference compared with wild-type tumors. The two patients with non-V600E mutations who underwent repeated metastasectomies showed no evidence of disease at final follow-up. Regarding the efficacy of anti-EGFR therapy, the patient with an I326V mutation had progressive disease (+115%) despite no genetic alterations detected in the EGFR pathway that could drive resistance, suggesting an alternate resistance mechanism. CONCLUSIONS: Non-V600E mutant-type is more likely to be left-sided and demonstrates better OS than V600E mutant-type. Further preclinical and clinical investigations are needed to clarify the role of non-V600E mutations in CRC.

DOI： 10.1016/j.jss.2018.06.020

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Language：English   Publishing type：Research paper (scientific journal)  

This study aimed to compare common histologic markers at the invasive front of colon adenocarcinoma in terms of prognostic accuracy and interobserver agreement. Consecutive patients who underwent curative resection for stages I to III colon adenocarcinoma at a single institution in 2007 to 2014 were identified. Poorly differentiated clusters (PDCs), tumor budding, perineural invasion, desmoplastic reaction, and Crohn-like lymphoid reaction at the invasive front, as well as the World Health Organization (WHO) grade of the entire tumor, were analyzed. Prognostic accuracies for recurrence-free survival (RFS) were compared, and interobserver agreement among 3 pathologists was assessed. The study cohort consisted of 851 patients. Although all the histologic markers except WHO grade were significantly associated with RFS (PDCs, tumor budding, perineural invasion, and desmoplastic reaction: P<0.001; Crohn-like lymphoid reaction: P=0.021), PDCs (grade 1 [G1]: n=581; G2: n=145; G3: n=125) showed the largest separation of 3-year RFS in the full cohort (G1: 94.1%; G3: 63.7%; hazard ratio [HR], 6.39; 95% confidence interval [CI], 4.11-9.95; P<0.001), stage II patients (G1: 94.0%; G3: 67.3%; HR, 4.15; 95% CI, 1.96-8.82; P<0.001), and stage III patients (G1: 89.0%; G3: 59.4%; HR, 4.50; 95% CI, 2.41-8.41; P<0.001). PDCs had the highest prognostic accuracy for RFS with the concordance probability estimate of 0.642, whereas WHO grade had the lowest. Interobserver agreement was the highest for PDCs, with a weighted kappa of 0.824. The risk of recurrence over time peaked earlier for worse PDCs grade. Our findings indicate that PDCs are the best invasive-front histologic marker in terms of prognostic accuracy and interobserver agreement. PDCs may replace WHO grade as a prognostic indicator.

DOI： 10.1097/PAS.0000000000001059

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Language：English   Publishing type：Research paper (scientific journal)  

IMPORTANCE: Guidelines recommend measuring preoperative carcinoembryonic antigen (CEA) in patients with colon cancer. Although persistently elevated CEA after surgery has been associated with increased risk for metastatic disease, prognostic significance of elevated preoperative CEA that normalized after resection is unknown. OBJECTIVE: To investigate whether patients with elevated preoperative CEA that normalizes after colon cancer resection have a higher risk of recurrence than patients with normal preoperative CEA. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort analysis was conducted at a comprehensive cancer center. Consecutive patients with colon cancer who underwent curative resection for stage I to III colon adenocarcinoma at the center from January 2007 to December 2014 were identified. EXPOSURES: Patients were grouped into 3 cohorts: normal preoperative CEA, elevated preoperative but normalized postoperative CEA, and elevated preoperative and postoperative CEA. MAIN OUTCOMES AND MEASURES: Three-year recurrence-free survival (RFS) and hazard function curves over time were analyzed. RESULTS: A total of 1027 patients (461 [50.4%] male; median [IQR] age, 64 [53-75] years) were identified. Patients with normal preoperative CEA had 7.4% higher 3-year RFS (n = 715 [89.7%]) than the combined cohorts with elevated preoperative CEA (n = 312 [82.3%]) (P = .01) but had RFS similar to that of patients with normalized postoperative CEA (n = 142 [87.9%]) (P = .86). Patients with elevated postoperative CEA had 14.9% lower RFS (n = 57 [74.5%]) than the combined cohorts with normal postoperative CEA (n = 857 [89.4%]) (P = .001). The hazard function of recurrence for elevated postoperative CEA peaked earlier than for the other cohorts. Multivariate analyses confirmed that elevated postoperative CEA (hazard ratio [HR], 2.0; 95% CI, 1.1-3.5), but not normalized postoperative CEA (HR, 0.77; 95% CI, 0.45-1.30), was independently associated with shorter RFS. CONCLUSIONS AND RELEVANCE: Elevated preoperative CEA that normalizes after resection is not an indicator of poor prognosis. Routine measurement of postoperative, rather than preoperative, CEA is warranted. Patients with elevated postoperative CEA are at increased risk for recurrence, especially within the first 12 months after surgery.

DOI： 10.1001/jamaoncol.2017.4420

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：IMPACT JOURNALS LLC  

Objectives: Anti-epidermal growth factor receptor (EGFR) therapy has been found to be more effective against left-sided colorectal cancer (LCRC) than right-sided colorectal cancer (RCRC). We hypothesized that RCRC is more likely to harbor genetic alterations associated with resistance to anti-EGFR therapy and tested this using comprehensive genomic sequencing.
Materials and methods: A total of 201 patients with either primary RCRC or LCRC were analyzed. We investigated tumors for genetic alterations using a 415-gene panel, which included alterations associated with resistance to anti-EGFR therapy: TK receptors (ERBB2, MET, EGFR, FGFR1, and PDGFRA), RAS pathway (KRAS, NRAS, HRAS, BRAF, and MAPK2K1), and PI3K pathway (PTEN and PIK3CA). Patients whose tumors had no alterations in these 12 genes, theoretically considered to respond to anti-EGFR therapy, were defined as "all wild-type", while remaining patients were defined as "mutant-type".
Results: Fifty-six patients (28%) and 145 patients (72%) had RCRC and LCRC, respectively. Regarding genetic alterations associated with anti-EGFR therapy, only 6 of 56 patients (11%) with RCRC were "all wild-type" compared with 41 of 145 patients (28%) with LCRC (P = 0.009). Among the 49 patients who received anti-EGFR therapy, RCRC showed significantly worse progression-free survival (PFS) than LCRC (P = 0.022), and "mutant-type" RCRC showed significantly worse PFS compared with "all wild-type" LCRC (P = 0.004).
Conclusions: RCRC is more likely to harbor genetic alterations associated with resistance to anti-EGFR therapy compared with LCRC. Furthermore, our data shows primary tumor sidedness is a surrogate for the non-random distribution of genetic alterations in CRC.

DOI： 10.18632/oncotarget.20510

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

AIM: To assess the clinical significance of prophylactic lateral pelvic lymph node dissection (LPLND) in stage IV low rectal cancer. METHODS: We selected 71 consecutive stage IV low rectal cancer patients who underwent primary tumor resection, and enrolled 50 of these 71 patients without clinical LPLN metastasis. The patients had distant metastasis such as liver, lung, peritoneum, and paraaortic LN. Clinical LPLN metastasis was defined as LN with a maximum diameter of 10 mm or more on preoperative pelvic computed tomography scan. All patients underwent primary tumor resection, 27 patients underwent total mesorectal excision (TME) with LPLND (LPLND group), and 23 patients underwent only TME (TME group). Bilateral LPLND was performed simultaneously with primary tumor resection in LPLND group. R0 resection of both primary and metastatic sites was achieved in 20 of 50 patients. We evaluated possible prognostic factors for 5-year overall survival (OS), and compared 5-year cumulative local recurrence between the LPLND and TME groups. RESULTS: For OS, univariate analyses revealed no significant benefit in the LPLND compared with the TME group (28.7% vs 17.0%, P = 0.523); multivariate analysis revealed that R0 resection was an independent prognostic factor. Regarding cumulative local recurrence, the LPLND group showed no significant benefit compared with TME group (21.4% vs 14.8%, P = 0.833). CONCLUSION: Prophylactic LPLND shows no oncological benefits in patients with Stage IV low rectal cancer without clinical LPLN metastasis.

DOI： 10.5306/wjco.v8.i5.412

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：W B SAUNDERS CO-ELSEVIER INC  

HER2-targeted therapy is considered effective for KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (CRC). In general, HER2 status is determined by the use of immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). Comprehensive genomic sequencing (CGS) enables the detection of gene mutations and copy number alterations including KRAS mutation and HER2 amplification; however, little is known about the utility of CGS for detecting HER2-positive CRC. To assess its utility, we retrospectively investigated 201 patients with stage I-IV CRC. The HER2 status of the primary site was assessed using IHC and FISH, and HER2 amplification of the primary site was also assessed using CGS, and the findings of these approaches were compared in each patient. CGS successfully detected alterations in 415 genes including KRAS codon 12/13 mutation and HER2 amplification. Fifty-nine (29%) patients had a KRAS codon 12/13 mutation. Ten (5%) patients were diagnosed as HER2 positive because of HER2 MC 3+, and the same 10 (5%) patients had HER2 amplification evaluated using CGS. The results of HER2 status and HER2 amplification were completely identical in all 201 patients (P &lt; .001). Nine of the 10 HER2-positive patients were KRAS 12/13 wild-type and were considered possible candidates for HER2-targeted therapy. CGS has the same utility as IHC and FISH for detecting HER2-positive patients who are candidates for HER2-targeted therapy, and facilitates precision medicine and tailor-made treatment. (C) 2017 The Authors. Published by Elsevier Inc.

DOI： 10.1016/j.humpath.2017.02.004

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

Objective: Although poorly differentiated cluster has been reported to be a useful grading system for predicting prognosis in colorectal cancer, its relationship to chemotherapy efficacy has not been demonstrated. We aimed to investigate the association between poorly differentiated cluster and the efficacy of 5-fluorouracil-based adjuvant chemotherapy in stage III colorectal cancer.
Methods: This retrospective study enrolled 131 patients with stage III colorectal cancer who underwent curative resection: 72 received 5-fluorouracil-based adjuvant chemotherapy (chemotherapy group) and 59 did not (surgery-alone group). Poorly differentiated cluster was defined as a cancer cluster of &gt;= 5 cancer cells without gland-like structure, and was classified into poorly differentiated cluster G1, G2 and G3 according to the number of clusters. The benefit of 5-fluorouracil-based adjuvant chemotherapy was evaluated based on poorly differentiated cluster grade.
Results: Thirty-nine, 40 and 52 patients were classified as poorly differentiated cluster G1, G2 and G3, respectively. Significant differences in the 5-year cumulative recurrence rate and relapse-free survival were observed between poorly differentiated cluster G1/G2 and G3 (26.7% vs. 47.5%, P = 0.010; 66.0% vs. 43.9%, P = 0.004). A comparison of cumulative recurrence rate and relapse-free survival between the chemotherapy and surgery-alone groups showed a significant benefit of adjuvant chemotherapy in poorly differentiated cluster G1/G2 patients (cumulative recurrence rate: 17.4% vs. 37.3%, P = 0.035; relapse-free survival: 79.5% vs. 51.9%, P = 0.002), but not in poorly differentiated cluster G3 patients (cumulative recurrence rate: 48.6% vs. 44.8%, P = 0.885; relapse-free survival: 51.4% vs. 32.7%, P = 0.068).
Conclusions: In stage III colorectal cancer, poorly differentiated cluster G1/G2 predicts a significant benefit from 5-fluorouracil-based adjuvant chemotherapy, whereas poorly differentiated cluster G3 predicts a poor response to it.

DOI： 10.1093/jjco/hyw209

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

The presence of extramural tumor deposits without lymph node structure (EX) is an important prognostic factor for patients with colorectal cancer. However, the clinical significance of EX in the lateral pelvic lymph node area (LP-EX) remains unclear. This study aimed to determine the prognostic implications of LP-EX for patients with low rectal cancer.
This retrospective study involved 172 consecutive patients with stage 2 or 3 low rectal cancer who underwent curative surgery including lateral pelvic lymph node (LPLN) dissection. The patients were classified into the following three groups according to the metastatic status of the LPLN area: patients without metastasis (no-LP-M group), patients with lymph node metastasis (LP-LNM group), and patients with EX (LP-EX group). Potential prognostic factors of overall survival (OS) and relapse-free survival (RFS) were identified in uni- and multivariate analyses.
Classification assigned 131 patients (76 %) to the no-LP-M group, 27 patients (16 %) to the LP-LNM group, and 14 patients (8 %) to the LP-EX group. The 5-year OS rate was 80.3 % in the no-LP-M group, 61.1 % in the LP-LNM group, and 34.9 % in the LP-EX group (P &lt; 0.001). The corresponding 5-year RFS rates were 62.2, 33.8, and 14.3 %, respectively (P &lt; 0.001). A multivariate Cox proportional hazards regression analysis showed that the presence of LP-EX was an independent prognostic factor for OS (P = 0.006) and RFS (P = 0.001).
The LP-EX classification is a useful pathologic parameter that can be used to stratify patients with metastasis in the LPLN area.

DOI： 10.1245/s10434-016-5379-9

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

BACKGROUND: Tumor budding is recognized as an important risk factor for lymph node metastasis in pT1 colorectal cancer. Immunohistochemical staining for cytokeratin has the potential to improve the objective diagnosis of tumor budding over detection based on hematoxylin and eosin staining. However, it remains unclear whether tumor budding detected by immunohistochemical staining is a significant predictor of lymph node metastasis in pT1 colorectal cancer.
OBJECTIVE: The purpose of this study was to clarify the clinical significance of tumor budding detected by immunohistochemical staining in comparison with that detected by hematoxylin and eosin staining.
DESIGN: This was a retrospective study.
SETTINGS: The study was conducted at Niigata University Medical & Dental Hospital.
PATIENTS: We enrolled 265 patients with pT1 colorectal cancer who underwent surgery with lymph node dissection.
MAIN OUTCOME MEASURES: Tumor budding was evaluated by both hematoxylin and eosin and immunohistochemical staining with the use of CAM5.2 antibody. Receiver operating characteristic curve analyses were conducted to determine the optimal cutoff values for tumor budding detected by hematoxylin and eosin and CAM5.2 staining. Univariate and multivariate analyses were performed to identify the significant factors for predicting lymph node metastasis.
RESULTS: Receiver operating characteristic curve analyses revealed that the cutoff values for tumor budding detected by hematoxylin and eosin and CAM5.2 staining for predicting lymph node metastases were 5 and 8. On multivariate analysis, histopathological differentiation (OR, 6.21; 95% CI, 1.16-33.33; p = 0.03) and tumor budding detected by hematoxylin and eosin staining (OR, 4.91; 95% CI, 1.64-14.66; p = 0.004) were significant predictors for lymph node metastasis; however, tumor budding detected by CAM5.2 staining was not a significant predictor.
LIMITATIONS: This study was limited by potential selection bias because surgically resected specimens were collected instead of endoscopically resected specimens.
CONCLUSIONS: Tumor budding detected by CAM5.2 staining was not superior to hematoxylin and eosin staining for predicting lymph node metastasis in pT1 colorectal cancer.

DOI： 10.1097/DCR.0000000000000567

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：E-CENTURY PUBLISHING CORP  

MED12 is a transcriptional mediator complex subunit, which negatively regulates the transforming growth factor beta (TGF-beta) pathway. The TGF-beta pathway plays a major role in the induction of epithelial-mesenchymal transition 9EMT). MED12 loss induces activation of the TGF-beta pathway, resulting in EMT and drug resistance to epidermal growth factor receptor (EGFR)-targeted therapy. We aimed to investigate the clinical significance of MED12 loss detected by immunohistochemistry in patients with colorectal cancer (CRC). A total of 100 patients diagnosed with stage I-IV CRC were enrolled in this retrospective study. MED12 expression was evaluated immunohistochemically, and classified as either positive (&gt;= 20%) or negative (&lt;20%) with regard to the percentage of immunoreactive cells. The relationships between MED12 loss and clinicopathological characteristics and RAS mutation status were analyzed. Overall, 79 and 21 patients were classified as MED12 positive and MED12 negative, respectively. MED12 negativity was significantly associated with tumor budding (P = 0.034), N category (P = 0.010), and M category (P = 0.031). Among stage IV CRC patients, 18 of 31 patients had the RAS wild-type gene; 6 of these patients were MED12 negative, and were considered to have the potential for resistance to EGFR-targeted therapy despite the presence of the wild-type gene. In conclusion, MED12 loss is associated with tumor budding, nodal metastasis, and distant metastasis in patients with CRC, suggesting that MED12 loss induces activation of the TGF-beta pathway resulting in EMT. Future treatment strategies focusing on patients MED12 loss may improve the prognosis of patients with CRC.

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

BACKGROUND: The current Japanese general rules for clinical and pathologic studies on cancer of the colon, rectum, and anus state that a 3-cm distal resection margin is needed in resecting rectosigmoid cancer and rectal cancer with a distal edge above the peritoneal reflection, and 2 cm is needed for rectal cancer with a distal edge below the peritoneal reflection. The appropriateness of these rules has not been proved.
OBJECTIVE: Our aim was to evaluate the appropriateness of the Japanese rules.
DESIGN AND SETTING: We retrospectively analyzed surgical and pathology records of patients who underwent surgery at a tertiary care cancer center in Japan.
PATIENTS: The study included 381 consecutive patients with stage I to IV rectosigmoid or rectal cancer without preoperative chemotherapy or radiotherapy.
MAIN OUTCOME MEASURES: We investigated both intramural and mesorectal distal spread, using whole-mount sections to measure the maximum length of distal spread. Long distal spread was defined as distal spread longer than the distal resection margin stated in the Japanese general rules. Risk factors for both distal spread and long distal spread were evaluated.
RESULTS: Of 381 patients, 325 (85.3%) had no distal spread and a total of 56 (14.7%) had distal spread. Distal spread was within the limits specified by the Japanese general rules in 48 of the 381 patients (12.6%) and beyond the Japanese limits (long distal spread) in 8 patients (2.1%). The prevalence of distal spread increased with TNM stage (stage I, 2.7%; stage II, 5.3%; stage III, 17.4%; stage IV, 46.2%). Long distal spread was not observed in stage I or II, was found in only 1.4% of patients with stage III disease and in 11.5% of patients with stage IV. The maximum extent of distal spread in patients with rectosigmoid cancer or rectal cancer with the distal edge above the peritoneal reflection was 38 mm; in patients with rectal cancer with the distal edge below the peritoneal reflection, 35 mm. Multivariable analyses showed that nodal involvement and distant metastasis were independent risk factors for distal spread; distant metastasis was the only independent risk factor for long distal spread.
CONCLUSIONS: The Japanese general rules specifying the distal resection margin are appropriate for most patients who undergo surgery for rectosigmoid and rectal cancer without preoperative chemotherapy or radiotherapy. A further increase of 1 to 2 cm beyond the recommended distal resection margin may contribute to improved local control for patients with distant metastasis.

DOI： 10.1097/DCR.0b013e318233fc4a

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

PURPOSE: Mesorectal cancer deposits showing no histological evidence of lymph node structure (extranodal cancer tissue) are a common feature in rectal cancer. However, optimal categorization of extranodal cancer tissue using TNM grading is not yet established. We reviewed extranodal cancer tissue in detail using whole-mount sections to clarify its clinical impact.
METHODS: This retrospective study involved 214 consecutive patients with stage I-III rectal cancer. After fixation, the whole tumor mass including the mesorectum was sliced into longitudinal sections and stained. Mesorectal involvement was classified as direct tumor infiltration, lymph node involvement, or extranodal cancer tissue. Extranodal cancer tissue was classified morphologically, and its maximum size and distance from the primary tumor were measured. The clinical impact of extranodal cancer tissue was evaluated by univariate and multivariate analyses.
RESULTS: A total of 498 extranodal cancer deposits were detected in 88 patients (41.1%). Multivariate Cox proportional hazards model analysis indicated that the presence of extranodal cancer tissue was an independent prognostic factor for relapse-free (P &lt; .001) and overall survival (P &lt; .003). The hazard ratio for extranodal cancer tissue was higher than for nodal involvement, irrespective of morphological classification. The clinical impact differed significantly with the number of histological types of extranodal cancer tissue, the number of deposits, their maximum size, and their distance from the primary tumor.
CONCLUSIONS: In the present study, we have shown that extranodal cancer tissue detected by whole-mount sections has a clinical impact that is more severe than nodal involvement.

DOI： 10.1007/DCR.0b013e3181cf7fd8

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Authorship：Lead author   Language：English   Publishing type：Thesis (other)   Publisher：Niigata University  

To establish a standardized immunohistochemical method for detecting isolated tumor cells (ITC) in lymph nodes of patients with colorectal cancer (CRC), we examined the detection rates of ITC using sections of various thicknesses and two different kinds of cytokeratin monoclonal antibodies, CAM5.2 and AE1/AE3. According to the sixth edition of the TNM classification, ITC was defined as a single tumor cell or small cell clusters not greater than 0.2 mm. From 29 patients with stage III colorectal cancer, 149 lymph nodes diagnosed as negative for cancer metastasis by routine hematoxylin and eosin (H&E) staining were randomly selected. Twelve serial sections were cut for each lymph node. Sections one to eight were cut at a 4 μm thickness, and sections nine to 12 were cut at a 10 μm thickness. Sections one and eight, two to six and nine to 11, and seven and 12, were stained with H&E, the CAM5.2 antibody, and the AE1/AE3 antibody, respectively. Comparisons of cumulative ITC positive rates in sections of varying total thicknesses stained with the CAM5.2 antibody revealed that no significant differences were found when the total thickness of the sections examined exceeded 8 μm. There was no significant difference in ITC positive rates between CAM5.2 and AE1/AE3 staining. Our data indicate that, when monoclonal antibodies CAM5.2 or AE1/AE3 are used, ITC can be optimally detected immunohistochemically in sections with a total thickness of more than 8 μm. This practical suitable procedure can be used for standardizing the detection method for ITC.

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Other Link： http://search.jamas.or.jp/link/ui/2008231312

Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

The coexistence of abdominal aortic aneurysm (AAA) and colorectal carcinoma needs special operative consideration. A single-stage operation for concomitant AAA and colorectal carcinoma has been thought to increase the risk of vascular prosthetic graft infection. We report two patients who received a single-stage operation for AAA and colorectal carcinoma. The first patient had a fusiform aneurysm of the infrarenal aorta. The second patient had a saccular aneurysm of the infrarenal aorta and a fusiform aneurysm of the left internal iliac artery. Both patients had left-sided colorectal carcinoma classified as Dukes' stage B. The two patients underwent a single-stage operation with Hartmann's procedure to avoid graft infection caused by anastomotic leakage. They tolerated the operation and had no postoperative complications including graft infection. A single-stage operation for concomitant AAA and left-sided colorectal carcinoma could be safely performed with Hartmann's procedure in two cases.

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER TOKYO  

DOI： 10.1007/s00535-004-1522-7

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AIM: To clarify the usefulness of intraoperative lavage cytology in patients undergoing curative resection for pStage II-III colorectal cancer in a prospective multicenter study. METHODS: Patients preoperatively diagnosed with stage II-III colorectal cancer between 2013 and 2017 from 20 hospitals were enrolled. Lavage cytology was performed twice during the surgery. The primary endpoint was the effect of lavage cytology on the 5-year relapse-free survival (RFS) in patients with pStage II-III colorectal cancer. The secondary endpoint was the effect of lavage cytology on the 5-year overall survival (OS) and peritoneal recurrence. RESULTS: A total of 1378 patients were eligible for analysis. The number of patients with pStage II-III colorectal cancer was 670 and 708, respectively. Fifty-four patients (3.9%) had positive cytological results. In pStage II patients, the 5-year RFS rates with positive and negative cytology were 61.1% and 81.6%, respectively (p = 0.023). The 5-year OS rates were 67.1% and 91.7%, respectively (p = 0.0083). However, there was no difference in RFS or OS between pStage III patients with positive and negative cytology results. The peritoneal recurrence rates were 11.8% and 1.5% in pStage II patients with positive and negative cytology results, respectively (p = 0.032). These rates were 10.5% and 2.5% in patients with stage III disease, respectively (p = 0.022). CONCLUSION: Stage II colorectal cancer patients with negative cytology had better outcomes than those with positive cytology. Peritoneal lavage cytology is useful for predicting peritoneal recurrence after curative resection of stage II-III colorectal cancer.

DOI： 10.1002/ags3.12825

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BACKGROUND: Homologous recombination deficiency (HRD) is one of the crucial hallmarks of cancer. It is associated with a favorable response to platinum-based chemotherapy. We explored the distinctive clinicopathological features of gastric cancer (GC) with HRD and the clinical significance of HRD in platinum-based first-line chemotherapy for unresectable metastatic GC. METHODS: We enrolled 160 patients with GC in this study. Their tumor samples were subjected to genomic profiling utilizing targeted tumor sequencing. HRD was defined as the presence of alterations in any of 16 HR genes (BARD1, BLM, BRCA1, BRCA2, BRIP1, MRE11A, NBN, PALB2, PARP1, POLD1, RAD50, RAD51, RAD51C, RAD51D, WRN, and XRCC2). The clinicopathological features and treatment outcomes of first-line chemotherapy for unresectable metastatic GC were compared between HRD and non-HRD groups. RESULTS: Forty-seven patients (29.4%) were classified into the HRD group. This group had a significantly lower proportion of macroscopic type 3 or 4 tumors and higher TMB than the non-HRD group. Among patients who underwent platinum-based first-line chemotherapy, the HRD group had a greater response rate and longer progression-free survival after treatment (median 8.0 months vs. 3.0 months, P = 0.010), with an adjusted hazard ratio of 0.337 (95% confidence interval 0.151-0.753). HRD status was not associated with treatment outcomes in patients who did not undergo platinum-based chemotherapy. CONCLUSIONS: Low proportion of macroscopic type 3 or 4 tumors and a high TMB are distinctive features of GC with HRD. HRD status is a potential predictive marker in platinum-based first-line chemotherapy for unresectable metastatic GC.

DOI： 10.1007/s10120-024-01542-1

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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BACKGROUND: Evaluation of human epidermal growth factor receptor 2 (HER2) overexpression caused by erb-b2 receptor tyrosine kinase 2 (ERBB2) amplification (AMP) by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) is essential for treating unresectable metastatic gastric cancer (GC). A targeted tumour sequencing test enables comprehensive assessment of alterations in cancer-related genes, including ERBB2. This study aimed to evaluate the concordance between the targeted tumour sequencing test and IHC/FISH for detecting HER2-positive GC and to clarify the significance of ERBB2 AMP and concomitant genetic alterations in HER2 downstream pathways (DPs) in anti-HER2 therapy for unresectable metastatic GC patients. METHODS: ERBB2 copy number alteration (CNA) was examined via a targeted tumour sequencing test in 152 formalin-fixed paraffin-embedded (FFPE) GC tissues. ERBB2 CNA was compared to HER2 status evaluated by IHC/FISH in FFPE block sections, which were identical to those subjected to the targeted tumour sequencing test. Treatment outcomes of anti-HER2 therapy in 11 patients with unresectable metastatic GC was evaluated. RESULTS: ERBB2 AMP (≥ 2.5-fold change) was detected by the targeted tumour sequencing test in 15 patients (9.9%), and HER2 positivity (IHC 3 + or IHC 2+/FISH positive) was detected in 21 patients (13.8%). The overall percent agreement, positive percent agreement, negative percent agreement and Cohen's kappa between ERBB2 CNA and HER2 status were 94.7%, 66.7%, 99.2% and 0.75, respectively. Progression-free survival for trastuzumab therapy in patients with ERBB2 AMP was significantly longer than that in patients with no ERBB2 AMP detected by the targeted tumour sequencing test (median 14 months vs. 4 months, P = 0.007). Treatment response to trastuzumab therapy was reduced in patients with ERBB2 AMP and concomitant CNAs of genes in HER2 DPs. One patient with ERBB2 AMP and concomitant CNAs of genes in HER2 DPs achieved a durable response to trastuzumab deruxtecan as fourth-line therapy. CONCLUSIONS: A targeted tumour sequencing test is a reliable modality for identifying HER2-positive GC. ERBB2 AMP and concomitant genetic alterations detected through the targeted tumour sequencing test are potential indicators of treatment response to trastuzumab therapy. The targeted tumour sequencing test has emerged as a plausible candidate for companion diagnostics to determine indications for anti-HER2 therapy in the era of precision medicine for GC.

DOI： 10.1186/s12885-024-12482-5

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BACKGROUND: Initial chemotherapy (Initial-C) followed by surgery is a promising treatment strategy for peritoneal lavage cytology-positive gastric cancer (CY1 GC) with no other noncurative factors. The aim of this study was to investigate the survival advantage of Initial-C compared to initial surgery (Initial-S) for this disease according to the macroscopic type, which was associated with prognosis and the efficacy of chemotherapy in GC. METHODS: One hundred eighty-nine patients who were diagnosed with CY1 GC with no other noncurative factors at four institutions from January 2007 to December 2018 were enrolled. The patients were divided into a macroscopic type 4 group (N = 48) and a non-type 4 group (N = 141). The influence of initial treatment on overall survival (OS) in each group was evaluated. RESULTS: In the type 4 group, the 5-year OS rates of Initial-C (N = 35) and Initial-S (N = 13) were 11.6% and 0%, respectively (P = 0.801). The multivariate analysis could not show the survival advantage of Initial-C. In the non-type 4 group, the 5-year OS rates of Initial-C (N = 41) and Initial-S (N = 100) were 48.4% and 29.0%, respectively (P = 0.020). The multivariate analysis revealed that Initial-C was independently associated with prolonged OS (hazard ratio, 0.591; 95% confidence interval, 0.375-0.933: P = 0.023). CONCLUSIONS: Initial-C improves the prognosis of non-type 4 CY1 GC with no other noncurative factors. On the other hand, further development of effective chemotherapeutic regimens and innovative treatment strategies are required for type 4 CY1 GC.

DOI： 10.1007/s10147-024-02496-1

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BACKGROUND/AIM: NAD(P)H dehydrogenase [quinone] 1 (NQO1), an antioxidant enzyme, confers resistance to anticancer agents. NQO1 C609T is a single-nucleotide polymorphism associated with reduced protein expression in the non-neoplastic esophageal squamous epithelium (ESE). This study aimed to investigate immunohistochemical NQO1 expression in non-neoplastic ESE and to elucidate its prognostic significance in patients with esophageal squamous cell carcinoma (ESCC) undergoing neoadjuvant therapy followed by esophagectomy. MATERIALS AND METHODS: NQO1 expression in non-neoplastic ESE was determined in surgical specimens from 83 patients with ESCC using immunohistochemistry. The association between NQO1 expression and clinicopathological factors, and the prognostic significance of NQO1 expression for relapse-free survival (RFS) were statistically evaluated. RESULTS: Patients with complete loss or weak NQO1 expression and patients with moderate or strong NQO1 expression were classified into the NQO1-negative (n=29) and NQO1-positive (n=54) groups, respectively. The downstaging of T classification status after neoadjuvant therapy was significantly more frequent in the NQO1-negative group than in the NQO1-positive group (59% vs. 33%; p=0.036). The NQO1-negative group had significantly more favorable RFS than the NQO1-positive group (p=0.035). Multivariate survival analysis demonstrated that NQO1 negative expression had a favorable prognostic impact on RFS (HR=0.332; 95%CI=0.136-0.812; p=0.016). CONCLUSION: Immunohistochemical evaluation of NQO1 expression in non-neoplastic ESE has clinical utility for predicting patient prognosis after neoadjuvant therapy followed by esophagectomy and might be helpful for selecting candidates for adjuvant therapy to treat ESCC.

DOI： 10.21873/anticanres.16993

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BACKGROUND AND AIM: Colitis-associated intestinal cancer (CAC) can develop in patients with inflammatory bowel disease; however, the malignant grade of CAC may differ from that of sporadic colorectal cancer (CRC). Therefore, we compared histological findings distinct from cancer stage between CAC and sporadic CRC to evaluate the features of CAC. METHODS: We reviewed the clinical and histological data collected from a nationwide database in Japan between 1983 and 2020. Patient characteristics were compared to distinguish ulcerative colitis (UC), Crohn's disease (CD), and sporadic CRC. Comparisons were performed by using all collected data and propensity score-matched data. RESULTS: A total of 1077 patients with UC-CAC, 297 with CD-CAC, and 136 927 with sporadic CRC were included. Although the prevalence of well or moderately differentiated adenocarcinoma (Tub1 and Tub2) decreased according to tumor progression for all diseases (P < 0.01), the prevalence of other histological findings, including signet ring cell carcinoma, mucinous carcinoma, poorly differentiated adenocarcinoma, or squamous cell carcinoma, was significantly higher in CAC than in sporadic CRC. Based on propensity score-matched data for 982 patients with UC and 268 with CD, the prevalence of histological findings other than Tub1 and Tub2 was also significantly higher in those with CAC. At pT4, mucinous carcinoma occurred at a significantly higher rate in patients with CD (45/86 [52.3%]) than in those with sporadic CRC (13/88 [14.8%]) (P < 0.01). CONCLUSION: CAC, including early-stage CAC, has a higher malignant grade than sporadic CRC, and this difference increases in significance with tumor progression.

DOI： 10.1111/jgh.16496

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OBJECTIVES: De novo malignancy (DNM) is a major cause of death in long-term recipients of liver transplantation (LT). We herein report our experience with DNM after living-donor LT (LDLT). PATIENTS AND METHODS: A total of 111 LDLT procedures were performed in our institute from 1999 to 2022. Among them, 70 adult (>13 years old) LDLT recipients who survived for more than 1 year were included in this study. RESULTS: During a median follow-up of 146 (range, 12-285) months, 7 out of 70 recipients developed 8 DNMs, including lung cancer in 4, post-transplant lymphoproliferative disease in 3, and skin cancer in 1. One patient developed metachronal skin cancer and post-transplant lymphoproliferative disease. The pre-LT smoking history rate in patients with DNM was higher than in patients without DNM (P = .004). The survival time after DNM was 6 (1-166) months. Only 2 patients underwent R0 resection. DNM did not recur during follow-up. Other patients who underwent R1 resection and/or chemotherapy and/or radiotherapy all died due to DNMs during the follow-up. The cumulative DNM incidence was 3.5% at 10 years and 18.4% at 20 years after LDLT. The cumulative survival rate in patients with DNM was significantly worse than that in patients without DNM after LDLT (P = .049). CONCLUSION: The survival rate of patients with DNM was lower than that of those without DNM. A pre-LT smoking history is a risk factor for DNM. R0 resection is effective for improving the prognosis of patients with DNM. Regular cancer screening is important for detecting DNM early after LDLT.

DOI： 10.1016/j.transproceed.2024.02.015

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BACKGROUND: Recent advances in treatment are expected to bring a cure to more patients with gastric cancer (GC). Focusing on the risk of death from other diseases (DOD) has become a crucial issue in patients cured of GC. The aim of this study was to elucidate the risk factors for DOD in patients who underwent curative gastrectomy with lymph node dissection for GC. METHODS: We enrolled 810 patients who underwent curative gastrectomy with lymph node dissection for GC from January 1990 to December 2014 and had no recurrence or death of GC until December 2019. We investigated the risk factors for DOD defined as death excluding death from a malignant neoplasm, accident, or suicide after gastrectomy, focusing on the perioperative characteristics at gastrectomy. RESULTS: Among 315 deaths from any cause, 210 died from diseases other than malignancy, accidents and suicide. The leading cause of DOD was pneumonia in 54 patients (25.7%). The actual survival period in 167 patients (79.5%) with DOD was shorter than their estimated life expectancy at gastrectomy. Multivariate analysis revealed that a high Charlson Comorbidity Index score (score 1-2: hazard ratio [HR] 2.192, 95% confidence interval [CI] 1.713-2.804, P < 0.001 and score ≥ 3: HR 4.813, 95% CI 3.022-7.668, P < 0.001), total gastrectomy (HR 1.620, 95% CI 1.195-2.197, P = 0.002) and the presence of postoperative complications (HR 1.402, 95% CI 1.024-1.919, P = 0.035) were significant independent risk factors for DOD after gastrectomy for GC, in addition to age of 70 years or higher, performance status of one or higher and body mass index less than 22.0 at gastrectomy. CONCLUSIONS: Pneumonia is a leading cause of DOD after curative gastrectomy and lymph node dissection for GC. Paying attention to comorbidities, minimizing the choice of total gastrectomy and avoiding postoperative complications are essential to maintain the long-term prognosis after gastrectomy.

DOI： 10.1186/s12893-024-02313-6

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DOI： 10.1093/bjs/znad386

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Language：Japanese   Publishing type：Research paper (scientific journal)  

The patient was a 61-year-old man with a diagnosis of carcinoma of the pancreatic head. Abdominal computed tomography( CT)showed no distant metastasis, and he underwent subtotal stomach-preserving pancreatoduodenectomy. Immediately after surgery, he received liver perfusion chemotherapy with 5-fluorouracil followed by systemic gemcitabine. Eighteen months after surgery, CT revealed liver metastasis in the S6 segment, and partial hepatectomy was performed. The pathological diagnosis was liver metastasis of pancreatic cancer. Postoperatively, the patient was treated with gemcitabine and S-1 therapy for 1 year and then switched to S-1 monotherapy for about 6 months. Four years after the initial surgery, CT showed 2 metastases in the right lung. After 2 months of S-1 monotherapy, wedge resection of the upper and lower lobes of the right lung was performed. Gemcitabine and nab-paclitaxel therapy were administered, after the metastasectomy, but pleural dissemination appeared on CT 5 years after the initial surgery. Modified FOLFIRINOX therapy was started and continued for 8 months, but CT revealed further disseminated lesions in the diaphragm. Palliative irradiation was provided, but the disease gradually progressed. After multidisciplinary treatment, the patient survived for 6 years and 3 months after the initial surgery.

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A 66-year-old man was referred to our hospital with fever and abdominal pain. CT showed a mass in the intrapancreatic bile duct but no wall thickness in the perihilar bile ducts. Neither regional lymphadenopathy nor distant metastasis was observed. Biliary cytology showed adenocarcinoma. The diagnosis was distal cholangiocarcinoma, and pancreatoduodenectomy was performed. Intraoperative frozen section examination of the ductal resection margins at the right and left hepatic ducts was positive for carcinoma in situ, and the operation ultimately completed with R1 resection. Histological examination confirmed a diagnosis of cholangiocarcinoma with superficial spread and a single positive lymph node. Adjuvant chemotherapy with S-1 was administered for 1 year. Anastomotic recurrence at the hepaticojejunostomy was found 5 years after resection; biopsy specimens revealed adenocarcinoma. Thereafter, S-1 chemotherapy was resumed, and the patient remains alive and well 9 years and 1 month after resection.

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A 58-year-old woman presented with a complaint of weight loss. Abdominal computed tomography showed dilatation of the biliary and pancreatic ducts and a mural nodule in the pancreatic duct. The diagnosis was intraductal papillary mucinous neoplasm(IPMN). Endoscopic retrograde cholangiopancreatography(ERCP)and cholangioscopy revealed a fistula between the common bile duct and the IPMN. A sudden increase in hepatobiliary enzymes was noted preoperatively. ERCP showed that the common bile duct was obstructed by mucus. A nasobiliary drainage tube was inserted into the bile duct endoscopically and kept open by daily tube washing, and the liver dysfunction improved. Total pancreatectomy, splenectomy, and regional lymph node dissection were performed. Histological examination confirmed that the primary tumor was mixed invasive intraductal papillary mucinous adenocarcinoma. The patient remains alive and well with no evidence of recurrence 18 months after resection.

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We report a case of biliary cystadenocarcinoma in which long-term survival was achieved after 2 operations for intrahepatic recurrence. A 72-year-old man with biliary cystadenocarcinoma located mainly in segment 3 of the liver underwent left hepatectomy, extrahepatic bile duct resection, and lymph node dissection. Seven years and 9 months after the initial resection, he underwent partial liver resection(segment 5)for intrahepatic recurrence detected by computed tomography. Fifteen years and 7 months after the initial resection, he underwent repeat partial resection of the liver(segment 5)for intrahepatic recurrence. Histologically, these tumors were confirmed to be recurrence of biliary cystadenocarcinoma. He remains alive and well with no further recurrence 21 years and 6 months after the initial resection. This case and a literature review suggest that hepatic resection is a useful treatment option for intrahepatic recurrence of biliary cystadenocarcinoma.

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An 87-year-old woman with a gradually enlarging mass in her left breast, diagnosed as having left-sided breast cancer with skin invasion by a local practitioner, was referred to our hospital. Computed tomography revealed ascending colon cancer with abdominal wall invasion and a thoracic aortic aneurysm(Stanford type B), in addition to breast cancer with skin invasion. A thoracic endovascular aortic repair and bypass surgery between the subclavian arteries were both performed for the thoracic aortic aneurysm. After 6 days, a right hemicolectomy and D2 lymphadenectomy were performed for the ascending colon cancer. A postoperative pathological diagnosis of pT3N0M0, pStage Ⅱa, was made. A total left mastectomy with a full-thickness skin graft for left breast cancer was performed after 2 months following the ascending colon cancer surgery. The postoperative pathological diagnosis was pT3N0M0, pStage ⅡB. No evidence of local recurrence or distant metastasis of the ascending colon cancer has been observed at 20 months postoperatively, or of the breast cancer after 18 months following surgery.

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A 57-year-old man was diagnosed as having resectable advanced esophageal carcinoma adjacent to the trachea(Ut, cT3N0M0)and received preoperative docetaxel, cisplatin, and 5-fluorouracil therapy. Due to tracheal tumor invasion and upstaging to cT4bN0M0 after 1 course of chemotherapy, the treatment was converted to definitive chemoradiotherapy (CRT). A remarkable response with no evidence of tracheal invasion was observed on computed tomography following definitive CRT. He underwent successful curative resection with salvage esophagectomy, and the resected tumor was staged as pT1bN0M0. No adjuvant therapy was administered, and the patient was alive with no evidence of disease at the 5-year postoperative follow-up. The response to preoperative treatment should be meticulously assessed and appropriate treatment modalities used to avoid overlooking the potential for cure, even if the response to preoperative treatment with docetaxel, cisplatin, and 5-fluorouracil is poor.

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A 72-year-old woman presented with obstructive jaundice. Computed tomography revealed a 12-mm low-density mass in the head of the pancreas. She was diagnosed as having pancreatic cancer by endoscopic ultrasound-guided fine-needle aspiration. She received gemcitabine plus nab-paclitaxel as preoperative chemotherapy. After 2 courses, hepatoduodenal lymph node metastasis appeared and was accompanied by increased tumor marker levels. The regimen was changed to modified FOLFIRINOX. After 5 courses, the lymph node metastasis was reduced in size and the tumor marker levels were decreased, so subtotal stomach-preserving pancreaticoduodenectomy was performed. Adjuvant chemotherapy was administered postoperatively. The patient was alive and well without recurrence 2 years and 9 months after the surgery, but died of sepsis. Nevertheless, this case highlights that when preoperative chemotherapy for resectable pancreatic cancer appears to be ineffective, a change in regimen may be useful.

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BACKGROUND: This study aimed to evaluate the adequate extent of regional lymphadenectomy according to tumor location and the impact of number-based nodal classification on survival in patients with non-ampullary duodenal adenocarcinoma (NADAC). METHODS: A total of 85 patients with NADAC who underwent surgery were enrolled. The frequency of metastasis was calculated for each node group in the respective tumor locations for 63 patients who underwent lymphadenectomy for pT2-pT4 tumor. RESULTS: The frequency of metastasis in the pancreaticoduodenal (nos. 13 and 17) and superior mesenteric artery (no. 14) nodes was high (16.7 %-52.3 %) regardless of tumor location. Metastasis in the perigastric (nos. 3 and 4d) and right celiac artery (no. 9) nodes was not uncommon (14.3 %-22.2 %) for tumors in the first portion. The frequency of metastasis in the pyloric (nos. 5 and 6) and the other peripancreaticoduodenal (nos. 8 and 12) nodes varied depending on tumor location but could not be ignored for staging. When these nodes were classified as regional nodes, the 5-year survival in patients with pN0, pN1 (1-2 positive nodes), and pN2 (≥3 positive nodes) were 82.9 %, 51.7 %, and 19.2 %, respectively (p < 0.001). pN classification independently predicted survival (pN1, p = 0.022; pN2, p < 0.001). CONCLUSIONS: Nos. 5, 6, 8, 12, 13, 14, and 17 nodes in all advanced NADAC and nos. 3, 4d, and 9 nodes in advanced NADAC in the first portion should be considered as regional nodes for accurate staging. The number-based nodal classification allows good patients' prognostic stratification.

DOI： 10.1016/j.ejso.2023.107122

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BACKGROUND: Ceramide and sphingosine-1-phosphate (S1P) play opposing roles in cell death and survival, and maintain a dynamic balance called the sphingolipid rheostat. Glucosylceramide is a substrate to generate ceramide but its effect on breast cancer by oral administration was never tested. The purpose of this study was to reveal the anticancer activity of glucosylceramide and its potential as a new therapeutic agent in breast cancer. METHODS: E0771 cells were inoculated into the breast tissue of female C57BL/6NJcl mice. Glucosylceramide was administered orally to the mice for nine consecutive days. The concentrations of sphingolipid mediators including ceramide, glucosylceramide, and S1P in tumor tissues and serum were determined by mass spectrometry. RESULTS: Oral administration of glucosylceramide significantly suppressed E0771 tumor growth compared with the control group (P = 0.006). There were no significant differences in the serum concentrations of sphingolipid mediators including ceramide and S1P between the mice treated with glucosylceramide and control-treated mice. The ceramide concentration was significantly lower in tumor tissues (P = 0.026), and the S1P concentration was significantly higher than that in paired non-tumor tissues (P = 0.009). The S1P concentration in tumor tissues was significantly lower in mice treated with glucosylceramide than in control-treated mice (P = 0.001). The ceramide-to-S1P concentration ratio in tumor tissues was significantly higher in mice treated with glucosylceramide than in control-treated mice (P = 0.034). CONCLUSIONS: Breast tumors could enhance their survival by increasing S1P conversion from ceramide. Oral administration of glucosylceramide suppressed tumor growth by affecting the ceramide/S1P balance. Oral administration of glucosylceramide is a promising basis for a new therapeutic approach.

DOI： 10.14740/wjon1656

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BACKGROUND/AIM: Sphingosine-1-phosphate (S1P) is a pleiotropic, bioactive, lipid mediator, produced by sphingosine kinase 1 (SphK1). In this study, we evaluated the expression of phosphorylated SphK1 (pSphK1) in patients with pancreatic ductal adenocarcinoma (PDAC) and investigated its clinical significance. MATERIALS AND METHODS: A total of 111 patients who underwent curative-intent resection for PDAC were enrolled. We investigated pSphK1 (Ser-225) expression in surgically resected specimens of PDAC using immunohistochemistry. The patients were divided into two groups according to pSphK1 immunoreactive expression: a pSphK1-high group (n=63) and a pSphK1-low group (n=48). RESULTS: Logistic regression analyses revealed that lymphatic invasion (p=0.007) was a significantly independent factor associated with high pSphK1 immunoreactive expression. The pSphK1-high group showed significantly worse disease-specific survival (DSS) than the pSphK1-low group (5-year DSS rate, 19.6% vs. 58.7%; p=0.001). High pSphK1 immunoreactive expression (hazard ratio=2.547; 95% confidence interval= 1.434-4.527; p=0.001) was an independent prognostic factor for DSS. CONCLUSION: High pSphK1 expression is independently associated with lymphatic invasion and unfavorable prognosis in PDAC patients. Thus, the SphK1-S1P axis may be important in mechanisms of tumor progression, such as lymphatic invasion, in PDAC patients.

DOI： 10.21873/anticanres.16584

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Language：Japanese   Publisher：新潟医学会  

【緒言】2019年6月よりがん遺伝子パネル検査が保険収載され,本邦におけるがんゲノム医療が始動した.がんゲノム医療では,次世代シークエンサーによる「がん遺伝子パネル検査」を用いて個々の患者における癌の遺伝子変化を明らかにして,その特性に応じた最適な癌治療の機会を提供する.がんゲノム医療においては,多職種による専門家会議である「エキスパートパネル」が重要な位置を占める.エキスパートパネルでは,癌の遺伝子の変化に基づく推奨治療および遺伝性腫瘍に関連する遺伝子の変化(二次的所見)についての議論がなされる.「がんゲノム医療拠点病院」である新潟大学医歯学総合病院は,定期的にエキスパートパネルを開催し,新潟県内のがんゲノム医療を推進している.本研究の目的は,新潟県内におけるがんゲノム医療の現状と今後の課題を明らかにすることである.【方法】(1)2019年9月から2022年8月に,新潟県内のがんゲノム医療連携病院もしくはがんゲノム医療拠点病院においてがん遺伝子パネル検査を実施し,新潟大学医歯学総合病院でエキスパートパネルを実施した503例を対象とした.そして,原発臓器の内訳,がん遺伝子パネル検査の種類,エキスパートパネルで検討された治療推奨および二次的所見の現状を明らかにした.(2)2019年9月から2022年8月に,新潟大学医歯学総合病院からがん遺伝子パネル検査を提出した233例を対象とした.そして,検査提出から結果説明までにかかる期間(Turnaround Time:TAT),治療推奨および治療到達率を明らかにした.【結果】(1)503例の原発臓器の内訳は,消化管が150例(30%),肝胆膵が112例(22%),婦人科系臓器が69例(14%),泌尿器が45例(9%),その他が127例(25%)であった.がん遺伝子パネル検査の種類の内訳では,FoundationOne CDxが359例(72%),FoundationOne Liquid CDxが87例(17%),OncoGuideTM NCCオンコパネルが57例(11%)であった.エキスパートパネルで治療薬を推奨したのは74例(15%)あり,その内訳は治験薬が43例(9%),保険承認薬が32例(6%)であった.また,二次的所見を69例(14%)に認めた.(2)233例のTATの中央値は35日(範囲:19-179日)であった.エキスパートパネルでの治療推奨は36例(15%)であり,治療到達は17例(7%)であった.【結論】がんゲノム医療は,実臨床において着実に広がりつつある.がんゲノム医療では,多職種の専門家の参画が必要であるため,将来を見据えた人材育成が重要である.(著者抄録)

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DOI： 10.1245/s10434-023-13418-2

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DOI： 10.1245/s10434-023-13440-4

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BACKGROUND: Next-generation sequencing (NGS) has enabled comprehensive genomic profiling to identify gene alterations that play important roles in cancer biology. However, the clinical significance of these genomic alterations in triple-negative breast cancer (TNBC) patients has not yet been fully elucidated. The aim of this study was to clarify the clinical significance of genomic profiling data, including copy number alterations (CNA) and tumor mutation burden (TMB), in TNBC patients. METHODS: A total of 47 patients with Stage I-III TNBC with genomic profiling of 435 known cancer genes by NGS were enrolled in this study. Disease-free survival (DFS) and overall survival (OS) were evaluated for their association to gene profiling data. RESULTS: CNA-high patients showed significantly worse DFS and OS than CNA-low patients (p = 0.0009, p = 0.0041, respectively). TMB was not associated with DFS or OS in TNBC patients. Patients with TP53 alterations showed a tendency of worse DFS (p = 0.0953) and significantly worse OS (p = 0.0338) compared with patients without TP53 alterations. Multivariable analysis including CNA and other clinicopathological parameters revealed that CNA was an independent prognostic factor for DFS (p = 0.0104) and OS (p = 0.0306). Finally, multivariable analysis also revealed the combination of CNA-high and TP53 alterations is an independent prognostic factor for DFS (p = 0.0005) and OS (p = 0.0023). CONCLUSIONS: We revealed that CNA, but not TMB, is significantly associated with DFS and OS in TNBC patients. The combination of CNA-high and TP53 alterations may be a promising biomarker that can inform beyond standard clinicopathologic factors to identify a subgroup of TNBC patients with significantly worse prognosis.

DOI： 10.1007/s12282-023-01449-2

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BACKGROUND: The definition and classification of regional nodes are not standardized for perihilar cholangiocarcinoma. This study aimed to clarify the rational extent of regional lymphadenectomy and to elucidate the impact of number-based regional nodal classification on survival of patients with this disease. METHODS: Data of 136 patients with perihilar cholangiocarcinoma who underwent surgery were reviewed. The incidence of metastasis and the survival of patients with metastasis were calculated for each node group. RESULTS: The incidence of metastasis for the node groups in the hepatoduodenal ligament (denoted as no. 12) ranged from 3.7% to 25.4%, with 5-year disease-specific survival of 12.9% to 33.3% for patients with metastasis. The incidences of metastasis in the common hepatic artery (no. 8) and posterior superior pancreaticoduodenal (no. 13a) node groups were 14.4% and 11.2%, respectively, with 5-year disease-specific survival rates of 16.7% and 20.0% for the patients with metastasis. When these node groups were defined as regional nodes, the 5-year disease-specific survival rates for the patients with pN0 (n = 80), pN1 (1-3 positive nodes, n = 38), and pN2 (≥ 4 positive nodes, n = 18) were 61.4%, 22.9%, and 17.6%, respectively (p < 0.001). The pN classification was independently associated with disease-specific survival (p < 0.001). When only the no. 12 node groups were regarded as regional nodes, pN classification failed to stratify the patients prognostically. CONCLUSIONS: No. 8 and no. 13a node groups should be considered regional nodes in addition to no. 12 node groups and should be dissected. The number-based regional nodal classification allows patients with this disease to be stratified prognostically.

DOI： 10.1245/s10434-023-13361-2

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重症胆道感染症から敗血症性ショックに至った症例に対してエンドトキシン吸着療法(polymyxin-direct hemoperfusion:PMX-DHP)を行い,急性期から脱却後に手術を施行し得た2例を経験したので報告する.症例1は79歳の男性で,発熱と呼吸困難を主訴に救急外来を受診した.呼吸数36回/分,経皮的動脈血酸素飽和度81%(room air),心拍数71回/分,血圧85/61mmHgとショック状態であった.腹部造影CT検査で胆嚢結石と総胆管の拡張を認め,総胆管結石による重症急性胆管炎と診断した.気管内挿管と急速輸液,ノルアドレナリンの持続静注を開始し,経皮経肝胆道ドレナージを行なったが,敗血症性ショックが遷延したためPMX-DHPを施行した.PMX-DHP開始後4時間程度で循環動態は安定し,ノルアドレナリンの投与を終了した.急性胆管炎発症から3病日目に人工呼吸器管理を終了し,15病日目に内視鏡下に総胆管結石を採石した.29病日目に自宅へ退院となった.発症から3ヵ月後に腹腔鏡下胆嚢摘出術を施行した.術後2年2ヵ月が経過した現在,胆道感染症の再発なく経過している.症例2は86歳の女性で,大動脈弁置換術後のため入院加療中であった.術後21病日目に発熱し,呼吸数34回/分,経皮的動脈血酸素飽和度96%(酸素8L/分投与下),心拍数125回/分,血圧85/41mmHgとショック状態となった.腹部造影CT検査で腫大した胆嚢と周囲の脂肪織濃度の上昇を認め,重症急性胆嚢炎と診断した.急速輸液,ノルアドレナリンの持続静注を開始し,経皮経肝胆嚢ドレナージを施行した.敗血症性ショックが遷延したためPMX-DHPを施行し,血圧は上昇傾向となった.急性胆嚢炎発症から3病日目にノルアドレナリンの投与を終了できた.46病日目にリハビリ目的に他院へ転院となった.発症から3ヵ月後に開腹下胆嚢摘出術を施行した.術後1年6ヵ月が経過した現在,胆道感染症の再発なく経過している.重症胆道感染症により循環動態が不安定な症例では,PMX-DHPは支持療法として治療選択肢の1つになり得る.(著者抄録)

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BACKGROUND: This study aimed to clarify potential candidates for anatomic resection (AR) among patients with pathological T1-T2 (pT1-T2) hepatocellular carcinoma (HCC) and to determine whether AR is effective for HCC with microscopic vascular invasion (MVI). METHODS: We retrospectively analyzed 288 patients with pT1a (n = 50), pT1b (n = 134) or pT2 (n = 104) HCC who underwent curative-intent resection between 1990 and 2010. Surgical outcomes were compared between patients who underwent AR (n = 189) and those who underwent nonanatomic resection (NAR; n = 99) according to pT category and MVI status. RESULTS: Patients who underwent AR were more likely to have good hepatic functional reserve and an aggressive primary tumor than those who underwent NAR. When patients were stratified according to pT category, AR had a more favorable impact on survival than NAR only in patients with pT2 HCC in univariate (5-year survival, 51.5% vs. 34.6%; p = 0.010) and multivariate analysis (hazard ratio 0.505; p = 0.014). However, AR had no impact on survival in patients with pT1a or pT1b HCC. In patients with MVI (n = 57), AR achieved better survival than NAR (5-year survival, 52.0% vs. 16.7%; p = 0.019) and was an independent prognostic factor (hazard ratio 0.335; p = 0.020). In patients without MVI (n = 231), there was no significant difference in survival between the two groups (p = 0.221). CONCLUSION: AR was identified as an independent factor in improved survival in patients with pT2 HCC or HCC with MVI.

DOI： 10.1016/j.suronc.2023.101951

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【症例】60歳代女性.右乳癌に対して,右乳房切除術ならびに腋窩リンパ節郭清術を施行され,pT3N0M0,pStage IIB,ホルモン受容体陰性,human epidermal growth factor receptor type 2(HER2)陽性と診断された.術後補助療法(trastuzumab,pertuzumab併用療法)中の術後1年5ヵ月時に右胸壁再発(ホルモン受容体陰性,HER2陰性),多発肺転移再発をきたした.Paclitaxel,bevacizumab併用療法を開始したが,右胸壁再発巣が増大したため放射線治療を行い,縮小を得た.しかし,多発肺転移再発巣は増大したため,右胸壁再発巣の針生検検体でPD-L1(SP142)陽性であることを確認し,nab-paclitaxel,atezolizumab併用療法を施行した.3コース終了後,右胸壁再発巣と多発肺転移再発巣は縮小し,部分奏効と判断した.4コース目の治療中に下垂体機能低下症を発症したため治療を中止し,以後は無治療経過観察の方針とした.治療中止後1年8ヵ月経過時点で,全ての再発巣は縮小した状態を維持している.【結語】HER2陽性乳癌では再発巣がHER2陰性である可能性があり,再発巣のサブタイプに応じた適切な治療選択が重要である.(著者抄録)

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INTRODUCTION: Colorectal cancer (CRC) is one of the major life-threatening complications in patients with Crohn's disease (CD). Previous studies of CD-associated CRC (CD-CRC) have involved only small numbers of patients, and no large series have been reported from Asia. The aim of this study was to clarify the prognosis and clinicopathological features of CD-CRC compared with sporadic CRC. METHODS: A large nationwide database was used to identify patients with CD-CRC (n = 233) and sporadic CRC (n = 129,783) over a 40-year period, from 1980 to 2020. Five-year overall survival (OS), recurrence-free survival (RFS), and clinicopathological characteristics were investigated. The prognosis of CD-CRC was further evaluated in groups divided by colon cancer and anorectal cancer (RC). Multivariable Cox regression analysis was used to adjust for confounding by unbalanced covariables. RESULTS: Compared with sporadic cases, patients with CD-CRC were younger; more often had RC, multiple lesions, and mucinous adenocarcinoma; and had lower R0 resection rates. Five-year OS was worse for CD-CRC than for sporadic CRC (53.99% vs 71.17%, P < 0.001). Multivariable Cox regression analysis revealed that CD was associated with significantly poorer survival (hazard ratio 2.36, 95% confidence interval: 1.54-3.62, P < 0.0001). Evaluation by tumor location showed significantly worse 5-year OS and RFS of CD-RC compared with sporadic RC. Recurrence was identified in 39.57% of CD-RC cases and was mostly local. DISCUSSION: Poor prognosis of CD-CRC is attributable primarily to RC and high local recurrence. Local control is indispensable to improving prognosis.

DOI： 10.14309/ajg.0000000000002269

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INTRODUCTION: This study aimed to evaluate the association between the preoperative Controlling Nutritional Status (CONUT) score, survival outcomes, and recurrence pattern in patients with resectable biliary tract cancer (BTC). METHODS: A total of 224 BTC patients (gallbladder, n = 69; intrahepatic bile ducts, n = 26; perihilar bile ducts, n = 72; distal bile duct, n = 57) who underwent surgery with curative intent were enrolled. The best cutoff point of the preoperative CONUT score in discriminating survival was determined using χ2 scores. The sites of recurrence were subclassified as locoregional or distant. RESULTS: Patients were subdivided into the CONUT-low (score ≤ 3, n = 156) and the CONUT-high (score > 3; n = 68) groups. In-hospital mortality occurred more frequently in the CONUT-high group than in the CONUT-low group (7.4% vs. 1.3%; p = 0.028). A high preoperative CONUT score was independently associated with worse overall survival (hazard ratio [HR] 1.906, p = 0.001), worse disease-specific survival (HR 1.840, p = 0.006), and worse recurrence-free survival (HR 1.680, p = 0.005). Recurrence developed in 110 (49.1%) patients. A high preoperative CONUT score was independently associated with a higher risk of distant recurrence (HR 2.245, p = 0.001), but not locoregional recurrence. The incidences of distant recurrence at 5 years were 55.4% and 34.2% in the CONUT-high and CONUT-low groups, respectively (p = 0.001). CONCLUSIONS: The preoperative CONUT score independently predicts survival outcomes and may serve as a surrogate marker of aggressive systemic disease recurrence in patients with resectable BTC.

DOI： 10.1016/j.ejso.2022.11.003

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We report a case of intrahepatic cholangiocarcinoma(ICC)with lymph node metastases in which long-term survival was achieved after surgery followed by chemotherapy. A 69-year-old man underwent left hepatectomy, extrahepatic bile duct resection, and lymph node dissection for ICC located mainly in segment 4 of the liver with enlarged lymph nodes in the hepatoduodenal ligament. The histopathologically confirmed diagnosis was ICC(T2N1M0, Stage ⅣA)with 3 positive lymph nodes(No. 12a1, No. 12p1, and No. 12p2). He received chemotherapy with gemcitabine(GEM)plus cisplatin(CDDP)for 9 months, followed by GEM monotherapy for 4 months, and then S-1 monotherapy was started. A right lung nodule was detected 12 months after the initiation of S-1 monotherapy. He received GEM plus S-1 therapy for 28 months, followed by S-1 monotherapy, leading to disappearance of the lung nodule. He remains alive and well without disease 78 months after surgery. Our experience in this case suggests that radical resection followed by chemotherapy may provide a survival benefit in selected patients who have ICC with nodal disease.

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BACKGROUND: Anastomotic leakage (AL) is a serious complication after esophagectomy for esophageal cancer. The objective of this study was to identify the risk factors for AL. METHODS: Patients with esophageal cancer who underwent curative esophagectomy and cervical esophagogastric anastomosis between 2009 and 2019 (N = 346) and those between 2020 and 2022 (N = 17) were enrolled in the study to identify the risk factors for AL and the study to assess the association between the risk factors and blood flow in the gastric conduit evaluated by indocyanine green (ICG) fluorescence imaging, respectively. RESULTS: AL occurred in 17 out of 346 patients (4.9%). Peptic or endoscopic submucosal dissection (ESD) ulcer scars were independently associated with AL (OR 6.872, 95% CI 2.112-22.365) in addition to diabetes mellitus. The ulcer scars in the anterior/posterior gastric wall were more frequently observed in patients with AL than in those without AL (75.0% vs. 17.4%, P = 0.042). The median flow velocity of ICG fluorescence in the gastric conduits with the scars was significantly lower than in those without the scars (1.17 cm/s vs. 2.23 cm/s, P = 0.004). CONCLUSIONS: Peptic or ESD ulcer scarring is a risk factor for AL after esophagectomy in addition to diabetes mellitus. The scars in the anterior/posterior gastric wall are significantly associated with AL, impairing blood flow of the gastric conduit. Preventive interventions and careful postoperative management should be provided to minimize the risk and severity of AL in patients with these risk factors.

DOI： 10.1007/s11605-022-05545-0

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BACKGROUND: Patients with longstanding inflammatory bowel disease are at high risk of developing intestinal cancers. In this study, we aimed to elucidate the differences between intestinal cancers associated with ulcerative colitis and Crohn's disease. METHODS: Intestinal cancers in ulcerative colitis and Crohn's disease patients treated between 1983 and 2020 at 43 Japanese institutions were retrospectively analyzed.. RESULTS: A total of 1505 intestinal cancers in 1189 ulcerative colitis and 316 Crohn's disease patients were studied. Almost all of ulcerative colitis-associated cancers (99%) were in the colon and rectum, whereas half of Crohn's disease-associated cancers (44%) were in the anus, with 11% in the small intestine. Ulcerative colitis-associated cancers were diagnosed more frequently by surveillance (67% vs. 25%, P < 0.0001) and at earlier stages (stages 0-1, 71% vs. 27%, P < 0.0001) compared with Crohn's disease-associated cancers. Colorectal cancers associated with Crohn's disease showed a significantly worse 5-year overall survival rate than those associated with ulcerative colitis (stage 2, 76% vs. 89%, P = 0.01, stage 3, 18% vs. 68%, P = 0.0009, and stage 4, 0% vs. 13%, P = 0.04). Surveillance correlated with earlier diagnoses for ulcerative colitis- and Crohn's disease-associated intestinal cancers, whereas shorter intervals between endoscopic examinations correlated with an earlier cancer diagnosis in ulcerative colitis patients but not in Crohn's disease patients. CONCLUSIONS: The clinical and oncological features of ulcerative colitis- and Crohn's disease-associated cancers were very different. Crohn's disease-associated cancers were diagnosed at more advanced stages and were detected less frequently by surveillance. Additionally, they showed a significantly poorer prognosis.

DOI： 10.1007/s00535-022-01927-y

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BACKGROUND: Recent improvements in systemic chemotherapy have provided an opportunity for patients with stage IV gastric cancer (GC) to undergo conversion surgery (CS). The aim of this study was to evaluate the long-term outcomes of patients who underwent CS and to elucidate the prognostic factors for CS in stage IV GC. METHODS: A total of 79 patients who underwent CS with the aim of R0 resection for stage IV GC at six institutions from January 2008 to July 2019 were enrolled. We retrospectively reviewed the clinicopathological data and prognosis. RESULTS: Of the 79 patients, 23 (31.1%) had initially resectable disease (IR) before chemotherapy, defined as positive for cancer on peritoneal cytology (CY1), resectable hepatic metastasis, or para-aortic lymph node No. 16a2/b1 metastasis. Of the 56 remaining patients with primary unresectable disease, 39 had peritoneal dissemination. R0 resection was accomplished in 63 patients (79.7%). The 3-year OS rates for patients with IR and unresectable disease were 78.3% and 44.5%, respectively. Multivariate analysis showed that IR (P = 0.014) and R0 (P = 0.014) were statistically significant independent prognostic factors for favorable OS. Among patients with peritoneal dissemination alone, OS was significantly better for patients with R0 resection than for patients with R1/2 resection, with the 3-year OS rates of 65.5% and 23.1%, respectively (P = 0.011). CONCLUSIONS: CS is a treatment option for selected patients with stage IV GC. Patients with IR and patients who achieve R0 resection may obtain a survival benefit from CS.

DOI： 10.1186/s12893-022-01874-8

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Language：Japanese   Publishing type：Research paper (scientific journal)  

The patient was a 71-year-old man with a diagnosis of duodenal carcinoma. Abdominal computed tomography(CT) showed no distant metastasis, and he underwent subtotal stomach-preserving pancreaticoduodenectomy. Postoperative adjuvant chemotherapy was not administered. A left supraclavicular lymph node recurrence was detected on CT 15 months after surgery. Capecitabine and oxaliplatin(CAPOX)therapy was administered and the metastatic lesion shrank. Positron emission tomography(PET)-CT showed no lesions at other sites and left cervical lymph node dissection was performed 5 months after the recurrence. Postoperative adjuvant therapy with S-1 was administered for 6 months. However, 2 years and 10 months after the first recurrence, CT showed recurrence in the left supraclavicular lymph node. CAPOX therapy was resumed, but due to an allergic reaction to oxaliplatin, the patient was treated with capecitabine alone. The recurrent lesion was gradually increased in size, and FOLFIRI therapy was introduced. One year and 5 months after secondary recurrence, PET-CT showed that the second recurrent lesion had grown but was confined to the left supraclavicular lymph node, so radiation therapy(60 Gy)to the left neck was performed. The disease was stable for about 10 months and chemotherapy could be discontinued. The lesion increased in size thereafter, and the patient died 7 years after initial surgery.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elmer Press, Inc.  

BACKGROUND: Severe neutropenia, including febrile neutropenia, is a major toxicity of systemic chemotherapy that leads to delays in treatment, higher costs, and mortality. Severe neutropenia may occur during neoadjuvant chemotherapy even when the patients are free from known risk factors. Pegfilgrastim, a covalent conjugant of filgrastim that stimulate the production of neutrophils, is used for prevention. The current study aimed to reveal the characteristics of patients who need pegfilgrastim for primary prophylaxis to prevent severe neutropenia, including febrile neutropenia and grade 3 neutropenia, during neoadjuvant chemotherapy. METHODS: A retrospective analysis of 83 patients treated with neoadjuvant adriamycin/cyclophosphamide followed by docetaxel chemotherapy was performed. The factors which associated with severe neutropenia were examined by univariate and multivariate analyses. RESULTS: Severe neutropenia developed in one of 22 patients (5%) with pegfilgrastim for primary prophylaxis and in 17 of 61 patients (28%) without it. In 83 patients, the incidence of severe neutropenia was significantly decreased in the patients with pegfilgrastim for primary prophylaxis shown by the univariate analysis (P = 0.023) and multivariate analysis (P = 0.030). In 61 patients without pegfilgrastim for primary prophylaxis, the univariate analysis showed that severe neutropenia was associated with tumor size (P = 0.004), clinical stage (P = 0.009), and cancer antigen 15-3 (CA15-3) (P = 0.026). The multivariate analysis showed that clinical stage was associated with severe neutropenia (P = 0.021). CONCLUSIONS: The current study demonstrated that advanced stage is a risk for severe neutropenia in patients treated with neoadjuvant adriamycin/cyclophosphamide followed by docetaxel chemotherapy. Given that prophylaxis with pegfilgrastim was associated with significantly lower incidence of severe neutropenia, patient with advance stage breast cancer may benefit from pegfilgrastim during neoadjuvant chemotherapy.

DOI： 10.14740/wjon1530

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Language：Japanese   Publishing type：Research paper (scientific journal)  

A 53-year-old woman underwent subtotal stomach-preserving pancreaticoduodenectomy(SSPPD)for resectable pancreatic cancer after neoadjuvant chemotherapy. Postoperatively, she received hepatic arterial infusion of 5-FU and S-1 chemotherapy. Two years after SSPPD, abdominal computed tomography showed a 2-cm mass in the remnant pancreas, which was diagnosed as recurrence of cancer by endoscopic ultrasound-guided fine-needle aspiration. Staging laparoscopy was performed and peritoneal washing cytology(CY)was positive. She then received gemcitabine plus nab-paclitaxel chemotherapy for 8 months. After that, staging laparoscopy was performed again and negative CY was confirmed. A total remnant pancreatectomy with splenectomy was performed. She received chemotherapy after pancreatectomy and is now alive and well without recurrence 2 years and 1 month after the second surgery. Although positive CY is a poor prognostic factor, surgery combined with perioperative chemotherapy may contribute to prolonged survival for some patients who have recurrence in the remnant pancreas with positive CY.

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A 71-year-old man with middle thoracic esophageal cancer was treated with neoadjuvant chemotherapy using docetaxel plus 5-FU plus cisplatin therapy and was also administered pegfilgrastim. Blood tests showed elevated white blood cell counts and C-reactive protein levels before the start of the third course. Contrast-enhanced computed tomography revealed wall thickening of the aortic arch. We diagnosed this as aortitis due to pegfilgrastim. Inflammation was improved with conservative treatment. We then performed video-assisted thoracoscopic esophagectomy. Drug-induced vasculitis should be included in the differential diagnosis of patients with elevated inflammation markers of unknown cause following the administration of granulocyte colony-stimulating factor preparations.

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Neurenteric cyst (NC) shows benign histopathology and rarely demonstrate malignant transformation. We herein describe a case of NC that exhibited malignant transformation. A 65-year-old female presented with gait disturbance due to compression by a cystic mass on the dorsal surface of the medulla oblongata. Partial resection was performed twice, leading to improvement of her symptoms. Two years after the second surgery, gadolinium-perfused T1-weighted magnetic resonance imaging revealed an invasive lesion with contrast enhancement at the trigone of the left lateral ventricle for which partial resection followed by radiotherapy was performed. However, mass regrowth was observed, with the patient eventually succumbing to her disease 11 months after her third surgery. Histopathological analyses of the first and second surgical specimens identified pseudostratified cuboidal epithelial cells, with no nuclear or cellular atypia resembling gastrointestinal mucosa, lining the inner surface of the cystic wall. Based on these findings the lesion was diagnosed as NC. The third surgical specimen exhibited apparent malignant features of the epithelial cells with elongated and hyperchromatic nuclei, several mitotic figures, small necrotic foci, and a patternless or sheet-like arrangement. Based on these findings, the lesion was diagnosed as NC with malignant transformation. Next-generation sequencing revealed KRAS p.G12D mutation in all specimens. Additionally, the third surgical specimen harbored the following 12 de novo gene alterations: ARID1A loss, BAP1 p.F170L, CDKN1B loss, CDKN2A loss, CDKN2B loss, FLCN loss, PTCH1 loss, PTEN loss, PTPRD loss, SUFU loss, TP53 loss, and TSC1 loss. The aforementioned results suggest that KRAS mutation is associated with the development of the NC, and that the additional gene alterations contribute to malignant transformation of the NC.

DOI： 10.1111/neup.12822

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Language：Japanese   Publishing type：Research paper (scientific journal)  

A 74-year-old man presented to our hospital with a mass in the left supraclavicular fossa. He was diagnosed with advanced gastric cancer with liver metastasis and left supraclavicular and para-aortic lymph node metastasis, cT3N2M1 (LYM, HEP), cStage Ⅳ(the Union for International Cancer Control, TNM 7th edition). He received a total of 3 courses of S- 1 plus cisplatin therapy. Since he developed adverse reactions such as anorexia, renal dysfunction, and thrombocytopenia and the tumor was HER2-positive, he received 25 courses of capecitabine, cisplatin, and trastuzumab chemotherapy. Three years and 2 months after the first chemotherapy, remarkable tumor reduction was observed. The patient then underwent radical distal gastrectomy with D2 lymphadenectomy, and R0 resection was achieved. The histopathological diagnosis was ypT1aN0M0, ypStage ⅠA. Chemotherapy with trastuzumab may improve the long-term prognosis of HER2-positive Stage Ⅳ gastric cancer if the disease is controlled and radical resection can be achieved.

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A woman in her 60s had been aware of perianal erosions for 1 month. Skin biopsy showed Paget's cells in the stratified squamous epithelium, and immunohistochemistry showed negative staining for CK7 and positive staining for CK20. Colonoscopy revealed well-differentiated adenocarcinoma in the anal canal. Computed tomography showed neither regional lymph node metastasis nor distant metastasis. Hence, she was diagnosed with anal canal carcinoma with pagetoid spread. We determined the extent of resection of the skin lesion preoperatively by mapping biopsy, and performed laparoscopic abdominoperineal resection. The pathological findings revealed adenocarcinoma(tub1, tub2), and the skin resection margin was negative. Immunohistochemistry for Paget's cells in the stratified squamous epithelium showed negative staining for GCDFP-15 and CK7, and positive staining for CK20. Twenty-four months after surgery, we detected right inguinal lymph node metastasis and performed right inguinal lymphadenectomy. As of 4 months after the lymphadenectomy, no local recurrence or distant metastasis has been detected during follow-up examinations.

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The outer mucus layer of the colorectal epithelium is easily removable and colonized by commensal microbiota, while the inner mucus layer is firmly attached to the epithelium and devoid of bacteria. Although the specific bacteria penetrating the inner mucus layer can contact epithelial cells and trigger cancer development, most studies ignore the degree of mucus adhesion at sampling. Therefore, we evaluated whether bacteria adhering to tissues could be identified by removing the outer mucus layer. Our 16S rRNA gene sequencing analysis of 18 surgical specimens of human colorectal cancer revealed that Sutterella (P = 0.045) and Enterobacteriaceae (P = 0.045) were significantly enriched in the mucus covering the mucosa relative to the mucosa. Rikenellaceae (P = 0.026) was significantly enriched in the mucus covering cancer tissues compared with those same cancer tissues. Ruminococcaceae (P = 0.015), Enterobacteriaceae (P = 0.030), and Erysipelotrichaceae (P = 0.028) were significantly enriched in the mucus covering the mucosa compared with the mucus covering cancers. Fusobacterium (P = 0.038) was significantly enriched in the mucus covering cancers compared with the mucus covering the mucosa. Comparing the microbiomes of mucus and tissues with mucus removed may facilitate identifying bacteria that genuinely invade tissues and affect tumorigenesis.

DOI： 10.1038/s41598-022-21928-4

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Language：Japanese   Publisher：新潟医学会  

【目的】スフィンゴシン-1-リン酸(S1P)は様々な生理活性を持つスフィンゴ脂質であり,炎症や発癌に関与していると言われている.潰瘍性大腸炎術後回腸嚢炎は晩期合併症として注目されているが,原因については不明な点が多い.本研究では,S1Pと回腸嚢炎の関連を明らかにすることを目的とした.【対象と方法】2020年7月～2021年2月に潰瘍性大腸炎術後,回腸嚢から内視鏡的あるいは手術により組織生検が行われた6名を対象とした.臨床データ(採血結果,回腸嚢炎重症度,消化管内視鏡検査等)をカルテから後方視的に解析した.回腸嚢炎の診断は,厚生労働科学研究費補助金難治性疾患政策研究事業による「潰瘍性大腸炎・クローン病診断基準・治療指針」に準じた.回腸嚢組織における質量分析によるS1P測定,および抗リン酸化S1P産生酵素(pSphK1)抗体を用いた免疫組織化学染色を行った.回腸嚢炎の重症度とS1P値,抗pSphK1抗体免疫組織化学染色の関連について検討した.【結果】対象6名の内訳は,男性5名,女性1名,年齢の中央値は45歳(範囲:33-70歳)であった.回腸嚢の内視鏡所見として,1例は回腸嚢炎なし(正常),2例は軽度,3例は中等度であった.対象6例のS1P測定値(中央値)は0.2pmol/mg(範囲:0.1-0.8pmol/mg)であった.採血データで高度の炎症を伴った中等度症例のS1P値が高値を示していた.免疫組織化学染色の結果では,内視鏡的に回腸嚢炎の所見を認めた5例のうち4例で抗pSphK1抗体陽性が陽性であった.【結論】脂質メディエーターであるS1Pが,潰瘍性大腸炎術後回腸嚢炎の炎症増悪に関与している可能性が示唆された.(著者抄録)

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2022&ichushi_jid=J00990&link_issn=&doc_id=20230710120002&doc_link_id=%2Fdg3nigta%2F2022%2F013607%2F002%2F0219-0224%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdg3nigta%2F2022%2F013607%2F002%2F0219-0224%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

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With the discovery of bacterial symbiosis in the tissues of various cancers, the study of the tumor microbiome is attracting a great deal of attention. Anatomically, since the gastrointestinal tract, liver, and pancreas form a continuous ductal structure, the microbiomes in the digestive juices of these organs may influence each other. Here, we report a series of microbiome data in tumor-associated tissues such as tumor, non-tumor, and lymph nodes, and body fluids such as saliva, gastric juice, pancreatic juice, bile, and feces of patients with pancreatic or biliary tract cancers. The results show that the microbiome of tumor-associated tissues has a very similar bacterial composition, but that in body fluids has different bacterial composition which varies by location, where some bacteria localize to specific body fluids. Surprisingly, Akkermansia was only detected in the bile of patients with biliary tract cancer and its presence was significantly associated with the performance of external biliary drainage (P = 0.041). Furthermore, we found that tumor-associated tissues and body fluids in deep inner body are mostly inhabited by unidentified and uncharacterized bacteria, suggesting that such bacteria may be potential targets for precision therapy in the future.

DOI： 10.1038/s41598-022-12658-8

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Language：Japanese   Publisher：新潟医学会  

【目的】消化器外科術後に発症した播種性血管内凝固(disseminated intravascular coagulation;以下,DICと略記)に対する遺伝子組み換えトロンボモジュリン(recombinant human soluble thrombomodulin;以下,rTMと略記)の効果を検証し,治療成績改善に向けた方策を考察する.【方法】2016年1月から2021年5月に当科で消化器外科術後DICの改善を目的にrTMが投与された48例を対象とした.対象症例におけるDICの改善効果,および在院死亡の危険因子を検証した.DICの診断には,日本救急医学会の急性期DIC診断基準を使用した.患者背景および検査項目に関する2群間のカテゴリー変数の比較にはPearsonのχ2検定,Fisherの直接法を用いた.多変量解析はstepwise法によるロジスティック回帰分析を用いて行った.生存曲線はKaplan-Meier法で算出し,log rank検定で有意差検定を行った.有意水準5%(P<0.05)をもって有意差ありと判断した.【結果】年齢の中央値は76歳(59-91),男女比は21:27であった.原疾患は下部消化管穿孔が22例(45.8%),悪性腫瘍が11例(22.9%),消化管虚血が10例(20.8%),上部消化管穿孔が5例(10.4%)であった.DICを発症した原因は,急性汎発性腹膜炎が38例(79.2%),術後感染症が5例(10.4%),術後肝不全が4例(8.3%),術後出血が1例(2.1%)であった.rTM投与開始後7日目に28例(58.3%)で血小板数増加を認め,31例(64.6%)でDICスコアの改善を認めた.投与開始後28日の生存率は72.9%で,在院死亡率は41.7%であった.在院死亡群と生存群における比較では,在院死亡群において「悪性疾患あり」(P=0.034),「DICの原因が術後肝不全」(P=0.025),rTM投与開始時の「血小板数5万/μl未満」(P=0.009),「総ビリルビン2.0mg/dl以上」(P=0.002),rTM投与開始後7日目の「血小板数増加なし」(P=0.001),「DICスコア改善なし」(P=0.003)の占める割合が高かった.多変量解析ではrTM投与開始後7日目の「血小板数増加なし」(HR 5.076:95%CI 1.145-22.222:P=0.032)が独立した在院死亡の危険因子であった.【結語】消化器外科術後に発症するDICは極めて予後不良な病態であるが,rTM投与開始後早期に血小板数の増加を認めた場合,予後の改善を期待できる可能性がある.(著者抄録)

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OBJECTIVES: Diversion colitis (DC) is an inflammatory disorder caused by interruption of the fecal stream and subsequent nutrient deficiency from luminal bacteria. The utility of fecal microbiota transplantation (FMT) for DC was recently investigated; however, the precise pathogenesis of this condition remains unclear. This study aimed to evaluate the utility of autologous FMT in DC and to determine the related changes in the intestinal microbiota. METHODS: Autologous FMT was performed to reestablish the intestinal microbiota in five patients (average age, 64.6 ± 8.3 years) with DC. They underwent double-ended colostomy. We assessed the diverted colon by endoscopy and evaluated the microbiota before and after FMT using the 16S rRNA gene sequencing method. RESULTS: All five patients had mild inflammation (ulcerative colitis endoscopic index of severity [UCEIS] 2-3) in the diverted colon based on the colonoscopic findings. Three patients presented with symptoms, such as tenesmus, mucoid stool, and bloody stool. With FMT treatment, all patients achieved endoscopic remission (UCEIS score of 0 or 1) and symptomatic improvement. We observed a significantly decreased α-diversity in DC patients compared to healthy controls. The frequency of aerobic bacteria, such as Enterobacteriaceae, in the diverted colon decreased after autologous FMT. CONCLUSIONS: This study was the first to show that the microbiota in the diverted colon was significantly affected by autologous FMT. Since interruption of the fecal stream is central to the development of DC, FMT can be considered a promising treatment.

DOI： 10.1002/deo2.63

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Gastrointestinal duplications are congenital malformations that are usually observed in pediatric patients. Diagnosis in adulthood is quite rare, and preoperative diagnosis of gastrointestinal duplication is difficult, particularly in the small intestine. We encountered an extremely rare adult case of duplication of the jejunum, which showed a stomach-like form diagnosed using double-balloon enteroscopy (DBE). The patient was an 18-year-old male who had been experiencing upper abdominal pain and vomiting repeatedly without any triggers for 3 years. Various examinations were performed, but no cause of symptoms was found. DBE revealed a narrow opening of the lumen at the upper jejunum, and the lumen was covered with mucosal folds similar to those of the stomach. Enteroclysis via DBE showed a tubular structure on the mesenteric side of the jejunum. We diagnosed a jejunal tubular duplication with ectopic gastric mucosa and underwent partial small bowel resection. The patient's abdominal symptoms resolved. From this, DBE can be a useful tool for diagnosing intestinal duplication in adults. We believe that this case and literature review will facilitate the accurate and prompt diagnosis of small intestinal duplication.

DOI： 10.1007/s12328-022-01596-7

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

BACKGROUND: ARID1A is a component of the SWI/SNF complex, which controls the accessibility of proteins to DNA. ARID1A mutations are frequently observed in colorectal cancers (CRCs) and have been reported to be associated with high mutational burden and tumor PD-L1 expression in vitro. AIM: To clarify the role of ARID1A mutation in CRC. METHOD AND RESULTS: We used next generation sequencing (NGS) and immunohistochemistry on clinically obtained samples. A total of 201 CRC tissues from Niigata University and Niigata Center Hospital were processed by NGS using the CANCERPLEX panel. Immunohistochemistry for ARID1A, PD-L1, MLH1, and MSH2 was performed on 66 propensity-matched (33 microsatellite instability-high [MSI-H] and 33 microsatellite-stable [MSS]) cases among 499 cases from Kyushu University. TCGA data were downloaded from cBioPortal. NGS showed significantly more mutations in ARID1A mutated CRCs (p = 0.01), and the trend was stronger for right-sided CRCs than left-sided. TCGA data confirmed these findings (p < 0.01). BRAF V600E and ATM mutations were also found at higher frequencies. Immunohistochemistry showed that 30% of MSI-H CRCs had ARID1A loss, while this was true in only 6% of MSS CRCs. In both MSI-H and MSS, PD-L1 expression by stromal cells was enhanced in the ARID1A-mutant groups (90% vs 39% in MSI-H, 100% vs 26% in MSS). CONCLUSION: We found a higher mutational burden in ARID1A-mutant CRCs, and IHC study showed that ARID1A loss was correlated with high PD-L1 expression in stromal cells regardless of MSI status. These data support the idea that mutant ARID1A is a potential biomarker for CRCs.

DOI： 10.1002/cnr2.1420

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Language：Japanese   Publisher：アステラス製薬(株)  

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Although numerous experiments revealed an essential role of a lipid mediator, sphingosine-1-phosphate (S1P), in breast cancer (BC) progression, the clinical significance of S1P remains unclear due to the difficulty of measuring lipids in patients. The aim of this study was to determine the plasma concentration of S1P in estrogen receptor (ER)-positive BC patients, as well as to investigate its clinical significance. We further explored the possibility of a treatment strategy targeting S1P in ER-positive BC patients by examining the effect of FTY720, a functional antagonist of S1P receptors, on hormone therapy-resistant cells. Plasma S1P levels were significantly higher in patients negative for progesterone receptor (PgR) expression than in those positive for expression (p = 0.003). Plasma S1P levels were also significantly higher in patients with larger tumor size (p = 0.012), lymph node metastasis (p = 0.014), and advanced cancer stage (p = 0.003), suggesting that higher levels of plasma S1P are associated with cancer progression. FTY720 suppressed the viability of not only wildtype MCF-7 cells, but also hormone therapy-resistant MCF-7 cells. Targeting S1P signaling in ER-positive BC appears to be a possible new treatment strategy, even for hormone therapy-resistant patients.

DOI： 10.3390/ijms222413367

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A 62-year-old man was incidentally found to have a pancreatic tumor by CT. He was diagnosed with pancreatic cancer by EUS-FNAB. Gemcitabine(GEM)plus nab-paclitaxel(PTX)was started as neoadjuvant chemotherapy(NAC)for resectable pancreatic cancer. However, after the end of the second course, the tumor grew rapidly and invaded the stomach, so NAC was discontinued, and surgery was performed. The pathological diagnosis was anaplastic ductal carcinoma of the pleomorphic cell type, and the histological response was Grade 1a. Multiple liver metastases appeared during adjuvant chemotherapy with S-1, so GEM plus nab-PTX and modified FOLFIRINOX were administered, but the therapeutic response was poor, the patient died 9 months after surgery. Anaplastic carcinoma has a poor response to chemotherapy and may be included with cancers showing treatment resistance to NAC, as seen in our case. It is necessary to pay attention to anaplastic carcinoma during the course of NAC for pancreatic cancer.

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A 70-year-old female with liver metastases from gastrointestinal stromal tumor(GIST)that were found 3 months after partial gastrectomy for the primary GIST underwent Auchincloss operation for left breast cancer with ipsilateral axillary lymph node metastases. The diagnosis was microinvasive ductal cancer that was pT1miN1M0, pStage ⅡA, hormone receptor negative, and HER2 positive. Given the impact of this cancer on the prognosis of liver metastases of GIST, imatinib therapy, but not adjuvant chemotherapy, was started promptly for breast cancer after surgery. Four months after the surgery, left subclavian lymph node recurrence of breast cancer was found. Since the liver metastases of GIST had been stable, imatinib was discontinued, and paclitaxel and anti-HER2 therapy were administered. After confirming tolerability, imatinib was carefully added in combination. Because the lymph nodes shrank and liver metastases of GIST were stable, both anti-HER2 therapy and imatinib were continued. There are few reports of combined chemotherapy for synchronous double cancer, and we report our experience in which careful treatment was required.

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A 72-year-old man had a chief complaint of anal pain and difficulty in defecation. He was diagnosed with adenocarcinoma by biopsy from a tumor of the anal canal. A computed tomography scan revealed neither regional lymph node metastasis nor distant metastasis. Hence, he was diagnosed with cT3N0M0, cStage Ⅱa anal canal cancer. Preoperative capecitabine- based chemoradiotherapy(CRT)(50.4 Gy in 28 fractions of 1.8 Gy each)was implemented. Digital rectal examination and imaging evaluation 8 weeks after preoperative CRT revealed that the tumor had shrunk. Fifteen weeks after preoperative CRT, laparoscopic abdominoperineal resection was performed. The pathological findings showed mucinous adenocarcinoma associated with anal fistula. At present, 12 months after the operation, no local recurrence and distant metastasis has been detected under follow-up evaluations.

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The patient was a 64-year-old man with diagnosis of pancreatic head cancer. Initially, abdominal CT showed pancreatic head tumor with bile duct invasion and no distant metastases including para-aortic lymph nodes(PALN). Although, subtotal stomach-preserving pancreatoduodenectomy(SSPPD)and PALN sampling was performed, intraoperative frozen section examination revealed PALN metastasis. He had chronic kidney disease and was unsuitable for standard chemotherapy, SSPPD and PALN dissection was performed instead of standard chemotherapy. Histopathological examination of the resected specimens revealed invasive ductal carcinoma in the pancreatic head region and 11 nodes out of the 17 dissected PALN. Adjuvant chemotherapy with S-1 was performed. 22 months after surgery, intraabdominal lymph nodes metastasis and lung metastasis was found. 24 months after surgery, palliative radiation therapy at a dose of 40 Gy was performed. Systemic chemotherapy with gemcitabine alone was performed, but he was dead 67 months after the initial therapy.

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BACKGROUND: Chronic intestinal pseudo-obstruction (CIPO) is a severe and refractory intestinal motility disorder. However, due to its rarity and difficult histological investigation, its pathophysiology has not been characterized. AIM: Therefore, in this study, we aimed to determine the role of esophageal high-resolution manometry (HRM) in CIPO and the histological and clinical characteristics of the disease. METHODS: Patients with CIPO were analyzed for clinical characteristics; histological findings; and clinical courses after therapeutic intervention. In addition, HRM was performed to determine the esophageal involvement. RESULTS: Eleven patients were diagnosed with CIPO, and five required the long period of parenteral nutrition showing impaired esophageal motility including achalasia and absent contractility diagnosed with HRM. The four of these five cases showed acute onset of the CIPO following the triggering events of pregnancy, appendicitis, and surgery. In contrast, other six patients with normal or Jackhammer esophagus on HRM had moderate severity of CIPO with gradual onset. The histological analyses revealed that the loss of the intestinal neural ganglion cells and layers by inflammation, destruction, and atrophy are related to the severity of the clinical course of the disease and esophageal HRM findings of achalasia and absent contractility. CONCLUSIONS: HRM may be useful to diagnose the severity of the clinical course and to determine the therapeutic options for CIPO.

DOI： 10.1007/s10620-020-06701-9

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BACKGROUND: Activin A receptor type 2A (ACVR2A) is one of the most frequently mutated genes in microsatellite instability-high (MSI-H) gastric cancer. However, the clinical relevance of the ACVR2A mutation in MSI-H gastric cancer patients remains unclear. The aims of this study were to explore the effect of ACVR2A mutation on the tumor behavior and to identify the clinicopathological characteristics of gastric cancer patients with ACVR2A mutations. METHODS: An in vitro study was performed to investigate the biological role of ACVR2A via CRISPR/Cas9-mediated ACVR2A knockout MKN74 human gastric cancer cells. One hundred twenty-four patients with gastric cancer were retrospectively analyzed, and relations between MSI status, ACVR2A mutations, and clinicopathological factors were evaluated. RESULTS: ACVR2A knockout cells showed less aggressive tumor biology than mock-transfected cells, displaying reduced proliferation, migration, and invasion (P < 0.05). MSI mutations were found in 10% (13/124) of gastric cancer patients, and ACVR2A mutations were found in 8.1% (10/124) of patients. All ACVR2A mutations were accompanied by MSI. The 5-year overall survival rates of ACVR2A wild-type patients and ACVR2A-mutated patients were 57% and 90%, respectively (P = 0.048). Multivariate analysis revealed that older age (P = 0.015), distant metastasis (P < 0.001), and ACVR2A wild-type status (P = 0.040) were independent prognostic factors for overall survival. CONCLUSIONS: Our study demonstrated that gastric cancer patients with ACVR2A mutation have a significantly better prognosis than those without. Dysfunction of ACVR2A in MKN74 human gastric cancer cells caused less aggressive tumor biology, indicating the importance of ACVR2A in the progression of MSI-H tumors.

DOI： 10.1007/s11605-020-04889-9

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PURPOSE: This study aimed to elucidate the impact of anatomic location of residual disease (RD) after initial cholecystectomy on survival following re-resection of incidental gallbladder cancer (IGBC). METHODS: Patients with pT2 or pT3 gallbladder cancer (36 with IGBC and 171 with non-IGBC) who underwent resection were analyzed. Patients with IGBC were classified as follows according to the anatomic location of RD after initial cholecystectomy: no RD (group 1); RD in the gallbladder bed, stump of the cystic duct, and/or regional lymph nodes (group 2); and RD in the extrahepatic bile duct and/or distant sites (group 3). RESULTS: Timing of resection (IGBC vs. non-IGBC) did not affect survival in either multivariate or propensity score matching analysis. RD was found in 16 (44.4%) of the 36 patients with IGBC; R0 resection following re-resection was achieved in 32 patients (88.9%). Overall survival (OS) following re-resection was worse in group 3 (n = 7; 5-year OS, 14.3%) than in group 2 (n = 9; 5-year OS, 55.6%) (p = 0.035) or in group 1 (n = 20; 5-year OS, 88.7%) (p < 0.001). There was no survival difference between groups 1 and 2 (p = 0.256). Anatomic location of RD was independently associated with OS (group 2, HR 2.425, p = 0.223; group 3, HR 9.627, p = 0.024). CONCLUSION: The anatomic location of RD independently predicts survival following re-resection, which is effective for locoregional disease control in IGBC, similar to resection for non-IGBC. Not all patients with RD have poor survival following re-resection for IGBC.

DOI： 10.1007/s00423-021-02165-1

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AIMS: Tumour deposits (TDs) are an important prognostic marker in colorectal cancer. However, the classification, and inclusion in staging, of TDs has changed significantly in each tumour-node-metastasis (TNM) edition since their initial description in TNM-5, and terminology remains controversial. Expert consensus is needed to guide the future direction of precision staging. METHODS AND RESULTS: A modified Delphi consensus process was used. Statements were formulated and sent to participants as an online survey. Participants were asked to rate their agreement with each statement on a five-point Likert scale and also to suggest additional statements for discussion. These responses were circulated together with anonymised comments, and statements were modified prior to carrying out a second online round. Consensus was set at 70%. Overall, 32 statements reached consensus. There were concerns that TDs were currently incorrectly placed in the TNM system and that their prognostic importance was being underestimated. There were concerns regarding interobserver variation and it was felt that a clearer, more reproducible definition of TDs was needed. CONCLUSIONS: Our main recommendations are that the number of TDs should be recorded even if lymph node metastases (LNMs) are also present and that nodules with evidence of origin [extramural venous invasion (EMVI), perineural invasion (PNI), lymphatic invasion (LI)] should still be categorised as TDs and not excluded, as TNM-8 specifies. Whether TDs should continue to be included in the N category at all is controversial, and did not achieve consensus; however, participants agreed that TDs are prognostically worse than LNMs and the N1c category is suboptimal, as it does not reflect this.

DOI： 10.1111/his.14344

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier {BV}  

Background: Esophageal involvement length (EIL) is a promising indicator of metastasis or recurrence in mediastinal lymph nodes (MLNs) in adenocarcinoma of the esophagogastric junction (EGJ). This study aimed to elucidate the accuracy of the preoperative endoscopic evaluations of EIL and its clinical significance in this disease. Materials and methods: In total, 75 patients with Siewert type II (N = 53) or III (N = 22) adenocarcinoma of the EGJ, who underwent surgical resection without preoperative therapy between 1995 and 2016 were enrolled. We retrospectively examined the accuracy of the preoperative endoscopic evaluations of EIL (preoperative EIL), compared to the pathologically evaluated EIL. Finally, we investigated the association between preoperative EIL and metastasis or recurrence in MLNs. Results: The accuracy of the preoperative EIL within a 1-cm interval was only 53.3%. Among patients with discordance between the pre- and postoperative evaluations, 68.6 % had the underestimation in the preoperative EIL. pN1-3 (OR = 5.85, 95% CI: 1.03-33.17) and undifferentiated histologic type (OR = 2.52, 95% CI: 0.89-7.14) were potential risk factors for the discordance. Regarding metastasis or recurrence in MLNs, preoperative EIL of 2-3 cm (OR = 10.41, 95% CI: 1.35-80.11) and >3 cm (OR = 8.33, 95% CI: 1.09-63.96) were independent predictors. Conclusion: Although the accuracy of the endoscopic evaluations of EIL is insufficient with many underestimations, EIL should be assessed in preoperative staging because of significant predictive power for metastasis or recurrence in MLNs.

DOI： 10.1016/j.amsu.2021.102590

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Language：Japanese   Publisher：(株)癌と化学療法社  

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Language：Japanese   Publisher：(一社)日本消化器外科学会  

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Language：Japanese   Publisher：(一社)日本消化器外科学会  

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Language：Japanese   Publisher：(一社)日本消化器外科学会  

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Language：Japanese   Publisher：(一社)日本大腸肛門病学会  

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PURPOSE: Outcomes following surgery for advanced gallbladder carcinoma remain unsatisfactory. This study aimed to determine the surgical outcome and effectiveness of adjuvant chemotherapy according to TNM stage in patients with gallbladder carcinoma. METHODS: A total of 200 patients undergoing surgery for gallbladder carcinoma were enrolled. Clinicopathological data were evaluated and surgical outcomes were compared between patients with and without adjuvant chemotherapy according to TNM stage. RESULTS: The 5-year overall survival (OS) after resection for patients with stage I (n = 27), IIA (n = 18), IIB (n = 28), IIIA (n = 25), IIIB (n = 43), IVA (n = 7), and IVB (n = 52) disease was 90.8%, 94.4%, 73.6%, 33.7%, 57.7%, 14.3%, and 11.8%, respectively (p < 0.001). R0 resection was performed in all patients with stage I or II disease, in 89.7% of those with stage III disease, and 69.5% of those with stage IV disease. For patients with stage III disease, adjuvant chemotherapy was associated with improved OS (5-year OS, 60.9% vs. 41.1%; p = 0.028) and was an independent prognostic factor (hazard ratio, 2.045; p = 0.039). For patients with stage IV disease, adjuvant chemotherapy appeared to affect OS (5-year OS, 25.1% vs. 5.3%; p = 0.041); R0 resection (hazard ratio, 1.882; p = 0.040) was the only independent prognostic factor. CONCLUSION: TNM stage clearly predicts survival after resection of gallbladder carcinoma. R0 resection with adjuvant chemotherapy is recommended for long-term survival in the multimodal management of patients with stage III or IV gallbladder carcinoma.

DOI： 10.1007/s00423-020-02068-7

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DOI： 10.1111/1346-8138.15800

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Language：Japanese   Publisher：(一社)日本外科学会  

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Language：Japanese   Publisher：(一社)日本外科学会  

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Language：Japanese   Publisher：(一社)日本外科学会  

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Language：Japanese   Publisher：(一社)日本外科学会  

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Language：Japanese   Publisher：(一社)日本外科学会  

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Language：Japanese   Publisher：(一社)日本外科学会  

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It is reported that an increase in aerobic bacteria, a lack of short-chain fatty acids (SCFAs), and immune disorders in the diverted colon are major causes of diversion colitis. However, the precise pathogenesis of this condition remains unclear. The aim of the present study was to examine the microbiota, intestinal SCFAs, and immunoglobulin A (IgA) in the diverted colon. Eight patients underwent operative procedures for colostomies. We assessed the diverted colon using endoscopy and obtained intestinal samples from the diverted colon and oral colon in these patients. We analyzed the microbiota and SCFAs of the intestinal samples. The bacterial communities were investigated using a 16S rRNA gene sequencing method. The microbiota demonstrated a change in the proportion of some species, especially Lactobacillus, which significantly decreased in the diverted colon at the genus level. We also showed that intestinal SCFA values were significantly decreased in the diverted colon. Furthermore, intestinal IgA levels were significantly increased in the diverted colon. This study was the first to show that intestinal SCFAs were significantly decreased and intestinal IgA was significantly increased in the diverted colon. Our data suggest that SCFAs affect the microbiota and may play an immunological role in diversion colitis.

DOI： 10.1016/j.bbrep.2020.100892

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BACKGROUND/AIM: This study aimed to evaluate how NAD(P)H: quinone oxidoreductase-1 (NQO1) affects survival after hepatectomy in patients with colorectal liver metastasis (CRLM). PATIENTS AND METHODS: A retrospective analysis was conducted of 88 consecutive patients who underwent hepatectomy for CRLM. Of the 88 patients, preoperative chemotherapy was administered to 30 patients. Immunohistochemistry of the resected specimens was conducted using monoclonal anti-NQO1 antibody. RESULTS: NQO1-positive expression in tumor cells of CRLM was associated with worse overall survival (p=0.026) and was an independent adverse prognostic factor in multivariate analysis (hazard ratio=5.296, p=0.007). Among 30 patients who received preoperative chemotherapy, patients with loss of NQO1 expression in non-neoplastic epithelial cells of the bile ducts (NQO1 polymorphism: n=19) showed significantly better response to preoperative chemotherapy for CRLM (p=0.004). CONCLUSION: NQO1-positive expression in tumor cells of CRLM may be an adverse prognostic factor after hepatectomy for CRLM.

DOI： 10.21873/anticanres.14916

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AIM: The role of preoperative frailty assessment in patients with gastrointestinal (GI) disease remains unclear. This study aimed to clarify the relationship between frailty and postoperative outcomes in patients with GI disease. METHODS: This study investigated 42 patients (aged ≥65 years) with GI disease who underwent abdominal surgery. The frailty status was analyzed using the Japanese version of the Cardiovascular Health Study criteria. We also investigated postoperative outcomes. RESULTS: Of the 42 patients, seven (16.7%) were robust, 24 (57.1%) were prefrail and 11 (26.2%) were frail. Postoperative complications were observed in 45.5% and 63.6% of prefrail and frail patients, respectively, whereas no complications were found in robust patients (P = 0.026). The median hospital stay was 15, 19.5 and 27 days in robust, prefrail and frail patients, respectively (P < 0.01). CONCLUSION: Preoperative frailty status based on the Japanese version of the Cardiovascular Health Study criteria is associated with postoperative complication incidence and hospital stay extension in patients with GI disease. Geriatr Gerontol Int 2021; ••: ••-••.

DOI： 10.1111/ggi.14134

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Language：Japanese   Publisher：(株)へるす出版  

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BACKGROUND: This study aimed to investigate the impact of surgery on outcomes in patients with recurrent biliary tract cancer (BTC) and elucidate factors affecting survival after surgery for this disease. METHODS: A single-center study was undertaken in 178 patients with recurrent BTC, of whom 24 underwent surgery for recurrence, 85 received chemotherapy, and 69 received best supportive care. Then, we carried out a multicenter study in 52 patients undergoing surgery for recurrent BTC (gallbladder cancer, 39%; distal cholangiocarcinoma, 27%; perihilar cholangiocarcinoma, 21%; intrahepatic cholangiocarcinoma, 13%). RESULTS: In the single-center study, 3-year survival after recurrence was 53% in patients who underwent surgery, 4% in those who received chemotherapy, and 0% in those who received best supportive care (p < 0.001). Surgery was an independently prognostic factor (p < 0.001). In the multicenter series, the respective 3-year and 5-year survival after surgery for recurrence was 50% and 29% in the 52 patients. Initial site of recurrence was the only independent prognostic factor (p = 0.019). Five-year survival after surgery for recurrence in patients with single distant, multifocal distant, and locoregional recurrence was 51%, 0%, and 0%, respectively (p = 0.002). Sites of single distant recurrence included the liver (n = 13, 54%), distant lymph nodes (all from gallbladder cancer, n = 7, 29%), lung (n = 2, 9%), peritoneum (n = 1, 4%), and abdominal wall (n = 1, 4%). CONCLUSION: Surgery may be an effective option for patients with less aggressive tumor biology characterized by single distant recurrence in recurrent BTC.

DOI： 10.1016/j.hpb.2021.01.007

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Language：Japanese   Publisher：(株)篠原出版新社  

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A 64-year-old man with liver dysfunction was given a diagnosis of perihilar cholangiocarcinoma(Bismuth type Ⅳ). The tumor was predominantly right-sided and invaded to the bifurcation of the right and left portal veins. After confirming sufficient liver functional reserve and future liver remnant, the patient underwent extended right hepatectomy, extrahepatic bile duct resection, and portal vein resection and reconstruction. Intraoperative examination of frozen sections revealed the presence of residual invasive carcinoma on both the hepatic and duodenal sides of the ductal resection margins. However, we did not perform pancreaticoduodenectomy or additional resection of the margin-positive proximal bile duct considering the curability and invasiveness of these procedures. He received postoperative chemotherapy with biweekly gemcitabine plus cisplatin for 1 year, followed by gemcitabine monotherapy for 1 year, and S-1 monotherapy has been performed since then. He remains alive and well with no evidence of disease 63 months after surgery.

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The patient was a 63-year-old woman with diagnosis of pancreatic cancer. Abdominal CT showed pancreatic head tumor and paraaortic lymph node metastasis. We performed chemotherapy with nab-paclitaxel plus gemcitabine. After 5 courses of chemotherapy, the tumor reduced in size. Pancreaticoduodenectomy followed by adjuvant chemotherapy with S-1 was performed. Fourteen months after surgery, umbilical metastasis(Sister Mary Joseph's nodule: SMJN)was found in the umbilicus near the abdominal incisional hernia. There was no evidence of metastasis except in the umbilicus, we performed the umbilical tumor resection and abdominal incisional hernia repair. Pathological diagnosis was pancreatic cancer metastasis. Although following chemotherapy, multiple skin metastases was found in the lower abdomen 3 months after umbilical resection. We performed skin metastases resection to relieve pain and symptoms of bleeding. But she died 29 months after the initial therapy(7 months after umbilical resection).

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A 73-year-old man presented with anemia, and gastroscopy showed a nonpigmented tumor in the esophagogastric junction. The result of the tumor biopsy initially suspected poorly differentiated adenocarcinoma. However, additional immunohistochemical examination revealed malignant melanoma. The final diagnosis was amelanotic malignant melanoma of the esophagogastric junction with adrenal and spinal metastasis. Although immunotherapy was performed, the patient died 132 days after diagnosis.

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A 72-year-old man was referred to our hospital for treatment for rectal cancer. Digital rectal examination and colonoscopy revealed a 4 cm tumor located at the anterior rectal wall 5 cm away from the anal verge, and pathological examination confirmed that the tumor was adenocarcinoma. A computed tomography scan detected neither regional lymph node metastasis nor distant metastasis. Hence, he was diagnosed with cT3N0M0, cStage Ⅱa rectal cancer. The preoperative general examination revealed bradyarrhythmia and severe emphysema, and he was considered to be high risk for general anesthesia. After placement of a pacemaker, preoperative capecitabine-based chemoradiotherapy(CRT)(50.4 Gy in 28 fractions of 1.8 Gy each)was implemented. The digital rectal examination and imaging evaluation 4 weeks after preoperative CRT revealed that the tumor disappeared, and pathological examination showed no malignant findings. Considering the risks of general anesthesia, the"watch and wait therapy"approach was adopted with sufficient informed consent. At present, 15 months after preoperative CRT, no evidence of regrowth or distant metastasis has been detected under rigorous follow- up evaluations.

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BACKGROUND: Solitary fibrous tumor (SFT), a mesenchymal fibroblastic tumor with a hypervascular nature, rarely develops in the pelvis. Resection of a giant SFT occupying the pelvic cavity poses an increased risk of developing massive hemorrhage during resection, although surgical resection is the most effective treatment method for this tumor to achieve a potential cure. SFT rarely develops with Doege-Potter syndrome, which is known as a paraneoplastic syndrome characterized by non-islet cell tumor hypoglycemia (NICTH) secondary to SFT that secretes insulin-like growth factor-II (IGF-II). We present a case of a giant pelvic SFT with Doege-Potter syndrome, which was successfully treated with transcatheter arterial embolization (TAE) followed by surgical resection. CASE PRESENTATION: A 46-year-old woman presented with a disorder of consciousness due to refractory hypoglycemia. Images of the pelvis showed a giant and heterogeneously hypervascular mass displacing and compressing the rectum. Endocrinological evaluation revealed low serum levels of insulin and C-peptide consistent with NICTH. Angiography identified both the inferior mesenteric artery and the bilateral internal iliac artery as the main feeders of the tumor. To avoid intraoperative massive bleeding, super-selective TAE was performed for the tumor 2 days prior to surgery. Hypoglycemia disappeared after TAE. The tumor was resected completely, with no massive hemorrhage during resection. Histologically, it was diagnosed as IGF-II-secreting SFT. Partial necrosis of the rectum in the specimen was observed due to TAE. The patient was followed up for 2 years and no evidence of disease has been reported. CONCLUSIONS: Preoperative angiography followed by TAE is an exceedingly helpful method to reduce intraoperative hemorrhage when planning to resect SFT occupying the pelvic cavity. Complications related to ischemia should be kept in mind after TAE, which needs to be planned within 1 or 2 days before surgery. TAE for tumors may be an option in addition to medical and surgical treatment for persistent hypoglycemia in Doege-Potter syndrome.

DOI： 10.1186/s40792-020-01076-5

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Tumor infiltrating lymphocytes (TIL), which represent host adaptive response to the tumor, were first identified at scanning magnification to select areas with the highest counts on hematoxylin and eosin slides, quantitated per high-power field (HPF), and analyzed for association with recurrence-free survival (RFS) in 848 patients. Highest TIL in a single HPF was analyzed as a continuous and categorical variable, and optimal cutoff analysis was performed to predict RFS. Highest TIL count in a single HPF ranged from 0 to 45, and the optimal cutoff for TIL high vs TIL low was determined to be ≥ 3 vs < 3 with a concordance probability estimate of 0.74. In the entire cohort, 5-year RFS was 90.2% (95% CI = 83.7-94.2) in TIL high compared to 78.9% (95% CI = 74.1-82.9) in TIL low (log rank P < .0001). TIL remained significant in the mismatch repair-proficient (pMMR) cohort where 5-year RFS was 94.6% (95% CI = 88.3-97.5) in TIL high compared to 77.9% (95% CI = 69.2-84.4) in TIL low (P = .008). On multivariable analysis, TIL and AJCC Stage were independently associated with RFS in the pMMR cohort. Qualitatively in the pMMR cohort, RFS in Stage II TIL high patients was similar to that in Stage I patients and RFS in Stage III TIL high was similar to that in Stage II TIL low patients. Assessment of TIL in a single HPF using standard H&E slides provides important prognostic information independent of MMR status and AJCC stage.

DOI： 10.1080/2162402X.2020.1841948

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Language：Japanese   Publisher：新潟県医師会  

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BACKGROUND: The 8th edition of the American Joint Committee on Cancer (AJCC) TNM staging system provided a specific 'ypTNM' stage grouping for patients with esophageal cancer. OBJECTIVE: This study aimed to evaluate the clinical utility of the AJCC 8th edition ypTNM stage grouping for patients with esophageal squamous cell carcinoma (ESCC). METHODS: We enrolled 152 patients with ESCC who underwent surgery after neoadjuvant cisplatin plus 5-fluorouracil (CF) therapy between June 2005 and December 2011. ypStage was evaluated according to the AJCC 7th and 8th editions. Predictive performance for disease-specific survival (DSS) and overall survival (OS) was compared between both editions. The prognostic significance of ypTNM stage grouping was evaluated using univariate and multivariate analyses. RESULTS: Revision of the AJCC 7th edition to the 8th edition was associated with a change in ypStage in 96 patients (63.2%). The AJCC 8th edition revealed a better predictive performance than the 7th edition in terms of DSS (Akaike's information criterion [AIC] 499 vs. 513; Bayesian information criterion [BIC] 505 versus 519; concordance index [C-index] 0.725 versus 0.679) and OS (AIC 662 vs. 674; BIC 669 vs. 681; C-index 0.662 vs. 0.622). On univariate and multivariate analyses, ypStage in the 8th edition was an independent prognostic factor for both DSS and OS. CONCLUSIONS: ypTNM stage grouping in the AJCC 8th edition provided a better predictive performance for DSS and OS than that in the 7th edition. ypStage in the 8th edition was the most reliable prognostic factor for ESCC patients who underwent surgery after neoadjuvant CF therapy.

DOI： 10.1245/s10434-020-09181-3

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DOI： 10.1245/s10434-020-09184-0

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Language：Japanese   Publishing type：Research paper (scientific journal)  

Here, we report about a woman in her 30s who had peritoneal dissemination and multiple colon cancer with high-frequency microsatellite instability(MSI-H). Her father, paternal grandfather, and maternal grandmother had a history of colorectal cancer treatment. Thus, Lynch syndrome was suspected. We performed R0 resection for peritoneal dissemination and subsequent peritoneal dissemination. A 435-gene panel testing using a next-generation sequencer identified MSH2 and other mutations in the tumor. Hence, we speculated that she could have a germline mutation of MSH2, which causes Lynch syndrome. In the future, if she wishes to receive genetic counseling and undergo germline testing for variants to confirm the diagnosis of Lynch syndrome, we will perform them after receiving informed consent.

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Biliary tract cancer (BTC) is clinically and pathologically heterogeneous and responds inadequately to treatment. A small section of patients develop resectable disease, although the relapse rates are high; the benefits of adjuvant capecitabine chemotherapy for BTC are now understood, and gemcitabine-based combination chemotherapy is the first line of therapeutic strategy for BTC; however, alternative therapy for BTC is not known. Genomic profiling can provide detailed information regarding the carcinogenesis, identification, and therapy for BTC. Currently, confirmed restorative targets for BTC are lacking. In this review, we aimed to analyze the preclinical and clinical implications of a spectrum of genomic alterations associated with new potentially remedial targets. We focused on eight draggable genes for BTC, which were described as having evidence of therapeutic impact (evidence level 2A-3B) based on the clinical practice guidance for next-generation sequencing in cancer diagnosis and treatment; these include ERBB2, NTRK1, RNF43, CDK6, CDKN2B, FGFR2, IDH1, and IDH2. Moreover, some of the BTC present microsatellite instability, hypermutation, and germline variants, which we also reviewed. Finally, we discussed the therapeutic options based on the next-generation sequencing findings in BTC. Studies have demonstrated that BTC includes subgroups with individually distinct driver mutations, most of which will be targeted with new treatment plans.

DOI： 10.1002/ags3.12334

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Introduction: There are no specific standards for the timing of surgery to treat ulcerative colitis, so reaching a decision on timing is often difficult. Objective: The aim of this study was to evaluate the timing of surgery from the patients' perspective. Methods: From among 203 patients who underwent restorative proctocolectomy with ileal pouch anal anastomosis to treat ulcerative colitis at our hospital from 1985 to 2013, we mailed a questionnaire to 101 of those who are currently attending periodic follow-up at our hospital. Results: We analyzed 72 valid responses (71.2%). Overall, 65 patients (90.3%) responded that they were happy that they underwent surgery, 38 patients (52.8%) responded that the timing of surgery was appropriate, and 32 patients (44.4%) responded that they would have preferred to have had surgery earlier. The group of patients who would have preferred to have had surgery earlier included 23 patients (71.9%) who had undergone emergency surgery; the incidence of emergency surgery was significantly higher than in the group of 13 patients (34.2%) who had responded that the timing of surgery was appropriate (p = 0.002). Scores on the Medical Outcomes Study 36-Item Short-Form Health Survey (SF36), which reflect postoperative quality of life, were maintained at the same level as the Japanese standard values in our Japanese patients. Conclusion: The degree of satisfaction of patients who underwent surgery for ulcerative colitis was favorable, although it is important to consider surgery at an earlier stage in patients who may need emergency surgery.

DOI： 10.1159/000504885

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Gastric cancer is one of the most common and clinically important diseases worldwide. The traditional Laeuren classification divides gastric cancer into two histopathological subtypes: diffuse and intestinal. Recent cancer genomics research has led to the development of a new classification based on molecular characteristics. The newly defined genomically stable (GS) subtype shares many cases with the histopathologically diffuse type. In this study, we performed genetic profiling of recurrently and significantly mutated genes in diffuse type and GS subtype tumors. We observed significantly different genetic characteristics, although the two subtypes overlapped in many cases. In addition, based on the profiles of the significantly mutated genes, we identified molecular functions and mutational signatures characteristic of each subtype. These results will advance the clinical application of the diffuse type and GS subtype gastric cancer in precision medicine for treating gastric cancer.

DOI： 10.1016/j.csbj.2020.10.021

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A 78-year-old woman was endoscopically followed up for benign melanocytosis in the middle thoracic esophagus that was detected 3 years prior. She presented with chest tightness, and an endoscopic examination revealed a protruding tumor at the melanotic lesion. She was histologically diagnosedwith an esophageal primary malignant melanoma. Computedtomography showedno metastatic lesions. She underwent minimally invasive esophagectomy with 2-fieldlymphad enectomy. Immunotherapy with nivolumab is ongoing for liver metastasis, which developed1 year and6 months after esophagectomy. Careful follow-up for esophageal melanocytosis is important for early diagnosis of esophageal primary malignant melanoma.

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A 66-year-old man with middle thoracic esophageal squamous cell carcinoma with supraclavicular lymph node metastasis visited our hospital. He underwent 3 courses of preoperative chemotherapy with docetaxel, cisplatin, and 5-FU(DCF)with a clinically-determined partial response. Minimally-invasive esophagectomy with 3-fieldlymphad enectomy was subsequently performed. Histopathologic examination revealedno viable tumor cells in the resectedesophagus andsupraclavicular lymph node. DCF is a promising preoperative chemotherapy regimen for locally advanced esophageal cancer because of its higher complete response rate comparedto that for cisplatin plus 5-FU.

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Language：Japanese   Publishing type：Research paper (scientific journal)  

A 37-year-old man was admitted to our hospital for the treatment of familial adenomatous polyposis and rectal carcinoma. He underwent total colectomy with ileoanal anastomosis(pT3N1M0, pStage Ⅲa)followed by adjuvant therapy with S-1. Three months after primary surgery, CT and MRIrevealed liver metastases(S5, S6). Laparoscopic partial hepatectomy was performed. Two years after primary surgery, new liver metastases(S2, S8)were found and we performed open partial hepatectomy and administered mFOLFOX6. Three years and 5 months after primary surgery, right lung metastases(S6, S9) were detected and the patient underwent a thoracoscopic-assisted right lung wedge resection. Repeated resection of metastases might have contributed to the long-survival in our case.

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A 77-year-old woman presented with peritoneal metastases from a pancreatic neuroendocrine tumor(p-NET). At the age of 56 years, she underwent distal pancreatectomy for p-NET, which was pathologically diagnosed as G2. She underwent right hemihepatectomy for liver metastasis(S6)from the p-NET 10 years post-pancreatectomy. Eight years post-hepatectomy, radiofrequency ablation(RFA)was attempted for liver metastasis(S4)from the p-NET. However, RFA was not completed because of hematoma development along the needle tract of RFA. She underwent partial hepatectomy for this lesion 6 months post-RFA. Two years post-RFA, localized peritoneal metastases on the right diaphragm were detected. She underwent en bloc tumor resection with partial resection of the diaphragm. She remains alive and well with no evidence of disease 2 years post-resection of the peritoneal metastases from the p-NET.

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BACKGROUND: The Memorial Sloan Kettering Cancer Center (MSK) colon cancer recurrence nomogram is a risk calculator that provides patients and clinicians with individualized prediction of recurrence following curative resection of colon cancer. Although validated on multiple separate cohorts, the nomogram requires periodic updating as patient care changes over time. The aim of this study was to evaluate the nomogram's accuracy in a contemporary cohort and modify the tool to reflect improvements in outcome related to advances in colon cancer therapy. METHODS: A contemporary patient cohort was compiled, including consecutive colon cancer patients undergoing curative resection for stage I-III colon adenocarcinoma at MSK from 2007 to 2014. The nomogram's predictive accuracy was assessed by concordance index and calibration plots of predicted vs actual freedom from recurrence at 5 years after surgery. RESULTS: Data from a total of 999 eligible patients with complete records were used for validation. Median follow-up among survivors was 37 months. The concordance index was 0.756 (95% confidence interval = 0.707 to 0.805), indicating continued discriminating power, but the calibration plot revealed that the nomogram overestimated recurrence risk. Recalibration of the nomogram by estimating a new baseline freedom-from-recurrence function restored the nomogram's accuracy. CONCLUSION: The updated nomogram retains the original nomogram's variables but includes a lower baseline estimation of recurrence risk, reflecting improvements in outcomes for all stages of colon cancer, likely resulting from advances in imaging and integration of multiple treatment modalities.

DOI： 10.1093/jncics/pkz015

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BACKGROUND: Surgical stress and inflammation can cause hyperbilirubinemia, which sometimes occurs after esophagectomy for esophageal cancer (EC). The aim of this study was to elucidate the clinical significance of postoperative hyperbilirubinemia in the management of EC patients. MATERIALS AND METHODS: We retrospectively reviewed records of 81 EC patients who underwent esophagectomy from 2009 to 2014. We compared the clinicopathological and perioperative factors, including the presence of hyperbilirubinemia (total bilirubin ≥1.5 mg/dL), between patients with postoperative infectious complications (PIC group) and those without (Non-PIC group). RESULTS: PIC developed in 52 patients (64.2%). There were significant differences in incidence of postoperative hyperbilirubinemia between the PIC group and the non-PIC group (34.6% vs. 3.4%, P = 0.002), as well as the approach of esophagectomy (P = 0.045), the surgical duration (469 vs. 389 min, P < 0.001), the amount of blood loss (420 vs. 300 mL, P = 0.018), the frequency of intraoperative blood transfusions (32.7% vs. 6.9%, P = 0.012) and the peak postoperative C-reactive protein level (17.3 vs. 8.6 mg/dL, P = 0.007). Multivariate analysis revealed hyperbilirubinemia was independently associated with the occurrence of PICs (odds ratio: 38.6, P = 0.010). The median time to the diagnosis of hyperbilirubinemia was significantly shorter than that of PICs (3.0 vs. 4.5 days, P = 0.025). CONCLUSIONS: Postoperative hyperbilirubinemia was associated with the occurrence of PICs and frequently occurred before any PICs become apparent. More attention should be paid to the serum bilirubin level in the management after esophagectomy for EC.

DOI： 10.1016/j.amsu.2019.02.004

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Language：Japanese   Publishing type：Research paper (scientific journal)  

A 78-year-old woman with jaundice was referred to our hospital. On admission, serological testing for viral hepatitis was negative and serum levels of AFP and PIVKA-Ⅱ were elevated(925 ng/mL and 6,820 mAU/mL, respectively). Computed tomography revealed a main tumor measuring 3 cm in size at segment 1 of the liver and bile duct tumor thrombus extending to the right hepatic duct. A diagnosis of hepatocellular carcinoma with a bile duct tumor thrombus was made. After endoscopic biliary drainage for obstructive jaundice and transarterial chemoembolization for the lesions, she underwent left hepatectomy, resection of the caudate lobe, extrahepatic bile duct resection, and cholecystectomy. The hepatic side of the extrahepatic bile duct was transected at the confluence of the right anterior and posterior ducts because invasion of the tumor thrombus to the right hepatic duct was suspected on cholangioscopy. Histological examination revealed the tumor to be a moderately differentiated hepatocellular carcinoma with bile duct tumor thrombus. Surgical margins were negative, and vascular invasion was not found. She remains alive and well with no evidence of disease 64 months after hepatectomy.

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An 82-year-old man with a diagnosis ofintraductal papillary mucinous carcinoma(IPMC)underwent pancreaticoduodenectomy followed by adjuvant chemotherapy with S-1. Six months after surgery, he had upper abdominal pain, and CT demonstrated a recurrent intraabdominal tumor located at the surgical incision scar. It was diagnosed as a solitary peritoneal recurrence, and palliative radiation therapy at a dose of 30 Gy was performed for the relief of abdominal pain after administration ofoxycodone. He was free ofpain without pharmacological therapy and received subsequent chemotherapy with nabpaclitaxel plus gemcitabine(GnP). He remains free ofpain and alive without progression ofthe disease 24 months after recurrence. Hypofractionated-accelerated radiotherapy is feasible and results in pain relief for local recurrence of IPMC.

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Numerous technical and functional advances in next-generation sequencing (NGS) have led to the adoption of this technique in conventional clinical practice. Recently, large-scale genomic research and NGS technological innovation have revealed many more details of somatic and germline mutations in solid tumors. This development is allowing for the classification of tumor type sub-categories based on genetic alterations in solid tumors, and based on this information, new drugs and targeted therapies are being administered to patients. This has largely been facilitated by gene panel testing, which allows for a better understanding of the genetic basis for an individual's response to therapy. NGS-based comprehensive gene panel testing is a clinically useful approach to investigate genomic mechanisms, including therapy-related signaling pathways, microsatellite instability, hypermutated phenotypes, and tumor mutation burden. In this review, we describe the concept of precision medicine in solid tumors using NGS-based comprehensive gene panel testing, as well as the importance of quality control of tissue sample handling in routine NGS-based genomic testing, and we discuss issues for the future adoption of this technique in Japan.

DOI： 10.1007/s10147-018-1375-3

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BACKGROUND: Neurofibromatosis type 1 (NF1) is an autosomal dominant disease of the skin and soft tissue. Aneurysms associated with NF1 can occur, but a secondary aneurysm rupture is very rare, with very few cases reported in literature. CASE PRESENTATION: We describe the case of a 67-year-old female with NF1 who underwent endovascular aneurysm repair (EVAR) for an abdominal aortic aneurysm (AAA) rupture. She developed a type Ib endoleak requiring a redo-EVAR. Eighteen days after her primary operation, she was found to have two new left colic artery aneurysms. She required emergency surgery consisting of a left hemicolectomy and transverse colon colostomy. Pathology showed neurofibromatous changes to the peri-vasculature tissue, consistent with her underlying disease. CONCLUSIONS: Although rare, secondary aneurysms can occur following AAA repair. Patients with soft tissue connective tissue disorders, like NF1, may be at an increased risk for development of these secondary aneurysms. Endovascular repair appears to be a safe approach for NF1 patients with AAA, but endovascular management can be challenging in the setting of NF1. Surgeons should be ready to convert to open surgery if the patient displays persistent signs of bleeding or structural changes related to connective tissue disorders like NF1.

DOI： 10.1186/s40792-019-0570-4

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Language：Japanese   Publishing type：Research paper (scientific journal)  

A 59-year-old woman with pancreatic cancer underwent pancreaticoduodenectomy. The tumor was histologically diagnosed as a well-differentiated tubular adenocarcinoma with a small amount of mucinous component. After resection, the patient underwent hepatic perfusion therapy using 5-FU and gemcitabine chemotherapy for 1 year. 7 years after the initial surgery, CT and PET-CT revealed an isolated enlarged lymph node in the left neck. As the patient had no other metastasis, lymphadenectomy was performed. A diagnosis of lymph node metastasis originating from pancreatic cancer was confirmed on the basis of histological and immunohistopathological assessments. After the second resection, chemotherapy with S-1 was administered for 1 year. The patient has been alive without tumor relapse for 11 years. In patients with late recurrence after pancreatectomy, aggressive isolated lymph node resection and maintained chemotherapy may contribute to the improvement in prognosis.

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Language：Japanese   Publishing type：Research paper (scientific journal)  

We present a case of long-term survival in a patient with advanced ascending colon cancer and multiple liver metastases after receiving multimodality therapy, which included hepatic atrial infusion(HAI)and 4 hepatectomies. At diagnosis, the 65- year-old woman underwent right hemicolectomy for advanced ascending colon cancer with multiple liver metastases (T3N1M1[H2], Stage Ⅳ). The 11 liver metastatic lesions were treated by weekly HAI of 5-fluorouracil(5-FU). The lesions reduced in size(response rate 28.9%)immediately following treatment, and no new lesions were detected, but 10 months after treatment the size of the S2 tumor had increased. Systemic chemotherapy with irinotecan and S-1 was administered. Continued development of the S2 tumor in the liver prompted a radical lateral segment hepatectomy. Four months later, a computed tomography(CT)scan revealed a S6 tumor of the liver, for which a posterior segment hepatectomy was performed. A CT scan showing a S1 tumor in the liver 9 months later resulted in chemotherapeutic treatment with CapeOX, followed by mFOLFOX6. Despite treatment, the S1 tumor developed further, prompting a S1 partial hepatectomy. A further partial S8 hepatectomy was performed 7 years after surgery for the primary lesion following a CT scan that revealed a S8 tumor in the liver. There has been no recurrence of tumors in the 5 years and 5 months since this last hepatectomy.

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Peritoneal metastasis is relatively rare in patients with hepatocellular carcinoma(HCC). No consensus has been reached regarding the treatment of this type of metastasis. Herein, we report 3 patients who underwent resection of peritoneal metastasis due to HCC. Case 1: A 48-year-old man underwent hepatectomy twice and radiofrequency ablation(RFA)once for HCC. Eight years after the initial resection, he underwent resection of peritoneal metastasis in the pelvic floor. He is alive with disease 17 months after the last operation. Case 2: A 71-year-old man with a history of percutaneous ablation therapy for HCC 3 times underwent hepatectomy for recurrent HCC. During the laparotomy, a peritoneal metastatic tumor was found near the live tumor, and simultaneous resection of both the tumors was performed. The patient died of recurrent disease 20 months after the last resection. Case 3: A 58-year-old man underwent hepatectomy for HCC and RFA for its recurrence. Peritoneal metastasis that invaded the duodenum was detected 8 years after the hepatectomy. Although the metastatic tumor was resected, he died of the carcinoma 2 months after the resection. We concluded that resection of peritoneal metastasis provides a survival benefit for selected patients with HCC.

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Language：Japanese   Publishing type：Research paper (scientific journal)  

A 78-year-old man was admitted with diarrhea. Colonoscopy and computed tomography(CT)revealed rectal cancer with multiple liver metastases. Low anterior resection was performed for local control. After the operation, 5 courses of mFOLFOX6 plus bevacizumab chemotherapy were administered as first-line systemic therapy, but CT showed progressive disease with liver metastases. After the first-line systemic therapy, 2 courses of FOLFIRI plus bevacizumab chemotherapy were performed as second-line systemic therapy, but CT also revealed progressive disease with liver metastases. We retrospectively performed comprehensive genomic sequencing with a 415-gene panel and found that the patient had a hypermutation subtype. Interestingly, the panel also revealed that he had mismatch-repair(MMR)deficiency with MSH2 mutation, which is reported as a possible cause of resistance to 5-fluorouracil in colorectal cancer.

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Language：Japanese   Publishing type：Research paper (scientific journal)  

Here, we reported a case of a 39-year-old woman having rectal cancer with multiple liver metastases who underwent staged laparoscopic resection. She was diagnosed with low rectal cancer and multiple liver metastases; thus, she underwent low anterior resection and diverting colostomy. Following the neoadjuvant chemotherapy, she underwent colostomy closure and subsequent hand-assisted laparoscopic partial hepatectomy using the operative site during the colostomy closure. The postoperative course was uneventful, and adjuvant chemotherapy with CapeOX was performed 3 weeks post-surgery. Minimally invasive surgery was performed using hand-assisted laparoscopy.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Academic Press Inc.  

Background: Colitis-associated cancer (CAC) is the most serious complication of inflammatory bowel disease. Sphingosine-1-phosphate (S1P) is a bioactive lipid mediator that is generated by sphingosine kinase 1 (SphK1) and is known to play an important role in inflammation and cancer progression. Moreover, SphK1 and S1P act as upstream mediators of proinflammatory cytokine interleukin 6 (IL-6) and signal transducer and activator of transcription-3 (STAT3). We hypothesized that the expression levels of phosphorylated SphK1 (pSphK1), phosphorylated STAT3 (pSTAT3), and IL-6 are universally higher in CAC patients than in sporadic colorectal cancer (CRC) patients because all of these factors are associated with inflammation. In this study, we determined the expression levels of pSphK1 in patients with sporadic CRC and CAC and clarified the importance of S1P in CAC patients. Materials and methods: We randomly selected 10 sporadic CRC patients and 10 CAC patients who underwent curative resection, and we examined their surgical specimens by immunohistochemistry. We determined the expression levels of pSphK1, pSTAT3, and IL-6 in these samples. Results: We found pSphK1 expression to be more prevalent in CAC patients (P = 0.019) and to have a higher immunohistochemistry score (P = 0.005) than in sporadic CRC patients. However, the expression of pSTAT3 and IL-6 did not differ between the patient groups. Conclusions: To our knowledge, this is the first report comparing pSphK1 expression levels in CAC with those in sporadic CRC. The high levels of pSphK1 expression in CAC suggest an important role of S1P in the disease process of CAC.

DOI： 10.1016/j.jss.2018.05.085

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Language：Japanese   Publisher：(株)南江堂  

＜文献概要＞次世代シークエンサーを用いた癌遺伝子パネル検査によって,RAS/RAF遺伝子をはじめとする薬剤耐性関連の遺伝子変異や,HER2遺伝子増幅などの治療標的の候補となる遺伝子変異の網羅的検索が大腸癌において可能となる.今後の遺伝子解析に備え,手術や生検組織検体の適切な保存について熟知しておくことが重要である.Lynch症候群の大腸癌はマイクロサテライト不安定性を呈し,免疫チェックポイント阻害薬が有効である可能性が示唆され注目を集めている.癌遺伝子パネル検査の普及によって,Lynch症候群などの遺伝性腫瘍と診断される症例が今後増加することが予想され,遺伝カウンセリングやサーベイランスなどの患者,家族の支援体制の整備が急務である.

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2018&ichushi_jid=J00393&link_issn=&doc_id=20181106040006&doc_link_id=issn%3D0016-593X%26volume%3D80%26issue%3D12%26spage%3D1218&url=http%3A%2F%2Fwww.pieronline.jp%2Fopenurl%3Fissn%3D0016-593X%26volume%3D80%26issue%3D12%26spage%3D1218&type=PierOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00005_2.gif

Language：Japanese   Publisher：日本消化器病学会-甲信越支部  

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Language：Japanese   Publisher：(株)医学書院  

＜文献概要＞ポイント ◆内科,外科が緊密な連携をとり,ステロイド・免疫調節薬・生物学的製剤などの薬剤管理を行う.◆炎症性腸疾患に特徴的な,日和見感染,血栓症などの合併症も考慮に入れた適切な周術期管理が重要である.◆分割手術,ストーマ管理,合併症について,適切な対応と十分なインフォームド・コンセントが必要である.

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Language：Japanese   Publisher：新潟医学会  

【目的】近年、加齢に伴う様々な機能低下、いわゆる「フレイル」が注目されている。要介護の主な原因となる運動器障害、脳血管障害、認知症などの領域ではフレイルの研究が進んでいるが、消化器外科領域では報告が少ない。本研究では、消化器外科患者における術前フレイルの現状を把握し、フレイルの状態が術後成績に与える影響を明らかにすることを目的とした。【対象と方法】2017年10月〜2018年1月に、手術を目的として新潟大学医歯学総合病院消化器外科外来を受診した消化器外科疾患患者61名を対象とした。外来受診時に日本版Cardiovascular Health Study基準によるフレイル評価を行った。また、手術症例において、術後合併症の有無、入院期間、術後転帰について健常群/プレフレイル群/フレイル群に分けて比較検討した。【結果】対象61名の内訳は、男性40名、女性21名、年齢の中央値は67歳(範囲:18-89歳)であった。51名(83.6%)では手術が施行されたが、10名(16.4%)は、切除不能(6名)、耐術不能(4名)の理由により手術適応なしと判断された。手術適応なしの症例では、健常群は認めず、フレイル群は3名(30.0%)認められた。手術施行症例では健常群は12名(23.5%)認められ、フレイル群は7名(13.7%)であった。術後合併症は健常群では1名(8.3%)、プレフレイル群では9名(28.1%)、フレイル群では4名(57.1%)で認められた(P=0.07)。手術症例における入院期間の検討では、フレイルの進行によって入院期間が有意に延長していた(P=0.008)。転帰としては、自宅退院が50名(98.0%)、転院が1名(2.0%)、死亡退院は認めなかった。【結論】消化器外科領域における術前フレイル評価は、手術適応判断、周術期管理において有用である可能性が示唆された。(著者抄録)

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BACKGROUND: Recent progress in genomic analysis using next-generation sequencing technology has enabled the comprehensive detection of mutations and tumor mutation burden (TMB) in patients. A high TMB (TMB-H) tumor is defined as one with high somatic mutational rates, which correlates with clinical responses to certain treatments such as immunotherapies. We determined TMB in lung adenocarcinoma and clarified the characteristics of patients with TMB-H in relation to common driver mutations and smoking history. MATERIALS AND METHODS: Genomic aberrations and TMB were determined in Japanese patients with lung adenocarcinoma (n = 100) using next-generation sequencing of 415 known cancer genes. TMB-H was defined as > 20 mutations per megabase (Mb) of sequenced DNA. RESULTS: The median TMB was 13.5 (5-33) mutations/Mb. Ten of 100 (10%) patients showed TMB-H, and the others showed low TMB (TMB-L). Only two of 10 (20%) patients with TMB-H had one of the common driver mutations (ALK and ERBB2 mutation), whereas 57 of 90 (63%) patients with TMB-L had one of the driver mutations, including ALK, EGFR, ERBB2, ROS, RET, and MET (P < 0.05). Notably, no EGFR mutation was observed in patients with TMB-H. Eight of 10 (80%) patients with TMB-H had recent smoking history, whereas only 17 of 90 (19%) patients with TMB-L had recent smoking history (P < 0.001). CONCLUSIONS: We found that TMB-H is associated with smoking history, whereas TMB-L is associated with the common driver mutations in lung adenocarcinoma, which may impact treatment strategies for these patients.

DOI： 10.1016/j.jss.2018.07.007

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Next generation sequencing (NGS) has been an invaluable tool to put genomic sequencing into clinical practice. The incorporation of clinically relevant target sequences into NGS-based gene panel tests has generated practical diagnostic tools that enable individualized cancer-patient care. The clinical utility of gene panel testing includes investigation of the genetic basis for an individual's response to therapy, such as signaling pathways associated with a response to specific therapies, microsatellite instability and a hypermutated phenotype, and deficiency in the DNA double-strand break repair pathway. In this review, we describe the concept of precision cancer medicine using target sequences in gene panel tests as well as the importance of the control of sample quality in routine NGS-based genomic testing. We describe geographic and ethnic differences in cancer genomes, and discuss issues that need to be addressed in the future based on our experiences in Japan.

DOI： 10.1111/cas.13837

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Language：Japanese   Publisher：(株)メディカルドゥ  

次世代シークエンサーによるがんゲノム解析に使用するホルマリン固定パラフィン包埋サンプルの作製にあたっては、10%中性緩衝ホルマリン固定液を使用すること、固定は48時間以内とすることが肝要である。がんゲノム解析では、マイクロサテライト不安定性を有するグループを同定することが可能であり、大腸がんや胃がんにおける周術期化学療法の適応決定に有用である。また切除不能進行再発大腸がんでは、ゲノム情報に基づいて治療効果の高い薬剤を選択することにより、効率よくconversion surgeryを行えるようになることが期待される。(著者抄録)

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Lymphatic metastasis is known to contribute to worse prognosis of biliary tract cancer (BTC). Recently, sphingosine-1-phosphate (S1P), a bioactive lipid mediator generated by sphingosine kinase 1 (SPHK1), has been shown to play an important role in lymphangiogenesis and lymph node metastasis in several types of cancer. However, the role of the lipid mediator in BTC has never been examined. Here we found that S1P is elevated in BTC with the activation of ceramide-synthetic pathways, suggesting that BTC utilizes SPHK1 to promote lymphatic metastasis. We found that S1P, sphingosine and ceramide precursors such as monohexosyl-ceramide and sphingomyelin, but not ceramide, were significantly increased in BTC compared to normal biliary tract tissue using LC-ESI-MS/MS. Utilizing The Cancer Genome Atlas cohort, we demonstrated that S1P in BTC is generated via de novo pathway and exported via ABCC1. Further, we found that SPHK1 expression positively correlated with factors related to lymphatic metastasis in BTC. Finally, immunohistochemical examination revealed that gallbladder cancer with lymph node metastasis had significantly higher expression of phospho-SPHK1 than that without. Taken together, our data suggest that S1P generated in BTC contributes to lymphatic metastasis.

DOI： 10.1038/s41598-018-29144-9

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BACKGROUND: Inflammatory bowel disease (IBD), which includes ulcerative colitis (UC) and Crohn's disease (CD), is a chronic, idiopathic, repeated inflammatory disease. Colorectal cancer (CRC) that develops in patients with IBD is known as colitis-associated colorectal cancer (CAC), but the underlying carcinogenic mechanism remains unclear. Genomic analysis of sporadic CRC has been well described based on next-generation sequencing (NGS) data. Using NGS, we compared all exons of 415 cancer-associated genes in patients in Japan and the USA who had CRC and found similar genomic alteration patterns among the two populations. However, genomic analysis of CAC has not been thoroughly investigated. MAIN BODY: The molecular pathogenesis of CAC shares many features with sporadic CRC, but there are distinct variations in the time and frequency of some alterations. Gene alterations in CAC are gradually being elucidated using genomic sequencing analyses. Some studies have shown that gene alteration patterns differ between UC and CD. The carcinogenesis of CAC depends on unique environmental, genetic, and immunological factors. CONCLUSIONS: In this review, we have discussed the differences in genomic alterations between sporadic CRC and CAC. NGS in patients with IBD has the potential to detect early CAC and to suggest therapeutic targets.

DOI： 10.1186/s12957-018-1428-0

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BACKGROUND: Lung squamous cell carcinoma (LSCC) is a major histological subtype of lung cancer. In this study, we investigated genomic alterations in LSCC and evaluated the clinical implications of mutation burden (MB) in LSCC. METHODS: Genomic alterations were determined in Japanese patients with LSCC (N = 67) using next-generation sequencing of 415 known cancer genes. MB was defined as the number of non-synonymous mutations per 1 Mbp. Programmed death-ligand 1 (PD-L1) protein expression in cancer cells was evaluated by immunohistochemical analysis. RESULTS: TP53 gene mutations were the most common alteration (n = 51/67, 76.1%), followed by gene alterations in cyclin-dependent kinase inhibitor 2B (CDKN2B; 35.8%), CDKN2A (31.3%), phosphatase and tensin homolog (30.0%), and sex-determining region Y-box 2 (SOX2, 28.3%). Histological differentiation was significantly poorer in tumors with high MB (greater than or equal to the median MB) compared with that in tumors with low MB (less than the median MB; p = 0.0446). The high MB group had more tumors located in the upper or middle lobe than tumors located in the lower lobe (p = 0.0019). Moreover, cancers in the upper or middle lobes had significantly higher MB than cancers in the lower lobes (p = 0.0005), and tended to show higher PD-L1 protein expression (p = 0.0573). SOX2 and tyrosine kinase non-receptor 2 amplifications were associated with high MB (p = 0.0065 and p = 0.0010, respectively). CONCLUSIONS: The MB level differed according to the tumor location in LSCC, suggesting that the location of cancer development may influence the genomic background of the tumor.

DOI： 10.1245/s10434-018-6401-1

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PURPOSE: Small bowel obstruction (SBO) remains a common complication after pelvic or abdominal surgery. However, the risk factors for SBO in ulcerative colitis (UC) surgery are not well known. The aim of the present study was to clarify the risk factors associated with SBO after ileal pouch-anal anastomosis (IPAA) with a loop ileostomy for patients with UC. METHODS: The medical records of 96 patients who underwent IPAA for UC between 1999 and 2011 were reviewed. SBO was confirmed based on the presence of clinical symptoms and radiographic findings. The patients were divided into 2 groups: the SBO group and the non-SBO group. We also analyzed the relationship between SBO and computed tomography (CT) scan image parameters. RESULTS: The study included 49 male and 47 female patients. The median age was 35.5 years (range, 14-72 years). We performed a 2- or 3-stage procedure as a total proctocolectomy and IPAA for patients with UC. SBO in the pretakedown of the loop ileostomy after IPAA occurred in 22 patients (22.9%). Moreover, surgical intervention for SBO was required for 11 patients. In brief, closure of the loop ileostomy was performed earlier than expected. A multivariate logistic regression analysis revealed that the 2-stage procedure (odds ratio, 2.850; 95% confidence interval, 1.009-8.044; P = 0.048) was a significant independent risk factor associated with SBO. CT scan image parameters were not significant risk factors of SBO. CONCLUSION: The present study suggests that a 2-stage procedure is a significant risk factor associated with SBO after IPAA in patients with UC.

DOI： 10.3393/ac.2017.06.14

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Language：Japanese   Publisher：(株)篠原出版新社  

Stage IV大腸癌109例を対象とし、次世代シークエンサーを用いた癌遺伝子変異解析パネル(415遺伝子)で遺伝子変異を解析した。RAS変異群26例(23.9%)、RAS変異+PTEN欠失群16例(14.7%)、PTEN欠失+ERBB2増幅群16例(14.7%)、PTEN欠失+SRC増幅/欠失群8例(7.3%)、A11野生型群27例(24.8%)、BRAF変異+RNF43変異群9例(7.3%)、その他8例(7.3%)にカテゴリー分類された。実際に抗EGFR抗体薬を使用した40例の検討では、A11野生型群は、RASKETで判定できるKRAS/NRAS遺伝子以外の遺伝子に変異のある群に比べて、無増悪生存率(PFS)が有意に良好であった。

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Gastrointestinal stromal tumor (GIST) is the most common mesenchymal neoplasm of the gastrointestinal tract. However, rectal GIST is rare, the incident rate of it is approximately 5% of all GISTs. Rectal GIST symptoms generally include bleeding and/or pain and occasionally, urinary symptoms. Immunohistochemical evaluation finds that most rectal GIST tumors are CD117 (KIT) positive, and are sometimes CD34, platelet-derived growth factor receptor alpha (PDGFRA), smooth muscle actin, S-100, or vimentin positive. The National Institutes of Health (NIH) classifies rectal GIST as very-low risk, low risk, intermediate risk, or high risk, and the frequencies have been estimated as 0-23.8% for very-low risk, 0-45% for low risk, 0-34% for intermediate risk, and 21-100% for high risk tumors. The first-line treatment for localized GIST is curative resection, but is difficult in rectal GIST because of anatomical characteristics such as the deep, narrow pelvis and proximity to the sphincter muscle or other organs. Several studies noted the efficacy of the minimally invasive surgery, such as trans-anal, trans-sacral, trans-vaginal resection, or laparoscopic resection. The appropriate surgical procedure should be selected depending on the case. Imatinib mesylate (IM) is indicated as first-line treatment of metastatic or unresectable GIST, and clinical outcomes are correlated with KIT mutation genotype. However, the KIT mutation genotypes in rectal GIST are not well known. In this review, as in other GISTs, a large proportion (59-100%) of rectal GISTs carry exon 11 mutations. Although curative resection is indicated for localized rectal GIST, a high rate of local recurrence is a problem. Multimodal therapy including perioperative IM may improve postoperative outcomes, contributing to anus-preserving surgery. Moreover, KIT mutation analysis before IM treatment is important. This review summarizes current treatment strategies for rectal GIST.

DOI： 10.21037/tgh.2018.01.08

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Next-generation sequencing (NGS) has enabled comprehensive detection of genomic alterations in lung cancer. Ethnic differences may play a critical role in the efficacy of targeted therapies. The aim of this study was to identify and compare genomic alterations of lung adenocarcinoma between Japanese patients and the Cancer Genome Atlas (TCGA), which majority of patients are from the US. We also aimed to examine prognostic impact of additional genomic alterations in patients harboring EGFR mutations. Genomic alterations were determined in Japanese patients with lung adenocarcinoma (N = 100) using NGS-based sequencing of 415 known cancer genes, and correlated with clinical outcome. EGFR active mutations, i.e., those involving exon 19 deletion or an L858R point mutation, were seen in 43% of patients. Some differences in driver gene mutation prevalence were observed between the Japanese cohort described in the present study and the TCGA. Japanese cohort had significantly more genomic alterations in cell cycle pathway, i.e., CDKN2B and RB1 than TCGA. Concurrent mutations, in genes such as CDKN2B or RB1, were associated with worse clinical outcome in patients with EGFR active mutations. Our data support the utility of comprehensive sequencing to detect concurrent genomic variations that may affect clinical outcomes in this disease.

DOI： 10.1038/s41598-017-18560-y

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Language：Japanese   Publisher：(株)医学書院  

＜ポイント＞閉塞性大腸炎をきたす疾患として大腸癌が最も多いが,憩室炎,虚血性腸疾患,便秘なども原因となりうる.閉塞部から離れた口側腸管にびらん・潰瘍を認めることが多く,切除範囲の設定には注意を要する.ステント治療により,口側腸管の評価や減圧が可能となり,閉塞性大腸炎のマネジメントに変化がみられる.(著者抄録)

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PURPOSE: It has been suggested that the biological characteristics of breast cancer may differ among different geographic or ethnic populations. Indeed, triple-negative breast cancer (TNBC), the most lethal breast cancer subgroup, has been reported to show a higher incidence in Japan than in the US. However, most genomic studies of these tumors are from Western countries and the genomic landscape of TNBC in an Asian population has not been thoroughly investigated. Here, we sought to elucidate the geographic and ethnic diversity of breast cancer by examining actionable driver alterations in TNBC tumors from Japanese patients and comparing them with The Cancer Genome Atlas (TCGA) database, which gather data primarily from non-Asian patients. MATERIALS AND METHODS: We performed comprehensive genomic profiling, including an analysis of 435 known cancer genes on Japanese TNBC patients (N=53) and compared the results to independent data obtained from TCGA (N=123). RESULTS: Driver alterations were identified in 51 out of 53 Japanese patients (96%). Although the overall alteration spectrum of Japanese patients was similar to that of the TCGA, we found significant differences in the frequencies of alterations in MYC and PTK2. We identified three patients (5.7%) with a high tumor mutation burden, although no microsatellite instability was observed in any of the Japanese patients. Importantly, pathway analysis revealed that 66.0% (35/53) of Japanese patients, as well as 66.7% (82/123) of the TCGA cohort, had alterations in at least one actionable gene targetable by an FDA-approved drug. CONCLUSION: Our study identified actionable driver alterations in Japanese patients with TNBC, revealing new opportunities for targeted therapies in Asian patients.

DOI： 10.1200/po.17.00211

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Language：English   Publisher：(一社)日本胃癌学会  

DOI： 10.1200/PO.18.00097

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INTRODUCTION: Precision medicine is only possible in oncology practice if targetable genes in fragmented DNA, such as DNA from formalin-fixed paraffin-embedded (FFPE) samples, can be sequenced using next generation sequencing (NGS). The aim of this study was to examine the quality and quantity of DNA from FFPE cancerous tissue samples from surgically resected and biopsy specimens. METHODS: DNA was extracted from unstained FFPE tissue sections prepared from surgically resected specimens of breast, colorectal and gastric cancer, and biopsy specimens of breast cancer. A total quantity of DNA ≥60 ng from a sample was considered adequate for NGS. The DNA quality was assessed by Q-ratios, with a Q-ratio >0.1 considered sufficient for NGS. RESULTS: The Q-ratio for DNA from FFPE tissue processed with neutral-buffered formalin was significantly better than that processed with unbuffered formalin. All Q-ratios for DNA from breast, colorectal and gastric cancer samples indicated DNA levels sufficient for NGS. DNA extracted from gastric cancer FFPE samples prepared within the last 7 years is suitable for NGS analysis, whereas those older than 7 years may not be suitable. Our data suggested that adequate amounts of DNA can be extracted from FFPE samples, not only of surgically resected tissue but also of biopsy specimens. CONCLUSIONS: The type of formalin used for fixation and the time since FFPE sample preparation affect DNA quality. Sufficient amounts of DNA can be extracted from FFPE samples of both surgically resected and biopsy tissue, thus expanding the potential diagnostic uses of NGS in a clinical setting.

DOI： 10.1016/j.jss.2017.06.077

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The patient was a 73-year-old man with ascending colon cancer and synchronous liver metastases. A right hemicolectomy with a lymph node dissection was performed for the primary lesion. The resected specimen revealed a KRAS codon 12 mutation. After 6 courses of chemotherapy with capecitabine, oxaliplatin, and bevacizumab(Bv), we performed a partial hepatectomy and resection of the peritoneal dissemination. A computed tomography(CT)scan 5 months later revealed the recurrence of the liver metastases. After 8 courses of chemotherapy with 5-fluorouracil, Leucovorin, irinotecan, and Bv, we performed a partial hepatectomy. CT scan after 13 months revealed a recurrence in the peritoneal dissemination in the Douglas pouch and the right subphrenic space; therefore, we performed a low anterior resection and resection of the peritoneal dissemination with curative intent. CT scan after 19 months revealed a recurrence in the right subphrenic dissemination, a lung metastasis, and pleural dissemination. Chemotherapy with 5-fluorouracil, Leucovorin, and Bv was administered for 2 years and 5 months. After 5 years and 9 months of the primary operation, the patient is alive. Recently, we have focused on the mechanism of multidrug resistance through NAD(P)H: quinone oxidoreductase-1(NQO1)overexpression, which can be used to determine the role of an enzyme in sensitivity to toxicity and carcinogenesis. In this case, the pathological examination of the resected specimen revealed NQO1 negative expression. In conclusion, NQO1 may play a significant role in chemotherapy resistance in colorectal cancer patients.

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Lymph node metastasis has a poor prognosis in patients with hepatocellular carcinoma(HCC). We report a case of HCC with lymph node metastasis successfully treated by multidisciplinary treatment. An 81-year-old woman who was followed up for liver cirrhosis received a diagnosis of HCC, which was detected by CT as a solitary tumor 20mm in diameter in the couinaud segment 7 of the liver. She underwent transcatheter arterial chemoembolization(TACE)twice for HCC because of her advanced age and no intention to undergo hepatectomy. Some 12 months later, local recurrence was managed by repeat TACE and paraaortic lymph node metastasis by surgical resection. The patient received radiotherapy for mediastinal nodal disease 6 months after the resection. She remains alive and well without no evidence of disease 84 months after the initial treatment. This case and a review of the literature suggest that multidisciplinary treatment with TACE, surgical resection and radiotherapy may provide a survival benefit for selected patients with HCC with isolated lymph node metastasis.

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Language：Japanese  

This study aimed to evaluate the health-related quality of life(QOL)using EQ-5D-5L scores for patients who underwent surgery for colorectal cancer. A total of 30 consecutive patients(14 men and 16 women; median age: 67.5 years)from the outpatient clinic of our institute in January 2017 were eligible for this study. The primary tumor was located in the colon(n= 18)or rectum/anu(s n=12). Twelve patient(s 40.0%)had cancer recurrence, and 3 patient(s 10.0%)had a stoma. In addition, 11 patients(36.7%)underwent chemotherapy. The median EQ-5D-5L score for all the patients was 0.867(range, 0.324- 1.000). The EQ-5D-5L score of patients with recurrence was significantly lower(0.820)than that of patients without recurrence( 0.948)(p=0.002). Furthermore, the EQ-5D-5L score of women(0.834)was significantly lower than that of men (0.942)(p=0.015). No significant difference was noted between the EQ-5D-5L score and other factors, such as age, cancer stage, location of primary tumor, absence/presence of chemotherapy, and absence/presence of stoma. In conclusion, using EQ-5D-5L scores, female gender and cancer recurrence were found to be associated with low QOL of patients after surgery for colorectal cancer.

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A 71-year-old man presented with sudden abdominal pain. He had past history of atrial fibrillation, cerebral infarction and heart-valve replacement and received anticoagulant therapy with warfarin. Computed tomography of the abdomen revealed bloody ascites and a huge mass in contact with the third portion of the duodenum. The mass was encapsulated and consisted of a solid component with calcification and hematoma. Under the preoperative diagnosis of gastrointestinal stromal tumor with intra-abdominal bleeding, laparotomy was performed. Intraoperative findings revealed the tumor arising from the right mesocolon and excision of the tumor with right hemicolectomy was performed. Histologic examination confirmed a diagnosis of mixed type liposarcoma. No postoperative complication was observed and he was discharged home on the 8th postoperative day. He remains alive and well with no evidence of disease 52 months after resection.

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Carcinoma with elevated SRC expression is associated with distant metastasis and drug resistance. We report 2 cases of SRC amplification observed after retrospective comprehensive genomic sequencing. Case 1 was a 62-year-old man who had RAS wild-type stage IV carcinoma of the sigmoid colon with multiple liver metastases in both lobes. He underwent low anterior resection and systemic chemotherapy was initiated to treat the unresectable multiple liver metastases. Case 2 was a 73-yearold man who had RAS wild-type stage IV carcinoma of the descending colon with metastasis in the lateral segment of the liver. He underwent left hemicolectomy and lateral segmentectomy. He subsequently underwent open radiofrequency ablation and systemic chemotherapy to treat a hepatic recurrence. Several previous studies have found that molecular targeted therapy with tyrosine kinase inhibitors is effective against colorectal cancer with elevated SRC expression. This suggests that the results of comprehensive genomic sequencing may support the implementation of new treatments.

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Language：Japanese   Publisher：新潟医学会  

次世代シークエンサーを用いた包括的な癌関連遺伝子変異解析により、大腸癌を含む固形癌患者に対するPrecision Medicineが可能となる。次世代シークエンサーによる遺伝子変異解析においては、ホルマリン固定パラフィン包埋サンプルの精度管理が重要である。ホルマリン固定パラフィン包埋サンプル作製において重要な点は、10%中性緩衝ホルマリン固定液を使用すること、固定時間は48時間以内とすることである。また、ホルマリン固定パラフィン包埋サンプルの経年劣化を考慮して7年以内に解析を行うことである。これまで大腸癌を含む固形癌患者に対する薬物療法は、臓器ごとに縦割りに行われてきた。しかし、現在ではドライバー遺伝子変異により、対応する薬剤が臓器横断的に使用されるようになってきている。例えば、HER2陽性の乳癌および胃癌に対して、抗HER2療法が有効である。近年では、HER2陽性の大腸癌に対しても、抗HER2療法の有効性が示されている。このように、今後はHER2などの分子標的薬と関連するバイオマーカーを基盤とした臓器横断的分類が重要となると考えられる。(著者抄録)

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BACKGROUND: A prospective randomized study was performed to investigate the validity of intravenous carnitine administration during postoperative parenteral nutrition (PN) with lipid emulsion. METHODS: Patients undergoing surgery for gastric or colorectal cancer were enrolled in the study and were randomly divided into two groups (n = 8 in each group): 1) group L, who received a peripheral PN (PPN) solution of 7.5% glucose, 30% amino acid, and 20% lipid emulsion; and 2) group LC, who received the same PPN solution, as well as carnitine intravenously. PPN was performed from postoperative day (POD) 1 to POD4. Clinical and laboratory parameters were compared between the two groups; statistical significance was set at P < 0.05. RESULTS: Serum carnitine concentrations were significantly higher in group LC on POD3 (P < 0.01) and POD7 (P = 0.01). Postoperative changes in laboratory parameters and morbidity were comparable between the two groups. However, the decrease in C-reactive protein from POD3 to POD7 was significantly greater in group LC than in group L (P = 0.011). CONCLUSION: The results show that intravenous carnitine administration in addition to PN is safe and may be beneficial for recovery from postoperative inflammatory reactions.

DOI： 10.14740/jocmr3113w

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMED CENTRAL LTD  

Background: Intertumoral heterogeneity represents a significant hurdle to identifying optimized targeted therapies in gastric cancer (GC). To realize precision medicine for GC patients, an actionable gene alteration-based molecular classification that directly associates GCs with targeted therapies is needed.& para;& para;Methods: A total of 207 Japanese patients with GC were included in this study. Formalin-fixed, paraffin-embedded (FFPE) tum or tissues were obtained from surgical or biopsy specimens and were subjected, to DMA extraction. We generated comprehensive genomic profiling data using a 435-gene panel including 69 actionable genes paired, with US Food and Drug Administration-approved targeted therapies, and the evaluation o f Epstein-Barr virus (EBV) infection and microsatellite instability (MSI) status.& para;& para;Results: Comprehensive genomic sequencing detected at least one alteration o f 435 cancer-related genes in 194 GCs (93.7%) and o f 69 actionable genes in 141 GCs (68.1%). We classified the 207 GCs into four The Cancer Genome Atlas (TCGA) subtypes using the genomic profiling data; EBV (N = 9), MSI (N = 17), chromosomal instability (N = 119), and genomicaliy stable subtype (N = 62). Actionable gene alterations were not specific and were widely observed throughout all TCGA subtypes. To discover a novel classification which more precisely selects candidates for targeted therapies, 207 GCs were classified using hypermutated. phenotype and the mutation profile of 69 actionable genes. We identified a hypermutated group (N = 32), while the others (N = 175) were sub-divided into six dusters including five with actionable gene alterations: ERBB2 (N = 25), CDKN2A, and CDKN2B (N = 10), KRAS (N = 10), BRCA2 (N = 9), and ATM duster (N = 12). The clinical utility of this classification was demonstrated by a case of unresectable GC. with a remarkable response to anti-HER2 therapy in the ERBB2 duster.& para;& para;Conclusions: This actionable gene-based classification creates a framework for further studies for realizing precision medicine in GC.

DOI： 10.1186/s13073-017-0484-3

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A ciliated muconodular papillary tumor (CMPT) has been reported to be a low-grade malignant tumor or benign tumor, consisting of ciliated columnar cells and goblet cells with basaloid cell proliferation, occur in the peripheral lung. We present a case of CMPT in this report. A 42-year-old male was referred to our department due to a nodule detected in the peripheral left lower lobe of lung. The nodule was resected via wedge resection based on a suspected diagnosis of carcinoma. Intraoperative analysis of the frozen sections was suggestive of mucinous adenocarcinoma. A left lower lobectomy and mediastinal lymph node dissection were performed. The resected specimen was characterized as a papillary tumor with central fibrosis, proliferating along the alveolar walls, surrounded by mucous lakes, and consisting of ciliated columnar cells and goblet cells. Nuclear atypia was mild, and no mitotic activity was observed. Based on these findings, the tumor was finally diagnosed as CMPT. No recurrence has been noted for 24 months after surgery.

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症例は77歳、男性。統合失調症で他院に通院していた。4年前にS状結腸癌に対して腹腔鏡補助下S状結腸切除術を施行されていた。経過観察目的の腹部CT検査で肝内と胃前庭部に迷入する針状異物を2本認めた。問診から統合失調症の妄想により数ヵ月前に裁縫針を誤飲したことが判明した。腸管穿孔・出血・胆汁漏などの危険性があると判断し、異物を摘出するために腹腔鏡下手術を施行した。肝内に迷入していた異物を把持鉗子で摘出した。胃前庭部への迷入が疑われた異物は腹腔鏡および術中上部消化管内視鏡検査では確認できず、術中X線透視検査により盲腸に移動していたことが判明した。腹腔鏡下に回盲部を授動し、臍部小切開創より挙上し、盲腸に小切開を加え、異物を摘出した。経過良好で第4病日に退院した。伏針に対する腹腔鏡下手術は低侵襲であること、および腹腔内全体にわたる詳細な観察と操作が可能であることから有用であると考える。(著者抄録)

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japanese Society of Gastroenterological Surgery  

We report the case of a 45-year-old man, who at the age of 24 had total proctocolectomy with ileal W-pouch anal anastomosis for familial adenomatous polyposis. A follow-up transanal endoscopy performed at the age of 38 revealed approximately 30 polyps in the ileal pouch, which were then confirmed by biopsy to be tubular adenomas. A transanal endoscopy performed at the age of 44 revealed an 8 mm 0-Is lesion located approximately 1 cm proximal to the ileal pouch-anal anastomosis, which was then removed by EMR. Histopathological analysis showed the presence of well-differentiated tubular adenocarcinoma in adenoma. To date, no recurrence of adenocarcinoma has been confirmed in follow-up transanal endoscopies. We have experienced treating a case of adenocarcinoma arising in the ileal pouch through the adenoma-carcinoma sequence after total proctocolectomy with ileal pouch-anal anastomosis for familial adenomatous polyposis. For early diagnosis and prompt treatment, it is important to perform periodic surveillance of the ileal pouch and conduct aggressive endoscopic resection when a large adenoma exceeding 10 mm is found.

DOI： 10.5833/jjgs.2016.0055

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NAD(P)H: quinone oxidoreductase-1 (NQO1) protects cells against redox cycling and oxidative stress; however, in cancer cells, NQO1 confers resistance against anticancer agents. The aim of this study was to evaluate the association between NQO1 expression and prognosis in patients with advanced (locally advanced or metastatic/recurrent) colorectal cancer (CRC). A retrospective analysis of 47 patients [28 male and 19 female; median age: 62 years (range, 17-78)] with advanced CRC was conducted. Immunohistochemical examination of tumor tissue specimens was performed using monoclonal anti-NQO1 antibody. The association of NQO1 expression with patient characteristics, chemotherapeutic response, and clinical prognosis was assessed. Therapeutic efficacy (complete response, partial response, stable disease, and progressive disease) was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. We compared the therapeutic efficacy in KRAS wild and mutant CRC because epidermal growth factor receptor (EGFR)-signaling pathway plays a pivotal role in CRC. Of the 47 patients, 31 (66.0%) had KRAS wild CRC and 16 (34.0%) had KRAS mutant CRC. Moreover, 37 (78.7%) had NQO1-positive tumors and 10 (21.3%) had NQO1-negative tumors. Among the patients with KRAS wild CRC, NQO1-negative patients showed significantly better disease control rate (complete response + partial response + stable disease) than NQO1-positive patients (P = 0.028). Moreover, NQO1-negative patients had longer progression-free survival and overall survival than NQO1-positive patients (P = 0.041 and P = 0.043, respectively). NQO1 expression in the tumor may be a predictor of therapeutic efficacy and prognosis in patients with KRAS wild advanced CRC.

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© 2016 The Authors Background and aims Transthoracic esophagectomy using 3-field lymphadenectomy (TTE-3FL) for esophageal cancer is one of the most aggressive gastrointestinal surgeries. Early enteral nutrition (EN) for TTE-3FL patients is useful and valid for early recovery; however, EN using a fat-containing formula risks inducing chyle leak. In the present study, we retrospectively examined esophageal cancer patients treated byTTE-3FL and administered postoperative EN to elucidate the validity of lowering the fat levels in elemental formulas to prevent postoperative chyle leak and improve postoperative recovery. Methods A total of 74 patients who received TTE-3FL for esophageal cancer were retrospectively examined. Patients were classified into two groups according to the type of postoperative EN: Group LF patients received a low-fat elemental formula, and Group F patients received a standard fat-containing polymeric formula. The following clinical factors were compared between the groups: EN start day, maximum EN calories administered, duration of respirator use, length of ICU stay, incidence of postoperative infectious complications, use of parenteral nutrition (PN), and incidence of postoperative chyle leak. Results Patients in Group LF were started on EN significantly earlier after surgery and they consumed significantly higher maximum EN calories compared to Group F patients (P &lt; 0.01). Duration of respirator use and length of ICU stay were also significantly shorter, and TPN was used significantly less in Group LF compared to Group F (P &lt; 0.05). Postoperative chyle leak was observed in six patients in total (8.1%); five patients in Group F and one patient in Group LF, although there was no significant difference in frequency of chyle leak per patient between Group LF and Group F. Conclusions Early EN using low-fat elemental formula after esophagectomy with three-field lymphadenectomy was safe and valid for postoperative recovery and potentially useful in preventing chyle leak.

DOI： 10.1016/j.clnu.2016.03.018

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Background: Comprehensive genomic sequencing (CGS) has the potential to revolutionize precision medicine for cancer patients across the globe. However, to date large-scale genomic sequencing of cancer patients has been limited to Western populations. In order to understand possible ethnic and geographic differences and to explore the broader application of CGS to other populations, we sequenced a panel of 415 important cancer genes to characterize clinically actionable genomic driver events in 201 Japanese patients with colorectal cancer (CRC).
Methods: Using next-generation sequencing methods, we examined all exons of 415 known cancer genes in Japanese CRC patients (n = 201) and evaluated for concordance among independent data obtained from US patients with CRC (n = 108) and from The Cancer Genome Atlas-CRC whole exome sequencing (WES) database (n = 224). Mutation data from non-hypermutated Japanese CRC patients were extracted and clustered by gene mutation patterns. Two different sets of genes from the 415-gene panel were used for clustering: 61 genes with frequent alteration in CRC and 26 genes that are clinically actionable in CRC.
Results: The 415-gene panel is able to identify all of the critical mutations in tumor samples as well as WES, including identifying hypermutated tumors. Although the overall mutation spectrum of the Japanese patients is similar to that of the Western population, we found significant differences in the frequencies of mutations in ERBB2 and BRAF. We show that the 415-gene panel identifies a number of clinically actionable mutations in KRAS, NRAS, and BRAF that are not detected by hot-spot testing. We also discovered that 26% of cases have mutations in genes involved in DNA double strand break repair pathway. Unsupervised clustering revealed that a panel of 26 genes can be used to classify the patients into eight different categories, each of which can optimally be treated with a particular combination therapy.
Conclusions: Use of a panel of 415 genes can reliably identify all of the critical mutations in CRC patients and this information of CGS can be used to determine the most optimal treatment for patients of all ethnicities.

DOI： 10.1186/s13073-016-0387-8

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A 58-year-old man was admitted with the complaint of bloody stools. Colonoscopy and computed tomography revealed a rectal cancer with a liver metastasis and multiple lung metastases. After administering a regimen comprising 3 courses of XELOX plus bevacizumab chemotherapy, the sizes of the primary and metastatic lesions decreased remarkably. Abdominoperineal resection was performed for local control of the cancer; the specimen from the initial tumor was found to be KRAS wild type. After 14 courses of XELOX chemotherapy, brain metastases were detected. Although 3 courses of IRIS plus panitumumab were administered, the liver, lung, and brain metastases spread rapidly. A comprehensive genomic analysis focused on cancer-related genes with CancerPlex®found a mutation of the BRAF gene(I326V). BRAF is a downstream molecule of KRAS in the RAS-RAF-MAPK pathway. Therefore, this mutation of the BRAF gene has the possibility of causing resistance against panitumumab that was found in this case. Furthermore, we expect that the systematic analysis of oncogene and suppressor oncogenes will enable us to choose the optimal regimen of chemotherapy or molecular targeting therapy for each patient with colorectal cancer.

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Recently, targeted drugs have been developed for the treatment of colorectal cancer(CRC). Among targets, it is well known that KRAS mutations are associated with resistance to epidermal growth factor receptor(EGFR)monoclonal antibodies. However, response rates using anti-EGFR monotherapy for CRC were less than 20-30% in previous clinical studies. Thus, because the RAS/MAP2K/MAPK and PI3K/AKT pathways are associated with CRC resistance to chemotherapy, we analyzed gene mutations in Stage IV CRC patients using a genomic test(CancerPlex®). Medical records were reviewed for 112 patients who received treatment for CRC between 2007 and 2015 in Niigata University Medical and Dental Hospital or Niigata Cancer Center Hospital. There were 66 male and 46 female patients, and their median age was 62.5(range, 30-86) years. Cluster analyses were performed in 110 non-hypermutated Japanese CRC patients using Euclidean distance and Ward's clustering method, and 6 typical groups were identified. Among these, patients with all wild-type actionable genes benefited from anti-EGFR therapies. The expense of targeted drugs warrants consideration of cost-effectiveness during treatment decision-making for advanced CRC patients. To this end, based on the genetic information on CRC, it is possible to develop precision medicine using CancerPlex®.

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We report a case of panitumumab-resistant rectal cancer with HER2 gene amplification detected by CancerPlex®. A 51- year-old man was diagnosed with an obstructive rectal cancer having lung and adrenal metastases. He underwent the Hartmann 's operation, and KRAS mutations were not detected. After the surgery, 3 courses of CapeOx plus bevacizumab were administered as first-line chemotherapy; however, the lung and adrenal metastases progressed. Subsequently, 24 courses of IRIS/panitumumab was administered as second-line chemotherapy, and the metastases slowly progressed. Six courses of regorafenib were administered as third-line chemotherapy followed by a course of TAS-102 as fourth-line chemotherapy. Subsequently, a left femoral head metastasis and cerebellar metastases were detected. The patient received best supportive care including palliative femoral head replacement and stereotactic irradiation for the cerebellar metastases, and he died of cancer 3 years 5 months after the primary surgery. The comprehensive genomic analysis focusing on 413 cancer-related genes with CancerPlex®revealed that EGFR, BRAF, KRAS, NRAS, and HRAS had no mutations; however, ERBB2 amplification was detected. Furthermore, immunohistochemical staining revealed overexpression of HER2 protein in both the primary and bone metastatictumor. HER2 and EGFR independently promote the RAS-RAF-MAPK pathway. In the present case, the efficacy of anti-EGFR therapy may be attenuated because of ERBB2 amplification in the metastatic tumor.

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A46 -year-old male presented with bloody stool and a descending colon tumor, as identified using colon fiberscopy. The patient did not complain of any remarkable abdominal symptoms. Computed tomography revealed descending colon tumor intussusception. We performed partial resection of the descending colon and D2 lymphadenectomy without intraoperative reduction. The descending colon was barely attached to the retroperitoneum and was mobile. The underlying tumor was type 1 and measured 8.3×5.8 cm. The pathology report indicated a mucinous adenocarcinoma with extension through the submucosa into the subserosa, and metastasis in 6 nearby lymph nodes(n2). Intussusception is relatively rare in adults, particularly in portions of the colon fixed to the retroperitoneum, such as the descending colon. In contrast to previous reports of descending colon intussusception caused by age-related tissue dysfunction, we report our experience with a young patient and present the results obtained.

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Background: Meigs' syndrome is defined as the co-existence of benign ovarian fibroma or fibroma-like tumor, ascites, and pleural effusion. In contrast, pseudo-Meigs' syndrome is defined as the co-existence of other ovarian or pelvic tumors, ascites, and pleural effusion. In Meigs' and pseudo-Meigs' syndromes, ascites and pleural effusion resolve promptly after the complete resection of the ovarian or pelvic tumor(s). Secondary ovarian tumors from colorectal gastrointestinal metastases rarely cause pseudo-Meigs' syndrome; only 11 cases of pseudo-Meigs' syndrome secondary to colorectal cancers have been reported in the literature. Therefore, the prognosis and etiology of pseudo-Meigs' syndrome caused by ovarian metastasis from colorectal cancers remain unclear.
Case presentation: We report here a rare case of pseudo-Meigs' syndrome caused by ovarian metastases from sigmoid colon cancer with long-term survival. A 47-year-old woman presented with abdominal distention of 1month duration. She developed acute dyspnea 2 weeks after the initial presentation. Colonoscopy and computed tomography revealed sigmoid colon cancer with an ovarian metastasis, along with massive ascites and bilateral pleural effusion. Emergency operation, including bilateral oophorectomy and sigmoidectomy, was performed. Subsequently, ascites and bilateral pleural effusion resolved rapidly. Curative hepatic resection was performed for liver metastases 29 months after the first operation, and as of this writing, the patient is alive with no evidence of a disease 78 months after the first operation. In general, colorectal cancer with ovarian metastasis is hard to cure, and long-term survival in patients with colorectal cancer with pseudo-Meigs' syndrome is rare. Our experience suggests that curative resection for pseudo-Meigs' syndrome caused by ovarian metastasis from colorectal cancer may offer long-term survival.
Conclusions: Our experience suggests that pseudo-Meigs' syndrome can occur in a patient with colorectal cancer after metastasis to the ovaries, causing massive ascites and pleural effusion. Aggressive treatment, including R0 resection, for this disease if allowed by the patient's general condition may offer long-term survival.

DOI： 10.1186/s12957-016-1040-0

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RAS mutation is an established predictive biomarker of resistance to anti-epidermal growth factor receptor(EGFR)therapy in metastatic colorectal cancer. In addition, previous studies identified mutations in ERBB2, FGFR1, PDGFRA, BRAF, MAP2K1, PTEN, and PIK3CA as potential mechanisms of resistance to anti-EGFR therapy. Testing for these mutations might be necessary to determine eligibility for anti-EGFR therapy in patients with metastatic colorectal cancer. CancerPlex®is a nextgeneration sequencer for 413 cancer genes. An analysis panel includes genes that may be associated with resistance to anti- EGFR therapy. A 65-year-old man with unresectable rectal cancer, multiple lung metastases, and a bulky liver metastasis was evaluated for expression of genes associated with resistance to anti-EGFR. The analysis found that all genes indicating resistance were wild-type genes. Cetuximab monotherapy was administered after rectal resection, with dramatic shrinkage of the metastatic tumors. A more accurate selection of patients according to tumor genetic status using CancerPlex®might improve the risk-benefit profile of anti-EGFR therapy.

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We report here a case of long-term survival with repeated peritoneal recurrences after resection of perforated sigmoid colon cancer. A 65-year-old man presented with diarrhea and abdominal pain. Computed tomography(CT)revealed diffuse peritonitis caused by perforated sigmoid colon cancer. We performed sigmoidectomy with D2 lymphadenectomy and descending colostomy. Postoperatively, S-1 was administered for 12 months as adjuvant chemotherapy. CT showed peritoneal nodules 56 months after the surgery. After 10 courses of mFOLFOX6 plus bevacizumab, the tumors decreased in size (reduction rate of 34.4%; a partial response). Subsequently, 3 peritoneal nodules were resected with curative intent. Another peritoneal nodule was detected 57 months after the second surgery. After 3 courses of XELOX plus bevacizumab, the nodule decreased in size(reduction rate of 69.0%; a partial response). The nodule was resected with a curative intent. At the last follow-up 135 months after the first surgery, the patient remains alive with no evidence of disease.

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【緒言】次世代シーケンサーによってがん薬物療法の効果を予測するdriver mutationを網羅的に解析することが可能となり、がん薬物療法は個別化治療の時代に入りつつある。最大で数百程度までのがん関連遺伝子変異を対象にしたtarget sequencingでは日常臨床で普及しているホルマリン固定パラフィン包埋(Formalin-fixed paraffin-embedded:FFPE)サンプルを利用することができる。FFPEサンプル作製に際しては、DNAの質と量の確保が重要である。FFPEサンプルでは、ホルマリン固定によるDNAの断片化が生じるため、各医療施設での病理標本固定条件がDNAの質に影響する。一方、生検材料などの微小検体においても、次世代シーケンサーによる遺伝子変異解析に耐えうるDNAの量が確保できるか否かは臨床上の重要な問題である。本研究の目的は、次世代シーケンサーによる遺伝子変異解析のためのFFPEサンプル作製方法を確立すること、および微小検体からのDNA抽出方法を明らかにすることである。また、実際にFFPEサンプルを用いて次世代シーケンサーによる癌の遺伝子変異解析が可能であることを明らかにすることである。【方法】1)過去に作製された10%酸性ホルマリン固定FFPEサンプルを用いて、次世代シーケンサーによる遺伝子変異解析が可能か否かを検討した。2)FFPEサンプル作製時のホルマリン固定法を標準化するために、ホルマリン種類および固定時間の条件を変えてFFPEサンプルを作製し、DNA濃度とDNAの断片化を評価した。3)次世代シーケンサーによる遺伝子変異解析に必要な最低限のサンプルサイズを決定するために、組織採取面積の条件を変えてDNAを抽出し、それぞれのDNA濃度を測定した。4)生検材料を用いて次世代シーケンサーによる遺伝子変異解析が可能か否かを明らかにするために、生検材料からDNAを抽出し、DNA濃度を測定した。5)次世代シーケンサーによる固形癌の遺伝子変異解析ツール(CancerPlex)にて、大腸癌外科切除100症例の10%中性緩衝ホルマリン固定FFPEサンプルを使用し、415の重要な癌の遺伝子変異を解析した。そして、1症例あたりの遺伝子変異数、および変異の頻度が高い遺伝子を求めた。【結果】1)過去に作製された10%酸性ホルマリン固定FFPEでは、DNAの断片化が高度であり、次世代シーケンサーによる遺伝子変異解析を行うことができなかった。2)固定液の種類に関わらず、ホルマリン固定時間が経過するとDNAの断片化が進行した。しかし、10%中性緩衝ホルマリンでは、10%酸性ホルマリンと比較してDNAの断片化が起こりにくかった。3)20μm未染プレパラート1枚から3×3mmの組織採取を行うことで最低限のDNA濃度を確保できた。4)生検材料においても20μm未染プレパラート1枚から組織採取を行うことで最低限のDNA濃度を確保できた。5)大腸癌100症例で全例に有意な癌の遺伝子変異が検出され、1症例あたりの遺伝子変異数は中央値10(範囲:2-49)であった。大腸癌100例全体で247種類の癌の遺伝子変異が検出可能であった。【結論】次世代シーケンサーによる遺伝子変異解析において理想的なFFPEサンプルを作製するためには、10%中性緩衝ホルマリンを使用し、固定時間は24時間程度として必要最低限とすることが肝要である。また、生検材料などの微小な検体からも次世代シーケンサーによる遺伝子変異解析が可能であることから、この技術の適応範囲は広く、より多くの患者に適切ながん薬物療法の提案ができるものと期待される。(著者抄録)

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A 63-year-old woman was found to have a mass in her right breast and visited our hospital to undergo a detailed examination. A histopathological examination by using ultrasound-guided core needle biopsy revealed ductal carcinoma in situ. A partial mastectomy with sentinel lymph node biopsy was performed for the cancer of the right breast. The postoperative histopathological examination indicated apocrine carcinoma with a predominantly intraductal component without lymph node metastasis. The discrimination between ductal adenoma and apocrine carcinoma sometimes becomes a problem in making decisions about treatment. We need to take care when making a diagnosis.

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A 71-year-old woman diagnosed with Fournier's gangrene caused by penetration of a rectal carcinoma was referred to our hospital. Emergency drainage and sigmoid colostomy were performed. Pathological examination of a biopsy sample showed moderately differentiated tubular adenocarcinoma. Abdominoperineal resection with bilateral salpingo-oophorectomy and hysterectomy was performed with curative intent after 4 courses of chemotherapy with S-1 and oxaliplatin. The postoperative pathological diagnosis was StageⅡ (pT4bN0M0). The patient received tegafur/uracil and Leucovorin as adjuvant chemotherapy. Seven months after the curative operation, partial pneumonectomy was performed for the recurrence of the rectal carcinoma in the right lung. Eight months after pneumonectomy, recurrent tumors were observed in the right lung and subcutaneous fat layer of the right buttock along the drainage site. The tumor in the right buttock was excised along with part of the gluteus maximus, and partial pneumonectomy was then performed. Three years and 6 months after the emergency drainage, the patient is alive with no evidence of recurrence. After drainage for rectal carcinoma complicated by Fournier's gangrene, the possibility of recurrence around the drainage site should be considered.

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A 64-year-old woman discovered a mass in her left breast and visited our hospital. A thorough examination resulted in a diagnosis of left, locally advanced breast cancer (cT4bN3, M0, cStage Ⅲc) with muscle invasion and Level Ⅲ lymph node metastases. Because of drug-induced lung disease following 4 courses of adriamycin and cyclophosphamide, the chemotherapy had to be stopped. Halsted&#039;s operation and postoperative radiotherapy (50 Gy) were performed. The patient was alive with no evidence of recurrence 9 months after surgery. Although multidisciplinary therapy is recommended in locally advanced breast cancer, chemotherapy sometimes cannot be performed due to factors such as age and physical status. Halsted&#039;s operation could be considered as a treatment of choice in patients with locally advanced breast cancer. It is important to choose the treatment strategy based on the condition of the patient.

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症例は80歳女性. 前医で下部直腸癌に対し経肛門的局所切除術が施行された. 局所切除後2年1か月目に, 外陰部から肛門にかけて掻痒を伴う紅色扁平隆起性病変が明らかとなった. 生検でPaget細胞が認められた. 乳房外Paget病は, 皮膚原発の一次性乳房外Paget病と二次性乳房外Paget病に分類され, 鑑別診断には免疫組織化学染色が有用である. 本症例では, 免疫組織化学染色でGCDFP-15陰性, CK20陽性, CK7陰性であり, Pagetoid spreadを伴う直腸癌局所再発と診断した. CT検査で所属リンパ節および遠隔転移を認めなかった. 外陰部膣合併切除を伴う腹会陰式直腸切断術を行うことで, 治癒切除となった. 直腸癌局所切除後のPagetoid spreadを伴う再発形式は稀であるが, Paget細胞遺残の可能性を考慮し, 外来通院時の肛門皮膚観察に注意すべきである.

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A 58-year-old woman presenting with abdominal distension was diagnosed with a tumor in the right ovary. A chest-abdominal-pelvic computed tomography scan revealed multiple lung metastases, multiple liver metastases, and peritoneal dissemination. Invasion of the rectum by peritoneal dissemination of the Douglas' pouch was suspected. She was diagnosed with Stage Ⅳ right ovarian cancer and was treated with preoperative chemotherapy. After chemotherapy, debulking surgery of the abdominal cavity (total hysterectomy, bilateral salpingo-oophorectomy, partial omentectomy, and Hartmann's procedure) was performed. Because there was swelling observed in multiple mesorectal lymph nodes, lymph node dissection was performed based on methods used for rectal cancer surgery. Postoperative histopathological examination revealed multiple mesorectal lymph node metastases arising from ovarian cancer. We suggest that mesorectal lymph node dissection be considered a part of debulking surgery for ovarian cancers that have invaded the rectum.

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The patient was a 73-year-old woman. She underwent right hemicolectomy and D3 lymph node dissection for cecal cancer in June 2003. Although a peritoneal dissemination was intraoperatively noted around the primary tumor lesion, it was resected concurrently and thus R0 surgery was accomplished. Postoperative adjuvant chemotherapy was not performed. During the follow-up on an outpatient basis, a solitary left lung metastasis was found and partial left upper lobectomy of the lung was performed in December 2004. A solitary liver metastasis was identified in the liver (S3), and lateral segmentectomy of the liver was performed in June 2007. The patient was alive with no evidence of recurrence 11 years and 9 months after resection of the primary lesion and 7 years and 9 months after the hepatectomy. Long-term survival can be achieved by performing resection without residual cancer even in some cases with metachronous metastatic recurrences in multiple organs. Metastasectomy should be considered proactively when the patient is in a good general condition and R0 resection is possible.

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Case 1: A 61-year-old man who had a diagnosis of low rectal cancer with lateral pelvic lymph node (LPLN) metastasis and multiple liver metastases underwent low anterior resection with LPLN dissection. The initial surgery was followed by chemotherapy, and then an extended right hepatectomy with partial resection of the liver was performed. Subsequently, a lung metastasis was detected, and the lung was partially resected. The patient was alive 9 years and 6 months after the initial operation. Case 2: A 53-year-old man had a diagnosis of low rectal cancer. After 5 courses of mFOLFOX6 plus bevacizumab, he underwent low anterior resection with LPLN dissection and resection of the peritoneal metastasis. The patient was alive 6 years and 3 months after the surgery without any signs of recurrence. Case 3: A 48-year-old man had a diagnosis of low rectal cancer and multiple liver metastases. He underwent low anterior resection with LPLN dissection and right hepatic lobectomy. He subsequently showed liver and lung metastases. The patient received systemic chemotherapy, and is alive with recurrent disease. We report 3 cases of Stage Ⅳ low rectal cancer with LPLN metastasis, and propose that LPLN dissection is important as a part of R0 resection for Stage Ⅳ low rectal cancer.

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症例は76歳の女性。主訴は右鼠径部腫瘤。肛門指診で、肛門縁から2.5cmに下縁を有する2cm大の隆起性病変、および主病巣より肛門側に0.5cm大の粘膜下腫瘤を触知した。大腸内視鏡検査で、下部直腸に主座を有し一部肛門管に進展する2cmの2型腫瘍を認め、生検で中分化型腺癌と診断された。胸腹骨盤部CT検査では、右閉鎖、右総腸骨、右鼠径リンパ節の腫大を認めた。下部直腸癌cStage IIIbの術前診断にて、腹会陰式直腸切断術D3郭清、右鼠径リンパ節郭清を施行した。術後の病理組織学的検査では、組織型は中分化〜低分化充実型腺癌、主病巣の深達度はMPで、ly2、v1と脈管侵襲を認めた。また、右閉鎖リンパ節に2個、右総腸骨リンパ節に1個、そして右鼠径リンパ節に3個それぞれ転移を認め、下部直腸癌pStage IIIbの診断となった。主病巣の肛門側に、主病巣と非連続性で低分化充実型腺癌の粘膜下腫瘍を認め、そのさらに肛門側にリンパ管侵襲を認めた。同粘膜下腫瘍は、主病巣と非連続性であること、および主病巣と類似した組織型であることから直腸癌の壁内転移と診断された。また、同粘膜下腫瘍は、周囲にリンパ管侵襲を認め、さらに鼠径リンパ節転移を認めたことから、直腸における下方向リンパ流を介した壁内転移と推定された。(著者抄録)

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Pneumatosis cystoides intestinalis (PCI) is a relatively rare condition, characterized by subserosal or submucosal air within the bowel wall. Herein, we report a rare case of PCI secondary to treatment with an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI). A 71-year-old man, who had received gefitinib therapy for 2 years and 5 months for lung adenocarcinoma with metastases to the bones and brain, presented with abdominal pain, diarrhea, and vomiting. Computed tomography of the abdomen revealed intramural air in the small bowel, free air in the abdomen, and moderate ascites. A diagnosis of PCI was made, and the patient was managed conservatively by discontinuing gefitinib treatment, because his vital signs were stable and there was no sign of peritonitis. The patient&#039;s symptoms gradually improved, and follow-up CT after 1 week revealed that the initial findings had almost completely resolved. Clinicians should note that treatment with gefitinib might cause PCI.

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Background. The aims of this study were to identify prognostic factors of patients with submucosa-invasive (T1b) gastric cancer and to verify the validity of adjuvant chemotherapy for this disease.
Methods. We retrospectively examined the cases of 1,236 consecutive patients in our prospectively maintained database with T1b gastric cancer who underwent gastrectomy in 1995-2012. We used 11 clinicopathologic characteristics to identify prognostic factors by univariate and multivariate analyses. We compared the survival of the 160 node-positive T1b gastric cancer patients with that of 133 patients in the same database who had node-positive muscularis propria-invasive (T2) gastric cancer and had undergone gastrectomy without adjuvant chemotherapy during the same period, as a reference cohort.
Results. The 5-year overall survival rate was 91.4% for all 1,236 patients. Advanced age (hazard ratio [HR] 4.51; 95% confidence interval [CI] 3.26-6.24; P &lt; .01), male sex (HR 2.26; 95% CI 1.5- 3.26; P &lt; .01), and the presence of lymph node metastasis (HR 1.89; 95% CI 1.33-2.70; P &lt; .01) were independent prognostic factors. The 5-year overall survival rates were 92.5 % in node-negative patients, 84.5% in patients with 1 or 2 metastatic nodes, and 80.1% in patients with 3 or more metastatic nodes (P &lt;.01). The 5-year overall survival rates of the node-positive T1b and T2 gastric cancer patients were 83.6% and 81.2%, respectively (P = .73).
Conclusion. The prognosis of node-positive T1b gastric cancer patients after curative gastrectomy was unsatisfactory. Adjuvant chemotherapy should be considered for these patients, especially those with 3 or more metastatic nodes.

DOI： 10.1016/j.surg.2014.10.009

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Language：Japanese   Publisher：(株)日本臨床社  

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Language：Japanese   Publisher：(株)ドラッグマガジン  

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Language：Japanese   Publisher：(一社)日本大腸肛門病学会  

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Language：Japanese   Publisher：(一社)日本大腸肛門病学会  

同一病巣内に神経内分泌腫瘍(neuroendocrine tumor;NET)と腺癌の成分を認める直腸腫瘍は非常に稀である.このような腫瘍の発生過程は,NETと腺癌の両者への分化傾向をもつ単一クローン由来,それぞれ別のクローンから発生した腫瘍の衝突の2つの可能性がある.症例は52歳,男性.便潜血陽性で下部消化管内視鏡検査を施行され,下部直腸に10mm大の粘膜下腫瘍様病変を指摘された.生検でNETの診断となり,同病巣に対し内視鏡的粘膜下層剥離術を施行した.病理診断では,病巣は径8mmで,病巣内にNETと腺癌の成分があり,両成分の粘膜下層までの浸潤を認めた.病巣構築より一方から他方が発生した経路を除外できること,明らかな組織移行像を認めないこと,および免疫組織化学の染色態度の相違から,NETと腺癌が別々のクローンから発生した衝突腫瘍であると診断した.追加腸切除の適応とされ,腹腔鏡補助下超低位前方切除術,D2郭清を施行し,現在まで再発を認めていない.(著者抄録)

DOI： 10.3862/jcoloproctology.68.55

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DOI： 10.4172/2165-7920.1000635

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Language：Japanese   Publishing type：Research paper (scientific journal)  

Herein, we present a case of advanced rectal cancer surgically resected after chemotherapy. A 65-year-old woman presented with anal pain, and rectal cancer extending beyond the anus was diagnosed. The primary tumor was a well-differentiated adenocarcinoma with a KRAS mutation. Computed tomography revealed cancer invasion into the vagina and sacral and coccygeal bones, and cancer metastases to the bilateral inguinal lymph nodes and the left lung. Sigmoid colostomy and subcutaneous venous port insertion were performed. The patient was treated with modified oxaliplatin, leucovorin, and 5-fluorouracil (FOLFOX6) plus bevacizumab. She showed a partial response according to the Response Evaluation Criteria in Solid Tumors after 13 courses of chemotherapy. The primary tumor was then resected via posterior pelvic exenteration, bilateral inguinal lymphadenectomy, and sacral/coccygeal resection. Histological examination of the resected specimens revealed moderately differentiated adenocarcinoma with vaginal invasion. Metastasis to a right inguinal lymph node was observed. The pathological stage was ypT4bN0M1b, ypStage IV according to the tumor-node-metastasis system of the eighth edition of the Japanese Classification of Colorectal Carcinoma. The pathological response grade of the tumor after chemotherapy was determined to be Grade 1b.

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A 69-year-old man underwent right hemicolectomy and D3 lymphadenectomy for transverse colon cancer in 2009. Under the postoperative pathological diagnosis of Stage IIIb (pT3pN2cM0) cancer, he was given 8 courses of adjuvant chemotherapy with capecitabine. After the chemotherapy, in April 2013, we detected recurrence of the multiple liver and lung metastases; thus, we administered modified 5-fluorouracil, Leucovorin, oxaliplatin (mFOLFOX6) and bevacizumab. Six courses of oxaliplatin infusion were completed uneventfully. However, 3 min after starting the seventh infusion courses, the patient experienced cardiopulmonary arrest. We immediately performed cardiopulmonary resuscitation. The patient's anaphylaxis symptoms resolved after treatment with intravenous epinephrine. He was discharged 3 days after the event with no further complications. Clinicians should be aware that oxaliplatin-induced anaphylactic shock often occurs during the eighth infusion cycle and that this severe hypersensitivity reaction is difficult to predict and prevent.

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A 57-year-old woman was referred to our hospital because of descending colon cancer with multiple liver metastases. Abdominal magnetic resonance imaging (MRI) revealed 13 liver metastases across the lobes. We started combination chemotherapy with capecitabine/oxaliplatin (CapeOX) and bevacizumab. After 9 courses of the treatment, the number and size of the liver metastases were remarkably reduced on MRI. Left colectomy and partial hepatectomy were performed. Histopathological examination revealed no residual cancer cells in the colon but revealed a few cancer cells in 4 of 7 resected liver specimens. At 11 postoperative months, 1 liver metastasis reappeared, for which we performed laparoscopy-assisted partial hepatectomy. At 21 months after the second operation, the patient was well without any signs of recurrence. Thus, the combination chemotherapy with CapeOX and bevacizumab allowed for the successful resection of the tumor and metastasis in our patient who initially had unresectable colon cancer and multiple liver metastases.

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A 70-year-old man was referred to our hospital with ascending colon cancer (cT3N1M0, Stage IIIa), which was found during examinations following a positive fecal occult blood test. The patient was also diagnosed with early gastric cancer (cT1a, NO, MO, Stage IA) during a preoperative gastroscopy examination. A laparoscopically assisted right colectomy and D3 lymphadenectomy was performed for the ascending colon cancer. The postoperative pathological diagnosis was Stage IIIb (pT3N2), he was administered in combination with capecitabine plus oxaliplatin (CapeOX) as adjuvant chemotherapy before the treatment for the colon cancer. After 6 months of adjuvant chemotherapy, we were unable to detect any gastric lesions at the same location using gastroscopy, and so diagnosed a clinical complete response. A follow-up gastroscopy 6 months later showed the same findings. The patient has had no recurrence of gastric cancer for 18 months after the initial operation. He will continue to be followed up closely using gastroscopy. In this case, CapeOX as adjuvant chemotherapy for advanced colon cancer was also effective for early gastric cancer.

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A 69-year-old man with advanced rectal cancer and liver metastases was treated with 2 courses of chemotherapy with irinotecan and S-1 followed by low anterior resection and partial hepatectomy. Chemotherapy with S-1 was then administered for 22 months. However, lung metastases developed, for which partial pneumonectomy was performed. Seven months later, computed tomography (CT) revealed swelling of the left supraclavicular lymph node. Despite chemotherapy with 5-fluorouracil, Leucovorin, and oxaliplatin (mFOLFOX6); 5-fluorouracil, Leucovorin and irinotecan (FOLFIRI); and capecitabine plus bevacizumab, the lung metastases recurred and Virchow lymph node swelling was noted again. Accordingly, palliative therapy was administered. The patient died 3 years 1 month after Virchow lymph node resection. Herein, we describe a case of advanced rectal cancer, in which lung and Virchow lymph node metastases developed after liver metastasis. Surgical excision of the metastases resulted in long-term survival of 6 years following the first operation.

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A 71-year-old man was referred to our hospital because of repeated bowel obstruction. He had previously undergone cystectomy with ileal conduit urinary diversion for the treatment of bladder cancer at the age of 28 years. Computed tomography revealed a mass in the ascending colon. Ileostomy was initially performed because of poor general condition that improved with postoperative nutrition management. Enema findings revealed ascending colon cancer and we therefore decided to perform curative surgery. Intraoperative findings revealed that the ascending colon cancer had invaded the ileal conduit. However, it was confirmed that the ureter-ileal conduit anastomosis and the mesentery of the ileal conduit could be preserved. We performed right colectomy and partial resection of the ileal conduit with curative intent. The pathological stage was pT4bpN0cM0, pStage II. There were no signs of recurrence 15 months after curative surgery.

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A 34-year-old woman presenting with bloody stools was diagnosed with a rectal tumor. Computed tomography (CT) revealed multiple liver masses in Couinaud segments IV, V, and VU. The lesions were diagnosed as multiple liver metastases from rectal cancer. Right trisegmentectomy of the liver was considered the optimal treatment option for curative resection; however, liver volumetric examination using CT estimated that the remnant liver volume after right trisegmentectomy would be only 24.6 % of the total liver volume. Therefore, she underwent resection of the primary lesion followed by systemic chemotherapy for multiple liver metastases. She showed a partial response, according to the Response Evaluation Criteria in Solid Tumors, after 5 courses of capecitabine/oxaliplatin plus bevacizumab. Embolization of the right branch of the portal vein was performed to increase liver volume. A subsequent liver volumetric examination with CT estimated that the remnant liver volume after right trisegmentectomy would be 38.4 % of the total liver volume. Therefore, she underwent right trisegmentectomy of the liver for curative resection of the liver metastases. She had had no signs of recurrence at 3 years and 6 months after initial surgery.

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Purpose: In the present study, we aimed to describe the surgical results of single-port laparoscopic stoma creation in our institution. Methods: We examined the safety of the surgical procedure and short-term results in 10 consecutive patients who underwent single-port laparoscopic stoma creation at our hospital between April 2011 and July 2013. Results: The median age of the patients was 60.5 (range, 31-75) years. Five patients were men, and 5 were women. There were 5 cases of colorectal cancer, 2 each of extramammary Paget&#039;s disease and uterine cancer, and one of perineal neurofibroma. Eight surgeries were performed for bowel obstruction or stenosis, and two surgeries were performed for other reasons. The median operative time was 59.5 (range, 40-91) min, blood loss volume was 0 (range, 0-10) mL, postoperative duration before commencement of oral intake was 2.5 (range, 1-4) days, and duration of postoperative hospital stay was 11 (range, 5-19) days. No short-term complications were noted after the surgery. Conclusion: Single-port laparoscopic stoma creation appears to be feasible in terms of safety and short-term surgical results, and may improve the quality of life of patients requiring fecal diversion.

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Herein, we present a case of long-term survival after lateral pelvic lymph node dissection for recurrence in the form of skip metastasis of rectal cancer. A 63-year-old man underwent abdominoperineal resection without lateral pelvic lymph node dissection for advanced lower rectal cancer. The histological diagnosis was type 2, 85×50 mm, tub1, pT4a, ly0, v1, pPM0, pDM0 and pN0, pStage II (Japanese Classification of Colorectal Carcinoma, 8th edition). Six months after surgery, enhanced computed tomography showed right obturator lymph node metastasis. We performed lateral pelvic lymph node dissection. Histological examination revealed moderately differentiated adenocarcinoma in the right obturator lymph node. The lymph node metastasis was diagnosed as a skip metastasis of the rectal cancer. The patient has had no recurrence for 9 years after resection of the lateral pelvic lymph node.

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An 81-year-old man presented with chief complaints of abdominal pain and vomiting. Intestinal obstruction was found at the time of admission to a local hospital in October 2011. Conservative treatment provided symptomatic relief; however, he was readmitted with similar symptoms in December 2011. Small-intestinal wall thickening was detected by abdominal and pelvic computed tomography, and he was referred to our hospital. Small-bowel endoscopy revealed an elevated subcircumferential tumor in the jejunum. Biopsy revealed well to moderately differentiated adenocarcinoma diagnosed as jejunal cancer, which caused narrowing of the jejunum. Single-incision laparoscopy-assisted small-bowel resection was performed. The intraoperative findings were a tumor with inflammatory changes in the jejunum and enlarged surrounding lymph nodes. We performed regional lymph node dissection. Histopathological analysis showed moderately differentiated small-intestinal tubular adenocarcinoma and 2 of 5 lymph nodes positive for metastatic cancer cells. After an uneventful postoperative course, he was discharged on day 7. He preferred not to undergo postoperative adjuvant chemotherapy and quickly recovered his activities of daily living postoperatively. He stayed home until he developed abdominal distention resulting from peritoneal recurrence 1 year and 6 months postoperatively and died 1 month later.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

The study aimed to determine the value of a novel site-specific grading system based on quantifying poorly differentiated clusters (PDC; Grade(PDC)) in colorectal cancer (CRC). A multicenter pathologic review involving 12 institutions was performed on 3243 CRC cases (stage I, 583; II, 1331; III, 1329). Cancer clusters of 5 cancer cells and lacking a gland-like structure (PDCs) were counted under a x20 objective lens in a field containing the maximum clusters. Tumors with &lt;5, 5 to 9, and 10 PDCs were classified as grades G1, G2, and G3, respectively. According to Grade(PDC), 1594, 1005, and 644 tumors were classified as G1, G2, and G3 and had 5-year recurrence-free survival rates of 91.6%, 75.4%, and 59.6%, respectively (P&lt;0.0001). Multivariate analysis showed that Grade(PDC) exerted an influence on prognostic outcome independently of TNM staging; approximately 20% and 46% of stage I and II patients, respectively, were selected by Grade(PDC) as a population whose survival estimate was comparable to or even worse than that of stage III patients. Grade(PDC) surpassed TNM staging in the ability to stratify patients by recurrence-free survival (Akaike information criterion, 2915.6 vs. 2994.0) and had a higher prognostic value than American Joint Committee on Cancer (AJCC) grading (Grade(AJCC)) at all stages. Regarding judgment reproducibility of grading tumors, weighted among the 12 institutions was 0.40 for Grade(AJCC) and 0.52 for Grade(PDC). Grade(PDC) has a robust prognostic power and promises to be of sufficient clinical value to merit implementation as a site-specific grading system in CRC.

DOI： 10.1097/PAS.0000000000000113

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Language：Japanese   Publishing type：Research paper (scientific journal)  

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Language：Japanese   Publisher：新潟医学会  

【緒言】消化器外科領域では、術前・術後の栄養管理に加え、昨今では化学療法の重要性が急速に増してきており、CVカテーテルの必要性が増大している。体表解剖に基づいたランドマーク法による鎖骨下静脈(以下SCV)穿刺は、ブラインド穿刺のため、時に気胸・動脈穿刺など、種々の合併症を引き起こすことがある。リアルタイムエコーガイド下のSCV(USgSCV)穿刺で、これらの合併症が激減することが報告されているが、主に放射線科で実施されており、広く普及するには至っていない。そこで、我々は一般外科診療において、市中病院で容易に入手可能な材料を用いて、安全にSCVの穿刺を行える手技の工夫および検証を行ったため、報告する。【方法・結果】Sakamotoらの穿刺法に筆者の工夫を加え、7.5MHzの体表プローベを用いてSCVを長軸に描出し、エコー観察下にフリーハンドでSCV穿刺を行う手技を施行した。USgSCV穿刺施行例のうちCVポート増設を行ったものは3施設18例で、合併症の発生はみられなかった。平均手術時間は30分であり、経験症例数やBMIによって手術時間は影響を受けなかった。【結語】USgSCV穿刺法は、動脈・静脈の走行を直接確認しながら、合併症フリーでのSCV穿刺が可能であった。手術室のみならず、病棟での処置にも十分応用可能であり、エクストラコストを最小限に留めながら安全性のメリットを享受できうる方法であった。(著者抄録)

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2014&ichushi_jid=J00990&link_issn=&doc_id=20140918060005&doc_link_id=%2Fdg3nigta%2F2014%2F012806%2F005%2F0264-0268%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdg3nigta%2F2014%2F012806%2F005%2F0264-0268%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

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The clinical significance of micrometastasis in patients with colorectal cancer has been investigated by immunohistochemical and molecular biological methods for several decades. However, no general consensus of the clinical significance of micrometastasis has been established. The presence of isolated tumor cells and occult micrometastases in lymph nodes may be an important information to determine the candidate for adjuvant chemotherapy among patients with colorectal cancer without overt lymph node metastasis. The research of circulating tumor cells and disseminated tumor cells would be expected to elucidate the mechanism of chemo-resistance and apply developing new anti-cancer agents. The detection of micrometastasis may contribute to create "tailor-maid treatment" for patients with colorectal cancer.

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Language：Japanese   Publisher：新潟医学会  

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Language：Japanese   Publisher：(一社)日本消化器外科学会  

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Language：Japanese   Publisher：(株)永井書店  

開腹手術後の腸管蠕動の低下は生理的なものであり、特別な処置をしなくても通常は2～4日程度で回復する。しかしその回復が遅れた場合、入院期間を延長させるだけでなく術後合併症の誘因にもなり、患者のQOL(quality of life)を低下させ医療経済的にも大きな損失となる。術後腸管蠕動障害を予防するには、術前からの対策や手術の工夫、早期離床を中心とした術後管理が重要になる。外科医は術後腸管蠕動障害の病態を理解し、予防対策や治療に精通することが必要である。(著者抄録)

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Language：Japanese   Publisher：(株)東京医学社  

・外科的には、肛門縁から恥骨直腸筋付着部上縁までを肛門管と定義しており、これを外科的肛門管と呼ぶ。・歯状線は、上皮構造、静脈叢、そして神経支配の境界部であり、肛門疾患の理解に重要である。(著者抄録)

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＜ポイント＞◆一般的に,わが国では腹膜炎手術後にドレーンを留置するが,欧米ではドレーンを留置しないことが多い.◆腹膜炎手術後のドレーン留置を支持するエビデンスはなく,むしろ合併症の原因となるという報告がある.◆ドレーン留置の目的と弊害を理解し,不要なドレーンを留置しないことを心がけるべきである.(著者抄録)

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Language：Japanese   Publisher：(株)メディカルレビュー社  

肛門管癌はまれな疾患であるが、発生部位の解剖学的・組織学的特殊性から臨床像が多彩であり、診断には苦慮する。早期診断が困難であるため、診断時には隣接臓器浸潤、リンパ節転移や遠隔転移をきたした状態であることがしばしばあり、治療成績も一般の大腸癌と比較すると不良である。また、組織型によって治療戦略が異なり、迅速かつ正確な診断が求められる。本稿では肛門管の解剖を概説し、肛門管癌の診断について肛門部の診察、内視鏡検査、画像検査の所見を各組織型別に解説する。(著者抄録)

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DOI： 10.11477/mf.1407103961

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Language：Japanese   Publishing type：Research paper (scientific journal)  

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Language：Japanese   Publisher：(株)日本臨床社  

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A 23-year-old woman presented with a history of repeated abdominal pain and vomiting since the 12th gestational week. Radiological studies revealed dilatation of the entire small intestine without mechanical obstruction, and dysmotility of the ileocecal region was suspected. Her symptoms continued after delivery, despite conservative treatment, and ileocecal resection was performed at age 24 years. The resected specimen showed a remarkable decrease in the density of enteric ganglion cells, therefore chronic idiopathic intestinal pseudo-obstruction (CUP) was diagnosed. Subtotal colectomy was subsequently performed at 25 years of age, but her symptoms persisted. Long-term parenteral nutrition became difficult because of catheter-related complications and her nutritional status worsened. Therefore, at age 29 she underwent jejunostomy, and her symptoms improved. She is now able to eat and her nutritional status continues to improve. Autoimmune abnormality has recently been reported to be one of the causes of CUP, and some relation between pregnancy and autoimmune disease has been recognized. Our case suggests that immunological changes during pregnancy may cause CUP. © 2012 The Japanese Society of Gastroenterological Surgery.

DOI： 10.5833/jjgs.45.326

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Language：Japanese   Publisher：(株)医学書院  

＜ポイント＞◆大腸内視鏡検査においては,通常観察で粘膜の発赤,血管透見性の消失,粘膜襞の形状変化などの微細な所見を見逃さずに認識することが重要である.◆病変の質的診断は色素内視鏡,狭帯域光観察(NBI),拡大観察,超音波内視鏡検査などを駆使して行う.◆直腸・肛門管の観察では病変と肛門管の構造物との位置関係を正確に認識することが重要である.(著者抄録)

DOI： 10.11477/mf.1407103868

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2011&ichushi_jid=J01539&link_issn=&doc_id=20111207590010&doc_link_id=10.11477%2Fmf.1407103868&url=https%3A%2F%2Fdoi.org%2F10.11477%2Fmf.1407103868&type=%E5%8C%BB%E6%9B%B8.jp_%E3%82%AA%E3%83%BC%E3%83%AB%E3%82%A2%E3%82%AF%E3%82%BB%E3%82%B9&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

Language：Japanese   Publisher：(株)へるす出版  

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Language：Japanese   Publisher：(株)医学書院  

DOI： 10.11477/mf.1407103796

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Language：Japanese   Publishing type：Research paper (scientific journal)  

We report a case of a super-elderly patient with recurrent rectal cancer effectively treated with CapeOX chemotherapy. A 85-year-old man who had a low anterior resection was diagnosed with rectal cancer in July 2009. Although peritoneal dissemination near the main tumor was disclosed during the operation, a R0 and Cur B operation was performed. After the operation, an elevation of tumor markers was detected in October. A chest-abdominal-pelvic CT scan revealed multiple liver metastases of the bilateral lobe and a metastasis of the right iliac bone. We attempted CapeOX chemotherapy from November. After 3 courses of CapeOX chemotherapy, the multiple liver metastases shrank and the bone metastasis changed to a consolidation. Although grade 1 chronic peripheral neuropathy appeared after 8 courses of chemotherapy, no other adverse event appeared. After 10 courses of CapeOX chemotherapy, the chemotherapy was changed to capecitabine at the patient's request. A chest-abdominal-pelvic CT scan after 10 courses of CapeOX chemotherapy revealed that the multiple liver metastases were shrinking. As of September 2010, the patient's PS score is 0, and he has been under treatment as an outpatient.

PubMed

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Language：Japanese   Publisher：金原出版(株)  

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Language：Japanese   Publisher：日本臨床外科学会  

症例は78歳,女性.検診で便潜血陽性を指摘されて近医を受診し,精査・加療目的に当院を受診した.上部・下部消化管内視鏡で異常を認めず,カプセル内視鏡およびダブルバルーン内視鏡で終末回腸に表面型腫瘍を認め,生検では高分化腺癌であった.CTでは明らかなリンパ節転移や遠隔転移を認めなかった.以上より原発性小腸癌と診断し,単孔式腹腔鏡下小腸部分切除術を施行した.病理組織学検査ではwell differentiated adenocarcinoma,pM,ly0,v0,pN0,pStage 0であった.近年の小腸内視鏡の普及により,早期に発見される原発性小腸癌が増えている.本症例のように広範囲のリンパ節郭清が必要でない小さな小腸病変に対しては,単孔式腹腔鏡下手術は非常に良い適応と思われた.(著者抄録)

DOI： 10.3919/jjsa.72.1465

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2011&ichushi_jid=J03156&link_issn=&doc_id=20110706200025&doc_link_id=10.3919%2Fjjsa.72.1465&url=https%3A%2F%2Fdoi.org%2F10.3919%2Fjjsa.72.1465&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Language：Japanese   Publisher：(株)医学書院  

＜ポイント＞◆直腸手術の際は,疾患の良・悪性にかかわらず術後の排便障害は不可避の問題であり,その病態の理解と対策を熟知しておく必要がある.◆肛門機能障害の軽減のためには新直腸再建法が重要であり,J型結腸嚢再建やtransverse coloplasty pouchなどが用いられている.◆術後に排便機能障害が認められた場合は薬物療法が第一選択であり,約7割の患者に有効である.(著者抄録)

DOI： 10.11477/mf.1407103464

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2011&ichushi_jid=J01539&link_issn=&doc_id=20110222440016&doc_link_id=10.11477%2Fmf.1407103464&url=https%3A%2F%2Fdoi.org%2F10.11477%2Fmf.1407103464&type=%E5%8C%BB%E6%9B%B8.jp_%E3%82%AA%E3%83%BC%E3%83%AB%E3%82%A2%E3%82%AF%E3%82%BB%E3%82%B9&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

Language：Japanese  

DOI： 10.11477/mf.1407103414

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Other Link： http://search.jamas.or.jp/link/ui/2011128312

Language：Japanese  

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CiNii Books

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Language：Japanese   Publisher：Japanese Society of Gastroenterological Surgery  

An evaluation of quality of life (QOL) after surgery in ulcerative colitis patients in Japan is not clarified. We studied long-term postoperative case for QOL via questionnaires (SF36v2) mailed to subjects. Methods : Subjects were 138 of 151 cases of ulcerative colitis surgery conducted from 1984 to 2008 and still being followed up. Two surveys had been conducted in 2005 and 2008 on postoperative QOL inquiring about the correlation between the postoperative period and QOL, time-dependent changes in personal QOL, and the correlation between bowel function and QOL. The national average SF36 score is 50. Results : The response was 83.5% (96/115) to the first questionnaire and 76.1% (105/138) to the second. SF36 scores for (the first/second questionnaire) were PF 54.0/52.6, RP 50.9/49.6, BP 52.3/53.7, GH 47.3/47.7, VT 52.2/49.7, SF 50.5/49.8, RE 51.1/49.2 and MH 52.1/49.1. Four subscales showed scores under 50 for within two years after surgery (six subscales for the second questionnaire) but scores were improved after five years. A high score group (higher than 14) of the defecation score (0-18) showed high significantly favorable scores of QOL in five subscales compared with a low score group. The SF36 scores of 78 patients from whom we received a questionnaire two times in a row showed around 50. Conclusions : The QOL for those undergoing postoperative ulcerative colitis was equivalent to the national average, and improved as postoperative time passed. Satisfaction with bowel function influenced postoperative QOL. © 2010 The Japanese Society of Gastroenterological Surgery.

DOI： 10.5833/jjgs.43.777

Scopus

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2010&ichushi_jid=J01117&link_issn=&doc_id=20100811180001&doc_link_id=10.5833%2Fjjgs.43.777&url=https%3A%2F%2Fdoi.org%2F10.5833%2Fjjgs.43.777&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Language：Japanese   Publisher：(株)日本臨床社  

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Language：Japanese   Publishing type：Research paper (scientific journal)  

The patient was a 73-year-old male. Under a diagnosis of advanced cecal colon cancer with metastasis to Virchow's and paraaortic lymph nodes and lungs, a laparoscopic-assisted ileocecal resection with D2 lymph node dissection was performed. Histological examination of the resected specimens revealed moderately-differentiated adenocarcinoma which had invaded the terminal ileum. The lesion was judged to be SI(ileum), N2, H0, P0, M1(Virchow's lymph node, No. 216, lungs), Stage IV. After the operation, he received chemotherapy with 5-FU/l-LV(RPMI method), LV/UFT, FOLFOX, FOLFIRI in succession, and cancer aggravation was generally controlled. He has survived for 3 years since operation, and shows good QOL under the treatment.

PubMed

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Language：Japanese   Publisher：Japanese Society of Gastroenterological Surgery  

We report the case of patient with cytomegalovirus infection and rectovaginal fistula associated with ulcerative colitis. A 40-year-old woman was diagnosed with ulcerative colitis of left-sided colitis 4 years earlier. Her clinical course was relapse-remitting type. She was relapsed, and received steroid injection therapy and leuko-cytapheresis. After then, she had defecation from vagina. Double contrast study of the colon and rectum revealed rectovaginal fistula. Colonoscopy showed geographical ulcer and peripheral blood cytology showed CMVpp65 positive cells. Deep ulceration created by cytomegalovirus infection seems a possible cause of rectovaginal fistula. Her activity of ulcerative colitis was improved after antivirus treatment by ganciclovir. We conducted diverting sigmoid colostomy for rectovaginal fistula. Eight months later, she was underwent total colectomy, ileal pouch anal anastomosis and setting of diverting ileostomy. Rectovaginal fistula should be taken into account in cases of ulcerative colitis with cytomegalovirus infection. © 2009 The Japanese Society of Gastroenterological Surgery.

DOI： 10.5833/jjgs.42.288

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2009&ichushi_jid=J01117&link_issn=&doc_id=20090310120010&doc_link_id=10.5833%2Fjjgs.42.288&url=https%3A%2F%2Fdoi.org%2F10.5833%2Fjjgs.42.288&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Authorship：Lead author,　Corresponding author   Language：Japanese   Publisher：Japanese Society of Gastroenterological Surgery  

Background: General Rules for Clinical and Pathological Studies on Cancer of the Colon, Rectum, and Anus (Japanese-language edition 7) state that a 3cm distal resection margin is needed in patients with rectal cancer in whom the distal edge is located above the peritoneal reflection (RS, Ra) and 2cm needed when the distal edge is below it (Rb). To determine the optimal margin, we analyzed clinicopathologic features in the intestinal and mesorectal distal spread of rectal cancer using whole mounted sections of the mesorectum. Methods: We studied intestinal and mesorectal distal spread using whole mounted sections from 213 specimens of rectosigmoid and rectal cancer, analyzing the risk factors in intestinal and mesorectal distal spread. We defined the long distal spread as 30mm or more in patients with RS/Ra cancer and 20mm or more in those with Rb/P cancer, clarifying their clinicopathological features. Results: We found that 31 patients (15%) had distal spread, 20 intestinal distal spread alone, five mesorectal distal spread alone, and six both intestinal and mesorectal distal spread. Multivariate analysis indicated risk factors for intestinal distal spread to be histologi-cal grade (tub2, por) and distant metastasis and for mesorectal distal spread to be distant metastasis. All of the three (1.4%) having long distal spread, four or more lymph node involved (pN2) and two had distant metastasis. Conclusions: Distant metastasis is a risk factor in intestinal and mesorectal distal spread. Distal resection margins defined by the general rules are therefore appropriate for most patients with rectosigmoid and rectal cancer, but it should be considered that long distal spread may be observed in patients with pN2 and distant metastasis. © 2009 The Japanese Society of Gastroenterological Surgery.

DOI： 10.5833/jjgs.42.1643

Scopus

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2009&ichushi_jid=J01117&link_issn=&doc_id=20091109090001&doc_link_id=10.5833%2Fjjgs.42.1643&url=https%3A%2F%2Fdoi.org%2F10.5833%2Fjjgs.42.1643&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Language：Japanese   Publisher：新潟医学会  

症例は45歳男性。健診の腹部エコーで左上腹部腫瘤を指摘され、近医を受診し、膵尾部腫瘍の診断で当科紹介入院となった。CT,MRI検査で膵solid-pseudopapillary tumor(以下、SPT)の診断で、脾合併膵体尾部切除術を施行した。腫瘍割面は白色調の充実性部分と嚢胞性部分を認め、嚢胞性部分には出血壊死を認めた。組織学的には充実性部分と血管を軸とした偽乳頭構造で構成されており、SPTに合致する所見であった。周囲脂肪組織への浸潤を認め、組織学的にはmalignant potentialを有する腫瘍と考えられた。免疫組織化学検査ではCD10,CD56,NSE,Vimentin,α1-antitrypsin,Chromogranin Aが陽性であり、多方向に分化を示す腫瘍と考えられた。膵SPTは若年女性に好発することが知られているが、近年男性例の報告も散見される。膵嚢胞性腫瘍の鑑業別診断の際には本疾患は男性にも発症しうることを念頭に置くべきである。本疾患は術後再発や原病死がまれなことから低悪性度腫瘍の位置づけであり、治療の原則は外科切除である。(著者抄録)

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2008&ichushi_jid=J00990&link_issn=&doc_id=20081105040004&doc_link_id=%2Fdg3nigta%2F2008%2F012208%2F004%2F0453-0457%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdg3nigta%2F2008%2F012208%2F004%2F0453-0457%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：(株)永井書店  

癌の微小転移の定義は、"HE標本による組織検索では検出できない癌の転移"から「HE標本で認識可能な2mm以下、0.2mm以上の癌細胞集団」に変更された。従来の意味での微小転移は、現在ではisolated tumor cell(ITC)にほぼ相当している。ITCの病理学的検索は抗サイトケラチン抗体を用いた免疫染色により行われるが、その検索精度の標準化が必要である。またITCの臨床的意義を解明するためには、その同定に留まらず、量や質の評価を行うことが今後の課題である。(著者抄録)

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2008&ichushi_jid=J00396&link_issn=&doc_id=20080508080002&doc_link_id=%2Faf2gktye%2F2008%2F009805%2F002%2F0786-0792%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Faf2gktye%2F2008%2F009805%2F002%2F0786-0792%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：(株)メディカルレビュー社  

旧来の微小転移は、"HE標本による組織検索では検出できない癌の転移"から「HE標本で認識可能な0.2mm未満の癌細胞集団」にその定義が変更され、isolated tumor cell(ITC)の名称が当てられている。大腸進行癌ITCの臨床的意義についてはこれまで多くの検討がなされているが、統一的見解は得られていない。筆者らのデータではITC陽性リンパ節3個以上の症例は、2個未満に比べ有意に予後不良であった。大腸SM癌でもその15%前後にはITCが存在する。これまでSM癌のITCと予後との関連を検討した報告はないが、ITCと相関する原発巣SM癌の病理組織学的因子を検討することで、内視鏡的切除SM癌の治療方針を決定する有用な情報が得られる可能性がある。低異型度癌、SM垂直浸潤距離850μm未満の病変はITC陰性であり、これらの癌は内視鏡的切除でのより確実な根治が期待される。(著者抄録)

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2008&ichushi_jid=J05173&link_issn=&doc_id=20080711180009&doc_link_id=%2Fai1coloe%2F2008%2F000102%2F009%2F0138-0142%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fai1coloe%2F2008%2F000102%2F009%2F0138-0142%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：新潟医学会  

症例は45歳男性。健診の腹部エコーで左上腹部腫瘤を指摘され、近医を受診し、膵尾部腫瘍の診断で当科紹介入院となった。CT,MRI検査で膵solid-pseudopapillary tumor(以下、SPT)の診断で、脾合併膵体尾部切除術を施行した。腫瘍割面は白色調の充実性部分と嚢胞性部分を認め、嚢胞性部分には出血壊死を認めた。組織学的には充実性部分と血管を軸とした偽乳頭構造で構成されており、SPTに合致する所見であった。周囲脂肪組織への浸潤を認め、組織学的にはmalignant potentialを有する腫瘍と考えられた。免疫組織化学検査ではCD10,CD56,NSE,Vimentin,α1-antitrypsin,Chromogranin Aが陽性であり、多方向に分化を示す腫瘍と考えられた。膵SPTは若年女性に好発することが知られているが、近年男性例の報告も散見される。膵嚢胞性腫瘍の鑑業別診断の際には本疾患は男性にも発症しうることを念頭に置くべきである。本疾患は術後再発や原病死がまれなことから低悪性度腫瘍の位置づけであり、治療の原則は外科切除である。(著者抄録)

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2008&ichushi_jid=J00990&link_issn=&doc_id=20081105040017&doc_link_id=%2Fdg3nigta%2F2008%2F012208%2F017%2F0469-0469%26dl%3D2&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdg3nigta%2F2008%2F012208%2F017%2F0469-0469%26dl%3D2&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_5.gif

Language：Japanese   Publisher：日本臨床外科学会  

潰瘍性大腸炎手術前のCTで発見された深部静脈血栓に対して,下大静脈フィルターを挿入し周術期管理を行った2例を経験したので報告する.症例1は33歳,女性.29歳時に発症した左側大腸炎型の潰瘍性大腸炎で,難治性のため手術適応とされた.術前CTで右内腸骨静脈から右総腸骨静脈の血栓を指摘され,さらに肺血流シンチグラフィーで肺塞栓を認めたため,下大静脈フィルター挿入後に手術を施行した.症例2は59歳,女性.52歳時に発症した全大腸炎型の潰瘍性大腸炎で,内科治療を目的に当院へ入院した.入院後に腹痛の訴えありCTを施行したところ,free airおよび右総腸骨静脈から左腎静脈分岐部より末梢側の下大静脈に血栓を認めた.緊急手術を行い,術後に下大静脈フィルター挿入した.潰瘍性大腸炎の腸管外合併症の一つとして深部静脈血栓症および肺塞栓症を発症することがあり,周術期には特に注意を要すると考えられた.(著者抄録)

DOI： 10.3919/jjsa.68.379

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2007&ichushi_jid=J03156&link_issn=&doc_id=20070302080022&doc_link_id=10.3919%2Fjjsa.68.379&url=https%3A%2F%2Fdoi.org%2F10.3919%2Fjjsa.68.379&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Language：Japanese   Publisher：医歯薬出版(株)  

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Language：Japanese   Publisher：(一社)日本外科感染症学会  

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2006&ichushi_jid=J04188&link_issn=&doc_id=20060328060004&doc_link_id=%2Fdg9srgif%2F2006%2F000301%2F004%2F0029-0031%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdg9srgif%2F2006%2F000301%2F004%2F0029-0031%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Authorship：Lead author,　Corresponding author   Language：Japanese   Publisher：Japan Surgical Association  

We routinely perform screening annual mammography (MMG) for patients undergoing mastectomy or breast-conserving treatment (BCT) for primary breast cancer from April 2001. In this study we investigated whether screening annual MMG is beneficial for early detection of metachronous contralateral breast cancer (MCBC). Subjects were a series of 44 patients operated on at the hospital for MCBC from April 1997 through January 2004. We classified the patients into two groups; 21 patients treated from April 1997 to March 2001 were assigned to group A, and 23 patients treated from April 2001 to January 2004 were assigned to group B. The patients of group B received screening MMG annually. The mean time between the operation for the first breast cancer and the operation for MCBC was 121 months in group A versus 100 months in group B. There was, no significant difference between them (P=0.37), but early detection of MCBC predominated in group B. The mean diameters of the lumps were 2.5 cm in group A and 1.7 cm in group B. The mean diameter in group B was significantly smaller than that of group A (P<0.05). Seven patients (30%) from group B were detected to have MCBC by screening MMG after the operation for the first breast cancer, and all of them underwent BCT. This study indicates that screening annual MMG may contribute to early detection of MCBC.

DOI： 10.3919/jjsa.65.2829

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Authorship：Lead author,　Corresponding author   Language：Japanese   Publisher：Niigata University  

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Other Link： http://hdl.handle.net/10191/4550

Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER-VERLAG TOKYO  

DOI： 10.1007/s00535-003-1217-5

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Language：Japanese   Publisher：(一社)日本外科学会  

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Language：Japanese   Publisher：(一社)日本外科学会  

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Language：Japanese   Publisher：(一社)日本外科学会  

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Language：Japanese   Publisher：(一社)日本外科学会  

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Language：Japanese   Publisher：(一社)日本外科学会  

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Language：Japanese   Publisher：(一社)日本大腸肛門病学会  

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Language：Japanese   Publisher：(一社)日本外科学会  

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Language：Japanese   Publisher：(一社)日本外科学会  

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Language：Japanese   Publisher：(一社)日本外科学会  

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Language：English   Publisher：(一社)日本胃癌学会  

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Language：English   Publisher：(一社)日本胃癌学会  

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Language：Japanese   Publisher：(株)篠原出版新社  

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Language：Japanese   Publisher：(株)癌と化学療法社  

症例は61歳,男性。閉塞性黄疸で発症し,切除可能膵頭部癌と診断し,亜全胃温存膵頭十二指腸切除術を施行した。術後5-FUの肝灌流化学療法を行い,引き続きgemcitabine(GEM)療法を6ヵ月間施行した。術後1年6ヵ月のCTで肝S6に肝転移が出現し,肝部分切除術を施行した。病理診断では膵癌肝転移であった。術後にGEM+S-1療法を1年間行い,S-1単独療法に切り替え約6ヵ月間施行した。初回手術後4年のCTで右肺に2ヶ所の肺転移を認めた。S-1療法を2ヵ月間施行後に右肺部分切除術を施行した。術後にGEM+nab-paclitaxel療法を開始したが,初回手術後5年のCTで胸膜播種が出現した。modified FOLFIRINOX療法へ変更し8ヵ月治療を継続したが,CTで横隔膜にも播種性病変が出現した。病変に緩和照射を行ったが,病状は徐々に進行した。初回手術から6年3ヵ月で死亡したが,再発後約5年の長期生存を得た。(著者抄録)

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2024&ichushi_jid=J00296&link_issn=&doc_id=20240124460012&doc_link_id=%2Fab8gtkrc%2F2024%2F005101%2F014%2F0072-0074%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fab8gtkrc%2F2024%2F005101%2F014%2F0072-0074%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：(一社)日本内視鏡外科学会  

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Language：Japanese   Publisher：(株)癌と化学療法社  

症例は58歳,女性。体重減少を主訴に来院した。腹部CT検査で胆管および膵管の拡張と膵管内に造影される壁在結節が認められ,膵管内乳頭粘液性腫瘍(IPMN)と診断された。内視鏡的逆行性胆管造影(ERCP)および胆道鏡で総胆管とIPMNとの間の瘻孔が確認された。IPMNの総胆管穿破と診断し,手術適応と判断した。術前待機中に急激な肝胆道系酵素の増加が認められ,ERCPを施行したところ粘液により総胆管が閉塞していたため,内視鏡的経鼻胆道ドレナージ(ENBD)チューブを挿入した。連日の洗浄によりチューブ開存を維持することで,肝機能障害は改善した。膵全摘術,脾臓合併切除,領域リンパ節郭清を施行した。病理診断は混合型浸潤性膵管内乳頭粘液性腺癌であった。術後18ヵ月が経過した現在,無再発生存している。胆管穿破を伴うIPMNに対する胆道ドレナージは,排液量の観察と洗浄が可能なENBDが妥当である。(著者抄録)

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2023&ichushi_jid=J00296&link_issn=&doc_id=20240115320172&doc_link_id=%2Fab8gtkrc%2F2023%2F005013%2F172%2F1872-1874%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fab8gtkrc%2F2023%2F005013%2F172%2F1872-1874%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：(株)癌と化学療法社  

症例は66歳,男性。発熱と腹痛の精査で肝機能障害を認めた。精査で膵内胆管の不整な壁肥厚と狭窄を認め,遠位胆管癌と診断された。根治切除の方針となり,亜全胃温存膵頭十二指腸切除術を施行された。肝側胆管切離断端は切離限界まで追加切除を行ったが,術中迅速組織診断で上皮内癌陽性であった。病理所見では膵内胆管に浸潤癌が存在し,そこより肝側の切除胆管全域に上皮内癌を認めた。また,No.13aリンパ節に転移を1個認めた。最終診断はpT3N1M0,pStage IIBであった。術後補助化学療法として1年間,S-1を内服した。術後5年目に胆管空腸吻合部に乳頭状隆起性病変を認め,生検で腺癌の診断であった。S-1内服を再開し,その後は腫瘍の増大を認めていない。術後9年1ヵ月現在,生存中である。(著者抄録)

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Language：Japanese   Publisher：(一社)日本内視鏡外科学会  

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Language：Japanese   Publisher：(株)癌と化学療法社  

今回,2回の肝内再発巣切除を施行して長期生存が得られた肝嚢胞腺癌の1例を経験したので報告する。症例は72歳,男性。肝S3を主座とする肝嚢胞腺癌に対して,肝左葉切除+肝外胆管切除+リンパ節郭清を施行した。術後7年9ヵ月目のCTで単発の肝内再発を指摘され,肝S5部分切除を施行した。初回手術から15年7ヵ月目には再度S5に肝内再発を来し,肝部分切除術を施行した。これらの肝再発巣は,病理組織学的に肝嚢胞腺癌の転移であることが確認された。以降は再発を認めず,初回手術から21年6ヵ月を経過した現在,生存中である。本症例の経験および文献的考察から,肝嚢胞腺癌の肝内再発に対して,再発巣切除は有用な治療選択肢の一つとなる可能性があることが示された。(著者抄録)

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Language：Japanese   Publisher：(株)癌と化学療法社  

症例は87歳,女性。左乳房腫瘤が徐々に増大したため近医を受診した。皮膚浸潤を伴う左乳癌と診断され,当科を受診した。精査の結果,左乳癌に加え,上行結腸癌と胸部大動脈瘤を認めた。上行結腸癌(cT4bN1bM0,cStage IIIc,大腸癌取扱い規約第9版),左乳癌(cT3N0M0,cStage IIB,乳癌取扱い規約第18版),胸部大動脈瘤(Stanford B型)と診断した。まず,胸部大動脈瘤に対して胸部大動脈ステント内挿術,両側鎖骨下動脈バイパス術を施行した。その6日後,上行結腸癌に対して結腸右半切除術,D2郭清を施行した。病理組織診断の結果,pT3N0M0,pStage IIaであった。上行結腸癌手術の2ヵ月後に左乳癌に対して左乳房全切除術,全層植皮術を施行した。病理組織診断の結果,pT3N0M0,pStage IIBであった。上行結腸癌術後20ヵ月,左乳癌術後18ヵ月無再発生存中である。(著者抄録)

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2023&ichushi_jid=J00296&link_issn=&doc_id=20240115320011&doc_link_id=%2Fab8gtkrc%2F2023%2F005013%2F011%2F1393-1395%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fab8gtkrc%2F2023%2F005013%2F011%2F1393-1395%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：(株)癌と化学療法社  

症例は72歳,女性。黄疸精査のCTで膵頭部に12mm大の乏血性腫瘤を認め,超音波内視鏡下穿刺吸引法で膵癌と診断した。術前化学療法としてGEM+nab-PTX療法を施行し,2コース終了後に肝十二指腸間膜リンパ節転移,腫瘍マーカーの上昇を認めた。modified FOLFIRINOX療法へレジメン変更を行い,5コース終了後,リンパ節転移の縮小,腫瘍マーカーの低下を認めたため亜全胃温存膵頭十二指腸切除術を施行した。S-1による術後補助化学療法を施行し,膵癌切除後2年9ヵ月間,無再発で経過したが,敗血症で他病死した。切除可能膵癌に対する術前化学療法中,病勢進行時にはレジメン変更が有用な可能性がある。(著者抄録)

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2023&ichushi_jid=J00296&link_issn=&doc_id=20240115320070&doc_link_id=%2Fab8gtkrc%2F2023%2F005013%2F070%2F1569-1571%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fab8gtkrc%2F2023%2F005013%2F070%2F1569-1571%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：(株)癌と化学療法社  

症例は57歳,男性。嚥下困難と嘔吐の精査で進行食道扁平上皮癌(Ut,cT3N0M0)と診断した。経鼻栄養チューブによる栄養管理を行いながら,術前docetaxel,cisplatin,5-fluorouracil併用(DCF)療法を実施した。1コース終了後に気管浸潤を認めた(cT4bN0M0)。根治的化学放射線療法(CF療法併用,照射60Gy)を実施し,気管浸潤の解除を認めた(cT3N0M0)。生検では癌の検出はなかったが,肉眼的に遺残が疑われ狭窄の悪化も認められた。安全に根治切除が可能と判断し,右開胸食道切除術(D0),胸骨後経路胃管再建を行った。病理診断ではpT1bN0M0であった。術後補助治療は実施せず,術後5年が経過して無再発生存中である。術前治療中の注意深い治療効果判定と適切な治療選択により,術前DCF療法不応例であっても根治の可能性を逃さないことが重要である。(著者抄録)

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Language：Japanese   Publisher：(一社)日本内視鏡外科学会  

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Language：Japanese   Publisher：(一社)日本消化器外科学会  

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Language：Japanese   Publisher：(一社)日本消化器外科学会  

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Language：Japanese   Publisher：(一社)日本消化器外科学会  

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Language：Japanese   Publisher：(一社)日本消化器外科学会  

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Language：Japanese   Publisher：(一社)日本消化器外科学会  

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Language：Japanese   Publisher：(一社)日本消化器外科学会  

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Language：Japanese   Publisher：(一社)日本消化器外科学会  

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Language：Japanese   Publisher：(一社)日本消化器外科学会  

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Language：Japanese   Publisher：(一社)日本消化器外科学会  

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Language：Japanese   Publisher：(一社)日本移植学会  

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2023&ichushi_jid=J00083&link_issn=&doc_id=20230919470476&doc_link_id=%2Fcl8isoke%2F2023%2Ft058s1%2F015%2F0318-0318%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcl8isoke%2F2023%2Ft058s1%2F015%2F0318-0318%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：English   Publisher：(一社)日本癌学会  

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Language：Japanese   Publisher：(一社)日本移植学会  

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Language：Japanese   Publisher：(一社)日本移植学会  

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Language：Japanese   Publisher：(一社)日本移植学会  

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Language：Japanese   Publisher：(一社)日本胆道学会  

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Language：Japanese   Publisher：(一社)日本胆道学会  

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Language：Japanese   Publisher：(一社)日本消化器外科学会  

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Language：Japanese   Publisher：(一社)日本消化器外科学会  

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