記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Lung cancer combined by chronic obstructive pulmonary disease (LC-COPD) is a common comorbidity and their interaction with each other poses significant clinical challenges. However, there is a lack of well-established consensus on the diagnosis and treatment of LC-COPD. METHODS: A panel of experts, comprising specialists in oncology, respiratory medicine, radiology, interventional medicine, and thoracic surgery, was convened. The panel was presented with a comprehensive review of the current evidence pertaining to LC-COPD. After thorough discussions, the panel reached a consensus on 17 recommendations with over 70% agreement in voting to enhance the management of LC-COPD and optimize the care of these patients. RESULTS: The 17 statements focused on pathogenic mechanisms (n=2), general strategies (n=4), and clinical application in COPD (n=2) and lung cancer (n=9) were developed and modified. These statements provide guidance on early screening and treatment selection of LC-COPD, the interplay of lung cancer and COPD on treatment, and considerations during treatment. This consensus also emphasizes patient-centered and personalized treatment in the management of LC-COPD. CONCLUSIONS: The consensus highlights the need for concurrent treatment for both lung cancer and COPD in LC-COPD patients, while being mindful of the mutual influence of the two conditions on treatment and monitoring for adverse reactions.

DOI： 10.21037/tlcr-23-339

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: A study is eagerly awaited that will reveal the unknown mechanisms of multiple system atrophy (MSA), in which the risk of sudden death is the greatest during sleep. The blunted pulse response to nocturnal respiratory events suggests an abnormal cardiac response to a sleep-related breathing disorder. Patients with MSA have a lower pulse event index (PEI), despite a greater hypoxic burden and a similar frequency of respiratory events. However, the evidence is speculative and not directly proven, and many limitations require further study. METHODS: We conducted a retrospective analysis of 26 patients with MSA who had undergone overnight oximetry between April 2016 and December 2022. RESULTS: The median 4% oxyhemoglobin desaturation index (ODI) was 11.6/h, the 6-bpm PEI was 8.9/h, and the PEI/ODI ratio was as low as 0.91. There were three patients with suspected sudden death; all had low PEI/ODI ratios. The PEI/ODI ratio was followed over time in seven patients, all of whom had a decrease in the ratio. However, the PEI was higher than the ODI in 12/26 (46%) of the patients. CONCLUSION: A low PEI/ODI ratio, reflecting a blunted pulse response to nocturnal respiratory events in patients with MSA, may indicate a worse prognosis. This finding and the significance of the longitudinal decrease in the PEI/ODI ratio will require a prospective study.

DOI： 10.1016/j.parkreldis.2023.105817

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Chronic intermittent hypoxia (IH) plays a significant role in the pathogenesis of obstructive sleep apnea (OSA) comorbidities. The prevalence of chronic kidney disease is higher in patients with OSA than the general population, and renal function decline is well correlated with renal tubular injury. However, little is known about the impact of OSA-induced chronic IH on the renal tubules. METHODS: We conducted a retrospective survey of clinical records performing multiple regression analysis and cluster analysis with particular attention to the 3% oxygen desaturation index (ODI) and urinary N-acetyl-β-d-glucosaminidase (NAG). RESULTS: In patients with suspicion of OSA, urinary NAG creatinine ratio (UNCR) was elevated as their 3% ODI increased (n = 197, p < 0.001), and the elevated UNCR decreased following CPAP treatment in patients with OSA (n = 46, p = 0.014). Multiple regression analysis showed that 3% ODI was associated with UNCR. Cluster analysis identified three clusters of patients with OSA, including two younger age clusters, one of which was characterized by high BMI, high 3% ODI, and high prevalence of major comorbidities. In a comparative analysis of younger age cases (age ≤ 55, n = 82), the UNCR level was higher in patients with severe 3% ODI (3% ODI > 40 events/h, n = 24) (p = 0.014). CONCLUSIONS: Our results indicate that even at younger ages, OSA patients with severe chronic IH and major comorbidities are susceptible to renal tubular damage. Early treatment with CPAP may attenuate renal tubular injury and progression toward end-stage renal disease.

DOI： 10.1016/j.sleep.2023.03.028

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Studies elucidating detailed characteristics of pneumonitis in association with chemo-immunotherapy are limited. We aimed to investigate the characteristics of images, prognostic factors, and clinical course of combination therapy associated with pneumonitis. A multicenter, retrospective cohort study of patients with non-squamous non-small cell lung cancer who received a combination of platinum, pemetrexed, and pembrolizumab was conducted. Patients with confirmed pneumonitis established by an independent multidisciplinary team were enrolled. For 53 patients with pneumonitis, radiographic features at diagnosis predominantly comprised an organizing pneumonia pattern (62%, 33/53). Twelve (23%) patients experienced a worsening respiratory status during pneumonitis management, which was associated with a high mortality rate (58%, 7/12) during treatment. Severe grade at pneumonitis diagnosis (p < 0.001), diffuse alveolar damage (DAD) pattern (p = 0.002), and disease extent ≥ 25% in the lungs (p = 0.009) were significantly associated with worsening respiratory status. Furthermore, post-diagnosis survival was significantly worse in severe pneumonitis (p = 0.02) than in mild and in patients with the DAD pattern than in those without (p < 0.0001). We showed detailed clinical course of patients with pneumonitis and reported several important influencing factors. Given the small number of trials on pneumonitis, our findings provide valuable information to guide the development of appropriate management guidelines and improve pneumonitis treatment.

DOI： 10.1038/s41598-023-30676-y

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Platinum-based combination therapy plus a programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) inhibitor is a standard treatment for patients with stage IV non-small cell lung cancer. However, necitumumab is used with gemcitabine and cisplatin as a first-line treatment option for squamous cell lung cancer (SqCLC). Furthermore, the combination of necitumumab with immune checkpoint inhibitors has the potential to enhance tumor immunity and improve the therapeutic effect. Thus, we planned and initiated this phase I/II study to evaluate the safety and efficacy of necitumumab plus pembrolizumab, nanoparticle albumin-bound (nab)-paclitaxel), and carboplatin therapy for patients with previously untreated SqCLC. PATIENTS AND METHODS: In phase I, the primary endpoint is the tolerability and recommended dose of necitumumab combined with pembrolizumab plus nab-paclitaxel and carboplatin. In phase II, the primary endpoint is the overall response rate. Secondary endpoints are disease control rate, progression-free survival, overall survival, and safety. Forty-two patients will be enrolled in phase II. CONCLUSION: This is the first study to investigate the efficacy and safety of necitumumab plus pembrolizumab combined with platinum-based chemotherapy in patients with previously untreated SqCLC.

DOI： 10.1016/j.cllc.2023.01.008

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記述言語：日本語   出版者・発行元：(一社)日本内科学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Nasal breathing disorders are associated with obstructive sleep apnea (OSA) syndrome and influence the availability of continuous positive airway pressure (CPAP) therapy. However, information is scarce about the impact of nasal resistance assessed by rhinomanometry on CPAP therapy. This study aimed to examine the relationship between CPAP adherence and nasal resistance evaluated by rhinomanometry, and to identify clinical findings that can affect adherence to CPAP therapy for patients with OSA. This study included 260 patients (199 men, 61 women; age 58 [interquartile ranges (IQR) 50-66] years) with a new diagnosis of OSA who underwent rhinomanometry (before, and 1 and 3 months after CPAP introduction) between January 2011 and December 2018. CPAP use was recorded, and the good and poor CPAP adherence groups at the time of patient registration were compared. Furthermore, those with improved and unimproved pre-CPAP high rhinomanometry values were also compared. Their apnea-hypopnea index (AHI) by polysomnography at diagnosis was 45.6 (IQR 33.7-61.6)/hour, but the residual respiratory event (estimated AHI) at enrollment was 2.5 (IQR 1.4-3.9)/hour and the usage time was 318 (IQR 226-397) minutes, indicating that CPAP was effective and adherence was good. CPAP adherence was negatively correlated with nasal resistance (r = -0.188, p = 0.002). The participants were divided into good (n = 153) and poor (n = 107) CPAP adherence groups. In the poor adherence group, rhinomanometry values before CPAP introduction were worse (inspiration, p = 0.003; expiration, p = 0.006). There was no significant difference in patient background when comparing those with improved (n = 16) and unimproved (n = 12) pre-CPAP high rhinomanometry values. However, CPAP usage time was significantly longer in the improved group 1 month (p = 0.002) and 3 months (p = 0.026) after CPAP introduction. The results suggest that nasal resistance evaluated by rhinomanometry is a useful predictor of CPAP adherence, and that improved rhinomanometry values may contribute to extending the duration of CPAP use.

DOI： 10.1371/journal.pone.0283070

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Anaplastic lymphoma kinase (ALK)-positive lung cancer is a rare cancer that occurs in approximately 5% of non-small-cell lung cancer (NSCLCs) patients. Despite the excellent efficacy of ALK-tyrosine kinase inhibitor in ALK-positive NSCLCs, most patients experience resistance. We conducted a phase II study to investigate the combination of alectinib with bevacizumab in ALK-positive NSCLC patients after failure of alectinib. In this study, ALK-positive nonsquamous NSCLC patients previously treated with alectinib received bevacizumab 15 mg/kg on day 1 every 3 weeks and alectinib 600 mg/day until disease progression. The primary endpoints were progression-free survival (PFS) and the safety of alectinib and bevacizumab. The secondary endpoints included overall survival (OS) and correlation of circulating tumor DNA and plasma proteins with PFS. Of the 12 patients treated, the median PFS was 3.1 months (95% CI 1.2-16.1), and the median OS was 24.1 months (95% CI 8.3-not estimable). The EML4-ALK fusion gene in circulating tumor DNA was significantly correlated with shorter PFS (1.2 months vs. 11.4 months, HR 5.2, p = 0.0153). Two patients experienced grade 3 adverse events; however, none of the patients required dose reduction. Although the primary endpoint was not met, alectinib combined with bevacizumab showed clinical efficacy in ALK-positive patients.

DOI： 10.3390/cancers15010204

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸ケア・リハビリテーション学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

For non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations, the initial therapeutic interventions will have crucial impacts on their clinical outcomes. Drug tolerant factors reportedly have an impact on EGFR-tyrosine kinase inhibitor sensitivity. This prospective study investigated the impacts of drug tolerant-related protein expression in tumors based on the efficacy of osimertinib in the first-setting of EGFR-mutated advanced NSCLC patients. A total of 92 patients with EGFR-mutated advanced or postoperative recurrent NSCLC were analyzed and treated with osimertinib at 14 institutions in Japan. AXL, p53, and programmed death-ligand 1 (PD-L1) expression in patient tumors was determined using immunohistochemistry. The AXL signaling pathway was investigated using a cell line-based assay and AXL-related gene expression in The Cancer Genome Atlas (TCGA) database. High levels of AXL and positive-p53 expression were detected in 26.1% and 53.3% of the pretreatment EGFR-mutated NSCLC tumors, respectively. High AXL expression levels were significantly associated with a shorter progression-free survival compared with low AXL expression levels, irrespective of the EGFR activating mutation status (p = 0.026). Cell line-based assays indicated that the overexpression of AXL protein accelerated PD-L1 expression, which induced insensitivity to osimertinib. In the TCGA database, AXL RNA levels were positively correlated with PD-L1 expression in the lung adenocarcinoma cohort. The results show that high AXL expression levels in tumors impact clinical predictions when using osimertinib to treat EGFR-mutated NSCLC patients. Trial Registration: UMIN000043942.

DOI： 10.1111/cas.15608

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Although the addition of immune checkpoint inhibitors (ICIs) to platinum-doublet chemotherapy has improved the efficacy of first-line therapy in extensive-disease small cell lung cancer (SCLC) patients, the best treatment option for patients with recurrent SCLC has not yet been determined. We conducted a retrospective study to evaluate the efficacy and safety of amrubicin (AMR) therapy after treatment with ICIs. METHODS: We retrospectively assessed patients with recurrent SCLC who received AMR after chemoimmunotherapy at the Niigata Lung Cancer Treatment Group from August 2019 to February 2021. RESULTS: This analysis included 30 patients. The median progression-free survival (PFS) and overall survival (OS) were 3.8 (95% CI: 2.7-4.2) and 10 (95% CI: 7.4-14.8) months, respectively. The median PFS and OS did not significantly differ between the sensitive and refractory groups [PFS; 3.1 (95% CI: 1.1-4.0) vs. 4.2 (95% CI: 2.3-4.8) months, P=0.1142, OS; 10.0 (95% CI: 5.2-14.8) vs. 10.4 (95% CI: 3.8-NE) months, P=0.5525]. The most common adverse event was grade ≥3 neutropenia, which occurred in 22 of 30 patients (73%), and 2 patients (7%) discontinued AMR due to adverse events. CONCLUSIONS: AMR after chemoimmunotherapy shows good clinical efficacy and safety in patients with recurrent SCLC.

DOI： 10.21037/tlcr-22-225

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記述言語：英語   出版者・発行元：(一社)日本癌学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: Malignant tumors are the major cause of death in hemodialysis patients. Management of these patients remains challenging as there is no evidence that chemotherapy is beneficial, and a lack of information about actual clinical practice. METHODS: This multicenter retrospective study included hemodialysis patients who were diagnosed with lung cancer from January 2002 to June 2018. We reviewed their clinical information including patient characteristics associated with lung cancer and end-stage renal disease, regimen, efficacy and safety of chemotherapy, and outcomes. RESULTS: A total of 162 patients from 22 institutions in Japan were registered. Of 158 eligible patients, 91 received chemotherapy (80 as palliative chemotherapy and 11 as chemoradiotherapy) and 67 received best supportive care only regardless of cancer stage. In small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) patients who received cytotoxic chemotherapy, the objective response rates (ORR) and median overall survival (OS) were 68.1 %, 12.3 months and 37.0 %, 8.5 months, respectively. The ORR and median OS in patients with EGFR-mutant NSCLC treated with EGFR-tyrosine kinase inhibitors (TKI) were 44.4 % and 38.6 months. The treatment-related adverse events (Grade 3 or higher) induced by cytotoxic chemotherapy were myelosuppression and febrile neutropenia; treatment-related death (TRD) was observed in one patient. TRD occurred in 3 of 18 patients who received EGFR-TKI. CONCLUSION: Chemotherapy should be considered for hemodialysis patients with EGFR-mutant NSCLC and SCLC. However, the survival benefits of chemotherapy for NSCLC patients with EGFR-wild type are unclear; physicians should carefully consider whether to offer chemotherapy to this patient subset.

DOI： 10.1016/j.lungcan.2022.07.009

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Frontiers Media SA  

Background

Checkpoint inhibitor–related pneumonitis (CIP) is a lethal immune-related adverse event. However, the development process of CIP, which may provide insight into more effective management, has not been extensively examined.

Methods

We conducted a multicenter retrospective analysis of 56 patients who developed CIP. Clinical characteristics, radiological features, histologic features, and laboratory tests were analyzed. After a comprehensive analysis, we proposed acute, subacute, and chronic phases of CIP and summarized each phase’s characteristics.

Results

There were 51 patients in the acute phase, 22 in the subacute phase, and 11 in the chronic phase. The median interval time from the beginning of CIP to the different phases was calculated (acute phase: ≤4.9 weeks; subacute phase: 4.9~13.1 weeks; and chronic phase: ≥13.1 weeks). The symptoms relieved from the acute phase to the chronic phase, and the CIP grade and Performance Status score decreased (P&amp;lt;0.05). The main change in radiologic features was the absorption of the lesions, and 3 (3/11) patients in the chronic phase had persistent traction bronchiectasis. For histologic features, most patients had acute fibrinous pneumonitis in the acute phase (5/8), and most had organizing pneumonia in the subacute phase (5/6). Other histologic changes advanced over time, with the lesions entering a state of fibrosis. Moreover, the levels of interleukin-6, interleukin-10 and high-sensitivity C-reactive protein (hsCRP) increased in the acute phase and decreased as CIP progressed (IL-6: 17.9 vs. 9.8 vs. 5.7, P=0.018; IL-10: 4.6 vs 3.0 vs. 2.0, P=0.041; hsCRP: 88.2 vs. 19.4 vs. 14.4, P=0.005).

Conclusions

The general development process of CIP can be divided into acute, subacute, and chronic phases, upon which a better management strategy might be based devised.

DOI： 10.3389/fimmu.2022.935779

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: This study aimed to examine the factors associated with cytomegalovirus (CMV) antigenemia and the time of onset of CMV antigenemia among patients with rheumatic diseases. METHODS: A single-center, retrospective, observational study was conducted in our institution from January 2009 to December 2017. This study included patients with rheumatic diseases who had at least one CMV antigen measurement. Multivariate analysis and receiver operating characteristic analysis was performed. RESULTS: A total of 249 patients underwent CMV antigenemia assay, and 84 (33.7%) patients tested positive. When the association between CMV antigenemia and possible associated factors was investigated, multivariate analysis showed that daily steroid dose increased the odds of having CMV [odds ratio 16.25, 95% confidence interval (CI), 5.360-49.253]. In this study, the cutoff value of daily steroid dose found in this study (0.45 mg/kg/day) was reasonable in clinical practice, and the area under the curve of the steroid dose was 0.838 [95% CI 0.781-0.882], which was the largest of the known indicators. Moreover, the median time from the start of immunosuppressive therapy to the onset of CMV antigenemia was 30 (interquartile range, 21-44) days, and most of the daily steroid users (85.7%) developed CMV antigenemia within 60 days. CONCLUSIONS: The daily steroid dose is the most important factor associated with CMV antigenemia. Therefore, monitoring and treatment strategies based on the steroid dose, especially in the initial 2 months, are important.

DOI： 10.1016/j.jiac.2022.07.004

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: This multicenter, open-label, single-arm phase II study [Niigata Lung Cancer Treatment Group (NLCTG) 1302] was conducted to evaluate the efficacy and safety of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) monotherapy for previously treated patients with advanced non-small cell lung cancer (NSCLC). We also investigated chemotherapy-induced peripheral neuropathy (CIPN) to evaluate the quality of life (QOL). METHODS: Sixty-five patients with advanced NSCLC from 14 participating institutions who had previously undergone one or two cytotoxic chemotherapy regimens were enrolled in this study. The patients received 100 mg/m2 nab-paclitaxel intravenously on days 1, 8, and 15, every 4 weeks. The primary endpoint was overall objective response rate. CIPN symptoms were prospectively assessed using the Patient Neurotoxicity Questionnaire (PNQ) and Common Terminology Criteria for Adverse Events (CTCAE). RESULTS: The overall response rate (ORR) was 18.5% [95% confidence interval (CI): 10.9-29.6%], and the median progression-free survival (PFS) was 3.4 (95% CI: 2.5-4.3) months. Median overall survival (OS) was 8.6 (95% CI: 7.1-10.2) months. The most common non-hematologic grade ≥3 adverse events were infection (7.7%) and hyponatremia (4.6%). Neutropenia was the most common grade 3 or 4 adverse event (30.8%), and febrile neutropenia developed in 6.2% patients. The PNQ and CTCAE scores for motor peripheral neuropathy were low (kappa =0.10). CONCLUSIONS: The primary endpoint was achieved. Nab-paclitaxel was well tolerated and showed anti-tumor activity in patients with previously treated NSCLC. This study demonstrates a low degree of concordance in CIPN grading between physicians and patients. TRIAL REGISTRATION: University hospital Medical Information Network Clinical Trial Registry (ID: UMIN000012343).

DOI： 10.21037/tlcr-22-89

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記述言語：日本語   出版者・発行元：(一社)日本睡眠学会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器内視鏡学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The identification of acquired resistance mutations has been essential in non-small-cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) active mutations. Rebiopsy plays a pivotal role in selecting the optimal treatment for patients who develop resistance to initial EGFR-tyrosine kinase inhibitors (EGFR-TKIs). This multicenter, observational study was conducted to investigate the details of rebiopsy in Japanese clinical practice. The primary endpoints were the implementation rate of rebiopsy and the concordance rate for T790M mutation detection between histological and cytological specimens using the cobas EGFR Mutation Test, version 2. One hundred ninety-four patients with EGFR-mutant NSCLC were enrolled, and 120 patients developed acquired resistance to EGFR-TKIs. The median age was 68 years (range 20-87), and 52.5% of the patients were women. Rebiopsy was performed in 109 patients, and the implementation rate of rebiopsy was 90.8%. The success rates of rebiopsy in the total, histology, cytology and liquid biopsy populations were 67.9%, 81.3%, 66.7% and 43.8%, respectively. The positive percent agreement and the negative percent agreement in the detection of the T790M mutation between the histological and cytological specimens were both 90.9%. Obtaining histological or cytological tissue samples at rebiopsy may contribute to improving the detection rate of the T790M mutation (trial registration number: UMIN000026019).

DOI： 10.1038/s41598-022-10288-8

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVES: Only a few prospective studies have been conducted to examine the efficacy and safety of systemic chemotherapy for patients with pulmonary sarcomatoid carcinomas (PSCs). There is, thus, a crucial need to develop novel treatment strategies for this rare tumor. PATIENTS AND METHODS: Chemotherapy-naïve patients with histologically confirmed PSCs were assigned to receive either carboplatin/paclitaxel alone (CP) or with bevacizumab (CPB) followed by bevacizumab maintenance. The primary endpoint was overall response rate (ORR). Secondary endpoints included overall survival (OS), progression-free survival (PFS), and safety. RESULTS: This study was closed before accumulating the expected number of cases due to slow patient accrual. Eventually, 16 patients were enrolled. The ORR was 25.0% and disease control rate was 56.3%. CPB was administered in all four patients with an objective response [partial response (PR)]; among the four PR cases, two patients had pleomorphic carcinoma, and two had carcinosarcoma. Median PFS and median survival time (MST) in all the enrolled patients were 2.6 months and 8.8 months, respectively. Median PFS was 1.2 months in the CP group and 4.2 months in the CPB group. In addition, MST was 7.9 months in the CP group and 11.2 months in the CPB group. Hematological and non-hematological adverse events were common and reversible, although ileus (grade 4) and nasal bleeding (grade 3) occurred in one case each in the CPB group. CONCLUSIONS: CPB might be effective as first-line treatment for PSCs. Further study is warranted to clarify the role of cytotoxic chemotherapy for this rare and aggressive tumor. CLINICAL TRIALS REGISTRATION: University Hospital Medical Information Network (UMIN) Clinical Trial Registry (UMIN000008707).

DOI： 10.1007/s10147-021-02113-5

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掲載種別：研究論文（学術雑誌）   出版者・発行元：AME Publishing Company  

DOI： 10.21037/tlcr-22-171

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Patients with advanced anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer who are prescribed ALK-tyrosine kinase inhibitors (ALK-TKIs) rarely have complete responses, with residual tumors relapsing as heterogeneous resistant phenotypes. Herein, we investigated new therapeutic strategies to reduce and eliminate residual tumors in the early treatment phase. Functional genomic screening using small guide RNA libraries showed that treatment-induced adaptive survival of ALK-rearranged lung cancer cells was predominantly dependent on STAT3 activity upon ALK inhibition. STAT3 inhibition effectively suppressed the adaptive survival of ALK-rearranged lung cancer cells by enhancing ALK inhibition-induced apoptosis. The combined effects were characterized by treatment-induced STAT3 dependence and transcriptional regulation of anti-apoptotic factor BCL-XL. In xenograft study, the combination of YHO-1701 (STAT3 inhibitor) and alectinib significantly suppressed tumor regrowth after treatment cessation with near tumor remission compared with alectinib alone. Hence, this study provides new insights into combined therapeutic strategies for patients with ALK-rearranged lung cancer.

DOI： 10.1038/s41698-022-00254-y

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記述言語：日本語   出版者・発行元：(一社)日本内科学会  

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記述言語：日本語   出版者・発行元：(一社)日本内科学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs) have shown dramatic efficacy in patients with ALK-rearranged lung cancer; however, complete response in these patients is rare. Here, we investigated the molecular mechanisms underlying the emergence and maintenance of drug-tolerant cells in ALK-rearranged lung cancer. Cell based-assays demonstrated that HER3 activation and mesenchymal-to-epithelial transition, mediated through ZEB1 proteins, help maintain cell survival and induce the emergence of ALK-TKI-tolerant cells. Compared with ALK-TKIs alone, cotreatment with pan-HER inhibitor afatinib and ALK-TKIs prevented tumor regrowth, leading to the eradication of tumors in ALK-rearranged tumors with mesenchymal features. Moreover, pre-treatment vimentin expression in clinical specimens obtained from patients with ALK-rearranged lung cancer was associated with poor ALK-TKI treatment outcomes. These results demonstrated that HER3 activation plays a pivotal role in the emergence of ALK-TKI-tolerant cells. Furthermore, the inhibition of HER3 signals combined with ALK-TKIs dramatically improves treatment outcomes for ALK-rearranged lung cancer with mesenchymal features.

DOI： 10.1038/s41698-021-00250-8

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掲載種別：研究論文（学術雑誌）   出版者・発行元：AME Publishing Company  

DOI： 10.21037/tlcr-21-838

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記述言語：英語  

Osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), shows great clinical activity in non-small cell lung cancer (NSCLC) patients with EGFR mutations regardless of T790M mutation at first-line chemotherapy. Previous studies demonstrated that there are few patients with initial resistance to osimertinib. Here, we describe a case to report the efficacy of afatinib in an EGFR-mutated NSCLC patient with early progression to first-line osimertinib treatment. A 68-year-old Japanese male was diagnosed with stage IVB lung adenocarcinoma with the EGFR L858R mutation in exon 21. Two months after the start of osimertinib, his tumor progressed at the initial response evaluation. Because he refused to receive cytotoxic chemotherapy, afatinib treatment was initiated. He was administered afatinib, and the tumor shrank. After five months of afatinib treatment, nevertheless the primary tumor was not enlarged, he experienced disease progression with leptomeningeal metastasis and passed away. To elucidate the resistance mechanisms of osimertinib in this patient, we performed next-generation sequencing (NGS) on tumor samples from pleural effusions after osimertinib failure. NGS revealed no specific gene mutations causing resistance to osimertinib except for the EGFR L858R mutation; however, his tumor had a relatively high tumor mutational burden. Afatinib is considered an option for EGFR-mutated patients with early progression to osimertinib.

DOI： 10.21037/tcr-21-1850

PubMed

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器内視鏡学会  

背景.気管支静脈瘤は稀な疾患であり,その治療法は確立されていない.症例.78歳,女性.小児期より気管支拡張症を罹患し,膿胸の既往があった.6年前から喀血を繰り返し,計3回の気管支動脈塞栓術が行われていた.今回,喀血を契機に入院し,止血薬投与を受けたが大量喀血を来したため,気管挿管の上で人工呼吸管理となった.左下横隔動脈と左気管支動脈をゼラチンスポンジで塞栓し,止血を得た.その際の選択的動脈造影で左下横隔動脈と肺静脈との動静脈シャントを認めた.気管支鏡で観察すると,左上下葉支分岐部に気管支静脈瘤がみられ,出血源と考えられた.動脈塞栓術の2週後の気管支鏡では同部位の瘤は退縮していた.その後,再喀血なく自宅退院した.結論.気管支静脈瘤は気管支拡張症や動脈塞栓に関連して発症する可能性があり,喀血時は気管支鏡による確認が必要である.治療として異常シャントの塞栓術が有効と考えられた.(著者抄録)

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その他リンク： https://search.jamas.or.jp/default/link?pub_year=2021&ichushi_jid=J00298&link_issn=&doc_id=20211216270004&doc_link_id=%2Fcf0brond%2F2021%2F004306%2F005%2F0589-0594%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcf0brond%2F2021%2F004306%2F005%2F0589-0594%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

記述言語：日本語   出版者・発行元：(NPO)日本呼吸器内視鏡学会  

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その他リンク： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2021&ichushi_jid=J00298&link_issn=&doc_id=20211216270004&doc_link_id=10.18907%2Fjjsre.43.6_589&url=https%3A%2F%2Fdoi.org%2F10.18907%2Fjjsre.43.6_589&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Lymphodepleting cytotoxic regimens enhance the antitumor effects of adoptively transferred effector and naïve T cells. Although the mechanisms of antitumor immunity augmentation by lymphodepletion have been intensively investigated, the effects of lymphodepletion followed by T cell transfer on immune checkpoints in the tumor microenvironment remain unclear. The current study demonstrated that the expression of immune checkpoint molecules on transferred donor CD4+ and CD8+ T cells was significantly decreased in lymphodepleted tumor-bearing mice. In contrast, lymphodepletion did not reduce immune checkpoint molecule levels on recipient CD4+ and CD8+ T cells. Administration of anti-PD-1 antibodies after lymphodepletion and adoptive transfer of T cells significantly inhibited tumor progression. Further analysis revealed that transfer of both donor CD4+ and CD8+ T cells was responsible for the antitumor effects of a combination therapy consisting of lymphodepletion, T cell transfer and anti-PD-1 treatment. Our findings indicate that a possible mechanism underlying the antitumor effects of lymphodepletion followed by T cell transfer is the prevention of donor T cell exhaustion and dysfunction. PD-1 blockade may reinvigorate exhausted recipient T cells and augment the antitumor effects of lymphodepletion and adoptive T cell transfer.

DOI： 10.1007/s00262-021-03078-0

PubMed

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Frontiers Media SA  

<sec><title>Objectives</title>Although immune checkpoint inhibitors (ICIs) have been shown to improve overall survival (OS) in advanced non-small-cell lung cancer (NSCLC) patients, ICIs sometimes cause various types of immune-related adverse events (irAEs), which lead to the interruption of ICI treatment. This study aims to evaluate the clinical significance of the continuation of ICIs in NSCLC patients with irAEs and to assess the safety and efficacy of the readministration of ICIs after their discontinuation due to irAEs.

</sec><sec><title>Methods</title>We retrospectively identified patients with advanced NSCLC who were treated with first- to third-line anti-programmed cell death-1 (PD-1) therapy from January 2016 through October 2017 at multiple institutions belonging to the Niigata Lung Cancer Treatment Group. Progression-free survival (PFS) and OS from the initiation of ICI treatment were analyzed in patients with and without irAEs, with and without ICI interruption, and with and without ICI readministration. A 6-week landmark analysis of PFS and OS was performed to minimize the lead-time bias associated with time-dependent factors.

</sec><sec><title>Results</title>Of 231 patients who received anti-PD-1 antibodies, 93 patients (40%) developed irAEs. Of 84 eligible patients with irAEs, 32 patients (14%) continued ICIs, and OS was significantly longer in patients who continued ICIs than that in patients who discontinued ICIs [not reached (95% CI: NE-NE) <italic>vs</italic>. not reached (95% CI: 22.4–NE); p = 0.025]. Of 52 patients who discontinued ICIs, 14 patients (6.1%) readministered ICIs, and OS in patients with ICI readministration was significantly longer than that in patients without ICI readministration [not reached (95% CI: NE-NE) <italic>vs</italic>. not reached (95% CI: 8.4–NE); p = 0.031].

</sec><sec><title>Conclusion</title>The current study demonstrated that both the continuation and readministration of ICIs after irAE occurrence improved OS compared to the permanent interruption of ICIs in NSCLC patients with ICI-related irAEs.

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DOI： 10.3389/fonc.2021.704475

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記述言語：英語   出版者・発行元：(一社)日本癌学会  

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記述言語：英語   出版者・発行元：(一社)日本癌学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.21037/tlcr-21-634

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Bevacizumab is a promising candidate for combination treatment with epidermal growth factor receptor tyrosine-kinase inhibitors (eg, erlotinib), which could improve outcomes for patients with metastatic EGFR-mutant non-small-cell lung cancer (NSCLC). We have previously shown in NEJ026, a phase 3 trial, that the combination of bevacizumab plus erlotinib significantly prolonged progression-free survival compared with erlotinib alone in these patients. In further analyses, we aimed to examine the effects of bevacizumab-erlotinib on overall survival, time from enrolment to progressive disease during second-line treatment or death, and quality of life. METHODS: This open-label, randomised, multicentre, phase 3 trial (NEJ026) was done in 69 hospitals and medical, community-based centres across Japan. Eligible patients had stage IIIB, stage IV, or postoperative recurrent, EGFR-mutant (exon 19 deletion or exon 21 Leu858Arg point mutation) NSCLC, had not previously received systemic chemotherapy, and were randomly assigned (1:1) by a computer-generated randomisation sequence and minimisation to receive either 150 mg oral erlotinib once daily plus 15 mg/kg intravenous bevacizumab once every 21 days, or 150 mg oral erlotinib once daily, until disease progression or intolerable toxicity. Randomisation was stratified according to sex, smoking status, EGFR mutation subtype, and clinical disease stage. All participants, investigators, and study personnel (including those assessing outcomes) were unmasked to treatment allocation. We report the secondary outcomes of overall survival and quality of life (the period from enrolment to confirmation of a minimally important difference on the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire [EORTC QLQ]-C30), and the exploratory outcome of time from enrolment to progressive disease during second-line treatment or death. Overall survival and the exploratory outcome were analysed in the modified intention-to-treat population, which comprised all randomly assigned patients who received at least one dose of the study drug and had response evaluations. Quality of life was analysed in patients in the modified intention-to-treat population who had completed the quality of life questionnaires. The trial is registered with the University Hospital Medical Information Network Clinical Trials Registry, UMIN000017069, and the Japan Registry of Clinical Trials, jRCTs031180056, and is currently closed. FINDINGS: Between June 3, 2015, and Aug 31, 2016, 228 patients were enrolled. 112 patients who received bevacizumab-erlotinib and 112 who received erlotinib only were included in the modified intention-to-treat population. At data cutoff (Nov 30, 2019) and a median follow-up of 39·2 months (IQR 23·9-43·5), the median overall survival was 50·7 months (95% CI 37·3-not estimable [NE]) in the bevacizumab-erlotinib group and 46·2 months (38·2-NE) in the erlotinib-only group (hazard ratio [HR] 1·007, 95% CI 0·681-1·490; p=0·97). In analysis of the exploratory outcome, after a median follow-up of 23·9 months (IQR 14·2-39·1), the median time from enrolment to progressive disease during second-line treatment or death was 28·6 months (95% CI 22·1-35·9) in the bevacizumab-erlotinib group and 24·3 months (20·4-29·1) in the erlotinib-only group (HR 0·773, 95% CI 0·562-1·065). The median time between enrolment and confirmation of a minimally important difference on the EORTC QLQ-C30 was 6·0 months (95% CI 5·2-11·3) in the bevacizumab-erlotinib group and 8·3 months (5·7-13·9) in the erlotinib-only group (p=0·47). INTERPRETATION: The addition of bevacizumab to erlotinib did not prolong survival in patients with metastatic EGFR-mutant NSCLC, but both treatment groups had relatively long survival durations. Why the addition of bevacizumab to erlotinib did not affect overall survival is unclear, but it is possible that the beneficial effects of combination therapy were not seen because overall survival was influenced by treatment regimens used after disease progression. FUNDING: Chugai Pharmaceutical.

DOI： 10.1016/S2213-2600(21)00166-1

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AME PUBL CO  

Background: Osimertinib monotherapy is currently the standard of care as a first-line treatment for patients harboring epidermal growth factor receptor (EGFR) mutations; however, some EGFR-mutated non-small cell lung cancer (NSCLC) patients exhibit primary resistance and an insufficient response to EGFR-tyrosine kinase inhibitors (EGFR-TKIs). Elevated programmed death-ligand 1 (PD-L1) expression in tumors was reported as a negative predictive factor for outcomes of first-or second-generation EGFR-TKIs. Methods: We prospectively assessed advanced NSCLC patients with EGFR mutations who were treated with osimertinib at 14 institutions in Japan between September 2019 and December 2020. Relationships between outcomes of osimertinib monotherapy and patients' characteristics were reviewed. Results: Seventy-one patients who underwent the tumor PD-L1 test were enrolled. Multivariate analysis identified tumor PD-L1 expression as an independent predictor for progression-free survival (PFS) with osimertinib treatment (P=0.029). The objective-response and disease-control rates for osimertinib treatment were significantly lower in patients demonstrating elevated PD-L1 levels relative to those with low or negative PD-L1 level (P=0.043 and P=0.007, respectively). Furthermore, among patients treated with osimertinib, those with high PD-L1 levels exhibited shorter PFS relative to those with low plus negative PD L1 level (median PFS: 5.0 vs. 17.4 months; P<0.001). Conclusions: Elevated tumor PD-L1 expression is associated with poor outcomes of osimertinib monotherapy in previously untreated advanced NSCLC patients with EGFR mutation. Further clinical trials are warranted to accumulate evidence demonstrating the effectiveness of combination therapy with osimertinib for EGFR-mutated advanced NSCLC patients with elevated tumor PD-L1 expression. Trial Registration: UMIN000043942.

DOI： 10.21037/tlcr-21-461

Web of Science

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Atezolizumab combined with bevacizumab plus platinum-based chemotherapy is a standard treatment for advanced non-squamous non-small-cell lung cancer (nsNSCLC). We aimed to determine the most effective platinum-based combination, such that future studies with atezolizumab can be conducted to further improve patient outcomes. Methods: This phase 2 study enrolled treatment-naïve patients with advanced or recurrent nsNSCLC who were randomly assigned to either cisplatin (75 mg/m2) + pemetrexed (500 mg/m2) + bevacizumab (15 mg/kg) (CisPemBev) followed by maintenance PemBev (N=132) or carboplatin (area under the concentration-time curve of 6 mg/mL/min) + paclitaxel (200 mg/m2) + bevacizumab (15 mg/kg) (CarPacBev) followed by maintenance Bev (N=67). The primary endpoint was progression-free survival (PFS, by central review). Secondary endpoints included overall survival (OS) and overall response rate (ORR). Adverse events (AEs) were evaluated for safety. This study was designed with the point estimate of the hazard ratio (HR) for PFS calculated based on an expected HR <0.830 with a probability ≥80%. Results: The HR for PFS (CisPemBev/CarPacBev) was 0.825 [95% confidence interval (CI), 0.600-1.134, median PFS, 7.6 vs. 7.0 months]. Because the observed point estimate of the HR for PFS was <0.830, the primary endpoint was met, and CisPem doublet therapy was deemed to be more effective than CarPac in terms of PFS. Median OS was 23.4 months for CisPemBev and 21.6 months for CarPacBev (HR 0.845; 95% CI, 0.583-1.242). The ORR was 57% for CisPemBev and 55% for CarPacBev. Both CisPemBev and CarPacBev were well tolerated; grade ≥3 AEs were reported in 67% and 82% of patients, respectively. Conclusions: CisPem combined with Bev was more effective in improving PFS compared with CarPacBev in patients with advanced nsNSCLC. CisPemBev was also well tolerated by this patient population. A study to evaluate the efficacy of atezolizumab plus CisPemBev is warranted. Trial Registration: University hospital Medical Information Network Clinical Trial Registry (ID: UMIN000013354).

DOI： 10.21037/tlcr-21-240

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Although immune checkpoint inhibitors (ICIs) are effective for advanced non-small cell lung cancer (NSCLC), ICIs may cause interstitial lung disease (ILD), which results in treatment discontinuation and is sometimes fatal. Despite the high incidence of ICI-related ILD, there are few cancer treatment options for patients. This study aimed to evaluate the safety and efficacy of subsequent systemic cancer therapy in NSCLC patients with ICI-related ILD. Methods: We retrospectively assessed NSCLC patients who received programmed cell death-1 (PD-1) inhibitors as first- to third-line therapy at participating institutions of the Niigata Lung Cancer Treatment Group from January 2016 to October 2017. Results: This analysis included 231 patients, 32 (14%) of whom developed ICI-related ILD. Of these patients, 16 (7%) received subsequent systemic cancer treatments. The median overall survival (OS) tended to be longer in the systemic cancer therapy group than in the no systemic cancer therapy group [22.2 months (95% CI: 1-NE) vs. 4.5 months (95% CI: 1-NE); P=0.067]. ICI-related ILD recurred in half of the patients who received systemic cancer therapy, and the median OS tended to be shorter in patients with recurrent ICI-related ILD [22.0 months (95% CI: 1-NE) vs. 7.0 months (95% CI: 1-NE); P=0.3154]. Conclusions: According to the current study, systemic cancer treatment is effective in patients with ICI-related ILD; however, its safety is uncertain because of the high risk of ICI-related ILD recurrence and poor survival outcome following ILD recurrence.

DOI： 10.21037/tlcr-21-198

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: The aim of this study was to evaluate the safety and survival outcomes of anti-programmed cell death (PD)-1/programmed cell death-ligand 1 (PD-L1) monotherapy in patients with advanced non-small cell lung cancer (NSCLC) and different hepatitis B virus (HBV) infection status. Methods: Patients with advanced NSCLC and both chronic and/or resolved HBV infection who were treated with anti-PD-(L)1 monotherapy were retrospectively enrolled. The primary endpoint was the safety of PD-1/PD-L1 monotherapy, while the secondary endpoints included the survival outcomes. Results: Of the 62 eligible patients, 10 (16.1%) were hepatitis B surface antigen (HBsAg) positive [chronic hepatitis B (CHB) infection] and 52 (83.9%) were HBsAg negative and HBcAb positive [resolved hepatitis B (RHB) infection]; 42 (67.7%) patients had at least 1 treatment-related adverse event (AE), with 4 patients (6.5%) developing grade 3 AEs and 6 (9.7%) developing hepatic AEs. One CHB patient experienced HBV reactivation during anti-PD-1 immunotherapy due to the interruption of antiviral prophylaxis. The objective response rate and durable clinical benefit (DCB) rate were 17.7% and 29.0%, respectively. Median overall survival (OS) and progression-free survival (PFS) were 23.6 months [95% confidence interval (CI): 14.4-32.8] and 2.1 months (95% CI: 1.2-3.0), respectively. The DCB rate was significantly higher in the CHB group than in the RHB group (60% vs. 23.1%; P=0.048). Patients with CHB experienced a longer PFS (8.3 vs. 2.0 months; P=0.103) and OS (35.0 vs. 18.2 months, P=0.119) than did RHB patients. Conclusions: Anti-PD-(L)1 monotherapy was safe and effective in patients with NSCLC and HBV infection. This population should not be excluded from receiving immunotherapy in routine clinical practice or within clinical trials if HBV biomarkers are monitored and antiviral prophylaxis is properly used.

DOI： 10.21037/tlcr-21-455

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.21037/tlcr-21-467

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: Despite the extensive use of the combination of cytotoxic chemotherapy and programmed cell death protein 1/programmed death-ligand 1 checkpoint inhibitors for cancer treatment, the incidence and characteristics of pneumonitis caused by this combination therapy have not been examined in clinical settings. METHODS: We conducted a 36-centre, retrospective cohort study in patients with chemo-naïve advanced non-squamous non-small cell lung cancer who received a combination of platinum, pemetrexed and pembrolizumab between December 2018 and June 2019. RESULTS: The study comprised 299 patients. The most frequent grade ≥3 non-hematologic adverse event was pneumonitis. There were 37 patients (12.4%, 95% CI 8.9-16.7) with all-grade pneumonitis and 10 (3.3%, 95% CI 1.6-6.1) with grade ≥3 pneumonitis. Of these, 21 (7.0%, 95% CI 4.4-10.5) and 9 patients (3.0%, 95% CI 1.4-5.6) developed all-grade and grade ≥3 pneumonitis within 90 days after initiating the combination therapy, respectively. The median time to treatment failure and progression-free survival was 5.9 (95% CI 5.0-6.8) and 7.5 (95% CI 6.5-8.7) months, respectively. In the survival analysis after adjusting for immortal time bias, pneumonitis was independently associated with shorter progression-free survival (HR 1.99, 95% CI 1.07-3.69, P = 0.03) and overall survival (HR 3.03, 95% CI 1.12-8.20, P = 0.03). CONCLUSIONS: Treatment-related pneumonitis occurred at a higher rate in the real-world population than that reported previously; it led to worse survival outcomes. Pneumonitis requires more attention. Additional studies are required to improve the safety of this combination therapy. TRIAL REGISTRATION NUMBER: UMIN000038084.

DOI： 10.1016/j.ejca.2021.03.016

PubMed

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器内視鏡学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Programmed death protein (ligand) 1 [PD-(L)1] inhibitors have provided new therapeutic options for advanced lung cancer. However, patients with hepatitis B virus (HBV) infection have been traditionally excluded from most registered trials of this form of treatment. Methods: We performed a retrospective analysis of patients with HBV and advanced lung cancer who received anti-PD-1 immunotherapy from September 2018 to May 2020 in our department. Treatment-related hepatotoxicity was evaluated and recorded. Overall response rate and progression free survival were also assessed in the patients using iRECIST. Results: Seventeen patients were evaluated in this analysis. Of these, six (35.3%) experienced hepatic transaminase elevation during immunotherapy. Three of these patients developed Grade 3 hepatic immune-related adverse events and received systemic corticosteroids, following which aminotransferase levels recovered to normal in all patients and no adverse events were observed in subsequent treatment. No patient experienced HBV reactivation or flare. One patient developed active pulmonary tuberculosis (TB). Other adverse events were mild, well tolerated and short term. The objective response rate (ORR) of the cohort was 62.5%, and the median progression-free survival (PFS) was 3 months. Conclusions: Lung cancer patients can be treated safely with anti-PD-1 inhibitors in the context of HBV infection. Close monitoring for hepatotoxicity and prophylactic antiviral therapy is advised. Further studies on the use of anti-PD-1 inhibitors in HBV-infected patients are needed.

DOI： 10.21037/tlcr-21-79

PubMed

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Lung cancer is most common among older individuals. However, polypharmacy and comorbidities, which are also more common in older individuals, can limit treatment options. Previous studies suggest that afatinib can be used safely and effectively in elderly patients. This study investigated the anti-tumour activity and safety profile of first-line afatinib in previously-untreated elderly Japanese patients with EGFR mutation-positive non-small cell lung cancer (NSCLC). METHODS: This was a single-arm, open-label, phase II study, performed in multiple centres in Japan. Previously untreated patients, aged ≥75 years, with EGFR mutation-positive (Del19 or L858R) advanced NSCLC were treated with afatinib 40 mg until disease progression or unacceptable toxicity. Adverse events (AEs) were managed with protocol-defined dose adjustments. The primary endpoint was objective response rate (ORR) by central review. RESULTS: In total, 38 patients received at least one dose of afatinib, and 37 were evaluable for response. Median age was 77.5 years (range 75-91), all patients had an Eastern Cooperative Oncology Group performance status of 0 or 1, and 60.5% had Del19-positive disease. Median follow-up was 838 days. ORR was 75.7% (2 complete responses and 26 partial responses). Median progression-free survival was 14.2 months (95% confidence interval [CI], 9.5-19.0). Median overall survival (OS) was 35.2 months (95% CI, 35.2-not reached); the 2-year OS rate was 78.3%. The most common grade 3/4 treatment-related AEs (TRAEs) were diarrhoea (28.9%), paronychia (23.7%), and rash/acne (15.8%). Dose reductions due to TRAEs were reported in 78.9% of patients, and eight (21.1%) patients discontinued afatinib due to TRAEs. No treatment-related deaths were reported. CONCLUSION: Although dose adjustments were relatively common in this small group of Japanese patients aged ≥75 years with EGFR mutation-positive NSCLC, discontinuation occurred much less frequently, and most patients were able to stay on treatment for well over a year. Further, afatinib was associated with high response rates and prolonged PFS and OS. TRIAL REGISTRATION: The trial is registered with Japan Registry of Clinical Trials (JRCT) as trial number 031180136 (date of initial registration: 19 February 2019), and the University Hospital Network (UMIN) as trial number 000017877 (date of initial registration: 11 June 2015).

DOI： 10.1186/s12885-021-07861-1

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The data of sequential therapy of anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) in clinical practice have been limited. METHODS: We reviewed the clinical data of patients with ALK-rearranged non-small cell lung cancer who received crizotinib (CRZ) or alectinib (ALEC) between May 2012 and December 2016. Patients were divided into two groups based on the first-administered ALK-TKI, the CRZ or ALEC group. The combined time-to-treatment failure (TTF) was defined as the sum of the 'TTF of CRZ' plus the 'TTF of ALEC' if patients were treated with CRZ followed by ALEC in the CRZ group. The primary end-point is the comparison between the combined TTF and the TTF of ALEC in the ALEC group. RESULTS: Of 864 patients enrolled from 61 institutions, 840 patients were analysed. There were 535 of 305 patients in the CRZ/ALEC groups. The combined TTF in the CRZ group was significantly longer than TTF in the ALEC group (median, 34.4 versus 27.2 months; hazard ratio [HR], 0.709; P = 0.0044). However, there was no significant difference in overall survival (OS) between the patients who received ALEC after CRZ in the CRZ group and the patients in the ALEC group (median, 88.4 months versus. not reached; HR, 1.048; P = 0.7770). In the whole population, the CRZ group had a significantly shorter OS than the ALEC group (median, 53.6 months versus not reached; HR, 1.821, P < 0.0001). CONCLUSION: The combined TTF in the CRZ group was significantly longer than the TTF in the ALEC group; however, OS benefit of sequential therapy against ALEC as the first ALK-TKI was not shown.

DOI： 10.1016/j.ejca.2020.12.026

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記述言語：日本語   出版者・発行元：(一社)日本内科学会  

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記述言語：日本語   出版者・発行元：(一社)日本内科学会  

症例1は67歳男性で、Behcet病に伴う皮疹と診断され、8ヵ月前より、皮膚科からプレドニゾロン(PSL)およびジアフェニルスルホン(DDS)が処方されていた。数日前からの頭痛を訴え、室内気でSpO2 89%と低下していた。Hb 7.5g/dlと貧血あり、白血球10950/μl、CRP 20.05mg/dlと高度の炎症所見を認めた。室内気での動脈血液ガス分析(BGA)でSaO2 95.6%であり、SpO2とSaO2の乖離(saturation gap)を認め、メトヘモグロビン(MetHb)3.3%と上昇していた。症例2は69歳男性で、骨髄異形成症候群に伴うSweet病のため、3ヵ月前より皮膚科からPSLおよびDDSが処方されていた。肝機能障害のために入院となり、無症状であったが入院時よりSpO2 90%以下が持続したため、酸素吸入を開始された。その後もSpO2低値が遷延した。酸素吸入下のBGAでSaO2 90.8%と軽度のsaturation gapを認め、MetHb 7.4%と上昇していた。症例3は40歳男性で、潰瘍性大腸炎に伴う壊疽性膿皮症のため、4ヵ月前より皮膚科からDDSが処方されていた。潰瘍性大腸炎の通院治療のために来院した際、無症状であったがSpO2低下を認めたため入院した。室内気でSpO2 92%と低下していた。軽度の炎症反応上昇が認められた。BGAでSaO2 97.7%とSaturation gapを認め、MetHb 3.2%と上昇を認めた。いずれの症例も、皮膚科より処方されていたDDSによる薬剤性MetHb血症を疑い、DDS内服を中止した。その結果、1週後にはMetHb分画の低下と共にSpO2の上昇が認められた。

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その他リンク： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2021&ichushi_jid=J01159&link_issn=&doc_id=20210316070034&doc_link_id=10.2169%2Fnaika.110.622&url=https%3A%2F%2Fdoi.org%2F10.2169%2Fnaika.110.622&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

記述言語：英語   掲載種別：研究論文（学術雑誌）  

A 31-year-old woman who was clinically diagnosed with Silver-Russell syndrome (SRS) in childhood was admitted with complaints of dyspnea. She had hypercapnic respiratory failure accompanied by nocturnal hypoventilation. Computed tomography revealed systemic muscle atrophy and superior mesenteric artery syndrome; however, the bilateral lung fields were normal. She was treated with nocturnal noninvasive positive pressure ventilation and showed improvement of respiratory failure. In this case, loss of methylation on chromosome 11p15 and maternal uniparental disomy of chromosome 7, which are the common causes of SRS, were not detected. This is a rare case of adult SRS manifesting as chronic hypercapnic respiratory failure.

DOI： 10.2169/internalmedicine.5479-20

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記述言語：日本語   出版者・発行元：(一社)日本呼吸ケア・リハビリテーション学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸ケア・リハビリテーション学会  

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記述言語：英語  

We herein report the case of a 20 year-old-man who developed bronchiolitis obliterans after living-donor renal transplantation. The patient presented with dyspnea on exertion and wheezing two years after renal transplantation, and spirometry showed an obstructive pattern. Surgical lung biopsy revealed subepithelial fibrosis that constricted and obstructed the intrabronchiolar space. Based on these findings, the patient was diagnosed with bronchiolitis obliterans. He was prescribed bronchodilators and azithromycin, and he achieved stable respiratory function for two years. The differential diagnosis of respiratory symptoms after renal transplantation includes opportunistic infection and drug-induced lung injury; however, bronchiolitis obliterans should also be considered.

DOI： 10.1016/j.resinv.2020.12.003

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

IMpower132 explored the safety and efficacy of atezolizumab plus pemetrexed and platinum-based chemotherapy as first-line treatment for advanced non-small-cell lung cancer (NSCLC). Key eligibility criteria for the phase 3, open-label, IMpower132 study included age ≥18 y, histologically or cytologically confirmed advanced non-squamous NSCLC per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, Eastern Cooperative Oncology Group performance status of 0/1, and no prior systemic treatment for stage IV NSCLC. Patients received atezolizumab (1200 mg) plus pemetrexed (500 mg/m2 ) and cisplatin (75 mg/m2 ) or carboplatin (area under the concentration curve, 6 mg/mL/min) (APP arm) or chemotherapy alone (PP arm). The co-primary study endpoints were overall survival (OS) and investigator-assessed progression-free survival (PFS) per RECIST 1.1 in the intention-to-treat population. A subgroup analysis was conducted in Japanese patients. In the Japanese subgroup (n = 101), median OS was 30.8 (95% CI, 24.3 to not estimable) mo in the APP arm (n = 48) and 22.2 (95% CI, 15.7-30.8) mo in the PP arm (n = 53; hazard ratio [HR], 0.63 [95% CI, 0.36-1.14]). PFS was 12.8 (95% CI, 8.6-16.6) mo in the APP arm vs 4.5 (95% CI, 4.1-6.7) mo in the PP arm (HR, 0.33 [95% CI, 0.21-0.58]). Grade 3/4 treatment-related adverse events (TRAEs) occurred in 68.8% of APP arm patients and 44.2% of PP arm patients. Consistent with global study results, atezolizumab plus pemetrexed and platinum-based chemotherapy improved efficacy and was well tolerated in Japanese patients with advanced NSCLC despite a higher incidence of grade 3/4 TRAEs.

DOI： 10.1111/cas.14817

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Cisplatin, one of the most active anticancer agents, is widely used in standard chemotherapy for various cancers. Cisplatin is more poorly tolerated than other chemotherapeutic drugs, and the main dose-limiting toxicity of cisplatin is its nephrotoxicity, which is dose-dependent. Although less toxic methods of cisplatin administration have been established, cisplatin-induced nephrotoxicity remains an unsolved problem. Megalin is an endocytic receptor expressed at the apical membrane of proximal tubules. We previously demonstrated that nephrotoxic drugs, including cisplatin, are reabsorbed through megalin and cause proximal tubular cell injury. We further found that cilastatin blocked the binding of cisplatin to megalin in vitro. In this study, we investigated whether cilastatin could reduce cisplatin-induced nephrotoxicity without influencing the antitumor effects of cisplatin. Nephrotoxicity was decreased or absent in mice treated with cisplatin and cilastatin, as determined by kidney injury molecule-1 staining and the blood urea nitrogen content. Combined with cilastatin, a twofold dose of cisplatin was used to successfully treat the mice, which enhanced the antitumor effects of cisplatin but reduced its nephrotoxicity. These findings suggest that we can increase the dose of cisplatin when combined with cilastatin and improve the outcome of cancer patients.

DOI： 10.1038/s41598-020-80853-6

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Afatinib has shown clinical benefits in patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations. Many patients treated with afatinib experience skin or gastrointestinal toxicity. However, an effective management strategy has not been established. This prospective study was conducted to evaluate the efficacy of multimodal prophylactic treatment for afatinib-induced toxicity. Methods: This single-arm prospective study was conducted to evaluate the efficacy of multimodal prophylactic treatment for afatinib-induced toxicity in patients with EGFR mutation positive advanced NSCLC who planned to receive a 40 mg dose of afatinib. Eligible patients were treated with oral loperamide (2 mg twice per day), prophylactic minocycline (100 mg once per day), topical medium-class steroids, and gargling with sodium azulene. The primary endpoint was the ability of prophylactic loperamide to prevent severe or intolerable diarrhea during the 4 weeks after the initial administration of afatinib. The incidence, severity and time to occurrence of diarrhea, rash, oral mucositis and paronychia were evaluated based on a daily patient questionnaire. Results: Forty-six patients were enrolled. The primary endpoint analysis was performed in 35 patients as the per-protocol (PP) population. The 4-week successful prophylaxis rate for severe or intolerable diarrhea was 82.9% (90% confidence interval: 70.1-91.9%). In the total population, the incidences of grade 3 or higher rash, oral mucositis and paronychia within 4 weeks were 4%, 2% and 4%, respectively. Conclusions: Prophylactic loperamide administration was not effective in preventing severe or intolerable diarrhea during afatinib treatment. Adequate dose reduction will be a better approach to manage afatinib-induced diarrhea. Multimodal prevention using minocycline, topical steroids and gargling with sodium azulene may be helpful to maintain compliance with afatinib treatment (UMIN000016167).

DOI： 10.21037/tlcr-20-649

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記述言語：英語  

A 70-year-old man, treated for asthma for 2 years and chronic sinusitis for several months, presented with fever, numbness in the lower limbs, heaviness in the head, gross hematuria, and black stools. He also had eosinophilia, elevated serum IgG4 levels, high levels of myeloperoxidase-anti-neutrophil cytoplasmic antibodies (MPO-ANCA), and pulmonary infiltrative shadows. Bronchoscopy revealed multiple white flattened lesions (white moss) on the airway mucosa, suggesting mycobacterial infection or malignancy. A biopsy from tracheal mucosa revealed airway inflammation with marked eosinophil infiltration. The patient was diagnosed with eosinophilic granulomatosis with polyangiitis (EGPA) and treated with steroids, and all findings improved. However, a year and a half after the initiation of treatment, eosinophils and IgE gradually increased; subjective symptoms, such as asthma symptoms and numbness in the lower limbs, worsened; and ANCA, which had been negative, turned positive. Therefore, we suspected disease relapse and anti-IL-5 antibody (mepolizumab) treatment was initiated. Thereafter, ANCA turned negative again, eosinophils and IgE normalized, and subjective symptoms decreased. The presence of airway mucosal lesions in EGPA is relatively rare, and we report this case as a valuable case owing to the interesting bronchoscopic findings that are worth comprehending as a respiratory physician.

DOI： 10.1016/j.rmcr.2021.101451

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Each of the currently available (1→3)-β-D-glucan (BDG) measurement kits follows a different measurement method and cut-off value. Comparisons of diagnostic performance for invasive fungal infections (IFIs) are desirable. Additionally, ecological considerations are becoming increasingly important in the development of new measurement kits. METHODS: The plasma BDG levels in clinical samples were measured using the following currently available kits: the Fungitec G test MKII, the Fungitec G test ES, Fungitell, the β-Glucan test Wako, and the newly developed Wako kit (Wako-Eu). Wako-Eu uses a pre-treatment solution that conforms to European regulations for the registration, evaluation, authorisation, and restriction of chemicals. The values obtained for the samples using each kit were studied and compared. RESULTS: Of the 165 patients evaluated, 12 had IFIs, including pneumocystis pneumonia, aspergillosis, and candidiasis. BDG values obtained using the kits were moderately correlated with each other. Clinical diagnoses of the evaluated cases indicated that 21 false positives were diagnosed by at least one kit. The sensitivity of the Fungitell kit was relatively low, but those of the other four were over 90%. The specificity was above 90% for all kits. For positive predictive value, the Wako and the Wako-Eu methods were superior to the others owing to fewer false positive results. CONCLUSIONS: The newly developed Wako-Eu method, which considers ecological concerns, shows diagnostic performance equivalent to that of its predecessor. To improve the diagnostic accuracy of IFIs, it is necessary to interpret the results carefully, giving due consideration to the characteristics of each measurement kit.

DOI： 10.1371/journal.pone.0255172

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Viral pneumonia caused by varicella-zoster virus (VZV) infection is a rare but important complication, especially regarding varicella infections. Although disseminated cutaneous herpes zoster (DCHZ) is often associated with visceral diseases, there have been few reports of DCHZ-related pneumonia. We herein report a rare case of a lethal disseminated VZV infection that caused severe pneumonia in a Japanese patient who had chronic interstitial pneumonia. Physicians should consider the possibility of VZV-related pneumonia, especially in patients with a medical history of hematopoietic stem cell transplantation and immunosuppressive therapy.

DOI： 10.2169/internalmedicine.5396-20

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Ribosomal RNA (rRNA), the most abundant non-coding RNA species, is a major component of the ribosome. Impaired ribosome biogenesis causes the dysfunction of protein synthesis and diseases called "ribosomopathies," including genetic disorders with cancer risk. However, the potential role of rRNA gene (rDNA) alterations in cancer is unknown. We investigated germline and somatic single-nucleotide variants (SNVs) in the rDNA promoter region (positions -248 to +100, relative to the transcription start site) in 82 lung adenocarcinomas (LUAC). Twenty-nine tumors (35.4%) carried germline SNVs, and eight tumors (9.8%) harbored somatic SNVs. Interestingly, the presence of germline SNVs between positions +1 and +100 (n = 12; 14.6%) was associated with significantly shorter recurrence-free survival (RFS) and overall survival (OS) by univariate analysis (p < 0.05, respectively), and was an independent prognostic factor for RFS and OS by multivariate analysis. LUAC cell line PC9, carrying rDNA promoter SNV at position +49, showed significantly higher ribosome biogenesis than H1650 cells without SNV. Upon nucleolar stress induced by actinomycin D, PC9 retained significantly higher ribosome biogenesis than H1650. These results highlight the possible functional role of SNVs at specific sites of the rDNA promoter region in ribosome biogenesis, the progression of LUAC, and their potential prognostic value.

DOI： 10.3390/cells9112409

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器内視鏡学会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器内視鏡学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：英語   出版者・発行元：(一社)日本癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(一社)日本癌治療学会  

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記述言語：英語   出版者・発行元：(一社)日本癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(一社)日本癌治療学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The NEJ026 Phase 3 study demonstrated that erlotinib and bevacizumab (BE)-treated NSCLC patients with EGFR mutations had significantly better progression-free survival (PFS) than those treated with erlotinib alone (E). This study included a prospective analysis of the relationship between the mutational status of EGFR in plasma circulating tumor DNA (ctDNA) and the efficacy of TKI monotherapy or combination therapy. We describe these results herein. METHODS: Plasma samples were collected from patients enrolled in NEJ026 at the start of treatment (P0), 6 weeks after the start of treatment (P1), and upon confirmation of progressive disease (P2). Plasma ctDNA was analyzed using a modified PNA-LNA PCR clamp method. PFS and OS according to EGFR status at the time of plasma collection were evaluated. FINDINGS: Plasma activating EGFR mutation (aEGFR) at P0 was detected in 68% of cases; patients without plasma aEGFR had longer PFS. The frequency of T790M mutation at P2 was similar in both arms: 8 (19.0%) in BE and 11 (20.8%) in E. Based on the aEGFR profiles, PFS was evaluated among three groups: type A [P0(-), P1(-)], type B [P0(+), P1(-)], and type C [P0(+), P1(+)]. This revealed that BE was more efficacious than E, and that BE was associated with improved PFS in all types. INTERPRETATION: Pre-treatment plasma aEGFR status have a potential of early predictor of response of TKI efficacy. Monitoring plasma aEGFR mutation will contribute to selection and continuation of treatment with BE or E. FUNDING: Chugai Pharmaceutical.

DOI： 10.1016/j.ebiom.2020.102861

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

It is well known that the prevalence of asthma is higher in athletes, including Olympic athletes, than in the general population. In this study, we analyzed the mechanism of exercise-induced bronchoconstriction by using animal models of athlete asthma. Mice were made to exercise on a treadmill for a total duration of 1 week, 3 weeks, or 5 weeks. We analyzed airway responsiveness, BAL fluid, lung homogenates, and tissue histology for each period. In mice that were treated (i.e., the treatment model), treatments were administered from the fourth to the fifth week. We also collected induced sputum from human athletes with asthma and analyzed the supernatants. Airway responsiveness to methacholine was enhanced with repeated exercise stimulation, although the cell composition in BAL fluid did not change. Exercise induced hypertrophy of airway smooth muscle and subepithelial collagen deposition. Cysteinyl-leukotriene (Cys-LT) levels were significantly increased with exercise duration. Montelukast treatment significantly reduced airway hyperresponsiveness (AHR) and airway remodeling. Expression of PLA2G4 (phospholipase A2 group IV) and leukotriene C4 synthase in the airway epithelium was upregulated in the exercise model, and inhibition of PLA2 ameliorated AHR and airway remodeling, with associated lower levels of Cys-LTs. The levels of Cys-LTs in sputum from athletes did not differ between those with and without sputum eosinophilia. These data suggest that AHR and airway remodeling were caused by repeated and strenuous exercise. Cys-LTs from the airway epithelium, but not inflammatory cells, may play an important role in this mouse model.

DOI： 10.1165/rcmb.2019-0325OC

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記述言語：英語  

DOI： 10.21037/tlcr.2020.03.31

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Interstitial lung disease (ILD) induced by anti-programmed-cell death-1 (PD-1) and anti-PD-ligand 1 (PD-L1) is potentially life-threatening and is a common reason of the discontinuation of therapy. In contrast, an enhancement in antitumor effects was reported in patients who developed immune-related adverse events, including ILD. Although recent evidence suggests that radiologic patterns of ILD may reflect the severity of ILD and the antitumor immune responses to anti-PD-1/PD-L1 therapies, the association between radiologic features and clinical outcomes remains unclear. METHODS: Patients with advanced non-small-cell lung cancer who were treated with 1st to 3rd line anti-PD-1 therapy from January 2016 through October 2017 were identified at multiple institutions belonging to the Niigata Lung Cancer Treatment Group. ILD was diagnosed by the treating physicians, and chest computed tomography scans were independently reviewed to assess the radiologic features of ILD. RESULTS: A total of 231 patients who received anti-PD-1 therapy were enrolled. Thirty-one patients (14%) developed ILD. Sixteen patients were classified as having ground glass opacities (GGO), 16 were classified as having cryptogenic organizing pneumonia (COP), and one was classified as having pneumonitis not otherwise specified. Patients with GGO had significantly worse overall survival time compared to patients with COP (7.8 months (95% CI: 2.2-NE) versus not reached (95% CI: 13.2-NE); P = 0.0175). Multivariate analysis of all 231 patients also revealed that PS = 1 and ≥2 and GGO were significant predictors of a worse overall survival. CONCLUSIONS: This study demonstrated that patients who developed GGO exhibited worse outcomes among non-small-cell lung cancer patients receiving anti-PD-1 therapies.

DOI： 10.1002/cam4.2974

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Owing to the rarity of this tumor, there is limited information about second-line chemotherapy for patients with previously treated advanced thymic carcinoma. MATERIAL AND METHODS: We performed a multi-institutional, retrospective study named NEJ023 for patients with advanced thymic carcinoma. Patients without indications for curative treatment were treated with chemotherapy from 1995 to 2014 at 40 institutions in the North East Japan Study Group. Demographic and clinicopathologic characteristics, data on treatment methods, and outcomes of second-line chemotherapy were obtained from medical records. RESULTS: In total, 191 patients were enrolled in this study. Second-line chemotherapy included platinum-based doublets in 57.6% of patients, other multidrug chemotherapy (e.g., cisplatin, doxorubicin, vincristine, and cyclophosphamide) in 13.6%, and monotherapy in 28.8%. The median follow-up time was 50.5 months, and the median overall survival (OS) from the start of second-line chemotherapy was 22.4 (95% confidence interval, 17.5-26.7) months. The average response rate (RR) was 20.0% overall; it was 21.6% for patients treated with platinum-based doublet chemotherapy, 13.6% for those treated with other multidrug chemotherapy, and 19.6% for those treated with single agent chemotherapy. There was no significant difference in OS between platinum-based doublet chemotherapy, other multidrug chemotherapy, and monotherapy (the median OS was 22.4, 25.7, and 21.4 months, respectively). CONCLUSION: The median OS was 22.4 months in patients with advanced thymic carcinoma treated with second-line chemotherapy. There were no significant differences in RR and OS between monotherapy and multidrug chemotherapy in this study. IMPLICATIONS FOR PRACTICE: Owing to the rarity of this tumor, there is limited information about second-line chemotherapy for patients with previously treated advanced thymic carcinoma. This is the largest data for those patients treated with second-line chemotherapy. This study suggests there is no significant difference in efficacy between monotherapy and multidrug chemotherapy for previously treated advanced thymic carcinoma. This result can support the adequacy to select monotherapy as treatment of those patients.

DOI： 10.1634/theoncologist.2019-0593

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記述言語：英語  

DOI： 10.1016/j.lungcan.2019.11.012

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記述言語：日本語   出版者・発行元：(一社)日本内科学会  

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記述言語：英語  

OBJECTIVES: The J-ALEX study compared the efficacy and safety of alectinib with crizotinib in Japanese patients with advanced ALK-positive non-small-cell lung cancer (NSCLC). Superiority in independent review facility (IRF)-assessed progression-free survival (PFS) was demonstrated for alectinib at the second pre-planned interim PFS analysis (data cutoff: December 3, 2015; hazard ratio [HR] 0.34, 99.7 % confidence interval [CI]: 0.17-0.71, P < 0.0001). We report final PFS data and the second pre-planned interim analysis of overall survival (OS) and safety (data cutoff: June 30, 2018). METHODS: Patients aged ≥20 years who were ALK inhibitor-naïve and chemotherapy-naïve, or had received one prior chemotherapy regimen, were randomized to receive alectinib 300 mg (n = 103) or crizotinib 250 mg (n = 104) twice daily. The primary end point was IRF-assessed PFS. Secondary end points included OS and safety. All patients entered survival follow-up in July 2018. RESULTS: Median follow-up was 42.4 months for alectinib and 42.2 months for crizotinib. Sustained improvement in IRF-assessed PFS with alectinib was shown (HR 0.37, 95 % CI: 0.26-0.52; median PFS 34.1 months vs 10.2 months crizotinib). At the second interim OS analysis, superiority of alectinib to crizotinib could not be concluded (stratified HR 0.80, 99.8799 % CI: 0.35-1.82, stratified log-rank P = 0.3860; median OS not reached alectinib vs 43.7 months crizotinib). Fewer alectinib-treated patients experienced grade ≥3 adverse events (36.9 % vs 60.6 % crizotinib). CONCLUSIONS: At the final PFS analysis, alectinib continued to demonstrate superiority in IRF-assessed PFS versus crizotinib in ALK-inhibitor-naïve ALK-positive NSCLC, with a favorable safety profile. OS follow-up continues.

DOI： 10.1016/j.lungcan.2019.11.025

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Adherence Starts with Knowledge-12 (ASK-12) is a useful indicator of drug adherence. In this study, we analyzed patient background including social and psychological factors in a low-adherence group of patients with asthma defined using ASK-12. METHODS: From a questionnaire survey for patients with asthma from the Niigata Prefecture, Japan, conducted in the fall of 2016, we enrolled patients who answered all ASK-12 items and underwent a measured respiratory function test within 1 year. The low-adherence group (ASK-12 ≥ 28) was compared with the control group (ASK-12 < 28), and we conducted a cluster analysis of the low-adherence group. RESULTS: There were 170 patients in the low-adherence group and 402 patients in the control group. There was a significant difference between age, gender, working status, smoking history, the percentage of forced expiratory volume in one second (%FEV1), asthma control test (ACT), and Patient Health Questionnaire-9 (PHQ-9) score between the two groups. Logistic analysis revealed that working status (working), % FEV1 (<90%), and PHQ-9 score (>5) were independent factors for the low-adherence group. The cluster analysis identified three clusters in the low-adherence group. Among these, one cluster was characterized by elderly males with chronic obstructive pulmonary disease and another by middle-aged nonsmoking females with a depression tendency, had problems with asthma control. CONCLUSIONS: Several factors were considered to be attributed to low drug-adherence. There were several phenotypes in the low-adherence population correlated with incomplete asthma control. Intervention with drug adherence should be a future goal for asthma treatment.

DOI： 10.1016/j.alit.2019.07.006

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: In the FLAURA trial, superiority of osimertinib over the standard of care (SOC) was not demonstrated in Asian patients; SOC seemed favorable among Japanese patients (hazard ratio 1.39, 95% confidence interval 0.82-2.33). Three reasons are suggested: since rechallenge with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is covered by health insurance in Japan, EGFR-TKI rechallenge rate was higher in SOC than in the osimertinib group, which resulted in a long-term sequential administration of EGFR-TKIs; treatment discontinuation rate was high in the osimertinib group due to adverse events such as interstitial pneumonia among Japanese patients. EGFR-TKIs enhance tumor antigen-specific cytotoxicity of T cells, especially first- and second-generation EGFR-TKIs, which are more active against various cells with wild-type EGFR, including regulatory T cells. Consequently, subsequent immune checkpoint inhibitor therapy seemed more promising in the SOC group. Therefore, optimal first-line EGFR-TKI for EGFR-mutant advanced lung cancer may not have been identified in Japanese patients. Methods: The Heat on Beat study is a randomized, open-label, multicenter, phase II study to compare OS between initial treatment with afatinib and osimertinib in treatment-naïve patients with advanced or recurrent EGFR-mutant NSCLC. Exploration of immunomonitoring through peripheral blood mononuclear cells will also be performed, before, during, and after treatment. Treatment-naïve EGFR mutation-positive non-small cell lung cancer (NSCLC) patients (N = 100) will be randomized to two groups in a 1:1 ratio. The co-primary endpoints are 3-year survival rate and characterization of immune environment associated with response to afatinib, osimertinib, or immune checkpoint inhibitors. Enrollment will start in May 2020 at 28 sites in Japan and continue for 1 year, with 3-year follow-up. Discussion: Because there is no clinical trial comparing second- with third-generation EGFR-TKI for advanced EGFR-mutant NSCLC, our study would provide a major impact on clinical practice. Trial registration Japan Registry of Clinical Trials, jRCTs031190221, registered date: 25 February 2020, https://jrct.niph.go.jp/en-latest-detail/jRCTs031190221.

DOI： 10.1177/1758835920967254

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Cisplatin is a potent chemotherapeutic agent used to treat a variety of solid tumors. One of the major side effects of cisplatin is dose-limiting nephrotoxicity. We recently demonstrated that the renal uptake of cisplatin and resultant cisplatin-induced nephrotoxicity are mediated in part by megalin, an endocytic receptor in proximal tubule epithelial cells (PTECs). We also developed sandwich enzyme-linked immunosorbent assays to measure the megalin ectodomain (A-megalin) and full-length megalin (C-megalin) in urine using monoclonal antibodies against the amino- and carboxyl-termini of megalin, respectively. The present study examined the correlation of urinary megalin level with cisplatin-induced nephrotoxicity and its utility as a biomarker in patients with thoracic cancer. METHODS: This prospective observational study involved 45 chemotherapy-naïve patients scheduled to receive chemotherapy with ≥60 mg/m2 cisplatin for histologically diagnosed small cell lung cancer, non-small cell lung cancer, or malignant pleural mesothelioma. Before and after the first course of chemotherapy, we measured urinary A- and C-megalin and other markers of PTEC injury, such as N-acetyl-β-D-glucosaminidase, α1-microglobulin, β2-microglobulin, neutrophil gelatinase-associated lipocalin, and liver-type fatty acid-binding protein, and compared the values with the change in the estimated glomerular filtration rate (eGFR) and clinical risk factors for renal impairment. RESULTS: A negative correlation was found between baseline urinary A-megalin levels and change in eGFR (r = - 0.458, P = 0.002). According to Kaplan-Meier survival curves, eGFR decline was associated with the baseline urinary A-megalin quartile (P = 0.038). In addition, according to the hazard ratios (HRs) for eGFR decline > 10 mL/min/1.73 m2 calculated using a Cox proportional hazard model, the highest quartile had a significantly higher risk of eGFR decline compared with the lowest quartile (HR 7.243; 95% confidence interval 1.545-33.962). Other baseline urinary markers showed no correlation with eGFR decline. CONCLUSIONS: This is the first report demonstrating that prechemotherapy urinary A-megalin levels are correlated with the development of cisplatin-induced nephrotoxicity. This finding has clinical implications for the identification of patients at risk for cisplatin-induced nephrotoxicity and the development of possible prophylactic therapies.

DOI： 10.1186/s12885-019-6398-2

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Although the clinical efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in EGFR-mutant non-small cell lung cancer (NSCLC) patients has been demonstrated, their efficacy in EGFR-mutant NSCLCs with central nervous system (CNS) metastases and the role of radiotherapy remain unclear. This study aimed to determine if it is preferable to add upfront cranial radiotherapy to EGFR-TKIs in patients with EGFR-mutant NSCLC with newly diagnosed brain metastases. METHODS: We retrospectively analyzed the data of EGFR-mutant NSCLC patients with CNS metastases who received EGFR-TKIs as a first-line therapy. RESULTS: A total of 104 patients were enrolled and 39 patients received upfront brain radiotherapy, while 65 patients received first and second generation EGFR-TKIs first. The median time to treatment failure (TTF) was 7.8 months (95% confidence interval [CI]: 6.3-9.4). The median survival time (MST) was 24.0 months (95% CI: 20.1-30.1). The overall response rate of the CNS was 37%. The median CNS progression-free survival (PFS) was 13.2 months (95% CI: 10.0-16.2). Brain radiotherapy prior to EGFR-TKI prolonged TTF (11.2 vs. 6.8 months, P = 0.038) and tended to prolong CNS-PFS (15.6 vs. 11.1 months, P = 0.096) but was not significantly associated with overall survival (MST 26.1 vs. 24.0 months, P = 0.525). Univariate and multivariate analyses indicated that poor performance status and the presence of extracranial metastases were poor prognostic factors related to overall survival. CONCLUSION: EGFR-TKI showed a favorable effect for EGFR-mutant NSCLC patients with CNS metastases. Prolonged TTF and CNS-PFS were observed with upfront brain radiotherapy.

DOI： 10.1111/1759-7714.13189

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：英語   出版者・発行元：日本癌学会  

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DOI： 10.1016/j.lungcan.2019.04.010

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記述言語：日本語   出版者・発行元：(一社)日本睡眠学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Resistance to first-generation or second-generation EGFR tyrosine kinase inhibitor (TKI) monotherapy develops in almost half of patients with EGFR-positive non-small-cell lung cancer (NSCLC) after 1 year of treatment. The JO25567 phase 2 trial comparing erlotinib plus bevacizumab combination therapy with erlotinib monotherapy established the activity and manageable toxicity of erlotinib plus bevacizumab in patients with NSCLC. We did a phase 3 trial to validate the results of the JO25567 study and report here the results from the preplanned interim analysis. METHODS: In this prespecified interim analysis of the randomised, open-label, phase 3 NEJ026 trial, we recruited patients with stage IIIB-IV disease or recurrent, cytologically or histologically confirmed non-squamous NSCLC with activating EGFR genomic aberrations from 69 centres across Japan. Eligible patients were at least 20 years old, and had an Eastern Cooperative Oncology Group performance status of 2 or lower, no previous chemotherapy for advanced disease, and one or more measurable lesions based on Response Evaluation Criteria in Solid Tumours (1.1). Patients were randomly assigned (1:1) to receive oral erlotinib 150 mg per day plus intravenous bevacizumab 15 mg/kg once every 21 days, or erlotinib 150 mg per day monotherapy. Randomisation was done by minimisation, stratified by sex, smoking status, clinical stage, and EGFR mutation subtype. The primary endpoint was progression-free survival. This study is ongoing; the data cutoff for this prespecified interim analysis was Sept 21, 2017. Efficacy was analysed in the modified intention-to-treat population, which included all randomly assigned patients who received at least one dose of treatment and had at least one response evaluation. Safety was analysed in all patients who received at least one dose of study drug. The trial is registered with the University Hospital Medical Information Network Clinical Trials Registry, number UMIN000017069. FINDINGS: Between June 3, 2015, and Aug 31, 2016, 228 patients were randomly assigned to receive erlotinib plus bevacizumab (n=114) or erlotinib alone (n=114). 112 patients in each group were evaluable for efficacy, and safety was evaluated in 112 patients in the combination therapy group and 114 in the monotherapy group. Median follow-up was 12·4 months (IQR 7·0-15·7). At the time of interim analysis, median progression-free survival for patients in the erlotinib plus bevacizumab group was 16·9 months (95% CI 14·2-21·0) compared with 13·3 months (11·1-15·3) for patients in the erlotinib group (hazard ratio 0·605, 95% CI 0·417-0·877; p=0·016). 98 (88%) of 112 patients in the erlotinib plus bevacizumab group and 53 (46%) of 114 patients in the erlotinib alone group had grade 3 or worse adverse events. The most common grade 3-4 adverse event was rash (23 [21%] of 112 patients in the erlotinib plus bevacizumab group vs 24 [21%] of 114 patients in the erlotinib alone group). Nine (8%) of 112 patients in the erlotinib plus bevacizumab group and five (4%) of 114 patients in the erlotinib alone group had serious adverse events. The most common serious adverse events were grade 4 neutropenia (two [2%] of 112 patients in the erlotinib plus bevacizumab group) and grade 4 hepatic dysfunction (one [1%] of 112 patients in the erlotinib plus bevacizumab group and one [1%] of 114 patients in the erlotinib alone group). No treatment-related deaths occurred. INTERPRETATION: The results of this interim analysis showed that bevacizumab plus erlotinib combination therapy improves progression-free survival compared with erlotinib alone in patients with EGFR-positive NSCLC. Future studies with longer follow-up, and overall survival and quality-of-life data will be required to further assess the efficacy of this combination in this setting. FUNDING: Chugai Pharmaceutical.

DOI： 10.1016/S1470-2045(19)30035-X

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記述言語：日本語   出版者・発行元：(一社)日本アレルギー学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Treatment with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) leads to initial response in most patients with EGFR-mutated non-small cell lung cancer (NSCLC). In contrast, little is known of the subpopulation of patients with NSCLC with EGFR mutations who exhibit clinical outcomes that require treatment with immune checkpoint inhibitors (ICIs). Therefore, to identify eligible cases to treat with ICIs, we retrospectively analyzed the correlation between clinical features and the efficacy of ICIs in patients with EGFR mutations. PATIENTS AND METHODS: We retrospectively analyzed patients with advanced NSCLC harboring EGFR mutations who were treated with ICIs after developing resistance to EGFR-TKIs between February 2016 and April 2018 at 6 institutions in Japan. The association between clinical outcomes and the efficacy of ICIs was investigated. RESULTS: We enrolled 27 patients who harbored EGFR-activating mutations. The objective response and disease control rates were higher in patients with uncommon EGFR mutations than in those with common EGFR mutations (71% vs 35.7% and 57% vs 7%, P = 0.14 and P < 0.01, respectively). Patients with uncommon EGFR mutations or without T790M mutations exhibited a significantly longer median progression-free survival than those with common EGFR mutations or with T790M mutations (P = 0.003 and P = 0.03, respectively). CONCLUSION: Patients with uncommon EGFR mutations and without T790M mutations are associated with the best outcomes for treatment with immunotherapy among those with EGFR-mutated NSCLC, based on retrospective analysis. Further research is needed to validate the clinical biomarkers involved in ICI responders with EGFR mutations.

DOI： 10.1002/cam4.2037

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Mycobacterium avium complex lung disease (MAC-LD) can deteriorate rapidly to become fatal. Reported poor prognostic factors include radiographic findings, undernutrition, anemia and high inflammation test values. However, the association of these prognostic factors with the pathophysiology of the disease remains unknown. We aimed to clarify the pathophysiology of MAC-LD and develop a new biomarker that reflects the immune response to the disease. METHODS: We performed the cytokine panel analyses of serum from patients with MAC-LD and compared each cytokine level with clinically negative prognostic factors (radiographic disease type, body mass index, albumin, C-reactive protein and hemoglobin) and high-resolution CT scores. RESULTS: We analyzed 27 patients with MAC-LD, 6 with the fibrocavitary form and 21 with the nodular bronchiectatic form on high-resolution CT. Serum CXC motif ligand 10 (CXCL10) concentration was significantly elevated in patients with the fibrocavitary form (p = 0.008). CXCL10 levels correlated with body mass index (r = - 0.60, p = 0.0008), serum albumin concentration (r = - 0.45, p = 0.016) and high-resolution CT scores (r = 0.61, p = 0.0006). Among 14 patients initially untreated, antibiotic therapy was initiated for five during the study period. CXCL10 concentration was significantly higher in these patients (p = 0.046), and receiver operating characteristic analysis for CXCL10 concentration on treatment initiation produced an area under the curve of 0.844, with a sensitivity of 100%, specificity of 66.7%, and cut-off value of 366.5 pg/mL. CONCLUSION: We revealed cytokine profiles in patients with MAC-LD. Serum CXCL10 levels probably reflect the severity of MAC-LD. Our findings suggest that CXCL10 concentration may be a promising biomarker for managing treatment for patients with MAC disease of the lung.

DOI： 10.1186/s12879-019-3888-4

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.lungcan.2019.01.005

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

A novel EGFR-tyrosine kinase inhibitor (TKI), osimertinib, has marked efficacy in patients with EGFR-mutated lung cancer. However, some patients show intrinsic resistance and an insufficient response to osimertinib. This study showed that osimertinib stimulated AXL by inhibiting a negative feedback loop. Activated AXL was associated with EGFR and HER3 in maintaining cell survival and inducing the emergence of cells tolerant to osimertinib. AXL inhibition reduced the viability of EGFR-mutated lung cancer cells overexpressing AXL that were exposed to osimertinib. The addition of an AXL inhibitor during either the initial or tolerant phases reduced tumor size and delayed tumor re-growth compared to osimertinib alone. AXL was highly expressed in clinical specimens of EGFR-mutated lung cancers and its high expression was associated with a low response rate to EGFR-TKI. These results indicated pivotal roles for AXL and its inhibition in the intrinsic resistance to osimertinib and the emergence of osimertinib-tolerant cells.

DOI： 10.1038/s41467-018-08074-0

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Although the blockade of programmed cell death 1 (PD-1)/PD-ligand (L) 1 has demonstrated promising and durable clinical responses for non-small-cell lung cancers (NSCLCs), NSCLC patients with epidermal growth factor receptor (EGFR) mutations responded poorly to PD-1/PD-L1 inhibitors. Previous studies have identified several predictive biomarkers, including the expression of PD-L1 on tumor cells, for PD-1/PD-L1 blockade therapies in NSCLC patients; however, the usefulness of these biomarkers in NSCLCs with EGFR mutations has not been elucidated. The present study was conducted to evaluate the predictive biomarkers for PD-1/PD-L1 inhibitors in EGFR-mutated NSCLCs. We retrospectively analyzed 9 patients treated with nivolumab for EGFR-mutated NSCLCs. All but one patient received EGFR-tyrosine kinase inhibitors before nivolumab treatment. The overall response rate and median progression-free survival were 11% and 33 days (95% confidence interval (CI); 7 to 51), respectively. Univariate analysis revealed that patients with a good performance status (P = 0.11; hazard ratio (HR) 0.183, 95% CI 0.0217 to 1.549), a high density of CD4+ T cells (P = 0.136; HR 0.313, 95% CI 0.045 to 1.417) and a high density of Foxp3+ cells (P = 0.09; HR 0.264, 95% CI 0.0372 to 1.222) in the tumor microenvironment tended to have longer progression-free survival with nivolumab. Multivariate analysis revealed that a high density of CD4+ T cells (P = 0.005; HR<0.001, 95% CI <0.001 to 0.28) and a high density of Foxp3+ cells (P = 0.003; HR<0.001, 95% CI NA) in tumor tissues were strongly correlated with better progression-free survival. In contrast to previous studies in wild type EGFR NSCLCs, PD-L1 expression was not associated with the clinical benefit of anti-PD-1 treatment in EGFR-mutated NSCLCs. The current study indicated that immune status in the tumor microenvironment may be important for the effectiveness of nivolumab in NSCLC patients with EGFR mutations.

DOI： 10.1371/journal.pone.0215292

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.jss.2018.07.007

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記述言語：日本語   出版者・発行元：(一社)日本呼吸ケア・リハビリテーション学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：英語   出版者・発行元：日本癌学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND/AIM: Promising reports have described the combination of first-generation epidermal growth factor receptor tyrosine-kinase inhibitors (EGFR-TKIs) with carboplatin plus pemetrexed or bevacizumab. However, no analysis of afatinib with platinum-doublet chemotherapies has been performed. PATIENTS AND METHODS: We evaluated the safety and antitumor efficacy of afatinib combined with carboplatin and pemetrexed in EGFR-mutated non-small-cell lung cancer (NSCLC) patients who progressed during first-generation EGFR-TKIs. RESULTS: Ten patients received 20 or 30 mg/day afatinib with carboplatin (area under the curve, 5) and pemetrexed (500 mg/m2). Dose-limiting toxicities included delay of afatinib ≥14 days, grade 3 diarrhea, grade 3 hypokalemia, grade 3 serum amylase increase and grade 4 thrombocytopenia. The recommended dose of afatinib was 20 mg/day in this combination therapy. Overall response rate was 30% and median progression-free survival was 13.7 months. CONCLUSION: This is the first study to investigate the combination of afatinib, carboplatin and pemetrexed. At the recommended dose, this combination was well tolerated and had a good clinical efficacy.

DOI： 10.21873/anticanres.12776

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer New York LLC  

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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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

A 52-year-old man with chronic myelogenous leukemia (CML) received dasatinib after the failure of imatinib and nilotinib therapy. Two years after the initiation of dasatinib, he developed shortness of breath that gradually worsened. Chest X-ray and computed tomography scan showed pulmonary infiltrative shadows and bilateral pleural effusion. We performed a transbronchial lung biopsy and diagnosed organizing pneumonia caused by dasatinib treatment. Corticosteroid therapy was initiated after the discontinuation of dasatinib and all his symptoms were significantly improved. Because of the exacerbation of CML, the patient was treated with imatinib and then nilotinib; however, these drugs failed to decrease the leukemic cells. Re - administration of dasatinib in combination with corticosteroid therapy successfully controlled CML without recurrence of organizing pneumonia.

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1093/cid/cix996

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Nature Publishing Group  

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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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Presepsin is a widely recognized biomarker for sepsis. However, little is known about the usefulness of presepsin in invasive fungal infection. The aim of this study was to determine the plasma levels of presepsin in fungal bloodstream infections and to investigate whether it reflects the disease severity, similar to its utility in bacterial infections. METHODS: We prospectively measured presepsin in plasma samples from participants with fungemia from April 2016 to December 2017. The associations of C-reactive protein, procalcitonin, and presepsin concentrations with the severity of fungemia were statistically analyzed. In vitro assay was performed by incubating Escherichia coli, Candida albicans, and lipopolysaccharide to whole blood cells collected from healthy subjects; after 3 h, the presepsin concentration was measured in the supernatant and was compared among the bacteria, fungi, and LPS groups. RESULTS: Presepsin was increased in 11 patients with fungal bloodstream infections. Serial measurement of presepsin levels demonstrated a prompt decrease in 7 patients in whom treatment was effective, but no decrease or further increase in the patients with poor improvement. Additionally, presepsin concentrations were significantly correlated with the Sequential Organ Failure Assessment score (r = 0.89, p < 0.001). In vitro assay with co-incubation of C. albicans and human whole blood cells indicated that the viable cells of C. albicans caused an increase in presepsin, as seen with E. coli. CONCLUSIONS: Plasma presepsin levels increased in patients with fungal bloodstream infection, with positive association with the disease severity. Presepsin could be a useful biomarker of sepsis secondary to fungal infections.

DOI： 10.1371/journal.pone.0206089

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：S. Karger AG  

OBJECTIVE: Chemotherapy with irinotecan plus cisplatin has shown promise in chemo-naïve small-cell lung cancer (SCLC) patients. However, irinotecan treatment for relapsed or refractory SCLC has not been adequately evaluated. This phase II study evaluated the appropriate treatment schedule of irinotecan as a single agent. This study was designed to determine the antitumor activity, toxicity, and survival in previously treated SCLC patients. METHODS: Previously treated SCLC patients with at least one platinum-based regimen received irinotecan (100 mg/m2) on days 1 and 8, every 3 weeks, until disease progression. The assessment of the response rate was the primary endpoint. RESULTS: Thirty patients were enrolled, with an objective response rate of 41.3% (95% confidence interval [CI] 25.5-59.3), and a disease control rate of 69%. Median progression-free and overall survival was 4.1 months (95% CI, 2.2-5.4) and 10.4 months (95% CI, 8.1-14), respectively. The grade 3/4 hematological toxicities were neutropenia (36.7%), thrombocytopenia (3.3%), anemia (13.3%), and febrile neutropenia (6.6%). There were no grade 4 nonhematological toxicities. Frequent grade 3 nonhematological toxicities included diarrhea (10%), anorexia (6.6%), and hyponatremia (6.6%). CONCLUSIONS: This phase II study showed a high objective response rate and long survival. Irinotecan monotherapy schedule used was well tolerated, and could be an active treatment option for these patients.

DOI： 10.1159/000486622

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Japan Lung Cancer Society  

Objective. Sarcoidosis is a systemic disease that causes the formation of noncaseating epithelioid granuloma in various organs and which often exhibits hilar and mediastinal lymphadenopathy. Among lung cancer patients with sarcoidosis or sarcoid reactions, it is difficult to evaluate the lymph node status and stage by CT and FDG-PET/CT scans. In this study, we examined the usefulness of EBUS-TBNA in the staging of the lung cancer in patients with sarcoidosis or sarcoid reactions. Materials and Methods. We evaluated the effectiveness of EBUS-TBNA in lung cancer patients with sarcoidosis or sarcoid reactions from January 2009 to December 2016. Results. We found 4 patients who were diagnosed with lung cancer accompanied by sarcoidosis and sarcoid reactions by EBUS-TBNA. All of these patients had hilar and mediastinal lymphadenopathy. EBUS-TBNA was useful for the differential diagnosis of lymph-node metastasis of lung cancer. Three of the 4 patients were diagnosed with stage I non-small cell lung cancer and surgery was performed in 2 cases. The histopathological examination of the surgical specimens confirmed that these patients had sarcoid reactions with no lymph-node metastasis. One of the 4 patients was diagnosed with stage III non-small cell lung cancer with systemic sarcoidosis. Conclusion. EBUS-TBNA seems to be useful for the evaluation of the lymph-node status of lung cancer patients with sarcoidosis and sarcoid reactions.

DOI： 10.2482/haigan.58.88

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: The North-East Japan Study Group (NEJ) 005/Tokyo Cooperative Oncology Group (TCOG) 0902 study has reported that first-line concurrent and sequential alternating combination therapies of an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (gefitinib) plus platinum-based doublet chemotherapy (carboplatin/pemetrexed) offer promising efficacy with predictable toxicities for patients with EGFR-mutant non-small cell lung cancer. However, overall survival (OS) data were insufficient in the primary report because of the lack of death events. Patients and methods: Progression-free survival (PFS) and OS were re-evaluated at the final data cut-off point (March 2017) for the entire population (n=80). Results: At the median follow-up time of 35.6 months, 88.8% of patients had progressive disease and 77.5% of patients had died. Median PFS was 17.5 months for the concurrent regimen and 15.3 months for the sequential alternating regimen (P=0.13). Median OS was 41.9 and 30.7 months, respectively (P=0.036). Updated response rates were similar in both groups (90.2% and 82.1%, respectively; P=0.34). Patients with Del19 tumours displayed relatively better OS (median: 45.3 vs 33.3 months, respectively) than those with L858R (31.4 vs 28.9 months, respectively). No severe adverse events, including interstitial lung disease, occurred in the period since the primary report. Conclusions: This updated analysis confirms that PFS is improved with first-line combination therapy compared with gefitinib monotherapy and that the concurrent regimen, in particular, offers an OS benefit of 42 months in the EGFR-mutated setting. Our ongoing NEJ009 study will clarify whether this combination strategy can be incorporated into routine clinical practice. Trial registration number: UMIN C000002789, Post-results.

DOI： 10.1136/esmoopen-2017-000313

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE INC  

Background Alectinib, a potent, highly selective, CNS-active inhibitor of anaplastic lymphoma kinase (ALK), showed promising efficacy and tolerability in the single-arm phase 1/2 AF-001JP trial in Japanese patients with ALK-positive non-small-cell lung cancer. Given those promising results, we did a phase 3 trial to directly compare the efficacy and safety of alectinib and crizotinib.
Methods J-ALEX was a randomised, open-label, phase 3 trial that recruited ALK inhibitor-naive Japanese patients with ALK-positive non-small-cell lung cancer, who were chemotherapy-naive or had received one previous chemotherapy regimen, from 41 study sites in Japan. Patients were randomly assigned (1: 1) via an interactive web response system using a permuted-block method stratified by Eastern Cooperative Oncology Group performance status, treatment line, and disease stage to receive oral alectinib 300 mg twice daily or crizotinib 250 mg twice daily until progressive disease, unacceptable toxicity, death, or withdrawal. The primary endpoint was progression-free survival assessed by an independent review facility. The efficacy analysis was done in the intention-to-treat population, and safety analyses were done in all patients who received at least one dose of the study drug. The study is ongoing and patient recruitment is closed. This study is registered with the Japan Pharmaceutical Information Center (number JapicCTI-132316).
Findings Between Nov 18, 2013, and Aug 4, 2015, 207 patients were recruited and assigned to the alectinib (n=103) or crizotinib (n=104) groups. At data cutoff for the second interim analysis, 24 patients in the alectinib group had discontinued treatment compared with 61 in the crizotinib group, mostly due to lack of efficacy or adverse events. At the second interim analysis (data cutoff date Dec 3, 2015), an independent data monitoring committee determined that the primary endpoint of the study had been met (hazard ratio 0.34 [99.7% CI 0.17-0.71], stratified log-rank p&lt; 0.0001) and recommended an immediate release of the data. Median progression-free survival had not yet been reached with alectinib (95% CI 20.3-not estimated) and was 10.2 months (8.2-12.0) with crizotinib. Grade 3 or 4 adverse events occurred at a greater frequency with crizotinib (54 [52%] of 104) than alectinib (27 [26%] of 103). Dose interruptions due to adverse events were also more prevalent with crizotinib (77 [74%] of 104) than with alectinib (30 [29%] of 103), and more patients receiving crizotinib (21 [20%]) than alectinib (nine [9%]) discontinued the study drug because of an adverse event. No adverse events with a fatal outcome occurred in either treatment group.
Interpretation These results provide the first head-to-head comparison of alectinib and crizotinib and have the potential to change the standard of care for the first-line treatment of ALK-positive non-small-cell lung cancer. The dose of alectinib (300 mg twice daily) used in this study is lower than the approved dose in countries other than Japan; however, this limitation is being addressed in the ongoing ALEX study.

DOI： 10.1016/S0140-6736(17)30565-2

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記述言語：英語   出版者・発行元：AMER SOC CLINICAL ONCOLOGY  

DOI： 10.1200/JCO.2017.35.15_suppl.9038

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：JAPANESE SOCIETY ALLERGOLOGY  

BACKGROUND: Sublingual immunotherapy (SLIT) has received attention as a method for allergen immunotherapy. However, the mechanism of SLIT has not yet been fully investigated. Therefore, we evaluated the effects of SLIT in a murine asthma model, sensitized by intranasal administration of house dust mite (HDM) extracts. METHODS: Female BALB/c mice were intranasally exposed to HDM for either 3 or 5 weeks (5 consecutive days per week). Mice were administered either low-dose (0.5 mg/day) or high-dose (5 mg/day) sublingual HDM extracts for 2 weeks, followed by an additional week of intranasal exposure. Airway hyperresponsiveness (AHR), bronchoalveolar lavage fluid (BALF) cell count, cytokine levels in the BALF and lymph node cell culture supernatants, and allergen-specific antibodies were measured. Lung histology was also investigated. RESULTS: In mice sensitized for 5 weeks, high-dose SLIT ameliorated AHR, airway eosinophilia and goblet cell metaplasia. In mice sensitized for 3 weeks, even low dose SLIT ameliorated AHR and airway eosinophilia. Th2 cytokine levels in culture supernatants of submandibular lymph node cells in high-dose SLIT mice decreased, whereas IL-10 levels increased. Total IgA in BALF increased in mice sensitized for 3 or 5 weeks, and high-dose SLIT also increased allergen-specific IgG2a in mice sensitized for 5 weeks. CONCLUSIONS: These data suggest that earlier induction of SLIT in HDM-sensitized mice provides superior suppression of AHR and goblet cell metaplasia. The modulation of allergen specific IgG2a and local IgA might play a role in the amelioration of AHR and airway inflammation.

DOI： 10.1016/j.alit.2016.05.012

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記述言語：英語   出版者・発行元：Impact Journals LLC  

Recent progress in cancer genome analysis using next-generation sequencing has revealed a high mutation burden in some tumors. The particularly high rate of somatic mutation in these tumors correlates with the generation of neo-antigens capable of eliciting an immune response. Identification of hypermutated tumors is therefore clinically valuable for selecting patients suitable for immunotherapy treatment. There are several known causes of hypermutation in tumors, such as ultraviolet light in melanoma, tobacco smoke in lung cancer, and excessive APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) activity in breast and gastric cancer. In gastrointestinal cancers, one of the leading causes of hypermutation is a defect in DNA mismatch repair, which results in microsatellite instability (MSI). This review will focus on the frequency, characteristics and genomic signature of hypermutated gastrointestinal cancers with MSI. Detection of tumor hypermutation in cancer is expected to not only predict the clinical benefit of immune checkpoint inhibitor treatment, but also to provide better surgical strategies for the patients with hypermutated tumors. Thus, in an era of precision medicine, identification of hypermutation and MSI will play an important role directing surgical and chemotherapeutic treatment.

DOI： 10.18632/oncotarget.22783

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1371/journal.pone.0183976

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Begell House Inc.  

The effectiveness of lymphodepletion in antitumor immunity has been well established. Although recent studies have elucidated some of the broad mechanisms underlying the augmentation of antitumor immunity by lymphodepletion, such as increased availability of cytokines due to the elimination of cellular elements and improvement in tumor antigen presentation, the precise mechanisms remain unclear. Previous studies have focused on the enhancement of the functions of transferred antitumor CD8+ T cells after lymphodepletion. In this review, we discuss the important role of other immune cells in the effectiveness of lymphodepletion. Recent studies have demonstrated that lymphodepletion enhances not only transferred tumor-specific CD8+ T cells but also tumor-specific CD4+ T cells and polyclonal naïve T cells. Moreover, recipient immune cells, including CD8+ T cells, regulatory T cells, dendritic cells, and macrophages, are involved in the augmentation of antitumor effects by lymphodepletion. These host cells can survive lymphodepletive therapies and play a role in the development of antitumor immunity after lymphodepletion. Improvements in the understanding of lymphodepletion allow us to design effective cancer immunotherapy.

DOI： 10.1615/CritRevImmunol.2018019497

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BIOMED CENTRAL LTD  

Background: Nephrotoxicity is the major side effect that limits the dose of cisplatin that can be safely administered, and it is a clinical problem in cancer patients who received cisplatin combination chemotherapy. Recent evidence has demonstrated that patients with chronic kidney disease (CKD) have an increased risk of developing acute kidney injury (AKI). The present study was conducted to evaluate the prevalence of CKD risk factors in patients who received cisplatin and to assess the correlation between CKD risk factors and cisplatin-induced AKI.
Methods: We retrospectively analyzed 84 patients treated with cisplatin combination chemotherapy for thoracic malignancies. AKI was defined as a decrease in the estimated glomerular filtration rate (eGFR) &gt; 25 % from base line, an increase in the serum creatinine (sCre) level of &gt; 0.3 mg/dl or &gt;= 1.5 times the baseline level.
Results: Eighty of the 84 patients (95.2 %) had at least one risk factor for CKD. All enrolled patients received cisplatin with hydration, magnesium supplementation and mannitol. Cisplatin-induced AKI was observed in 18 patients (21.4 %). Univariate analysis revealed that cardiac disease and use of non-steroidal anti-inflammatory drugs (NSAIDs) were associated with cisplatin-induced nephrotoxicity (odds ratios [OR] 6 and 3.56, 95 % confidence intervals [CI] 1.21-29.87 and 1.11-11.39, p = 0.04 and p = 0.04, respectively). Multivariate analysis revealed that cisplatin nephrotoxicity occurred significantly more often in patients with both risk factors (OR 13.64, 95 % CI 1.11-326.83, p = 0.04). Patients with more risk factors for CKD tended to have a greater risk of developing cisplatin-induced AKI.
Conclusions: We should consider avoiding administration of cisplatin to patients with CKD risk factors, particularly cardiac disease and NSAID use.

DOI： 10.1186/s12885-016-2271-8

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：INT INST ANTICANCER RESEARCH  

BACKGROUND: Second-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) afatinib as first-line treatment has been demonstrated to improve overall survival (OS) in patients with non-small cell lung cancer (NSCLC) harboring an exon 19 deletion (del19) of EGFR compared to platinum-doublet chemotherapy. However, it is unclear whether first-generation EGFR-TKIs improve OS in patients with del19 in the first-line treatment. PATIENTS AND METHODS: We performed a post-hoc analysis of patients with del19 or L858R mutation of EGFR who received gefitinib in the NEJ002 study, which compared gefitinib to carboplatin-paclitaxel. RESULTS: A total of 58 patients and 57 patients with del19 EGFR received gefitinib and carboplatin-paclitaxel, respectively. No OS differences were observed between patients receiving gefitinib and carboplatin-paclitaxel irrespective of del19 (29.3 months vs. 29.7 months, p=0.53) or L858R (28.4 months vs. 25.1 months, p=0.45). CONCLUSION: In contrast to afatinib, it is suggested that first-line gefitinib does not improve OS in patients with del19 of EGFR compared with platinum-doublet chemotherapy.

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Japanese Journal of Cancer and Chemotherapy Publishers Inc.  

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'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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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER ASSOC IMMUNOLOGISTS  

Antitumor immunity is augmented by cytotoxic lymphodepletion therapies. Adoptively transferred naive and effector T cells proliferate extensively and show enhanced antitumor effects in lymphopenic recipients. Although the impact of lymphodepletion on transferred donor T cells has been well evaluated, its influence on recipient T cells is largely unknown. The current study demonstrates that both regulatory T cells (Tregs) and effector CD8(+) T cells from lymphopenic recipients play critical roles in the development of antitumor immunity after lymphodepletion. Cyclophosphamide (CPA) treatment depleted lymphocytes more efficiently than other cytotoxic agents; however, the percentage of CD4(+)CD25(+) Foxp3(+) Tregs was significantly increased in CPA-treated lymphopenic mice. Depletion of these chemoresistant Tregs following CPA treatment and transfer of naive CD4(+) T cells augmented the antitumor immunity and significantly suppressed tumor progression. Further analyses revealed that recipient CD8(+) T cells were responsible for this augmentation. Using Rag2(-/-) mice or depletion of recipient CD8(+) T cells after CPA treatment abrogated the augmentation of antitumor effects in CPA-treated reconstituted mice. The transfer of donor CD4(+) T cells enhanced the proliferation of CD8(+) T cells and the priming of tumor-specific CD8(+) T cells originating from the lymphopenic recipients. These results highlight the importance of the recipient cells surviving cytotoxic regimens in cancer immunotherapies.

DOI： 10.4049/jimmunol.1401468

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記述言語：日本語   出版者・発行元：(株)癌と化学療法社  

症例は71歳、男性。骨転移、脳転移を伴う肺腺癌に対して、2年5ヵ月前よりgefitinib(250mg/日)を連日投与され、安定(stable disease:SD)を維持中に腹痛、下痢、嘔吐を発症した。腹部骨盤造影CT検査を施行すると小腸壁内ガス像、腹腔内遊離ガス像、中等量の腹水を認め、腸管嚢腫様気腫症(pneumatosis cystoides intestinalis:PCI)の診断となった。バイタルサインが安定し、腹部理学所見で腹膜炎を疑う所見がみられなかったため、gefitinibを休薬して保存的に治療を開始した。自覚症状は徐々に改善し、治療開始7日後の腹部骨盤造影CT検査では画像所見も著明に改善した。(著者抄録)

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2015&ichushi_jid=J00296&link_issn=&doc_id=20150729440015&doc_link_id=%2Fab8gtkrc%2F2015%2F004207%2F016%2F0847-0849%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fab8gtkrc%2F2015%2F004207%2F016%2F0847-0849%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：KARGER  

Background: Active suppression induced by regulatory T (Treg) cells is reported to be one of the mechanisms involved in oral tolerance. All-trans retinoic acid (ATRA) has been reported to affect Treg cell differentiation. The present study examined the effects of ATRA on the induction of oral tolerance in a murine model of bronchial asthma. Methods: BALB/c mice were sensitized to and challenged with ovalbumin (OVA) through feeding followed by OVA challenges. In some study groups ATRA was orally administered concomitantly with OVA feeding either in the presence or absence of the retinoic acid receptor antagonist LE135. Lung CD4(+) T cells were isolated from mice exposed to ATRA and/or OVA, and transferred to control mice. Airway hyperresponsiveness (AHR), cell counts and cytokine levels in bronchoalveolar lavage (BAL) fluid, and lung histology were assessed. Results: Concomitant administration of ATRA with OVA ameliorated AHR, airway eosinophilia, elevation of cytokines in BAL fluid and goblet cell metaplasia. The proportion of Treg cells in the lungs was increased in mice treated with OVA and ATRA, as compared to those treated with OVA only. Transfer of lung CD4(+) T cells from mice treated with OVA and ATRA induced suppression of AHR and airway inflammation. LE135 completely reversed the effects of ATRA on AHR, airway allergic inflammation and the number of Treg cells in the lungs. Conclusion: These data suggested that oral administration of ATRA with OVA had the potential to enhance oral tolerance in this murine model of bronchial asthma. These effects were mediated, at least in part, by Treg cell expansion. (C) 2015 S. Karger AG, Basel

DOI： 10.1159/000437326

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：JAPAN SOC INTERNAL MEDICINE  

A 53-year-old man with an asymptomatic anterior mediastinal tumor undergoing hemodialysis was referred to our institution. He was diagnosed with thymic basaloid carcinoma based on the findings of a chest tomography-guided biopsy and successfully treated with carboplatin (300 mg/m(2)/day) and paclitaxel (200 mg/ m2/day) on day 1 for six three-week cycles. To our knowledge, this is the first report regarding the efficiency of a carboplatin dose-definition method based on the body surface area with paclitaxel in a hemodialysis patient. This report may therefore be useful for treating hemodialysis patients who are candidates for carboplatin and paclitaxel therapy.

DOI： 10.2169/internalmedicine.54.3484

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Japanese Journal of Cancer and Chemotherapy Publishers Inc.  

A 65-year-old woman with left chest pain, back pain, and palpitation that had persisted for 2 months was referred to our hospital. Computed tomography of her chest showed an anterior mediastinal tumor with mediastinal lymphadenopathy, left pleural effusion, and pericardial effusion. Endobronchial ultrasound-guided transbronchial needle aspiration of the subcarinal lymphadenopathy was performed. The pathological findings and other examinations such as bone scintigraphy suggested advanced thymic cancer (stage IVb according to the Masaoka classification of thymic epithelial tumors). The patient was treated with combination chemotherapy of carboplatin (area under the curve [AUC]=6, 656mg/body, day 1) and weekly paclitaxel (70 mg/m2, 100 mg/body, days 1, 8, and 15). After 4 cycles of chemotherapy, a partial response was achieved and the pericardial effusion disappeared. The patient did not experience any severe toxicity, except for grade 1 nausea, grade 2 anemia, and grade 2 alopecia. Weekly paclitaxel combined with carboplatin appears to be a useful regimen with minimal toxicity for advanced thymic cancer.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PUBLIC LIBRARY SCIENCE  

The specific mechanisms how lung cancer cells harboring epidermal growth factor receptor (EGFR) activating mutations can survive treatment with EGFR-tyrosine kinase inhibitors (TKIs) until they eventually acquire treatment-resistance genetic mutations are unclear. The phenotypic diversity of cancer cells caused by genetic or epigenetic alterations (intratumor heterogeneity) confers treatment failure and may foster tumor evolution through Darwinian selection. Recently, we found DDX3X as the protein that was preferentially expressed in murine melanoma with cancer stem cell (CSC)-like phenotypes by proteome analysis. In this study, we transfected PC9, human lung cancer cells harboring EGFR exon19 deletion, with cDNA encoding DDX3X and found that DDX3X, an ATP-dependent RNA helicase, induced CSC-like phenotypes and the epithelial-mesenchymal transition (EMT) accompanied with loss of sensitivity to EGFR-TKI. DDX3X expression was associated with upregulation of Sox2 and increase of cancer cells exhibiting CSC-like phenotypes, such as anchorage-independent proliferation, strong expression of CD44, and aldehyde dehydrogenase (ALDH). The EMT with switching from E-cadherin to N-cadherin was also facilitated by DDX3X. Either ligand-independent or ligand-induced EGFR phosphorylation was inhibited in lung cancer cells that strongly expressed DDX3X. Lack of EGFR signal addiction resulted in resistance to EGFR-TKI. Moreover, we found a small nonadherent subpopulation that strongly expressed DDX3X accompanied by the same stem cell-like properties and the EMT in parental PC9 cells. The unique subpopulation lacked EGFR signaling and was highly resistant to EGFR-TKI. In conclusion, our data indicate that DDX3X may play a critical role for inducing phenotypic diversity, and that treatment targeting DDX3X may overcome primary resistance to EGFR-TKI resulting from intratumor heterogeneity.

DOI： 10.1371/journal.pone.0111019

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

INTRODUCTION: In non-small-cell lung cancer, an exon 19 deletion and an L858R point mutation in the epidermal growth factor receptor (EGFR) are predictors of a response to EGFR-tyrosine kinase inhibitors. However, it is uncertain whether other uncommon EGFR mutations are associated with sensitivity to EGFR-tyrosine kinase inhibitors. METHODS: A post-hoc analysis to assess prognostic factors was performed with the use of patients with EGFR mutations (exon 19 deletion, L858R, G719X, and L861Q) who were treated with gefitinib in the NEJ002 study, which compared gefitinib with carboplatin-paclitaxel as the first-line therapy. RESULTS: In the NEJ002 study, 225 patients with EGFR mutations received gefitinib at any treatment line. The Cox proportional hazards model indicated that performance status, response to chemotherapy, response to gefitinib, and mutation types were significant prognostic factors. Overall survival (OS) was significantly shorter among patients with uncommon EGFR mutations (G719X or L861Q) compared with OS of those with common EGFR mutations (12 versus 28.4 months; p = 0.002). In the gefitinib group (n = 114), patients with uncommon EGFR mutations had a significantly shorter OS (11.9 versus 29.3 months; p < 0.001). By contrast, OS was similar between patients with uncommon mutations and those with common mutations in the carboplatin-paclitaxel group (n = 111; 22.8 versus 28 months; p = 0.358). CONCLUSIONS: The post-hoc analyses clearly demonstrated shorter survival for gefitinib-treated patients with uncommon EGFR mutations compared with the survival of those with common mutations and suggest that the first-line chemotherapy may be relatively effective for non-small-cell lung cancer with uncommon EGFR mutations.

DOI： 10.1097/JTO.0000000000000048

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER  

Opioids including morphine are commonly used in pain management during and after cancer surgery but have been linked to a variety of pro- and anti-tumor effects. In the present study the effect of morphine administration on the localization and growth of breast tumor cells in lungs and the level of extracellular matrix (ECM) proteases were investigated. In a mouse syngeneic model of intravenously inoculated breast cancer cells, morphine administration led to a reduction in the localization and growth of tumors in the lungs and a reduction in circulating matrix metalloproteinase-9 (MMP-9) and urokinase-like plasminogen activator (uPA). To model the involvement of non-malignant cells of the tumor microenvironment in the changes we observed in the level of proteases, we co-cultured breast cancer cells with macrophages, endothelial cells and fibroblasts. We found a significant elevation of matrix proteases as well as matrix protease inhibitors in co-cultures of breast cancer cells with macrophages or endothelial cells. Interestingly, morphine treatment of these co-cultures reduced the level of MMP-9 and increased its endogenous inhibitor, TIMP-1, thereby altering the proteolytic profile. Morphine affected the level of enzymes in co-cultures but not in cells grown individually. This suggests that anti-tumor effects of morphine observed in our in vivo model could be mediated at least in part through modulation of paracrine communication between cancer cells and non-malignant cells in the tumor microenvironment.

DOI： 10.1007/s10585-013-9616-3

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Accumulating evidence suggests that most solid malignancies consist of heterogeneous tumor cells and that a relatively small subpopulation, which shares biological features with stem cells, survives through potentially lethal stresses such as chemotherapy and radiation treatment. Since the survival of this subpopulation of cancer stem cells (CSC) plays a critical role in recurrence, it must be eradicated in order to cure cancer. We previously reported that vaccination with CD133+ murine melanoma cells exhibiting biological CSC features induced CSC-specific effector T cells. These were capable of eradicating CD133+ tumor cells in vivo, thereby curing the parental tumor. In the current study, we indicated that DEAD/H (Asp-Glu-Ala-Asp/His) box polypeptide 3, X-linked (DDX3X) is an immunogenic protein preferentially expressed in CD133+ tumor cells. Vaccination with DDX3X primed specific T cells, resulting in protective and therapeutic antitumor immunity. The DDX3X-primed CD4+ T cells produced CD133 + tumor-specific IFNγ and IL-17 and mediated potent antitumor therapeutic efficacy. DDX3X is expressed in various human cancer cells, including lung, colon, and breast cancer cells. These results suggest that anti-DDX3X immunotherapy is a promising treatment option in efforts to eradicate CSC in the clinical setting. © 2013 Springer-Verlag Berlin Heidelberg.

DOI： 10.1007/s00262-013-1467-x

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER  

Chemotherapy-induced nausea and vomiting (CINV) are some of the most problematic symptoms for cancer patients. Triplet therapy consisting of a 5HT3 receptor antagonist, aprepitant, and dexamethasone is a guideline-recommended antiemetic prophylaxis for highly emetogenic chemotherapy (HEC). The efficacy and safety of triplet therapy using a 0.75-mg dose of palonosetron have not yet been investigated. We performed a prospective phase II study using triplet antiemetic therapy with 0.75 mg of palonosetron.
Chemotherapy-na &lt; ve lung cancer patients scheduled to receive HEC were enrolled. The eligible patients were pretreated with antiemetic therapy consisting of the intravenous administration of 0.75 mg of palonosetron, and 9.9 mg of dexamethasone and the oral administration of 125 mg of aprepitant on day 1, followed by the oral administration of 80 mg of aprepitant on days 2-3 and the oral administration of 8 mg of dexamethasone on days 2-4. The primary endpoint was the complete response rate (the CR rate; no vomiting and no rescue medication) during the overall phase (0-120 h).
The efficacy analysis was performed in 63 patients. The CR rates during the overall, acute and delayed phases were 81.0, 96.8, and 81.0 %, respectively. The no nausea and no significant nausea rate during the overall phase were 54.0 and 66.7 %, respectively. The most common adverse event was grade 1 or 2 constipation.
Triplet antiemetic therapy using a 0.75-mg dose of palonosetron shows a promising antiemetic effect in preventing CINV in lung cancer patients receiving HEC.

DOI： 10.1007/s00520-013-1835-2

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCI LTD  

MHC class I-restricted peptide-based vaccination therapies have been conducted to treat cancer patients, because CD8(+) CTL can efficiently induce apoptosis of tumor cells in an MHC class I-restricted epitope-specific manner. Interestingly, clinical responders are known to demonstrate reactivity to epitopes other than those used for vaccination: however, the mechanism underlying how antitumor T cells with diverse specificity are induced is unclear. In this study, we demonstrated that dendritic cells (DCs) that engulfed apoptotic tumor cells in the presence of non-tumor MHC class II-restricted epitope peptides, OVA(323-339), efficiently presented tumor-associated antigens upon effector-dominant CD4(+) T cell balance against regulatory T cells (Treg) for the OVA(323-339) epitope. Th1 and Th17 induced tumor-associated antigens presentation of DC, while Th2 ameliorated tumor-antigen presentation for CD8(+) T cells. Blocking experiments with anti-IL-23p19 antibody and anti-IL-23 receptor indicated that an autocrine mechanism of IL-23 likely mediated the diverted tumor-associated antigens presentation of DC. Tumor-associated antigens presentation of DC induced by OVA(323-339) epitope-specific CD4(+) T cells resulted in facilitated antitumor immunity in both priming and effector phase in vivo. Notably, this immunotherapy did not require pre-treatment to reduce Treg induced by tumor. This strategy may have clinical implications for designing effective antitumor immunotherapies. (c) 2012 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.vaccine.2012.07.060

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER SOC HEMATOLOGY  

Cytotoxic lymphodepletion therapies augment antitumor immune responses. The generation and therapeutic efficacy of antitumor effector T cells (T(E)s) are enhanced during recovery from lymphopenia. Although the effects of lymphodepletion on naive T cells (T(N)s) and T(E)s have been studied extensively, the influence of lymphodepletion on suppressor cells remains poorly understood. In this study, we demonstrate a significant increase of CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) in sublethally irradiated lymphopenic mice. These radio-resistant Tregs inhibited the induction of T(E)s in tumor-draining lymph-nodes (TDLNs) during recovery from lymphopenia. The transfer of T(N)s into lymphopenic tumor-bearing mice resulted in some antitumor effects; however, Treg depletion after whole-body irradiation and reconstitution strongly inhibited tumor progression. Further analyses revealed that tumor-specific T cells were primed from the transferred T(N)s, whereas the Tregs originated from irradiated recipient cells. As in irradiated lymphopenic mice, a high percentage of Tregs was observed in cyclophosphamide-treated lymphopenic mice. The inhibition of Tregs in cyclophosphamide-treated mice significantly reduced tumor growth. These results indicate that the Tregs that survive cytotoxic therapies suppress antitumor immunity during recovery from lymphopenia and suggest that approaches to deplete radio and chemo-resistant Tregs can enhance cancer immunotherapies. (Blood. 2012;120(12):2417-2427)

DOI： 10.1182/blood-2012-02-411124

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER  

Accumulating evidence suggests that cancer cells possess a small subpopulation that survives during potentially lethal stresses, including chemotherapy, radiation treatment, and molecular-targeting therapy. CD133 is a putative marker that distinguishes a minor subpopulation from normal differentiated tumor cells in many cancers. Although it is necessary to eradicate all cancer cells to obtain a cure, effective treatment to eliminate the CD133(+) treatment-tolerant cells has not been elucidated. In this study, we demonstrated that a CD133(+) subpopulation in murine melanoma is immunogenic and that effector T cells specific for the CD133(+) melanoma cells mediated potent antitumor reactivity, curing the mice of the parental melanoma. CD133(+) melanoma antigens preferentially induced type 17 T helper (Th17) cells and Th1 cells but not Th2 cells. CD133(+) melanoma cell-specific CD4(+) T-cell treatment eradicated not only CD133(+) tumor cells but also CD133(-) tumor cells while inducing long-lasting accumulation of lymphocytes and dendritic cells with upregulated MHC class II in tumor tissues. Further, the treatment prevented regulatory T-cell induction. These results indicate that T-cell immunotherapy is a promising treatment option to eradicate CD133(+) drug-tolerant cells to obtain a cure for cancer.

DOI： 10.1007/s00262-011-1063-x

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BIOMED CENTRAL LTD  

Background: Gefitinib was the first epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) approved for the treatment of advanced non-small cell lung cancer (NSCLC). Few treatment options are available for NSCLC patients who have responded to gefitinib treatment and demonstrated tumor progression. The present study was conducted to evaluate the efficacy and toxicity of the 2(nd) EGFR-TKI administration.
Methods: We retrospectively analyzed 11 patients who had obtained a partial response (PR) or stable disease (SD) with gefitinib treatment and were re-treated with EGFR-TKI after failure of the initial gefitinib treatment.
Results: Three patients (27%) were treated with gefitinib as the 2(nd) EGFR-TKI, and 8 patients (73%) received erlotinib. Only one patient (9%) showed PR, 7 (64%) achieved SD, and 3 (27%) had progressive disease. The disease control rate was 73% (95% CI, 43% - 91%) and the median progression-free survival was 3.4 months (95% CI, 2 - 5.2). The median overall survival from the beginning of the 2(nd) EGFR-TKI and from diagnosis were 7.3 months (95% CI, 2.7 - 13) and 36.7 months (95% CI, 23.6 - 43.9), respectively. No statistical differences in PFS or OS were observed between gefitinib and erlotinib as the 2(nd) EGFR-TKI (PFS, P = 0.23 and OS, P = 0.052). The toxicities associated with the 2(nd) EGFR-TKI were generally acceptable and comparable to those observed for the initial gefitinib therapy.
Conclusions: Our results indicate that a 2(nd) EGFR-TKI treatment can be an effective treatment option for gefitinib responders.

DOI： 10.1186/1471-2407-11-1

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1186/1752-1947-5-226

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：B M J PUBLISHING GROUP  

We report a female patient with small cell lung cancer (SCLC) and clinical findings consistent with polyglandular autoimmune syndrome type 2 (PGA2) and paraneoplastic neurological syndrome (PNS). To the best of our knowledge, this is the first reported case of SCLC associated with PGA2 and PNS. All of the autoantibodies detected before anticancer treatment decreased below the upper normal limits after serial treatment, and the patient&apos;s clinical symptoms also improved. Cross reactivity of autoantibodies may have contributed to the complicated clinical picture of this patient.

DOI： 10.1136/thx.2007.093211

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER ASSOC IMMUNOLOGISTS  

Suppression of tumor-specific T cell sensitization is a predominant mechanism of tumor escape. To identify tumor-induced suppressor cells, we transferred spleen cells from mice bearing progressive MCA205 sarcoma into sublethally irradiated mice. These mice were then inoculated subdermally with tumor cells to stimulate T cell response in the tumor-draining lymph-node (TDLN). Tumor progression induced splenomegaly with a dramatic increase (22.1%) in CD11b(+)Gr-1(+) myeloid-derived suppressor cells (MDSC) compared with 2.6% of that in normal mice. Analyses of therapeutic effects by the adoptive immunotherapy revealed that the transfer of spleen cells from tumor-bearing mice severely inhibited the generation of tumor-immune T cells in the TDLN. We further identified MDSC to be the dominant suppressor cells. However, cells of identical phenotype from normal spleens lacked the suppressive effects. The suppression was independent of CD4(+)CD25(+) regulatory T cells. Intracellular IFN-gamma staining revealed that the transfer of MDSC resulted in a decrease in numbers of tumor-specific CD4(+) and CD8(+) T cells. Transfer of MDSC from MCA207 tumor-bearing mice also suppressed the MCA205 immune response indicating a lack of immunologic specificity. Further analyses demonstrated that MDSC inhibited T cell activation that was triggered either by anti-CD3 mAb or by tumor cells. However, MDSC did not suppress the function of immune T cells in vivo at the effector phase. Our data provide the first evidence that the systemic transfer of MDSC inhibited and interfered with the sensitization of tumor-specific T cell responses in the TDLN.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Curative immunotherapy against spontaneous metastases of poorly immunogenic tumors has been difficult to demonstrate, but it is highly relevant to clinical disease conditions. The 4T1 mammary carcinoma shares many characteristics of human mammary cancer. Here, mice with 4T1 spontaneous metastases were treated effectively with a combination of dendritic (DC)-tumor hybrid vaccination and adoptive transfer of tumor-draining lymph node-derived immune T cells. This strategy significantly prolonged survival and cured some mice. In this model, the combined immunotherapy induced a dramatic increase of T cells in the lung where metastases were located and in the spleen where tumor was not present. The mechanism of increasing numbers of T cells is likely attributed to the ability of DC-tumor hybrids to stimulate vigorous proliferation of adoptively transferred T cells rather than to promote their infiltration into tumor-harboring and lymphoid organs. Taken together, the combined approach may be useful for clinical development of cancer immunotherapy.

DOI： 10.1016/j.clim.2007.12.001

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/j.1365-3083.2007.02012.x

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Dendritic-tumor heterokaryons generated by electrofusion are highly immunogenic. In animal studies, a single vaccination was therapeutic for tumors established in the lung, skin, and brain. However, effective therapy required a third signal which could be provided by exogenous IL-12 or the agonistic anti-OX-40R monoclonal antibody (mAb). In this study, we investigated the mechanism and mode of actions of these two seemingly distinct adjuvants. In immunotherapy of the MCA205 sarcoma, administration of the neutralizing anti-IL-12 mAb nearly completely blocked the adjuvant effect of IL-12, but had minimal inhibitory effects on anti-OX-40R mAb. By contrast, in vivo administration of the antagonistic anti-OX-40L mAb inhibited the adjuvant effects of both IL-12 and anti-OX-40R mAb. Thus, a common pathway of endogenous OX-40 interaction is critical for the development of a therapeutic immune response. Analysis of the third signal mechanism revealed that in the absence of an adjuvant, vaccination with fusion hybrids led to IL-10 production without eliciting IFN-gamma secreting cells. The addition of IL-12 to vaccination suppressed IL-10 production and initiated sensitization of specific IFN-gamma secreting cells, resulting in a type 1-like antitumor immunity. These findings underscore the significance of the third signal in the design of dendritic cell-based cancer vaccines.

DOI： 10.1016/j.cellimm.2006.11.002

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER ASSOC IMMUNOLOGISTS  

Although it has been demonstrated that the functions of dendritic cells (DCs), including Ag capture, Ag presentation, and migratory activity, change dynamically with their maturation, the most appropriate conditioning of DCs for anticancer immunotherapy is still unclear. The help signal is one of the most potent stimuli for DC maturation and is provided by the interaction of CD40 expressed on DCs with CD40 ligand on CD4(+) T cells. To elucidate the appropriate conditioning of DCs for anticancer immunotherapy, we examined the biological activity of DCs stimulated with immobilized anti-CD40 Ab. DCs stimulated for 3 h (3h-DCs) still showed an immature phenotype, but exhibited augmented migration toward secondary lymphoid tissues. Subcutaneous injection of 3h-DCs facilitated priming of T cells, which could mediate potent antitumor therapeutic efficacy, in draining lymph nodes and successfully induced protective immunity. In contrast, 24h-DCs showed a mature phenotype with good Ag presentation ability to induce cell killing by adoptively transferred CD8(+) T cells when injected at tumor sites; however, they showed no migratory activity and were unable to induce protective immunity when injected s.c.. This is the first report that functionally distinct I)Cs, either for the priming phase or for the effector phase, could be obtained by conditioning with CD40 stimulation and that the duration of stimulation determines the biological outcome. The usage of DCs conditioned for the priming phase might provide significant advantages in anticancer immunotherapy.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATURE PUBLISHING GROUP  

Although non-frozen storage of peripheral blood stem cells (PBSC) has been extensively studied and utilized clinically, the optimal storage conditions have not been determined. In order to improve the maintenance of clonogenic capacity during storage, we evaluated the feasibility of subzero non-freezing preservation of PBSC and attempted to determine the optimal conditions. Human PBSC were stored in different non-cryopreserved conditions. University of Wisconsin (UW) solution was used as the storage medium for PBSC. The stem cell integrity was optimally maintained when PBSC were preserved in a supercooled state at -2degreesC in UW solution without any cryoprotectants, and the highest values for nucleated cell survival (91.6%), CFU-GM survival (67.3%) and trypan blue viability (92%) were achieved at 72 h. CFU-GM survival in our storage conditions was significantly better than the survival achieved with hypothermic preservation in autologous serum and ACD-A solution at 4degreesC (67.3 +/- 9.2% vs 42.9 +/- 15.3%; P &lt; 0.01) or cryopreservation at -80&DEG;C (67.3 &PLUSMN; 9.2% vs 52.7 &PLUSMN; 10.7%; P &lt; 0.01). Thus, the combination of supercooling and UW solution was the optimal non-freezing method of preserving transplantable PBSC tested here. This method is of clinical utility in peripheral blood stem cell transplantation (PBSCT) for its simplicity and storage efficiency, and has value as a short-term storage method for PBSC to support dose-intensive multicyclic chemotherapy.

DOI： 10.1038/sj.bmt.1703692

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記述言語：日本語   出版者・発行元：(一社)日本呼吸ケア・リハビリテーション学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸ケア・リハビリテーション学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER ASSOC CANCER RESEARCH  

DOI： 10.1158/1538-7445.AM2019-4036

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記述言語：日本語   出版者・発行元：(一社)日本睡眠学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

J-GLOBAL

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER ASSOC CANCER RESEARCH  

DOI： 10.1158/1538-7445.AM2018-2717

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記述言語：日本語   出版者・発行元：(株)癌と化学療法社  

症例は52歳、男性。慢性骨髄性白血病(CML)に対してX-4年からメシル酸イマチニブ(imatinib mesylate、以下イマチニブ)、X-2年からニロチニブ、X-1年からダサチニブを開始された。X年11月ごろより息切れが出現し、胸部X線、胸部CTで浸潤影、両側胸水を認めた。抗菌薬と利尿剤を開始されたが改善を認めず、当科を紹介受診した。経気管支肺生検で得られた生検組織で肺胞腔内にポリープ状線維化巣を認め、器質化肺炎と診断した。ダサチニブを中止してステロイド治療を行い、臨床症状、画像所見の改善を認めた。その後CMLに対して、イマチニブ、ニロチニブを投与したが治療効果を認めなかった。ステロイド併用下でダサチニブを再投与し、器質化肺炎の再燃なくCMLをコントロールすることができた。ダサチニブによる器質化肺炎はまれであり、これまで報告はない。ステロイド治療によりダサチニブの再投与が可能であった器質化肺炎の症例を経験したので、文献的考察を含め報告する。(著者抄録)

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2018&ichushi_jid=J00296&link_issn=&doc_id=20180528410016&doc_link_id=%2Fab8gtkrc%2F2018%2F004505%2F017%2F0851-0854%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fab8gtkrc%2F2018%2F004505%2F017%2F0851-0854%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

記述言語：日本語   出版者・発行元：(NPO)日本呼吸器内視鏡学会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器内視鏡学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

目的. サルコイドーシスやサルコイド反応は肺門・縦隔リンパ節腫大を呈し、これらを合併した肺癌症例には、リンパ節病変の評価が治療方針決定上で問題となる。本研究では、これらサルコイド反応合併肺癌症例の病期診断におけるEBUS-TBNAの有用性を検討した。対象と方法. 2009年1月から2016年12月に気管支鏡検査を実施され、サルコイドーシス/サルコイド反応と肺癌の合併と診断された症例におけるEBUS-TBNAの有効性について検討した。結果. EBUS-TBNAにより、サルコイドーシス/サルコイド反応と肺癌との合併と診断された症例は4例であった。造影CT、FDG-PET/CTでは癌のリンパ節転移とサルコイドーシス/サルコイド反応の鑑別は困難であった。4例中3例はI期の非小細胞肺癌と診断され、2例は手術が施行された。術後検体でも転移はなく、granulomaが認められたことから、サルコイド反応と診断された。4例中1例は全身性サルコイドーシスに合併したIII期の肺癌症例であった。結論. サルコイドーシス/サルコイド反応合併肺癌症例におけるN因子の評価に、EBUS-TBNAは有用であると考えられる。(著者抄録)

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2018&ichushi_jid=J01244&link_issn=&doc_id=20180515270004&doc_link_id=%2Fec7jaluc%2F2018%2F005802%2F004%2F0088-0092%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fec7jaluc%2F2018%2F005802%2F004%2F0088-0092%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：WILEY  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：OXFORD UNIV PRESS  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：OXFORD UNIV PRESS  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：英語   出版者・発行元：日本癌学会  

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記述言語：日本語   出版者・発行元：(一社)日本睡眠学会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器内視鏡学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER SOC CLINICAL ONCOLOGY  

DOI： 10.1200/JCO.2017.35.15_suppl.9064

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：ELSEVIER SCIENCE INC  

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記述言語：日本語   出版者・発行元：新潟県医師会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

症例1は75歳、男性。症例2は64歳、男性。いずれも、術後再発非小細胞肺癌に対する胸部照射後に出現した浸潤影を放射線肺炎と診断し、ステロイド治療を行った。陰影は急速に増大したために抗菌薬治療を行ったが不応性であった。喀痰または肺洗浄検体よりアスペルギルス属を検出し、その後長期にわたる抗真菌薬治療を必要とした。呼吸器内科医として日常遭遇する可能性が高く、鑑別診断に慎重を要する2症例と考えられ報告する。(著者抄録)

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その他リンク： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2016&ichushi_jid=J05953&link_issn=&doc_id=20161205180012&doc_link_id=%2Fci6respo%2F2016%2F000506%2F012%2F0341-0345%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fci6respo%2F2016%2F000506%2F012%2F0341-0345%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：英語   出版者・発行元：日本癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器内視鏡学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER ASSOC CANCER RESEARCH  

DOI： 10.1158/1538-7445.AM2016-3206

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器内視鏡学会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器内視鏡学会  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器内視鏡学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER SOC CLINICAL ONCOLOGY  

DOI： 10.1200/JCO.2016.34.15_suppl.9008

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER SOC CLINICAL ONCOLOGY  

DOI： 10.1200/JCO.2016.34.15_suppl.8569

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記述言語：日本語   出版者・発行元：(一社)日本内科学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER THORACIC SOC  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：OXFORD UNIV PRESS  

Web of Science

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

J-GLOBAL

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：英語   出版者・発行元：日本癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：新潟医学会  

症例は71歳、男性。X-3年9月13日から左肺腺癌に対しゲフィチニブの内服治療を開始された。X年2月21日に腹痛、嘔吐を主訴に当科を受診。腹部造影CTで小腸腸管壁内ガス像および腹腔内遊離ガス像を指摘された。ゲフィチニブによる腸管気腫症と診断され、内服を中止し保存的治療で軽快した。ゲフィチニブ中止後、原病の増悪を認めたためX年4月15日からエルロチニブの内服を開始した。エルロチニブ内服開始後も腸管気腫症の再燃はなく、腫瘍の縮小を認めた。ゲフィチニブによる腸管気腫症は過去2例の報告のみである。今回我々は、ゲフィチニブにて腸管気腫症を発症し、エルロチニブにて安全に治療を再開可能であった症例を経験した。極めて稀な症例であり、文献的考察を含め報告した。(著者抄録)

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その他リンク： http://hdl.handle.net/10191/44200

記述言語：日本語   出版者・発行元：(一社)日本癌治療学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER ASSOC CANCER RESEARCH  

DOI： 10.1158/1538-7445.AM2015-3153

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.37.Special_S267_3

CiNii Article

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本内科学会  

DOI： 10.2169/naika.104.268

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記述言語：日本語   出版者・発行元：(株)癌と化学療法社  

症例は65歳、女性。約2ヵ月間続く左胸背部痛と動悸を主訴に前医を受診した。胸部CTで前縦隔腫瘤、縦隔リンパ節腫脹、左胸水、心嚢液貯留を認め、当院に紹介された。気管分岐下リンパ節に対する超音波気管支内視鏡下針生検および全身検索にて胸腺癌(正岡分類IVb期)と診断した。carboplatin(CBDCA)+weekly paclitaxel(PTX)療法を4サイクル施行後、腫瘍は著明に縮小し、心嚢液減少、左胸水消失を認めた。grade 1の嘔気、grade 2の貧血と脱毛以外に重篤な副作用は認められなかった。毒性が少なく、かつ腫瘍縮小効果が得られる治療法として、CBDCA+weekly PTX療法は胸腺癌に対する有用な治療選択肢の一つと考えられた。(著者抄録)

Scopus

PubMed

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：新潟医学会  

症例は54歳、男性。非小細胞肺癌(腺癌)、stage IV、上皮成長受容体遺伝子変異陽性と診断された。3次化学療法目的に入院した際、発熱、嘔気、低ナトリウム血症などの症状を認められた。血中コルチゾル低値、血中ACTH高値などから、急性副腎不全と診断した。両側副腎に巨大な肺癌の転移巣を認めており、副腎不全の原因と考えられた。ヒドロコルチゾン投与で症状は速やかに軽快した。肺癌は高率に副腎転移を来すが、両側副腎転移により副腎不全に至った報告例は少ない。我々は肺癌の両側副腎転移により副腎不全を来し、ステロイドホルモン補充により化学療法を再開しえた症例を経験したため、文献的考察を加え報告する。(著者抄録)

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その他リンク： http://hdl.handle.net/10191/43959

記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER ASSOC CANCER RESEARCH  

DOI： 10.1158/1538-7445.AM2014-200

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER ASSOC CANCER RESEARCH  

DOI： 10.1158/1538-7445.AM2014-2818

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：OXFORD UNIV PRESS  

DOI： 10.1093/annonc/mdu435.119

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER ASSOC CANCER RESEARCH  

DOI： 10.1158/1538-7445.AM2014-2554

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器内視鏡学会  

背景. 近年、肺末梢の病変に対するガイドシース併用気管支腔内超音波断層法(EBUS-GS)の有用性と安全性が報告されている。また、肺癌治療の進歩に伴い組織型の確定や遺伝子検索の必要性が増し、組織採取が重要になってきている。目的. 今回我々は肺末梢病変に対するEBUS-GS併用気管支鏡検査の有用性を検討した。対象と方法. 2011年8月から2013年3月の20ヵ月間に、肺末梢病変に対してEBUS-GS併用下に気管支鏡検査を施行した64例を評価した。結果. 悪性腫瘍に対する正診率、感度はそれぞれ72.6%、66.7%であった。気管支鏡検査で肺腺癌と診断された症例でのEGFR遺伝子変異陽性率は33.3%であった。結論. EBUS-GS併用にて得られた検体は、肺癌組織型の確定診断や遺伝子検索に有用であると考えられた。(著者抄録)

DOI： 10.18907/jjsre.36.5_456

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記述言語：英語   出版者・発行元：日本癌学会  

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記述言語：英語   出版者・発行元：日本癌学会  

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記述言語：日本語   出版者・発行元：日本シミュレーション医療教育学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER SOC CLINICAL ONCOLOGY  

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.36.Special_S190_1

CiNii Article

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記述言語：日本語   出版者・発行元：(一社)日本内科学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（全国大会，その他学術会議）  

Poster session (P1-35-1)in The Japanese Society of Medical Oncology 2014 Annual Meeting, Fukuoka, Japan

DOI： 10.1093/annonc/mdu436.71

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記述言語：日本語   出版者・発行元：新潟医学会  

症例は71歳男性。上縦隔腫瘤、左胸水、心嚢液貯留の精査目的に当科を紹介され入院した。心嚢水セルブロック法による組織学的診断で上皮型原発性心膜悪性中皮腫と診断された。ペメトレキセドとプラチナ併用化学療法を計4コース施行し、stable diseaseが得られた。2013年5月現在、抗癌剤の最終投与日から約18ヵ月間が経過し無増悪生存中である。原発性心膜悪性中皮腫は稀であり、標準治療は確立されていない。本症例から、ペメトレキセドを含むプラチナ併用化学療法が有効である可能性が示唆された。(著者抄録)

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その他リンク： http://hdl.handle.net/10191/36221

記述言語：英語   出版者・発行元：日本癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：新潟医学会  

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その他リンク： http://search.jamas.or.jp/link/ui/2014076237

記述言語：日本語   出版者・発行元：(NPO)日本緩和医療学会  

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記述言語：日本語   出版者・発行元：新潟医学会  

症例は39歳、男性。非小細胞肺癌(腺癌)、stage IV、上皮成長因子受容体遺伝子変異陰性と診断された。4次化学療法としてエルロチニブの内服を開始し、8日目に急性肺障害を発症した。副腎皮質ステロイド治療で急性肺障害は改善したが、骨転移巣に対する放射線照射、イリノテカン投与により急性肺障害の再燃を繰り返した。抗癌剤による急性肺障害の軽快後に照射や化学療法を行う際には、肺障害再燃の可能性を念頭におく必要がある。(著者抄録)

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その他リンク： http://hdl.handle.net/10191/35838

記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER ASSOC CANCER RESEARCH  

DOI： 10.1158/1538-7445.AM2013-3963

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(一社)日本癌治療学会  

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記述言語：英語   出版者・発行元：日本癌学会  

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記述言語：英語   出版者・発行元：日本癌学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER ASSOC CANCER RESEARCH  

DOI： 10.1158/1538-7445.AM2012-1550

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記述言語：日本語   出版者・発行元：新潟医学会  

症例は60歳、男性。2008年8月より湿性咳嗽が出現した。10月のCTで左肺上葉に45mm大の腫瘤影と両側肺門・縦隔・噴門部・傍大動脈リンパ節の腫大を認めた。気管支鏡検査、上部消化管内視鏡検査により、非小細胞肺癌、胃癌の同時重複癌と診断した。全身化学療法を施行したが徐々に原病は進行し、2009年7月1日のCTでは新たに両側副腎転移巣を認めた。2009年7月24日から腹痛、7月28日から発熱が出現した。7月29日のCTで右副腎転移巣の著明な増大、内部に高濃度域を認め、副腎出血と診断した。悪性腫瘍の副腎転移巣から出血を来す症例は稀であり、文献的考察を加え報告する。(著者抄録)

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その他リンク： http://search.jamas.or.jp/link/ui/2012333990

記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：英語   出版者・発行元：日本癌学会  

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記述言語：英語   出版者・発行元：日本癌学会  

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記述言語：日本語   出版者・発行元：(株)ヴァンメディカル  

がん化学療法時の悪心・嘔吐は患者QOLを低下させることはもとよりコンプライアンス低下を招き、治療に悪影響を与える可能性がある。今回、肺がん化学療法を受けた患者101名を対象に悪心・嘔吐の実態調査を実施した。その結果、悪心・嘔吐の「つらさ」に対して医師と患者の間での認識に乖離が認められ、遅発期の摂食障害がシスプラチン群で66%、カルボプラチン群で44%に発現することがわかった。制吐療法を行う際、遅発期まで含めた認識と対応が必要だと考えられる。(著者抄録)

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その他リンク： http://search.jamas.or.jp/link/ui/2011314339

記述言語：日本語   出版者・発行元：(株)日本医学館  

30歳女。16歳時にALL L1と診断され、19歳時にURBMTを施行された。21歳時にIPS after BMTを発症し、PSLを開始されたが徐々に増悪し、28歳時に妹、母親をドナーとする両肺生体移植を施行された。状態は安定していたが、その後急性拒絶反応を生じステロイド治療で改善した。今回、感冒様症状、発熱、呼吸困難が出現し、検査所見および画像所見よりARDSと診断して人工呼吸管理の上、ステロイドパルス療法、抗菌薬等を開始したが悪化した。PCPS導入して未分化ヘパリンを開始したところ改善傾向となったが、改善は不十分で徐々に悪化し、CMV抗原の上昇、LDH、FERの著明上昇、凝固マーカーの上昇などを来たし、VODを示唆する所見を認めた。ADAMTS13活性の低下やインヒビターを認めないことから、CMV感染、TMAの合併と判断してCHDF、血漿交換、次いでFFP連日投与を行い、抗凝固療法を再開して更に抗ウイルス療法を開始した。CMV抗原の減少とともに改善傾向となったが、脳内イベントによる突然の散瞳と完全房室ブロックで心肺停止となり永眠された。

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER ASSOC CANCER RESEARCH  

DOI： 10.1158/1538-7445.AM2011-2685

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER ASSOC CANCER RESEARCH  

DOI： 10.1158/1538-7445.AM2011-2694

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：英語   出版者・発行元：日本癌学会  

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記述言語：英語   出版者・発行元：日本癌学会  

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記述言語：日本語   出版者・発行元：新潟医学会  

症例は22歳、男性。2008年9月中旬より喫煙を開始した。同月下旬より乾性咳嗽、労作時の息切れが出現。同年10月1日、38℃台の発熱が加わり前医を受診した。低酸素血症と両肺野のびまん性すりガラス影を認め緊急入院したが、翌日には呼吸状態がさらに悪化したため当科へ転院した。気管支肺胞洗浄液にて好酸球増多の所見が得られ、その他の臨床所見をふまえ、急性好酸球性肺炎の診断に至った。ステロイド療法へ良好に反応し、呼吸不全の著明な改善が得られた。その後、喫煙の再開時期に一致して咳嗽や息切れの再燃、及び末梢血好酸球数の再上昇を認めた。急性好酸球性肺炎は病因不明の疾患概念であるが、吸入抗原に対するアレルギー反応の関与が疑われている。吸入抗原のチャレンジテストにより原因物質の特定が可能であると考えられるが、安全な負荷試験は確立されておらず施行は困難である。本例は喫煙の再開により急性好酸球性肺炎が再燃しており、発症の原因を特定し得た貴重な症例であった。(著者抄録)

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その他リンク： http://search.jamas.or.jp/link/ui/2011062658

記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER ASSOC CANCER RESEARCH  

DOI： 10.1158/1538-7445.AM10-1920

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：PERGAMON-ELSEVIER SCIENCE LTD  

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記述言語：英語   出版者・発行元：日本癌学会  

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記述言語：英語   出版者・発行元：日本癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER ASSOC CANCER RESEARCH  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER ASSOC CANCER RESEARCH  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER THORACIC SOC  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER THORACIC SOC  

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記述言語：日本語   出版者・発行元：(一社)日本結核病学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(一社)日本結核病学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(一社)日本癌治療学会  

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記述言語：日本語   出版者・発行元：日本癌学会  

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記述言語：日本語   出版者・発行元：日本癌学会  

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記述言語：日本語   出版者・発行元：(株)癌と化学療法社  

57歳女.胸部X線で異常陰影を指摘された.胸部CTで左肺下葉に腫瘤を認めた.術前に確定診断は得られなかったが,画像上遠隔転移は認めず,左肺下葉切除および縦隔リンパ節郭清を行った.病理組織でリンパ上皮腫様癌と診断した.経過観察していたが,胸部X線で左胸膜の肥厚が出現した.その後増大傾向を認め,左背部痛も出現した.carboplatin/paclitaxel併用化学療法を開始した.血液毒性としてgrade 2〜3の好中球減少と貧血を認めたが,いずれも重篤なものではなく輸血は必要としなかった.非血液毒性はgrade 1の筋痛,末梢神経障害とGOT,GPT上昇が認められたが,いずれも一過性で特に治療を必要としなかった.左背部痛は軽減し,疼痛コントロールのために内服していたloxoprofenを中止した.画像上も徐々に胸水は減少,胸膜肥厚もほぼ消失し,新病変も認められなかったのでCRと判定した

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記述言語：日本語   出版者・発行元：新潟医学会  

44歳男.声のかすれが出現し,前胸部の腫瘤を自覚した.胸部CTで上縦隔に腫瘍を指摘された.前胸部腫瘍の生検を施行し,胸腺癌(扁平上皮癌)と診断した.画像上,腕頭動脈への腫瘍の直接浸潤が疑われ,正岡分類III期と診断した.PACE療法を施行した.副作用としては,grade 4の好中球減少,grade 2の便秘が出現したが,補助療法にていずれも短期間で改善した.PRと判定した.腫瘍摘出術,胸腺摘出術を施行した.術後は合併症なく順調に経過し退院した.術後放射線療法を外来にて施行した.外来で経過観察中であり,これまでのところ再発を認めていない

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その他リンク： http://hdl.handle.net/10191/2832

記述言語：日本語   出版者・発行元：(NPO)日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.26.3_255_3

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記述言語：日本語   出版者・発行元：(一社)日本内科学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：OXFORD UNIV PRESS  

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記述言語：日本語   出版者・発行元：日本癌学会  

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記述言語：日本語   出版者・発行元：日本癌学会  

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記述言語：日本語   出版者・発行元：日本癌学会  

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記述言語：日本語   出版者・発行元：日本癌学会  

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