Language：Japanese   Publisher：(一社)日本リンパ網内系学会  

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Language：Japanese   Publisher：(一社)日本血栓止血学会  

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Language：English   Publisher：(一社)日本血液学会  

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Language：English   Publisher：(一社)日本血液学会  

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Language：English   Publisher：(一社)日本血液学会  

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

To elucidate the long-term outcomes of non-anthracycline-containing therapies and central nervous system (CNS) events in patients with extranodal NK/T-cell lymphoma, nasal type (ENKTL), the clinical data of 313 patients with ENKTL diagnosed between 2000 and 2013 in a nationwide retrospective study in Japan were updated and analyzed. At a median follow-up of 8.4 years, the 5-year overall survival (OS) and progression-free survival (PFS) were 71% and 64%, respectively, in 140 localized ENKTL patients who received radiotherapy-dexamethasone, etoposide, ifosfamide, and carboplatin (RT-DeVIC) in clinical practice. Nine (6.4%) patients experienced second malignancies. In 155 localized ENKTL patients treated with RT-DeVIC, 10 (6.5%) experienced CNS relapse (median, 12.8 months after diagnosis). In five of them, the events were confined to the CNS. Nine of the 10 patients who experienced CNS relapse died within 1 year after CNS relapse. Multivariate analysis identified gingival (hazard ratio [HR], 54.35; 95% confidence interval [CI], 8.60-343.35) and paranasal involvement (HR, 7.42; 95% CI, 1.78-30.89) as independent risk factors for CNS relapse. In 80 advanced ENKTL patients, 18 received steroid (dexamethasone), methotrexate, ifosfamide, L-asparaginase, and etoposide (SMILE) chemotherapy as first-line treatment. Patients who received SMILE as their first-line treatment tended to have better OS than those who did not (p = 0.071). Six (7.5%) advanced ENKTL patients experienced isolated CNS relapse (median, 2.6 months after diagnosis) and died within 4 months of relapse. No second malignancies were documented in advanced ENKTL patients. In the entire cohort, the median OS after first relapse or progression was 4.6 months. 12 patients who survived 5 years after PFS events were disease-free at the last follow-up. Of those, 11 (92%) underwent hematopoietic stem cell transplantation. Our 8-year follow-up revealed the long-term efficacy and safety of RT-DeVIC and SMILE. The risk of CNS relapse is an important consideration in advanced ENKTL.

DOI： 10.1002/hon.2977

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Language：Japanese   Publisher：(一社)日本血液学会-東京事務局  

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Language：Japanese   Publisher：(一社)日本血液学会-東京事務局  

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Language：English   Publisher：(一社)日本血液学会  

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

Polatuzumab vedotin (pola) is a CD79b-targeted antibody-drug conjugate delivering a potent antimitotic agent (monomethyl auristatin E) to B cells. This was an open-label, single-arm study of pola 1.8 mg/kg, bendamustine 90 mg/m2 , rituximab 375 mg/m2 (pola + BR) Q3W for up to six cycles in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) who received ≥1 prior line of therapy and were ineligible for autologous stem cell transplantation (ASCT) or experienced treatment failure with prior ASCT. Primary endpoint was complete response rate (CRR) at the end of the treatment (EOT) by positron emission tomography-computed tomography (PET-CT) using modified Lugano Response Criteria. Secondary endpoints included efficacy, safety, and pharmacokinetics. Thirty-five patients (median age 71 [range 46-86] years) were enrolled. Twenty-three (66%) patients had refractory disease, and 23 (66%) had ≥2 prior lines of therapy. At a median follow-up of 5.4 (0.7-11.9) months, patients received a median of five treatment cycles. CRR was 34.3% (95% confidence interval [CI] 19.1-52.2) at EOT. Overall response rate was 42.9% at EOT, and median progression-free survival was 5.2 months (95% CI 3.6-not evaluable). Median overall survival was not reached. No fatal adverse events (AEs) were observed. Grade 3-4 AEs were mainly hematological: anemia (37%), neutropenia (31%), white blood cell count decreased (23%), thrombocytopenia/platelet count decreased/neutrophil count decreased (20% each), and febrile neutropenia (11%). Grade 1-2 peripheral neuropathy (PN; sensory and/or motor) was reported in 14% of patients; there were no ≥grade 3 PN events. This study (JapicCTI-184048) demonstrated the efficacy and safety of pola + BR in Japanese patients with R/R DLBCL who were ineligible for ASCT.

DOI： 10.1111/cas.14937

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Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/cas.14937

Language：Japanese   Publisher：(一社)日本血液学会-東京事務局  

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Language：Japanese   Publisher：(一社)日本血液学会-東京事務局  

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Language：Japanese   Publisher：(一社)日本血液学会-東京事務局  

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Language：Japanese   Publisher：(一社)日本血液学会-東京事務局  

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Language：Japanese   Publisher：(一社)日本血栓止血学会  

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Language：Japanese   Publisher：(一社)日本リンパ網内系学会  

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Language：Japanese   Publisher：(一社)日本血液学会-東京事務局  

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Language：Japanese   Publisher：(一社)日本血液学会-東京事務局  

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Language：Japanese   Publisher：(一社)日本血栓止血学会  

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Language：Japanese   Publisher：(一社)日本血液学会-東京事務局  

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Language：Japanese   Publisher：(一社)日本リンパ網内系学会  

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Language：Japanese   Publisher：(一社)日本血液学会-東京事務局  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Oxford University Press (OUP)  

<title>Abstract</title>
<sec>
<title>Objective</title>
Fludarabine, cyclophosphamide and rituximab (FCR) is the standard regimen for fit patients with untreated CD20-positive chronic lymphocytic leukemia (CLL). However, this combination is unavailable in Japan because rituximab is not approved for CLL. We investigated the efficacy and safety of FCR in this single-arm, multicenter study designed as a bridging study to the CLL8 study by the German CLL Study Group.


</sec>
<sec>
<title>Methods</title>
The study enrolled previously untreated patients with CLL of Binet stage B or C with active disease. Patients with a Cumulative Illness Rating Scale score of ≤6 and creatinine clearance of ≥70 ml/min were eligible. Patients received 6 cycles of FCR every 28 days and were followed for up to 1 year.


</sec>
<sec>
<title>Results</title>
Seven patients were enrolled. The best overall response rate according to the 1996 NCI-WG Guidelines, the primary endpoint of the study, was 71.4% (95% confidence interval, 29.0–96.3%), with one patient achieving complete response. No deaths or progression occurred during follow-up. The main adverse event was hematotoxicity. CD4-positive T-cell count decreased in all patients; most patients showed no reduction in serum immunoglobulin G.


</sec>
<sec>
<title>Conclusion</title>
Although the number of patients was limited, FCR appears to be effective with manageable toxicity for treatment-naïve fit Japanese patients with CD20-positive CLL.


</sec>
<sec>
<title>Clinical trial number</title>
JapicCTI-132285.


</sec>

DOI： 10.1093/jjco/hyaa215

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Bendamustine and rituximab (BR) are widely used in patients with follicular lymphoma (FL) previously treated with conventional immunochemotherapy, but the role of consolidation radioimmunotherapy in these patients is unknown. This study evaluated the efficacy and safety of consolidation with 90 Yttrium-ibritumomab tiuxetan (90 Y-IT) after re-induction therapy with BR in patients with previously treated FL. This study included adult patients with relapsed FL who had undergone one or two prior therapies. Re-induction therapy with BR was administered every 4 weeks up to 4-6 cycles. If patients achieved at least partial response, 90 Y-IT was administered as consolidation therapy. The primary endpoint was 2-year progression-free survival (PFS) after consolidation. A total of 24 FL patients (median age 60 years) who had undergone one (n = 17) or two (n = 7) prior treatments received BR. After BR therapy, 22 patients proceeded to consolidation with 90 Y-IT, resulting in an overall 88% response rate to the protocol treatment. Within a median observation period of 46.8 months, the estimated 2-year PFS rate after the consolidation among the 22 patients receiving 90 Y-IT was 59% (95% confidence interval [CI], 38%-77%). Patients whose remission after previous treatment had lasted ≥2 years had a significantly higher 2-year PFS rate than patients whose remission after previous treatment had been <2 years (68% vs. 33%, Wilcoxon p = 0.0211). Major adverse events during the protocol treatment and within 2 years after the consolidation were hematological toxicities, but they were generally acceptable. Consequently, the estimated 2-year overall survival after the consolidation was 95% (95% CI, 74%-99%). In conclusion, in a subset of patients with previously treated FL, 90 Y-IT consolidation after BR re-induction conferred a durable remission, indicating that consolidation therapy using 90 Y-IT may be a novel therapeutic option for patients with relapsed FL (UMIN000008793).

DOI： 10.1002/hon.2809

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Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japanese Society for Lymphoreticular Tissue Research  

High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, also known as double-hit lymphoma, has been reported as refractory to R-CHOP therapy and requires more intensive regimens. However, intensive and safe regimens for patients with renal dysfunction are unknown. Herein, we report the successful use of DA-EPOCH-R therapy for double-hit lymphoma in a 64-year-old man with renal dysfunction. The patient had lymphoma-induced bilateral ureteral obstruction. Although renal dysfunction remained after removing the obstruction using R-CHOP therapy, we completed six cycles of DA-EPOCH-R therapy without any major adverse events. DA-EPOCH-R therapy may be a safe regimen for renal dysfunction patients.

DOI： 10.3960/jslrt.20043

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japanese Society for Lymphoreticular Tissue Research  

There are limited real-world data on the treatment practices and healthcare resource utilization associated with chronic lymphocytic leukemia (CLL) in Japan. In this study (CLIMBER-DBR), we performed retrospective analyses of the Japanese Medical Data Vision database, and extracted data for 2562 patients with newly diagnosed CLL (CLL-1 cohort) and 930 patients receiving CLL treatment (CLL-2 cohort) registered between March 1, 2013 and February 28, 2018. The median follow-up in the CLL-1 cohort was 721 (quartile 1-3: 363-1267) days and the median time to initial (first-line) treatment was 1331 (quartile 1-3: 189-not reached) days. In the CLL-2 cohort, the most frequently used regimens were fludarabine alone (17.7%), cyclophosphamide alone (13.7%), and bendamustine/rituximab (8.2%). The median (quartile 1-3) times to second-line and third-line treatments were 1066 (273-not reached) and 1795 (631-not reached) days, respectively. The CLIMBER-DBR was the first database research study to assess current treatment practices for CLL in Japan, where the treatment patterns were driven by the approval/reimbursement status of drugs in the study period. Our study provides an important benchmark for future studies of CLL in Japan.

DOI： 10.3960/jslrt.20044

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japanese Society for Lymphoreticular Tissue Research  

Mantle cell lymphoma (MCL) accounts for approximately 3% of all cases of malignant lymphoma in Japan. The CLIMBER-DBR (Treatment practices and patient burden in chronic lymphocytic leukemia and mantle cell lymphoma patients in the real world: An observational database research in Japan) study examined the clinical characteristics, treatment patterns, and health-care resource utilization of MCL in a real-world clinical setting in Japan. Using the Japanese Medical Data Vision database, we extracted data for 1130 patients with MCL (ICD-10 code C83.1) registered between March 1, 2013 and February 28, 2018. The date of first MCL diagnosis was taken as the index date. The mean (standard deviation) age, body weight, and modified Charlson Comorbidity Index were 71.4 (10.9) years, 58.3 (11.7) kg, and 1.9 (1.6). respectively, and 24.6% were <= 65 years old. The median follow-up period was 654 days (first-third quartile 290.5-1049 days). A total of 802 patients (71.0%) underwent first-line treatment. The most common first-line treatment was bendamustine/rituximab (BR; 27.8%), followed by rituximab/cyclophosphamide/doxorubicin/vincristine/prednisolone (R-CHOP; 15.6%) and rituximab/tetrahydropyranyl-adriamycin/cyclo-phosphamide/vincristine/prednisolone (R-THP-COP; 6.5%). The median (95% confidence interval) times to initial (first-line), second-line, and third-line treatments were 45 (36-62), 687 (624-734), and 1188 (1099-1444) days, respectively. Treatment practices for MCL in Japan are consistent with trends observed in Western countries. Our study can serve as a benchmark to assess future MCL treatments in Japan.

DOI： 10.3960/jslrt.20056

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

The interaction between CD47 and signal-regulatory protein-α (SIRPα) inhibits phagocytosis, thus affecting the clinical outcomes of neoplastic diseases. Although CD47 upregulation is associated with poor prognosis in several malignancies, the effect of SIRPα expression and its coexpression with CD47 remains unclear. This study aimed to investigate the clinicopathologic effect of CD47 and SIRPα expression in diffuse large B-cell lymphoma (DLBCL). Immunostaining of 120 biopsy samples showed that CD47 is primarily expressed in tumor cells, whereas SIRPα is expressed in nonneoplastic stromal cells, mostly macrophages. CD47high cases showed higher MYC protein expression and lower MYC translocation. The SIRPαhigh cases presented significantly shorter overall survival (OS) and progression-free survival (PFS) than SIRPαlow cases in the activated B-cell (ABC) subtype of DLBCL (P = .04 and P = .02, respectively). Both CD47high and SIRPαhigh presented significantly shorter OS and PFS than other cases among all DLBCL patients (P = .01 and P = .004, respectively), and the ABC type (P = .04 and P = .008, respectively) but not the germinal center B-cell type. Both CD47high and SIRPαhigh yielded a constant independent prognostic value for OS and PFS in multivariate analysis (hazard ratio [HR], 2.93; 95% confidence interval [CI], 1.20-7.43; P = .02; and HR, 2.87; 95% CI, 1.42-5.85; P = .003, respectively). To the best of our knowledge, this is the first study to report that combinatorial CD47 and SIRPα expression is a potential independent prognostic factor for DLBCL. Evaluation of CD47 and SIRPα expression could be useful before CD47 blockade therapy.

DOI： 10.1111/cas.14437

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Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/cas.14437

Language：Japanese   Publisher：(公社)日本皮膚科学会  

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

DOI： 10.1007/s12185-020-02867-0

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Other Link： http://link.springer.com/article/10.1007/s12185-020-02867-0/fulltext.html

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

BACKGROUND: Intravascular large B-cell lymphoma (IVLBCL) is a rare disease for which there is no available standard treatment. We aimed to ascertain the safety and activity of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) with high-dose methotrexate and intrathecal chemotherapy as CNS-oriented therapy for patients with previously untreated IVLBCL. METHODS: PRIMEUR-IVL is a multicentre, single-arm, phase 2 trial at 22 hospitals in Japan. Eligible patients had untreated histologically confirmed IVLBCL, were aged 20-79 years, had an Eastern Cooperative Group performance status of 0-3, and had no apparent CNS involvement at diagnosis. Patients received three cycles of R-CHOP (rituximab 375 mg/m2 intravenously on day 1 [except cycle one, which was on day 8]; cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1·4 mg/m2 [maximum 2·0 mg] intravenously on day 1 of cycle one and day 2 of cycles two and three; and prednisolone 100 mg/day orally on days 1-5 of cycle one and days 2-6 of cycles two and three) followed by two cycles of rituximab with high-dose methotrexate (3·5 g/m2 intravenously on day 2 of cycles four and five) every 2 weeks and three additional cycles of R-CHOP. Intrathecal chemotherapy (methotrexate 15 mg, cytarabine 40 mg, and prednisolone 10 mg) was administered four times during the R-CHOP phase. The primary endpoint was 2-year progression-free survival. Efficacy analyses were done in all enrolled patients; safety analyses were done in all enrolled and treated patients. The trial is registered in the UMIN Clinical Trials Registry (UMIN000005707) and the Japan Registry of Clinical Trials (jRCTs041180165); the trial is ongoing for long-term follow-up. FINDINGS: Between June 16, 2011, and July 21, 2016, 38 patients were enrolled, of whom 37 were eligible; one patient was excluded because of a history of testicular lymphoma. Median follow-up was 3·9 years (IQR 2·5-5·5). 2-year progression-free survival was 76% (95% CI 58-87). The most frequent adverse events of grade 3-4 were neutropenia and leucocytopenia, which were reported in all 38 (100%) patients. Serious adverse events were hypokalaemia, febrile neutropenia with hypotension, hypertension, and intracerebral haemorrhage (reported in one [3%] patient each). No treatment-related deaths occurred during protocol treatment. INTERPRETATION: R-CHOP combined with rituximab and high-dose methotrexate plus intrathecal chemotherapy is a safe and active treatment for patients with IVLBCL without apparent CNS involvement at diagnosis, and this regimen warrants future investigation. FUNDING: The Japan Agency for Medical Research and Development, the Center for Supporting Hematology-Oncology Trials, and the National Cancer Center.

DOI： 10.1016/s1470-2045(20)30059-0

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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

Primary splenic low-grade B-cell lymphoma of the red pulp comprises hairy cell leukemia (HCL) and splenic B-cell lymphoma/leukemia, unclassifiable (SPLL-U). SPLL-U is a rare disease that includes subtypes of a hairy cell leukemia-variant (HCL-v), splenic diffuse red pulp small B-cell lymphoma (SDRPL) and other types that are known as narrow sense SPLL-U (SPLL-U-NS). Notably, limited information is available regarding the BRAF mutation (V600E) and cyclin D3 expression in subtypes of SPLL-U. Therefore, we performed a pathological analysis of the BRAF mutation (V600E) and characterized pathological features of SPLL-U. We reviewed the pathological findings of 12 SPLL-U cases. The 12 cases considered included two cases of HCL-v, six cases of SPLL-U-NS and four undetermined cases. The BRAF mutation (V600E) was detected in three cases, which were all SPLL-U-NS. Cases with the BRAF mutation (V600E) have increased levels of CD103 expression and decreased cyclin D3 and cyclin D1 expression compared with cases that lacked the BRAF mutation. These findings suggest that the BRAF mutation might play a significant role in SPLL-U. Therefore, the significance of the BRAF mutation should be evaluated via genomic or transcriptional analyses of a large cohort of SPLL-U patients.

DOI： 10.1111/pin.12909

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Language：Japanese   Publisher：(一社)日本血液学会-東京事務局  

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

<sec><title>Objective</title>This study aimed to examine the natural course and relapse rate of IgG4-related ophthalmic disease (IgG4-ROD) after debulking surgery in Japanese patients.

</sec><sec><title>Methods and analysis</title>This retrospective review included patients with IgG4-ROD who did not undergo further treatment following debulking surgery. The patients were diagnosed between January 2009 and December 2018 at the Department of Ophthalmology and Pathology, Niigata University Medical and Dental Hospital. The main outcome measures included postoperative IgG4-ROD recurrence rate and differences between patients with and without recurrent disease.

</sec><sec><title>Results</title>Fifteen patients (six male, 9 female; 61.8±16.2 years) were included. Twelve patients (80.0%) had dacryoadenitis disease and three patients (20.0%) had orbital fat tissue disease. About 70%–100% of the lesion was resected in the debulking surgery and the pathological diagnosis was rendered. A definitive diagnosis was made in 13 cases (86.7%) and a probable diagnosis in 2 cases (13.3%). Patients were followed up for 39.0±25.5 months following operation. All patients had lesion volume reduction and patients with dacryoadenitis had eyelid swelling improvement after surgery. Two patients (13.3%) had disease recurrence and six patients (40.0%) had extraophthalmic lesions. There was no statistically significant difference in clinical features between relapsed and non-recurring cases.

</sec><sec><title>Conclusion</title>We observed a 13.3% relapse rate following debulking surgery in patients with IgG4-ROD who did not undergo further treatment. This rate is lower than the documented relapse rate of 30%–70% following oral prednisolone therapy. Therefore, debulking surgery may be a treatment option for IgG4-ROD.

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DOI： 10.1136/bmjophth-2019-000295

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Extranodal NK/T cell lymphoma (NKTCL), nasal type (ENKL) that shows no apparent nasal involvement, is termed extranasal NKTCL or non-nasal NKTCL. In this study, we aimed to explore therapeutic approaches and outcomes in patients with extranasal NKTCL in current clinical practice. A data set of patients with newly diagnosed NKTCL who were diagnosed at 31 institutes in Japan between 2000 and 2013 was used for analysis. The patients' fitness for steroid, methotrexate, ifosfamide, L-asparaginase, and etoposide (SMILE) chemotherapy was assessed using the major inclusion criteria of the SMILE phase 2 study. Of 358 patients, 47 (13%) had extranasal NKTCL. The most frequent extranodal sites of involvement in extranasal NKTCL were skin/subcutaneous tissue (n = 18). Six (13%) of the patients with extranasal NKTCL had localized disease and were diagnosed before 2010. With a median follow-up of 5.8 years, the 2-year overall survival (OS) in patients with nasal and extranasal NKTCL was 70% (95% confidence interval [CI], 65-75%) and 34% (95% CI, 21-47%), respectively. OS in patients with nasal NKTCL had a trend toward better according to treatment era (P = 0.063). In contrast, no obvious improvement of OS was observed in extranasal NKTCL (P = 0.43). The major inclusion criteria of the SMILE-P2 were met in 21% (10/47) of patients with extranasal NKTCL and 60% (188/311) of those with nasal NKTCL (P < 0.001). Despite the advent of new treatments for ENKL, OS remains unfavorable in extranasal NKTCL. A more effective therapy is needed for extranasal NKTCL.

DOI： 10.1007/s00277-019-03689-9

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Other Link： http://orcid.org/0000-0002-5974-7614

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The IgG-type neutralizing GM-CSF autoantibody (GMAb) is known to be the causative agent for autoimmune pulmonary alveolar proteinosis (APAP). Previous studies report that serum levels of IgG-GMAb are approximately 50-fold higher in APAP patients than in healthy subjects (HS). Serum levels of IgM-GMAb are also higher in APAP patients than in HS, but this has been assumed to be an etiological bystander. However, the mechanism for the excessive production of IgG-GMAb in APAP remains unclear. To investigate this, we detected putative GMAb-producing B cells (PGMPB) by inoculated B cells from the peripheral blood of APAP patients, HS, and umbilical cord blood mononuclear cells (UCBMNs) with Epstein-Barr virus. Both ELISA and ELISPOT assays showed that IgM-type GMAb was consistently and frequently present in all three groups, whereas IgG-type GMAb was high only in APAP patients, in whom it was exclusively produced in memory B cells and not in naive B cells. Since PGMPB in UCBMNs produced IgM-GMAb, but not IgG-GMAb, to the same extent as in HS and APAP patients, most IgM-GMAb reacted with GM-CSF in a non-specific manner. The memory B cell pool of APAP patients contain higher frequency of PGMPB than that of healthy subjects.

DOI： 10.1016/j.imlet.2019.05.013

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Language：Japanese   Publisher：(一社)日本リンパ網内系学会  

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Language：Japanese   Publisher：(一社)日本リンパ網内系学会  

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Authorship：Last author   Language：English  

DOI： 10.1002/hon.2565

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A 61-year-old woman exhibited right inguinal lymphadenopathy and right lower limb edema approximately 1 month prior to hospitalization. She was diagnosed with high grade B-cell lymphoma, and a lymph node biopsy and fluorescence in situ hybridization indicated MYC, BCL2, and BCL6 rearrangements (triple-hit lymphoma). She had progressive disease that was CD20-negative after two courses of rituximab, cyclophosphamide, doxorubicin, vincristine, methotrexate/ifosfamide, etoposide, high-dose cytarabine (R-CODOX-M/IVAC) therapy. Subsequent etoposide, prednisolone, vincristine, cyclophosphamide, doxorubicin (EPOCH) therapy was not effective. However, after two cycles of gemcitabine, dexamethasone, and cisplatin (GDP) therapy, she achieved a complete response and was able to undergo autologous peripheral blood stem cell transplantation. GDP therapy may be effective as salvage therapy for chemotherapy-resistant triple-hit lymphoma.

DOI： 10.2169/internalmedicine.1686-18

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Hypercalcemia due to malignant tumors including malignant lymphomas is relatively common. Among cancer patients with hypercalcemia, humoral hypercalcemia of malignancy is the most common and accounts for about 80% of all cases with hypercalcemia. 1,25-dihydroxyvitamin D3(1,25(OH)2D3)-mediated hypercalcemia is relatively rare. Although malignant lymphoma has been also reported to cause 1,25(OH)2D3-mediated hypercalcemia, it is not known whether there is any association between 1,25(OH)2D3-mediated hypercalcemia and any specific histological type of malignant lymphoma. We herein report a case of an anaplastic large cell lymphoma (ALCL), anaplastic lymphoma kinase (ALK) -negative with 1,25(OH)2D3-mediated hypercalcemia, which has never been previously reported. An 80-year-old Japanese man was admitted to our department due to acute exacerbation of hypercalcemia. He was diagnosed with ALCL, ALK-negative. Serum 1,25(OH)2D3 level was high and seemed to be associated with the lymphoma because the serum calcium and 1,25(OH)2D3 levels improved in response to chemotherapy. Histological findings showed that many CD68 positive macrophages were observed in the microenvironment of tumor cells. Lymphoma cells or tumor microenvironmental cells may produce 1,25(OH)2D3 because several previous reports showed the source of 1,25(OH)2D3 can be either lymphoma or tumor microenvironmental cells. Moreover, because 1,25(OH)2D3-mediated hypercalcemia has been reported regardless of the specific histological type of lymphoma, tumor microenvironmental cells may be involved in this condition. However, we could not identify the source of 1,25(OH)2D3 in this case. The association between 1,25(OH)2D3 production and prognosis in malignant lymphomas is yet unknown; further studies are needed to elucidate the clinical characteristics of malignant lymphoma with 1,25(OH)2D3-mediated hypercalcemia.

DOI： 10.3960/jslrt.18033

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

Erdheim-Chester disease (ECD), a rare form of non-Langerhans cell histiocytosis, is characterized by the infiltration of foamy CD68+ and CD1a- histiocytes into multiple organ systems. Central nervous system (CNS) involvement has recently been reported to be a poor prognostic factor when treating ECD with interferon alpha. We report the case of a 66-year-old Japanese patient with ECD involving the CNS who harbored the BRAF V600E mutation and also concomitantly developed polycythemia vera with the JAK2 V617F mutation. We confirmed 2-chlorodeoxyadenosine (cladribine) therapy to be effective for the patient in this case.

DOI： 10.3960/jslrt.18015

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DOI： 10.1007/s12185-018-2506-3

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Language：English   Publisher：(一社)日本血液学会-東京事務局  

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The characteristics of adult patients with chronic active Epstein-Barr virus infection are poorly recognized, hindering early diagnosis and an improved prognosis. We studied 54 patients with adult-onset chronic active Epstein-Barr virus infection diagnosed between 2005 and 2015. Adult onset was defined as an estimated age of onset of 15 years or older. To characterize the clinical features of these adults, we compared them to those of 75 pediatric cases (estimated age of onset <15 years). We compared the prognosis of adult-onset chronic active Epstein-Barr virus infection with that of patients with nasal-type (n=37) and non-nasal-type (n=45) extranodal NK/T-cell lymphoma. The median estimated age of onset of these lymphomas was 39 years (range, 16-86 years). Compared to patients with pediatric-onset disease, those in whom the chronic active Epstein-Barr virus infection developed in adulthood had a significantly decreased incidence of fever (P=0.005), but greater frequency of skin lesions (P<0.001). Moreover, hypersensitivity to mosquito bites and the occurrence of hydroa vacciniforme were less frequent in patients with adult-onset disease (P<0.001 and P=0.0238, respectively). Thrombocytopenia, high Epstein-Barr virus nuclear antigen antibody titer, and the presence of hemophagocytic syndrome were associated with a poor prognosis (P=0.0087, P=0.0236, and P=0.0149, respectively). Allogeneic hematopoietic stem cell transplantation may improve survival (P=0.0289). Compared to pediatric-onset chronic active Epstein-Barr virus infection and extranodal NK/T-cell lymphoma, adult-onset chronic active Epstein-Barr virus infection had a poorer prognosis (P<0.001 and P=0.0484, respectively). Chronic active Epstein-Barr virus infection can develop in a wide age range, with clinical differences between adult-onset and pediatric-onset disease. Adult-onset chronic active Epstein-Barr virus infection is a disease with a poor prognosis. Further research will be needed.

DOI： 10.3324/haematol.2017.174177

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Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare skin-tropic hematological malignancy of uncertain pathogenesis and poor prognosis. We examined 118 BPDCN cases for cytomorphology, MYC locus rearrangement, and MYC expression. Sixty-two (53%) and 41 (35%) cases showed the classic and immunoblastoid cytomorphology, respectively. Forty-one (38%) MYC+BPDCN (positive for rearrangement and expression) and 59 (54%) MYC-BPDCN (both negative) cases were identified. Immunoblastoid cytomorphology was significantly associated with MYC+BPDCN. All examined MYC+BPDCNs were negative for MYB/MYBL1 rearrangement (0/36). Clinically, MYC+BPDCN showed older onset, poorer outcome, and localized skin tumors more commonly than MYC-BPDCN. MYC was demonstrated by expression profiling as one of the clearest discriminators between CAL-1 (MYC+BPDCN) and PMDC05 (MYC-BPDCN) cell lines, and its shRNA knockdown suppressed CAL-1 viability. Inhibitors for bromodomain and extra-terminal protein (BETis), and aurora kinases (AKis) inhibited CAL-1 growth more effectively than PMDC05. We further showed that a BCL2 inhibitor was effective in both CAL-1 and PMDC05, indicating that this inhibitor can be used to treat MYC-BPDCN, to which BETis and AKis are probably less effective. Our data will provide a rationale for the development of new treatment strategies for patients with BPDCN, in accordance with precision medicine.

DOI： 10.1038/s41375-018-0154-5

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Language：Japanese   Publisher：(一社)日本血液学会-東京事務局  

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Myeloid sarcoma (MS) is a rare condition and is an extramedullary tumour of immature myeloid cells. It is now known that the programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) pathway suppresses the host antitumor responses and that these products are expressed on both tumour cells and tumour-infiltrating cells in various malignancies. However, little is known about the significance of PD-1/PD-L1 expression on tumour cells and tumour microenvironmental cells in MS. To investigate the clinicopathological significance of PD-1/PD-L1 expression in MS, we analyzed 98 patients by immunohistochemistry. Of these, 10.2% of cases had neoplastic tumour cells positive for PD-L1 (nPD-L1+ ). However, the rate of nPD-L1+ was <5% (range: 0.27 to 2.97%). On the other hand, PD-L1 expression on 1 or more of stromal cells in the tumour microenvironment (miPD-L1+ ) was observed in 37.8% of cases. Because all nPD-L1+ cases expressed PD-1 on less than 5% of tumour cells, we compared the miPD-L1+ and miPD-L1- groups. There was a correlation between miPD-L1+ status and the number of PD-1-expressing tumour -infiltrating lymphocytes (PD-1+ TILs; P = .0229). miPD-L1+ was found to be associated with poorer overall survival and progression-free survival (P = .00392, P = .00261, respectively). Multivariate analysis also confirmed miPD-L1+ to be an independent poor prognostic factor. In conclusion, our study indicated that the immunotherapy blocking the PD-1/PD-L1 pathway may improve the clinical outcome of MS.

DOI： 10.1002/hon.2506

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Membrane-associated guanylate kinase with inverted orientation protein 1 (MAGI-1) is a cytoplasmic scaffold protein that interacts with various signaling molecules; it negatively controls the cell growth of various types of cells and positively controls cell-cell interaction. In T cells, MAGI-1 has been shown to inhibit Akt activity through its interaction with PTEN and MEK1. In this study we found that MAGI-1 expression is decreased in multiple (9 out of 15) human T-cell leukemia cell lines, including adult T-cell leukemia (ATL), T-cell acute lymphoblastic leukemia and chronic T-cell lymphocytic leukemia. The overexpression of MAGI-1 protein in a MAGI-1-low ATL cell line reduced cellular growth. While the overexpression of MAGI-1 protein in a MAGI-1-low ATL cell line reduced the Akt and MEK activities, the knockdown of MAGI-1 in a MAGI-1-high ATL cell line augmented the Akt and MEK activities. Collectively, the findings of the present study suggest that the decreased expression of MAGI-1 in human T cells contributes to the development of several types of T-cell leukemia, partly through the stimulation of the Akt and MEK pathways.

DOI： 10.1007/s12185-017-2359-1

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

Most high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements are aggressive B-cell lymphomas. Occasional double-hit follicular lymphomas have been described but the clinicopathological features of these tumors are not well known. To clarify the characteristics of double-hit follicular lymphomas, we analyzed 10 cases of double-hit follicular lymphomas and 15 cases of high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements for clinicopathological and genome-wide copy-number alterations and copy-neutral loss-of-heterozygosity profiles. For double-hit follicular lymphomas, the median age was 67.5 years (range: 48-82 years). The female/male ratio was 2.3. Eight patients presented with advanced clinical stage. The median follow-up time was 20 months (range: 1-132 months). At the end of the follow-up, 8 patients were alive, 2 patients were dead including 1 patient with diffuse large B-cell lymphoma transformation. Rearrangements of MYC/BCL2, MYC/BCL6, and MYC/BCL2/BCL6 were seen in 8, 1, and 1 cases, respectively. The partner of MYC was IGH in 6 cases. There were no cases of histological grade 1, 4 cases of grade 2, 5 cases of grade 3a, and 1 case of grade 3b. Two cases of grade 3a exhibited immunoblast-like morphology. Immunohistochemistry demonstrated 9 cases with ≥50% MYC-positive cells. There was significant difference in MYC intensity (P=0.00004) and MIB-1 positivity (P=0.001) between double-hit follicular lymphomas and high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements. The genome profile of double-hit follicular lymphomas was comparable with conventional follicular lymphomas (GSE67385, n=198) with characteristic gains of 2p25.3-p11.1, 7p22.3-q36.3, 12q11-q24.33, and loss of 18q21.32-q23 (Po0.05). In comparison with highgrade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements, double-hit follicular lymphomas had fewer copy-number alterations and minimal common region of gain at 2p16.1 (70%), locus also significant against conventional follicular lymphomas (P=0.0001). In summary, double-hit follicular lymphomas tended to be high-grade histology, high MYC protein expression, high MYC/IGH fusion, and minimal common region of gain at 2p16.1. Double-hit follicular lymphomas seemed to be a different disease from high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements and have an indolent clinical behavior similar to follicular lymphomas without MYC rearrangement.

DOI： 10.1038/modpathol.2017.134

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Extranodal NK/T-cell lymphoma, nasal type (ENKTL) is a subtype of non-Hodgkin lymphoma with a poor prognosis. Although first-line treatments for patients with localized ENKTL have been established, there is no gold standard treatment for patients with advanced ENKTL and refractory and/or relapsed disease. Anti-CD30 antibody-based therapy, including brentuximab vedotin (BV), has been shown to target malignant lymphomas with CD30 expression. In particular, this therapeutic agent has recently been suggested to be effective for Hodgkin lymphoma and mature T-cell lymphoma. However, the efficacy of BV toward ENKTL has not yet been established. Therefore, we investigated the expression of CD30 in a large cohort to evaluate BV as a potential treatment for ENKTL. In this study, 97 Japanese patients with newly diagnosed ENKTL between January 2007 and December 2015 were enrolled. Flow cytometry and immunohistochemistry were performed for the evaluation of CD30 expression. If the cut-off value of CD30 expression is 1% or more, there were 55 positive cases (56.5%). According to the localization of lesion, the frequency of CD30 expression was significantly higher in the non-nasal type than in the nasal type (P = .0394). No differences were observed in almost all clinical characteristics between CD30-positive cases and CD30-negative cases. In addition, the expression of CD30 was not a prognostic factor for either overall survival or progression-free survival. In conclusion, frequent expression of CD30 in ENKTL suggests anti-CD30 antibody-based therapy may be an effective treatment.

DOI： 10.1002/hon.2482

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Language：Japanese   Publisher：日臨技北日本支部医学検査学会  

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Language：English   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Rationale: Myeloid sarcoma (MS) and leukemia cutis (LC) are extramedullary tumors comprising myeloid blasts. They can occur de novo or concurrently with hematological disorders, usually acute myeloid leukemia (AML). AML chemotherapy is generally the initial therapy for MS and LC, and hematopoietic stem cell transplantation (HSCT) can be considered as additional therapy. However, treatment for older patients who are unable to continue intensive chemotherapy is not currently standardized.
Patientconcerns: A 71-year-old Japanese woman was diagnosed with multiple MSs associated with myelodysplastic syndrome (MDS), using bone marrow aspiration and lymph node biopsy.
Diagnoses: Additionally, LC was diagnosed by skin biopsy. Extramedullary MS and LC lesions were formed by massive infiltration of myeloblastic cells.
Interventions: Twenty courses of 5-azacytidine (5-Aza) were administrated as maintenance therapy after induction therapy with daunorubicin and cytarabine.
Outcomes: Myeloblasts decreased in the bone marrow and the LC disappeared after induction therapy. The MSs completely disappeared, except for the palatine tonsil lesion, after 5-Aza maintenance therapy. 5-Aza treatment provided long-term partial response for more than 21 months.
Lessons: 5-Aza was well tolerated and may be a good option for the treatment of MS and LC associated with MDS, especially in older patients who cannot receive HSCT.

DOI： 10.1097/MD.0000000000007975

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Cryptococcosis is an invasive fungal infection in immunocompromised patients. The clinicopathological characteristics of cryptococcal lymphadenitis are not well known. We analyzed three cases of cryptococcal lymphadenitis and compared their characteristics with those in previous reports. Two patients were human immunodeficiency virus (HIV) carriers, and one patient was a human T-cell leukemia virus type-1 (HTLV-1) carrier. The age of the HTLV-1 carrier with cryptococcosis was much higher than that of the HIV-1 carriers. CD4-positive cell counts in peripheral blood were 5.8/μL (Case 1) and 79.9/μL (Case 2) in the HIV carriers and 3285/μL in the HTLV-1 carrier (Case 3). According to flow cytometric analysis of the lymph nodes of Cases 1, 2, and 3, 50.0%, 87.1%, and 85.9%, respectively, of the T-cells were CD3; 9.8%, 16.3%, and 75.8%, respectively, were CD4; and 35.5%, 77.3%, and 10.2%, respectively, were CD8. Cryptococcus neoformans was detected in tissue culture in all patients. Although gelatinous lesions and numerous fungal cocci were observed in the two HIV patients, the granuloma formation was small. Gelatinous formation and granuloma formation were observed in the HTLV-1 carrier. Necrosis was observed in all cases. In previous reports, granuloma formation, epithelioid cells, and necrotic lesions were observed in most cases. Most of the patients were also immunosuppressed. However, no HTLV-1 carrier was detected. In conclusion, lymphadenopathy in a HTLV-1 carrier may suggest the presence of cryptococcal lymphadenitis. The frequency of cryptococcosis in HTVL-1 carriers may increase with increase in the long-term survival rate of HTLV-1 carriers.

DOI： 10.3960/jslrt.17011

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

ObjectivesT-cell prolymphocytic leukemia (T-PLL) is a very rare, aggressive T-cell neoplasm. Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) is also a highly aggressive lymphoma. These two diseases can often be confused with each other; therefore, we aimed to determine the clinical and pathological differences between T-PLL and PTCL-NOS.
MethodsWe analyzed 15 T-PLL and 91 PTCL-NOS patients and also compared clinical features between T-PLL and PTCL-NOS with leukemic presentation. Peripheral blood images and biopsy specimens were analyzed, and treatment responses were determined via imaging modalities. The clinicopathological characteristics were statistically compared.
ResultsT-PLL cells were smaller in size than those of PTCL-NOS with leukemic presentation (P=.0068); moreover, PTCL-NOS cells with leukemic presentation were smaller than those of PTCL-NOS without leukemic presentation (P=.0017). Immunophenotypic patterns in T-PLL and PTCL-NOS were similar. Five-year overall survival rates of T-PLL and all PTCL-NOS patients were 57.5% and 36.8%, respectively. No significant differences were found in clinical manifestations or prognoses; T-PLL and PTCL-NOS with leukemic presentation had essentially equivalent characteristics.
ConclusionT-PLL and PTCL-NOS may share common biological and clinical characteristics in Japanese patients.

DOI： 10.1111/ejh.12856

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC CLINICAL ONCOLOGY  

Purpose
To elucidate the management and outcomes of patients with extranodal natural killer/T-cell lymphoma, nasal type (ENKL), who were diagnosed between 2000 and 2013 in Japan.
Patients and Methods
Data from 358 patients with ENKL diagnosed between 2000 and 2013 from 31 institutes were retrospectively analyzed.
Results
Patients' median age was 58 years, and 257 (72%) had localized disease. The most common first-line treatment was radiotherapy with dexamethasone, etoposide, ifosfamide, and carboplatin (RT-DeVIC) (66%) for localized ENKL and L-asparaginase-containing chemotherapy (30%) for advanced ENKL. With a median follow-up of 5.8 years, overall survival (OS) rates at 5 years for localized and advanced ENKL were 68% and 24%, respectively. The prognostic index of natural killer lymphoma was validated in our study, although only 4% of patients with localized ENKL were classified as high risk. With a median follow-up of 5.6 years, OS and progression-free survival at 5 years in the 150 patients who received RT-DeVIC in clinical practice were 72% (95% CI, 63% to 78%) and 61% (95% CI, 52% to 69%), respectively. Toxicities of RT-DeVIC were comparable to those in a previous trial. Multivariate analysis in patients with localized ENKL who received RT-DeVIC identified elevated soluble interleukin-2 receptor as an independent predictive factor for worse OS and progression-free survival (adjusted hazard ratios, 2.28 and 2.46; 95% CI, 1.24 to 4.23 and 1.42 to 4.28; P = .008 and .0014, respectively).
Conclusion
Favorable OS in response to new treatments was demonstrated in a large number of patients. Improved treatment approaches are needed for localized ENKL exhibiting elevated pretreatment soluble interleukin-2 receptor. (C) 2016 by American Society of Clinical Oncology

DOI： 10.1200/JCO.2016.68.1619

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Background. Decision-making models for elderly patients with diffuse large B-cell lymphoma (DLBCL) treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) are in great demand.
Patients and Methods. The Society of Lymphoma Treatment in Japan (SoLT-J), in collaboration with the West-Japan Hematology and Oncology Group (West-JHOG), collected and retrospectively analyzed the clinical records of &gt;= 65-year-old patients with DLBCL treated with R-CHOP from 19 sites across Japan to build an algorithm that can stratify adherence to R-CHOP.
Results. A total of 836 patients with a median age of 74 years ( range, 65-96 years) were analyzed. In the SoLT-J cohort (n=555), age &gt;75 years, serum albumin level &lt;3.7 g/dL, and Charlson Comorbidity Index score &gt;= 3 were independent adverse risk factors and were defined as the Age, Comorbidities, and Albumin (ACA) index. Based on their ACA index score, patients were categorized into "excellent" (0 points), "good" (1 point), "moderate" (2 points), and "poor" (3 points) groups. This grouping effectively discriminated the 3-year overall survival rates, mean relative total doses (or relative dose intensity) of anthracycline and cyclophosphamide, unanticipated R-CHOP discontinuance rates, febrile neutropenia rates, and treatment-related death rates. Additionally, the ACA index showed comparable results for these clinical parameters when it was applied to the West-JHOG cohort (n5281).
Conclusion. The ACA index has the ability to stratify the prognosis, tolerability to cytotoxic drugs, and adherence to treatment of elderly patients with DLBCL treated with R-CHOP.

DOI： 10.1634/theoncologist.2016-0260

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

A 62-year-old man with CHOP refractory adult T-cell leukemia/lymphoma (ATLL) received anti-CC chemokine receptor 4 antibody (mogamulizumab) combined with CHOP and achieved complete remission. At 71 days after the final administration of mogamulizumab, he received umbilical cord blood transplantation (CBT) using reduced intensity conditioning. Umbilical cord blood engraftment was confirmed on day16. Grade II acute graft-versus-host disease (GVHD) was diagnosed on day60 and was controlled by administration of methylprednisolone. There was no evidence of relapse at 9 months after CBT. Ratios of regulatory T cells in CD4 positive T cells were remarkably low during all of these periods. Since mogamulizumab reduces regulatory T cells, the frequency and severity of acute GVHD were reported to be increased in patients administered mogamulizumab before allogenic stem cell transplantation. Further experiences are needed for selecting optimal donor sources, the portability period and GVHD prophylaxis for patients using mogamulizumab before allogeneic stem cell transplantation.

DOI： 10.11406/rinketsu.58.32

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Language：Japanese   Publisher：The Japanese Society of Hematology  

<p>A 75-year-old woman suffered a cat bite 10 months after myelodysplastic syndrome (MDS) diagnosis. She visited our hospital because the internal bleeding of the wound did not improve. Although the wound was treated, the bleeding did not stop. She was hospitalized for emergency medical treatment because the bleeding volume exceeded 200 m<i>l</i>. Although her platelet count was normal, the platelet function test showed a decrease in collagen and arachidonic acid aggregation. After platelet transfusion, her bleeding stopped. Patients with MDS may potentially have platelet dysfunction. In the case of bleeding without thrombocytopenia, a platelet function test should be performed and treatment intervention, such as platelet transfusion, should be considered.</p>

DOI： 10.11406/rinketsu.58.2402

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Other Link： http://search.jamas.or.jp/link/ui/2018121562

Authorship：Last author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)  

We retrospectively analyzed clinical and pathological features, treatments, and prognoses in 28 patients with newly diagnosed peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) in Niigata University Medical and Dental Hospital. Of them, 16 were males and 12 were females, and their median age was 62.5 (range, 26-88) years. The International Prognostic Index was high-intermediate/high in 68% of patients. Twelve patients were treated with CHOP/THP-COP and nine with third-generation chemotherapy regimens. At a median follow-up period of 30 (range: 1-164) months, the 2-year overall survival and progression-free survival rates were 61% and 44%, respectively. Further investigation of novel agents for treating PTCL-NOS is warranted.

DOI： 10.11406/rinketsu.58.905

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS LTD  

We previously developed a prognostic index, SIL, which includes advanced stage (5), soluble interleukin-2 receptor level (I), and elevated lactate dehydrogenase level (L) in diffuse large B-cell lymphoma (DLBCL) patients treated with rituximab, cyclophosphamide, hydroxydaunomycin, oncovin, and prednisone (R-CHOP). This time we evaluated the index in a larger cohort and its utility in the risk stratification. The above three factors were independent risk of progression-free survival (PFS). Five-year PFS rates in the standard-risk (SIL index: 0 or 1, n = 367) and high-risk groups (SIL index: 2 or 3, n = 205) were 79% and 53%, respectively (p &lt; 0.0001). When the patients were divided by age (&lt;= 60 years and &gt;60 years), the SIL index was a good prognostic indicator for PFS in both groups as well as divided by the number of extranodal involvement site (0-1 and &gt;1). The SIL index is a simple and objective prognostic indicator in DLBCL.

DOI： 10.1080/10428194.2016.1195498

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

Myeloid sarcoma (MS) is an extramedullary tumor of immature myeloid cells. We analyzed 131 patients with MS, including: (1) de novo MS; (2) MS with concomitant acute myeloid leukemia (AML); (3) MS following myelodysplastic syndrome, myeloproliferative neoplasm, or chronic myelogenous leukemia; and (4) MS as a recurrence of AML. The most common development site was the lymph node. Testicular lesions were statistically more frequent in MS as a recurrence of AML than in other types of MS (P = 0.0183). MS tended to lack myeloid markers (myeloperoxidase was present in 63.2%, CD68 in 51.3%, CD13 in 48.7%, and CD33 in 48.7% of patients) and express T-cell markers such as CD3 (20.7%) and CD5 (34.2%). All T-cell marker-positive MS cases were negative for the alpha beta and gamma delta T-cell receptors on immunohistochemistry. Underlying myelodysplastic syndrome or myeloproliferative neoplasm was a poor prognostic factor (vs. de novo MS: P = 0.0383; vs. MS with concomitant AML: P = 0.0143). However, there was no statistical difference in prognosis between de novo MS and MS with concomitant AML (P = 0.288). There were no significant differences in prognosis between the prognoses of T-cell marker-positive and T-cell marker-negative MS cases. In addition, CXCR4 expression was a poor prognostic factor in MS (P = 0.0229). This study involves the largest MS cohort to date and expands the clinical and pathologic knowledge of the disease.

DOI： 10.1097/PAS.0000000000000727

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Language：Japanese   Publisher：(一社)日本血液学会-東京事務局  

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Language：English   Publisher：(一社)日本血液学会-東京事務局  

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Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Genomic alterations and protein expression levels have been established as prognostic factors for survival in patients with diffuse large B-cell lymphoma (DLBCL). In particular, double-hit DLBCL (DHL), which exhibits translocations in MYC and BCL2 and/or BCL6, is known to be associated with a poor prognosis. However, the clinical significance of gene alterations and protein expression levels for MYC, B-cell lymphoma (BCL)2, and BCL6 are unclear. In this study, we analyzed 61 adult patients diagnosed with DLBCL without DHL, who were treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone, or similar regimens. There were no differences in the distribution of MYC expression rates among the different MYC gene statuses. In log-rank tests, MYC translocation was a prognostic factor for overall survival (OS; P = 0.011), whereas BCL2 and BCL6 translocation were not prognostic indicators (P = 0.999 and P = 0.925, respectively). Although the expression levels of MYC and BCL6 were not significantly associated with OS, the expression of BCL2 was a prognostic factor for OS (P = 0.027). Furthermore, copy number gains in the MYC, BCL2, and BCL6 genes did not affect OS. MYC translocation (hazard ratio, 4.769; range, 1.518-14.98; P = 0.007) and BCL2 protein expression (hazard ratio, 3.072; range, 1.002-9.413; P = 0.049) were independent prognostic factors for survival in multivariate analyses. In conclusion, MYC translocation and BCL2 expression may need to be investigated at the initial diagnosis to predict prognosis in patients with DLBCL.

DOI： 10.1111/cas.12942

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DOI： 10.1200/JCO.2016.34.15_suppl.7541

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

DOI： 10.1038/bcj.2015.101

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Invasive tracheal aspergillosis (ITA) is an infection that is unique to patients who have undergone lung transplantation (LT). Although the activity of this disease often appears on imaging, we encountered a case of ITA that became exacerbated, despite few computed tomography (CT) findings, during rituximab combined chemotherapy for diffuse large B-cell lymphoma. ITA developed during immunosuppressive therapy after LT. Because CT findings may show false-negative results, bronchoscopy is recommended for such cases.

DOI： 10.1111/tid.12458

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Language：English   Publisher：(一社)日本血液学会-東京事務局  

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DOI： 10.1513/AnnalsATS.201503-175LE

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We focused on the level of reduction of Wilms' tumor gene 1 (WT1) mRNA in bone marrow as minimal residual disease during chemotherapies in adult acute myeloid leukemia (AML) patients. Forty-eight patients were enrolled in this study. Log levels of reduction of WT1 mRNA transcript after induction therapy compared with those at diagnosis were associated with disease-free survival (DFS) (P=0.0066) and overall survival (OS) (P=0.0074) in patients who achieved complete remission. Also log levels of reduction of WT1 mRNA transcript after final consolidation therapy compared with those at diagnosis were associated with DFS (P=0.015) and OS (P=0.012). By multivariate analysis, log levels of reduction of WT1 mRNA transcript after induction therapy and after final consolidation therapy compared with those at diagnosis were extracted as risk factors for outcome. Our results suggest that early and deep reduction of tumor burden may be important for the outcome of AML patients. In addition, it may be useful for the decision to proceed with allogeneic SCT as post-remission therapy.

DOI： 10.1016/j.leukres.2015.03.021

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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DOI： 10.2169/internalmedicine.54.2332

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：FERRATA STORTI FOUNDATION  

The prognosis of patients with primary mediastinal large B-cell lymphoma has improved over recent years. However, the optimal treatment strategy including the role of radiotherapy remains unknown. We retrospectively analyzed the clinical outcomes of 345 patients with newly diagnosed primary mediastinal large B-cell lymphoma in Japan. With a median follow up of 48 months, the overall survival at four years for patients treated with R-CHOP (n=187), CHOP (n=44), DA-EPOCH-R (n=9), 2nd- or 3rd-generation regimens, and chemotherapy followed by autologous stem cell transplantation were 90%, 67%, 100%, 91% and 92%, respectively. Focusing on patients treated with R-CHOP, a higher International Prognostic Index score and the presence of pleural or pericardial effusion were identified as adverse prognostic factors for overall survival in patients treated with R-CHOP without consolidative radiotherapy (IPI: hazard ratio 4.23, 95% confidence interval 1.48-12.13, P=0.007; effusion: hazard ratio 4.93, 95% confidence interval 1.37-17.69, P=0.015). Combined with the International Prognostic Index score and the presence of pleural or pericardial effusion for the stratification of patients treated with R-CHOP without radiotherapy, patients with lower International Prognostic Index score and the absence of effusion comprised approximately one-half of these patients and could be identified as curable patients (95% overall survival at 4 years). The DA-EPOCH-R regimen might overcome the effect of these adverse prognostic factors. Our simple indicators of International Prognostic Index score and the presence of pleural or pericardial effusion could stratify patients with primary mediastinal large B-cell lymphoma and help guide selection of treatment.

DOI： 10.3324/haematol.2014.111203

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Language：English   Publisher：AMER SOC HEMATOLOGY  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：INT INST ANTICANCER RESEARCH  

Background/Aim: Indoleamine-2,3-dioxygenase (IDO) is a rate-limiting enzyme for tryptophan metabolism and plays an immunosuppressive role. Antigen-presenting cells, when activated, increase the expression of IDO, which results in the suppression of subsequent immune reaction. A novel IDO inhibitor, Toho-1, was explored for its applicability to immunotherapy. Materials and Methods: We investigated the effects of Toho-1 on antigen presentation and antigen-specific cytotoxic T-lymphocyte-inducing ability of leukemia plasmacytoid dendritic cell line PMDC05, which was established in our laboratory. Results: While antigen presentation-associated molecules in PMDC05 cells were increased by stimulation with lipopolysaccharide and interferon-gamma, IDO mRNA and protein expression were also enhanced. Such treatment of PMDC05 cells in combination with Toho-1 enhanced the antigen-presenting and CTL-inducing ability of PMDC05 cells. Conclusion: These findings suggest the ability of Toho-1 to potentiate antigen-presenting cells and its applicability in immunotherapy of cancer.

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Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (DLBCL) of the elderly (EBV[+]DLBCL-E) is classified as a subtype of DLBCL. Until now, its molecular pathogenesis has remained unknown. To identify pathways characteristic of EBV(+)DLBCL-E, gene expression profiling of five EBV(+)DLBCL-E and seven EBV-negative DLBCL (EBV[-]DLBCL) cases was undertaken using human oligonucleotide microarray analysis. Gene set enrichment analysis and gene ontology analysis showed that gene sets of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) and nuclear factor kappa B (NF-B) pathways were enriched in EBV(+)DLBCL-E cases. To confirm the results of the expression profiles, in vitro analysis was performed. Expression profiling analysis showed that high activation of the JAK-STAT and NF-B pathways was induced by EBV infection into DLBCL cell lines. Activation of the NF-B pathway was confirmed in EBV-infected cell lines using an electrophoretic mobility shift assay. Western blot analysis revealed an increased protein expression level of phosphorylated signal transducer and activator of transcription 3 (STAT3) in an EBV-infected cell line. Protein expression of phosphorylated STAT3 was frequently observed in lymphoma cells of EBV(+)DLBCL-E clinical samples using immunohistochemistry (EBV[+]DLBCL-E: 80.0% [n=20/25] versus EBV[-]DLBCL: 38.9% [n=14/36]; P=0.001). The results of the present study suggest that activation of the JAK-STAT and NF-B pathways was characteristic of EBV(+)DLBCL-E, which may reflect the nature of EBV-positive tumor cells. Targeting these pathways as therapies might improve clinical outcomes of EBV(+)DLBCL-E.

DOI： 10.1111/cas.12389

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Language：English   Publisher：JAPAN SOC INTERNAL MEDICINE  

Hepatic intravascular large B-cell lymphoma (IVL) is a rare disease entity that involves invasion into various organs. Due to the aggressive behavior and poor prognosis of the disease and the difficulty in making an early diagnosis, some cases are diagnosed at autopsy. Early suspicion and the use of imaging studies and liver biopsies are key for diagnosing IVL; however, no reports have described the results of imaging studies due to the limited number of cases. We herein report the results of imaging studies of hepatic IVL, including the findings PET-CT, dynamic-CT, EOB-MRI and CEUS. These results may help physicians to make an early diagnosis and improve the prognosis.

DOI： 10.2169/internalmedicine.53.1812

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We herein report the case of a 22-year-old woman with severe aplastic anemia who underwent allogeneic hematopoietic stem cell transplantation (HSCT). After HSCT, the Epstein-Barr virus (EBV)-DNA load in the peripheral blood gradually increased, and the patient presented with a fever and lymphadenopathy on day 56 post-HSCT. Although we administered rituximab, her clinical condition worsened. After rituximab treatment, CD8 T-cells emerged and became dominant in the peripheral blood, some of which were positive on an EBV-specific tetramer analysis. However, an open biopsy of the lymphadenopathy lesions revealed the CD8 T-cells to be infected with EBV, exhibiting proliferation with oligoclonality. The patient ultimately died of multiple organ failure on day 99 post-HSCT.

DOI： 10.2169/internalmedicine.53.2384

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：The Japanese Society of Internal Medicine  

A 51-year-old man was admitted due to a severe bleeding tendency. After he was diagnosed with immune thrombocytopenia (ITP), several therapies, including steroids, steroid pulse, vincristine and rituximab, were administered; however, the patient's bleeding symptoms were not sufficiently controllable with these treatments. Subsequently, a diffuse alveolar hemorrhage was observed. Treatment with a thrombopoietin receptor agonist, romiplostim, was initiated to prevent lethal hemorrhaging, although the efficacy of thrombopoietic receptor agonists in such emergency situations has not been elucidated. The initiation of romiplostim achieved prompt remission in platelets. This case suggests that combination therapy with romiplostim, rituximab and vincristine is effective in cases of newly diagnosed severe therapy-resistant ITP.<br>

DOI： 10.2169/internalmedicine.52.0080

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Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma, and it has several morphologic and clinicopathologic variants. The prognosis of DLBCL can vary according to specific genetic and immunophenotypic abnormalities. The aim of this study was to investigate the prognostic impact of previously identified prognostic factors, such as activated B cell-like immunophenotype, CD5, BCL2 and MYC rearrangement (MYC-R), in patients treated with rituximab. We retrospectively analyzed the prognosis of 100 patients with DLBCL (median age, 66.5 years) treated with rituximab-containing chemotherapy. The 3-year overall survival (OS) and progression-free survival (PFS) were 66% and 62%. Outcomes were significantly worse in patients with MYC-R in 3-year OS (50% vs. 67.8%, p = 0.043) and PFS (30% vs. 57.8%, p = 0.003), and multivariate analysis showed that this finding was independent of the International Prognostic Index (IPI). Immunostaining by Muris algorithm had the highest predictive power among the three algorithms. However, other previously reported prognostic factors, such as BCL2 and CD5, were not good predictors of outcomes in these patients. In conclusion, our data suggest that fluorescence in situ hybridization (FISH) analysis for MYC-R can predict outcomes in response to rituximab-containing chemotherapy in Japanese patients with DLBCL. © 2013 Informa UK, Ltd.

DOI： 10.3109/10428194.2013.771398

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Primary central nervous system lymphoma (PCNSL) expressing T-cell markers is rare, among which nasal-type extranodal NK/T-cell lymphoma is an extremely rare subtype associated with Epstein-Barr virus (EBV) infection. Here we report the clinicopathologic features of a case of EBV-associated PCNSL showing a cytotoxic T-cell phenotype. The patient, a 73-year-old woman, presented with rapidly progressive mental deterioration. Brain MRI revealed multiple lesions with swelling in the bilateral cerebral hemispheres, which were hypointense on T1-weighted images, hyperintense on T2-weighted and fluid-attenuated inversion recovery images, and slightly hyperintense on diffusion-weighted images. Biopsy specimens from the temporal region showed many medium-sized anaplastic lymphocytic cells with perivascular and angio-invasive patterns in the cortex. Immunohistochemically, the cells were positive for CD3, CD8, T-cell-restricted intracellular antigen-1 (TIA-1), granzyme B and perforin, but negative for CD56 and CD20. In situ hybridization revealed EBV-encoded RNAs in the tumor cell nuclei. A rearrangement study showed T-cell receptor γ-chain gene rearrangement with a clonal appearance. The patient died 6 months after surgery, and a general autopsy revealed no lymphoma cells outside the brain. These cellular profiles are inconsistent with those of extranodal NK/T-cell lymphoma, and have not been previously described. This case appears to represent an unusual CNS manifestation of EBV-associated T-cell lymphoma.

DOI： 10.1111/neup.12005

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Language：English   Publisher：(一社)日本血液学会-東京事務局  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC CANCER RESEARCH  

Purpose: Extranodal NK/T-cell lymphoma, nasal type (ENKL) is an Epstein-Barr virus (EBV)-associated lymphoma for which a new chemotherapeutic regimen called SMILE (steroid, methotrexate, ifosfamide, L-asparaginase, and etoposide) recently showed promising results.
Experimental Design: The amount of EBV-DNA was prospectively measured in whole-blood and plasma samples by real-time quantitative PCR from 26 patients registered in the SMILE phase II study.
Results: Before treatment, the EBV-DNA was detected in 22 samples of whole blood with a median number of 3,691 copies/mL (range: 0-1.14 x 10(7)), but 15 samples of plasma with a median of 867 copies/mL (range: 0-1.27 x 10(7)). Results of these 2 measurements of EBV-DNA well correlated (R-2 = 0.994, P &lt; 0.001). The overall response rate to SMILE was significantly higher in patients with less than 10(5) copies/mL of EBV-DNA in whole blood at enrollment (90% vs. 20%, P = 0.007) and in patients with less than 10(4) copies/mL of EBV-DNA in plasma (95% vs. 29%, P = 0.002). The incidence of grade 4 toxicity of SMILE other than leukopenia/neutropenia was significantly higher in patients with 10(5) copies/mL of EBV-DNA or more in whole blood (100% vs. 29%, P = 0.007) than that of others and in patients with 10(4) copies/mL or more in plasma (86% vs. 26%, P = 0.002).
Conclusions: These findings suggest that whole blood is more sensitive for clinical use than plasma. The EBV-DNA amount in whole blood was useful for predicting tumor response, toxicity, and prognosis after SMILE chemotherapy for ENKL. Clin Cancer Res; 18(15); 4183-90. (C)2012 AACR.

DOI： 10.1158/1078-0432.CCR-12-1064

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Nei T, Urano S, Motoi N, Takizawa J, Kaneko C, Kanazawa H, Tazawa R, Nakagaki K, Akagawa KS, Akasaka K, Ichiwata T, Azuma A, Nakata K. IgM-type GM-CSF autoantibody is etiologically a bystander but associated with IgG-type autoantibody production in autoimmune pulmonary alveolar proteinosis. Am J Physiol Lung Cell Mol Physiol 302: L959-L964, 2012. First published February 24, 2012; doi: 10.1152/ajplung.00378.2011.-The granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibody (GMAb) is the causative agent underlying autoimmune pulmonary alveolar proteinosis (aPAP). It consists primarily of the IgG isotype. At present, information on other isotypes of the autoantibody is limited. We detected serum the IgM isotype of GMAb (IgM-GMAb) in more than 80% of patients with aPAP and 22% of healthy subjects, suggesting that a continuous antigen pressure may be present in most patients. Levels of the IgM isotype were weakly correlated with IgG-GMAb levels but not IgA-GMAb, suggesting that its production may be associated with that of IgG-GMAb. The mean binding avidity to GM-CSF of the IgM isotype was 100-fold lower than the IgG-GMAb isotype, whereas the IC50 value for neutralizing capacity was 20,000-fold higher than that of IgG-GMAb, indicating that IgM-GMAb is only a very weak neutralizer of GM-CSF. In bronchoalveolar lavage fluid from nine patients, IgG-GMAb was consistently detected, but IgM-GMAb was under the detection limit in most patients, confirming that IgM-GMAb is functionally a bystander in the pathogenesis of aPAP. It rather may be involved in the mechanism for development of IgG-GMAb in vivo.

DOI： 10.1152/ajplung.00378.2011

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Language：Japanese   Publisher：Japan Society of Ningen Dock  

<b>Objective:</b> Smoking has been reported to be one of the risk factors of myelodysplastic syndrome (MDS). In order to clarify the process of progression to MDS in a certain group of smokers, it is important to identify the initial hematological abnormalities associated with the early stage of MDS in smokers. <br><b>Methods:</b> Relationships of hematological parameters such as WBC count, RBC count, Hb, Ht, MCH and MCV with level of smoking were investigated by univariate and multivariate analyses in 234 male workers at a single workplace after obtaining informed consent.<br><b>Results:</b> Univariate analysis demonstrated that correlations of smoking-related factors (number of cigarettes per day, duration of smoking [years] and smoking index [defined as number of cigarettes per day x duration of smoking]) with WBC count, Ht, MCH and MCV were significantly positive. Multivariate analysis using age, smoking-related factors, alcohol intake and BMI as explanatory valuables showed that age, alcohol intake and BMI were not confounding variables for smoking-related factors and revealed a remarkable significant positive correlation between each smoking-related factor and MCV.<br><b>Conclusion:</b> Smoking-associated macrocytosis, which was demonstrated in the present study, was not due to deficiency of vitamin B₁₂ or folic acid because of no pancytopenia observed but was considered to be a qualitative abnormality of erythrocytes. Taken together with the findings of previous studies concerning smoking-associated functional abnormalities of erythrocytes and leukocytes and the high incidence of MDS in smokers, our results indicate that idiopathic macrocytosis in smokers could be an initial sign of progression to MDS, in which macrocytosis and multi-lineage abnormalities are characteristic findings.

DOI： 10.11320/ningendock.27.689

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Language：Japanese   Publisher：特定非営利活動法人 日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.34.4_407_4

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

DOI： 10.1007/s12185-011-0845-4

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DOI： 10.1007/s10384-011-0003-9

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC HEMATOLOGY  

The influence of hepatitis C virus (HCV) infection on prognosis and hepatic toxicity in patients with diffuse large B-cell lymphoma in the rituximab era is unclear. Thus, we analyzed 553 patients, 131 of whom were HCV-positive and 422 of whom were HCV-negative, with DLBCL treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP)-like chemotherapy. Survival outcomes and hepatic toxicity were compared according to HCV infection. The median follow-up was 31 and 32 months for patients who were HCV-positive and HCV-negative, respectively. HCV infection was not a significant risk factor for prognosis (3-year progression-free survival, 69% vs 77%, P = .22; overall survival, 75% vs 84%, P = .07). Of 131 patients who were HCV-positive, 36 (27%) had severe hepatic toxicity (grade 3-4), compared with 13 of 422 (3%) patients who were HCV-negative. Multivariate analysis revealed that HCV infection was a significant risk factor for severe hepatic toxicity (hazard ratio: 14.72; 95% confidence interval, 6.37-34.03; P &lt; .001). An exploratory analysis revealed that pretreatment transaminase was predictive of severe hepatic toxicity. HCV-RNA levels significantly increased during immunochemotherapy (P = .006). These results suggest that careful monitoring of hepatic function and viral load is indicated during immunochemotherapy for HCV-positive patients. (Blood. 2010;116(24):5119-5125)

DOI： 10.1182/blood-2010-06-289231

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DOI： 10.1007/s12185-010-0610-0

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Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC NEUROLOGICAL SURGEONS  

Object. The lack of primary lymphoid tissue within the central nervous system (CNS) confounds our understanding of the pathogenesis of primary CNS lymphomas (PCNSLs). Comparing the protein expression of PCNSLs and sporadic systemic lymphomas (SSLs) provides a useful strategy for identifying a molecular signature that characterizes disease-associated features and provides information regarding tumor initiation and progression.
Methods. Seven diffuse large B-cell PCNSLs were selected to undergo 2D gel electrophoresis, and profiled proteomes from these PCNSLs were compared with those from 7 diffuse large B-cell SSLs. Distinguishing proteins were sequenced using mass spectrometry.
Results. Two-dimensional get electrophoresis identified an average of 706 proteins from each specimen. Computerized gel analysis and manual reconfirmation revealed a 96% similarity in the proteomes of PCNSLs and SSLs. Comparative analysis identified 9 proteins significantly overexpressed (p &lt; 0.05) and 16 proteins downregulated in PCNSLs. The proteomic findings were further validated using Western blot and immunohistochemical staining.
Conclusions. The similarities in proteomic patterns between PCNSLs and SSLs suggest that these tumor types share structural similarities, acquired during differentiation. The ultimate fate of lymphomatous cells (CNS vs systemic) may be related to differentially expressed proteins, which function in homing and host processing. Elucidating the roles of these differentially expressed proteins will prove valuable in understanding the pathogenesis of PCNSL.

DOI： 10.3171/JNS/2008/109/9/0536

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：HUMANA PRESS INC  

In order to establish an efficient gamma delta T cell-mediated immunotherapy for hematological malignancies, we attempted to evaluate cytotoxicity against tumor cells by gamma delta T cells, which were generated from blood cells of patients with myeloma and lymphoma by culturing with zoledronate and a low dose of IL-2. Although gamma delta T cells were expanded in patients with myeloma and lymphoma as well as normal persons, the amplification rates of gamma delta T cells before and after culturing varied from patient to patient in myeloma and lymphoma. gamma delta T cells generated in patients with myeloma and lymphoma showed a potent cytotoxic ability against myeloma/lymphoma cell lines as shown in gamma delta T cells generated in normal subjects. In addition, gamma delta T cells generated in a patient with myeloma showed a cytotoxic ability against self myeloma cells freshly prepared from bone marrow. However, the same gamma delta T cells were demonstrated to be non-cytotoxic to normal cells of the patient. These data demonstrated that gamma delta T cells, which could be expanded in vitro from blood cells of patients with myeloma and lymphoma by culturing with zoledronate and IL-2, possess a sufficient cytotoxic ability against tumor cells. These findings suggested that in vitro generated patients&apos; gamma delta T cells could be applied to gamma delta T cell-mediated immunotherapy for hematological malignancies.

DOI： 10.1007/s12032-007-9004-4

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Language：Japanese   Publisher：新潟医学会  

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

This study reports the first well-documented case of adult T-cell leukemia (ATL) successfully treated with unrelated cord blood transplantation (UCBT). A 49-year-old woman was diagnosed with acute-type of ATL. Chemotherapy induced complete remission, but the human T-cell leukemia virus type 1 (HTLV-1) proviral load was detected in mononuclear cells of her peripheral blood. The patient received UCBT with a conditioning regimen consisting of total body irradiation, cytarabine, and cyclophosphamide. She remains in remission 30 months after UCBT and the HTLV-1 proviral load has fallen to undetectable levels. This result suggests that UCBT should be a therapeutic option for ATL patients who do not have suitable donors and those who urgently require treatment. Am. J. Hematol. 82:1113-1115, 2007. (c) 2007 Wiley-Liss, Inc.

DOI： 10.1002/ajh.21042

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：The Japanese Society for Lymphoreticular Tissue Research  

In order to establish the method of generating powerful γδ T cells for anti-tumor immunotherapy, we investigated the effects of monocyte-derived dendritic cells (mo-DCs) on anti-tumor cytotoxicity of expanded γδ T cells. Activation of γδ T cells co-cultured for 2-3 days with immature or mature mo-DCs was evaluated by CD69 expression and anti-tumor cytotoxicity using two assays : the 5- (and 6-) carboxyfluorescein diacetate, succinimidyl ester-based cytotoxicity assay and the calcein-AM-based Terascan assay. γδ T cells were used as effector cells and myeloma cell line (RPMI8226) or chronic myelogenous leukemia blastic crisis cell line (C2F8) were used as target cells. CD69 expression on γδ T cells was enhanced by co-culture with both immature and mature mo-DCs in a cell-number-dependent fashion. CD69 expression was enhanced after addition of mo-DCs of either autologous or allogeneic origin. Activation of γδ T cells with mo-DCs enhanced anti-tumor cytotoxicity of γδ T cells against RPMI8226 and C2F8 in an effector-to-target ratio-dependent manner. Activation of γδ T cells by mo-DCs was associated with the enhancement of anti-tumor cytotoxicity of γδ T cells. Potent γδ T cells activated by mo-DCs were considered to be applicable to an efficient γδ T cell-mediated immunotherapy for tumors. [<I>J Clin Exp Hematopathol 47(2) </I><I>: 61</I>-<I>72, 2007</I>]

DOI： 10.3960/jslrt.47.61

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

Objective. To identify leukemia-associated antigens, we applied the serological identification of antigens by the recombinant expression cloning (SEREX) method to a chronic myelogenous leukemia (CML) patient who achieved a cytogenetic response to interferon-alpha.
Materials and Methods. Immunoscreening of the cDNA library was performed with sera from a CML patient. Two isolated antigens were used to evaluate the expression pattern using Northern blot analysis and quantitative reverse transcriptase polymerase chain reaction. Western blotting and enzyme-linked immunosorbent assay were also performed for serological analysis.
Results. We identified 14 positive clones, representing five different antigens. Of these, two genes were further validated. One (clone 70) was the human polyribonucleotide nucleotidyltransferase 1 (PNPT1), which is the type I interferon (alpha/beta-responsive gene). The mRNA of clone 70 was ubiquitously expressed in normal human tissues. The other gene (clone 57) was the heat shock 70-kDa protein 4-like (HSPA4L), which is a member of the heat shock protein 110 family, whose mRNA is strongly expressed in normal human testis and overexpressed in leukemia cells. Seroactivity against HSPA4L was detected in 6 of 9 acute myeloid leukemia patients, 4 of 10 acute lymphoblastic leukemia patients, 9 of 11 CML patients, and none of 10 healthy volunteers. Leukemia patients had higher titer of the antibodies against the protein than healthy volunteers.
Conclusions. These results suggest that HSPA4L, a member of heat shock protein, is highly expressed by leukemia cells, and elicit humoral immune responses in leukemia patients, and it might be a potential target for antileukemia therapy and an antigen-specific immunotherapy for leukemia.

DOI： 10.1016/j.exphem.2007.03.015

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Language：English   Publisher：The Japanese Society of Internal Medicine  

<b>Objective:</b> Cardiovascular complication is one of the serious complications in stem cell transplantation (SCT). We measured plasma brain natriuretic peptide (BNP) concentrations in patients who received SCT to evaluate possible cardiac toxicity of the regimens employed in SCT.<br> <b>Patients:</b> Ten patients with allogeneic SCT and 5 patients with autologous SCT using myeloablative conditioning regimens were enrolled. The preparative chemotherapy for 8 patients with allogeneic SCT included cyclophosphamide (60 mg/kg i.v. for 2 days) and other drugs and that for autologous SCT included cyclophosphamide (50 mg/kg for 2 days) and other drugs. Total body irradiation (TBI) was employed only in the patients who received allogeneic SCT.<br> <b>Method:</b> Plasma BNP was measured using a radioimmunoassay for human BNP before and after SCT.<br> <b>Results:</b> In 13 of 15 patients, BNP levels were elevated after SCT. In patients who received a total body irradiation (TBI) of 13.2 Gy, BNP levels were higher than those without irradiation (p=0.01). The BNP level reached a peak within 6 months after SCT in most patients and fell thereafter. But 7 of the 15 patients (46.7%) had an abnormally high level of plasma BNP even after 6 months of SCT which suggests subclinical myocardial damage.<br> <b>Conclusion:</b> A rise in plasma BNP was frequently observed after SCT, and may be considered to represent cardiac damage caused by the preparative chemotherapy and/or total body irradiation. Since a rise was noted 6 months after SCT, long-term evaluation of cardiac function is important.<br>

DOI： 10.2169/internalmedicine.46.6188

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

BAFF-receptor (BAFF-R) is required for the successful maturation and survival of B-cells. We developed an anti-human BAFF-R monoclonal antibody (mAb), 8A7. The reactivity of 8A7 in normal and neoplastic tissue was examined by performing immunohistochemistry on paraffin-embedded sections. 8A7 reacted with lymphocytes in the mantle and marginal zones, but not with lymphocytes in the interfollicular area. Lymphocytes in the germinal centers were found to be negative or occasionally weakly positive for 8A7. BAFF-R expression was found only in B-cell lymphoma (44/80, positive cases/examined cases): B-lymphoblastic lymphoma 0/3, B-chronic lymphocytic leukemia/small lymphocytic lymphoma 4/4, mantle cell lymphoma 9/11, follicular lymphoma 10/14, diffuse large B-cell lymphoma (DLBCL) 11/25, marginal zone B-cell lymphoma 8/10, lymphoplasmacytic lymphoma 2/2, plasma cell myeloma 0/2, and Burkitt lymphoma 0/9, but not in T/NK cell lymphomas (0/19) or Hodgkin lymphoma (0/10). BAFF-R was expressed in most low-grade B-cell neoplasms and a small number of DLBCL, suggesting that BAFF-R may play an important role in the proliferation of neoplastic lymphoid cells. Thus, the mAb is very useful for further understanding of both healthy B-cell biology and its pathogenic neoplasms.

DOI： 10.1007/s00428-005-1275-6

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Language：Japanese   Publisher：新潟医学会  

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

Abnormalities of chromosome 1q21 are common in B cell malignancies, but their target genes are largely unknown. By cloning the breakpoints of a (1;14) (q21;q32) chromosomal translocation in a myeloma cell line, we have identified two novel genes, IRTA1 and IRTA2, encoding cell surface receptors homologous to the Fc and inhibitory receptor families. Both genes are selectively expressed in mature B cells: IRTA1 in marginal zone B cells and IRTA2 in centrocytes, marginal zone B cells, and immunoblasts. As a result of the t(1;14), IRTA1 is fused to the immunoglobulin C alpha domain to produce a chimeric IRTA1/C alpha fusion protein. In tumor cell lines with 1q21 abnormalities, IRTA2 expression is deregulated. Thus, IRTA1 and IRTA2 are novel immunoreceptors implicated in B cell development and lymphomagenesis.

DOI： 10.1016/S1074-7613(01)00109-1

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A 28-year-old Japanese woman with suspected essential thrombocythemia (ET) had marked thrombocytosis, mild leukocytosis with normal neutrophil alkaline phosphatase activity, and no anemia. She was monitored without being given any medication. Eleven years later, complete blood counts showed no remarkable changes but some non-lobulated mononuclear megakaryocytes were found in the bone marrow. Cytogenetic analysis revealed deletion of the long arm of chromosome 5 (5q-). Subsequently, hemoglobin and platelet counts decreased gradually, splenomegaly appeared and progressed, after which myelofibrosis developed. Acute leukemia developed 16 years after the first documentation of thrombocytosis. 5q- syndrome is known to be a myelodysplastic syndrome (MDS) with unique clinical features and cases with this syndrome presenting with thrombocytosis of more than 1,000 x 109/L but without anemia are rare. Furthermore, it is noteworthy that in this patient transition to acute leukemia occurred following development of myelofibrosis and marked splenomegaly, which are generally observed in blastic crises resulting from chronic myeloproliferative disorders (CMPD). The patient showed features indicative of CMPD rather than of MDS in spite of presenting with 5q- chromosomal abnormality. This case supports the concept of 'mixed myelodysplastic and myeloproliferative syndromes' and suggests the possibility of the appearance of CMPD-like manifestations in 5q- syndrome. (C) 2000 Wiley-Liss, Inc.

DOI： 10.1002/(SICI)1096-8652(200006)64:2<120::AID-AJH9>3.0.CO;2-M

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

DOI： 10.1038/sj.leu.2401267

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCI IRELAND LTD  

The TCL1 gene was recently cloned as a candidate target within the 14q32.1 breakpoint cluster region observed in T-cell malignancies. We examined the TCL1 gene expression in 21 patients with adult T-cell leukemia (ATL) and 5 cell Lines, because ATL is reported to have frequent chromosome 14 band (q32 aberrations, However, 20 of the ATL patients and all 5 cell lines lacked any TCL1 expression on northern blot analysis, and TCL1 transcripts were only very faintly detected in the remaining one patient, Expansion of our analysis to include other types of hematopoietic malignancies revealed strong expression of the TCL1 gene in almost all tumor cells of B-cell lineage except myelomas. However no TCL1 signals were encountered in cells of T-cell or myeloid lineages. In normal human tissues TCL1 was found to be expressed in the spleen. lymph nodes and B-lymphocytes of peripheral blood. These results indicate that TCL1 is not a major target gene for ATL, but that it may play a role in B-cell differentiation and proliferation.

DOI： 10.1111/j.1349-7006.1998.tb03275.x

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11q23 chromosome aberrations are frequently observed in infantile as well as therapy-related leukemias. The target gene at 11q23, MLL, is disrupted by the translocation and becomes fused to various translocation partner genes such as AF4/FEL, LTG9/AF9 and LTG19/ENL. The resulting chimeric mRNAs are fused in frame and have been predicted to encode leukemia-specific chimeric proteins. In the present study, we raised antibodies against MLL, LTG9 and LTG19 and demonstrated that MLL and chimeric MLL-LTG9 and MLL-LTG19 products are synthesized in vivo and are localized in the nuclei, using immunofluorescence and cell fractionation studies. The truncated N-terminal portion of the MLL product common to the various types of 11q23 translocation was also localized in the nuclei in a similar fashion. Murine 32Dc13 cells stably expressing the truncated N-terminal MLL protein exhibited an inhibition of differentiation and a growth advantage following stimulation by granulocyte-colony stimulating factor, although the IL-3 dependency was not significantly changed in comparison to the parental cells. These results suggest that the N-terminal portion common to various MLL-chimeric products plays an important role in leukemogenesis.

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Authorship：Lead author   Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：The Japanese Society of Hematology  

We report a case of a 19-year-old male with congenital aplastic anemia and multiple abnormalities; short stature, hypoplastic thumb, skin pigmentation and mental retardation. He was admitted to our hospital because of severe pancytopenia. Bone marrow aspiration showed markedly hypocellular marrow with 42% myeloblasts. He was diagnosed as AML (M2) transformed from Fanconi's anemia and underwent allo-BMT from an HLA-identical father. The conditioning regimen consisted of high dose Ara-C, high dose etoposide and 12Gy fractionated total body irradiation. Severe toxicity associated with the conditioning regimen was not observed. Ciclosporin A and short-term methotrexate were administered for prophylaxis of acute GVHD. Neither acute nor chronic GVHD were observed. He is well and free of disease for 15 months since BMT. Very few cases of Fanconi's anemia with leukemic transformation treated by BMT have been reported. Long-term observation will be necessary to evaluate our conditioning regimen for Fanconi's anemia with leukemic transformation.

DOI： 10.11406/rinketsu.36.615

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It is becoming clear that antigen-specific cytotoxic T cells (CTLs) play an important role in anti-tumor immune system due to the recent confirmation of clinical effects of immune-checkpoint inhibitors. We tried to amplify efficiently WT1 specific oligoclonal CTLs from the peripheral blood of the case treated with WT1 peptide vaccine using dendritic cell line PMDC 11 which was established in our laboratory. Antigen - specific IFN - γ - producing ability was confirmed in the amplified WT1- specific CTLs. This result means that the antigen - specific CTLs amplified by PMDC 11 maintain cytotoxic ability against to tumor specific antigen. This method of amplifying antigen-specific CTLs using MLPC and PMDC 11 will lead to application of CTL to clinical application and TCR and surface antigen analysis.

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DOI： 10.20837/5201802179

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症例は75歳の女性。血液検査で貧血と末梢血に芽球を認められたため、当院を紹介受診した。骨髄穿刺で骨髄異形成症候群(myelodysplastic syndrome with excess blasts 2, MDS-EB-2)と診断された。血球減少の進行や芽球の増加、および出血症状はなく経過していた。診断から10ヵ月後、左手母指球に外傷を負い、内出血が持続し、止血困難となったため緊急入院した。血小板数は正常範囲であったが、血小板機能検査でコラーゲン凝集能とアラキドン酸凝集能の低下を認められた。抗血小板薬の内服はなく、またこれまで出血傾向の既往もなかったことから、MDSによる二次性の血小板機能低下による出血と判断し、血小板輸血を行い止血した。MDSの患者では、潜在的に血小板凝集能が低下していることが多く、血小板数の割に出血傾向が強い場合には血小板凝集能を調べ、血小板輸血などの治療介入を検討する必要がある。(著者抄録)

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症例は成人T細胞白血病/リンパ腫(ATLL)急性型の62歳男性。CHOP療法単独では治療抵抗性であったが,抗CCR4抗体mogamulizumab併用CHOP療法が奏効し寛解を得た。HLA一致血縁・非血縁ドナーが得られず,mogamulizumab最終投与後71日目に骨髄非破壊的前処置を用いた臍帯血移植を施行した。急性移植片対宿主病(GVHD)grade II(皮膚stage2)を発症したが,methylprednisolone投与により制御可能であり,移植後9ヵ月時点まで寛解を維持している。経過中,制御性T細胞(Treg)は著減したままの状態であった。同種造血幹細胞移植はATLLの根治的治療であるが,移植前にmogamulizumabを使用する際,Tregの減少による急性GVHDの発症頻度・重症度が増加する可能性が報告されている。寛解期移植を目指すためにmogamulizumabを使用せざるを得ない症例における至適なドナーソースや移植時期,GVHD予防法に関して,更なる症例の蓄積が望まれる。(著者抄録)

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私たちは白血病性形質細胞様樹状細胞株(PMDC05)を樹立し、この細胞株が抗原特異的細胞傷害性T細胞(CTL)誘導能を有することを報告してきた。さらに、CD80遺伝子を導入したPMDC05であるPMDC11の抗原提示能がさらに増強することも報告した。エクソソームは、多くの細胞により分泌される30〜100nmの大きさの小粒子であり、抗原提示細胞(APC)由来エクソソームは主要組織適合抗原(MHC)や抗原提示関連分子などを多く含んでいることが知られており、単球由来樹状細胞(moDC)の分泌するエクソソーム(dexosome)が抗原提示能を有することが示され、これを用いた臨床研究も行われている。本研究では、PMDC11細胞由来エクソソームを同定するとともに、PMDC11細胞とそのエクソソームによるCTL誘導について検討した。抗原ペプチドをパルスしたPMDC11細胞またはmoDCの培養上清からExoQuick-TCを用いてエクソソームを抽出した。この抽出物がエクソソームであることを、磁気ビーズとフローサイトメトリーを用いて確認した。磁気ビーズで捕捉した抽出物は、HLA-DR、CD54、CD86、CD80、CD123陽性であり、さらにエクソソームマーカーであるCD63(LAMP3)が陽性であることから、PMDC11細胞はエクソソーム(PMDC11-dex)を放出することが確認された。次に、サイトメガロウイルス(CMV)pp65ペプチドまたは改変型ウィルムス腫瘍遺伝子(mWT1)ペプチドをパルスしたPMDC11細胞を用いてHLA-A*24:02健常人末梢血CD8+T細胞を刺激培養し、抗原特異的CTL誘導についてテトラマー解析を行った。PMDC11細胞刺激培養において、抗原特異的CTLの増幅が確認された。CMV pp65ペプチドまたはmWT1ペプチドをパルスしたPMDC11細胞培養上清より抽出したPMDC11-dexによる刺激培養では、PMDC11-dex添加培養系において抗原特異的CTLの増幅が確認された。これらの結果よりPMDC細胞株はエクソソーム分泌能有し、PMDC11-dexは抗原特異的CTL誘導能を有することが示唆された。PMDC11細胞は、細胞自体がCTL養子免疫療法に応用できるのみならず、エクソソームを用いた無細胞系ワクチンの開発にも有用であると思われた。(著者抄録)

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To clarify the effectiveness and safety of WT1 peptide vaccination against the residual CML cells, we started WT1 peptide vaccination in combination with regular dose of imatinib for a CML-CP patient who had been treated with 400 mg imatinib for 4 years but not achieved MMR. HLA-A*24:02-restricted mutant type WT1 peptide vaccination was undertaken 22 times totally. The appearance of WT1-specific CTLs in PB was confirmed by evaluating the frequency of MHC/WT1 tetramer+CD8+ T cells by using mixed lymphocyte peptide culture（MLPC）system every 4 weeks. WT1 tetramer+ cells detected by MLPC system were investigated for WT1 specific cytotoxicity. Bcr-abl transcripts have decreased to less than 500 copies by the administration of WT1 peptides every 4 weeks. After 7 months from the cessation of vaccination, transcripts decreased to the level of CMR, which is lasting thereafter Tumor antigen specific peptide vaccine therapy in combination with molecular targeted therapy is one of the potent methods for eradicating cancer stem cells.

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Other Link： http://search.jamas.or.jp/link/ui/1998122075

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Other Link： http://search.jamas.or.jp/link/ui/1997206499

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Language：Japanese   Publisher：Niigata University  

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Other Link： http://search.jamas.or.jp/link/ui/1994156607