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Neuroendocrine carcinoma (NEC) of the head and neck is a rare type of malignancy, accounting for only 0.3% of all head and neck cancers, and its clinicopathological and genomic features have not been fully characterized. We conducted a retrospective analysis of 27 patients with poorly differentiated NEC of the head and neck seen at our institution over a period of 15 years. Patient characteristics, adopted therapies, and clinical outcomes were reviewed based on the medical records. Pathological analysis and targeted sequencing of 523 cancer-related genes were performed using evaluable biopsied/resected specimens based on the clinical data. The most common tumor locations were the paranasal sinus (33%) and the oropharynx (19%). Eighty-one percent of the patients had locally advanced disease. The 3-year overall survival rates in all patients and in the 17 patients with locally advanced disease who received multimodal curative treatments were 39% and 53%, respectively. Histologically, large cell neuroendocrine carcinoma was the predominant subtype (58% of evaluable cases), and the Ki-67 labeling index ranged from 59 to 99% (median: 85%). Next-generation sequencing in 14 patients identified pathogenic/likely pathogenic variants in TP53, RB1, PIK3CA-related genes (PREX2, PIK3CA, and PTEN), NOTCH1, and SMARCA4 in six (43%), three (21%), two (14%), two (14%), and one (7%) patients, respectively. Sequencing also detected the FGFR3-TACC3 fusion gene in one patient. The median value of the total mutational burden (TMB) was 7.1/Mb, and three patients had TMB ≥ 10. Regardless of the aggressive pathological features, our data revealed favorable clinical characteristics in the patients with locally advanced disease who received curative treatment. The lower TP53 and RB1 mutation prevalence rates compared to those described for small cell lung cancer suggests the biological heterogeneity of NEC in different parts of the body. Furthermore, the FGFR3-TACC3 fusion gene and mutations in genes encoding the components of the NOTCH and PI3K/AKT/mTOR pathways found in our study may be promising targets for NEC of the head and neck.

Naomi Hayashi,1 Yasuyoshi Sato,1 Yu Fujiwara,1,2 Naoki Fukuda,1 Xiaofei Wang,1 Kenji Nakano,1 Testuya Urasaki,1 Akihiro Ohmoto,1 Makiko Ono,1 Junichi Tomomatsu,1 Yukiko Sato,3 Hiroki Mitani,4 Takashi Toshiyasu,5 Shunji Takahashi1 1Department of Medical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan; 2Department of Medicine, Icahn School of Medicine at Mount Sinai, Mount Sinai Beth Israel, New York City, NY, USA; 3Pathology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan; 4Head and Neck Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan; 5Radiation Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, JapanCorrespondence: Yasuyoshi SatoThe Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto, Tokyo, 135-8550, JapanTel +8135200111Fax +81335200141Email yasuyoshi.sato@jfcr.or.jpPurpose: There have been few reports on the evaluation of cancer cachexia based on skeletal muscle mass index (SMI) in patients with head and neck cancer.Patients and Methods: One hundred and ninety-two head and neck cancer patients were enrolled. In definitive and adjuvant chemoradiotherapy settings, clinical outcomes were compared between cachexia and non-cachexia patients.Results: Forty patients were diagnosed with cachexia (20.8%). In the definitive setting, overall survival (OS) was significantly shorter in the cachexia group (3-year OS: 50.0% vs 88.5%; p < 0.01), and multivariate analysis identified UICC stage IV, baseline albumin of < 4 and cachexia as poor prognostic factors. However, cachexia was not significant in the adjuvant setting.Conclusion: Cancer cachexia was negatively associated with prognosis in patients with HNC who received definitive chemoradiotherapy. Nutritional intervention during chemoradiotherapy may improve survival in these patients.Keywords: head and neck cancer, squamous cell carcinoma of head and neck, sarcopenia, cachexia, muscle, skeletal, chemoradiotherapy, prognosis

Advances in chemotherapy and supportive therapy have resulted in improved clinical outcomes in patients with hematological malignancies undergoing hematopoietic stem-cell transplantation (HSCT). However, the association between HSCT and early- and late-onset cardiotoxicity remains controversial as these cardiac complications, including acute heart failure and arrhythmia, such as atrial fibrillation, can occasionally be lethal. Although the overall pathophysiology has not been elucidated, initial/salvage chemotherapy before HSCT, such as anthracycline-combined regimens, conditioning regimens, thoracic radiotherapy, and pre-existing personal risk factors, could be associated with an increased risk of cardiac events. Routine monitoring of cardiac function using global longitudinal strain or left ventricular ejection fraction in echocardiogram and serum biomarkers could be an option to detect early changes in cardiac status before irreversible cardiac complications develop. While beta-blockers and angiotensin-converting enzyme inhibitors are commonly used for cardioprotection, their clinical benefit has not been fully established in HSCT-associated cardiotoxicity. In the future, genetic analysis to reveal individual vulnerability to cardiotoxicity and prospective trials assessing the clinical benefit of early interventions, including novel agents such as angiotensin receptor-neprilysin inhibitor, are warranted. Collaboration between oncologists and cardiologists is crucial to establishing a strategy to prevent cardiac complications.

BACKGROUND/AIM Lenvatinib is standard therapy for radioiodine-refractory differentiated thyroid cancer (RR-DTC), although the optimal timing for starting treatment is still controversial. The aim of this study was to evaluate the prognostic impact of baseline tumour size (BTS) in patients with RR-DTC treated with lenvatinib. PATIENTS AND METHODS Fifty-one RR-DTC patients who had at least one measurable lesion and treated with lenvatinib were retrospectively analysed. BTS was defined as the sum of the longest dimensions of all measurable target lesions. RESULTS Median progression-free survival (PFS) and overall survival (OS) in the larger BTS (≥42 mm) group were shorter than those in the smaller (

Adrenocortical carcinoma (ACC) is a rare malignancy with a poor prognosis. While mitotane is the only agent approved for ACC, clinical data are scarce, especially in the Asian population. We reviewed 10 patients with ACC who received mitotane as a single agent or in combination with other agents in our institution. Patient characteristics, clinical outcomes, and toxicities were analyzed. Mitotane was administered to 2 patients as an adjuvant therapy and to 8 patients for systemic control. In the latter 8 patients, 1 patient had locally advanced disease and 1 had metastatic disease at the time of initial diagnosis, whereas the other 6 patients experienced metastatic relapse at mitotane initiation. The administered regimen was mitotane alone in 7 patients, and mitotane plus cytotoxic chemotherapy in 3 patients. The initial daily mitotane dose was 3.0 g in 2 patients, 1.5 g in 7 patients, and 1.0 g in 1 patient. The median duration of treatment was 3.7 (range, 0.7-22.1) months. In 8 systemic cases, the median overall survival from chemotherapy initiation was 7.2 months, and only 1 patient survived over 1 year. The median interval from mitotane termination to death in systemic cases was 2.8 months, and the cause was progressive disease in 4 patients and toxicity (hallucination, mycobacteriosis, or liver injury) in 3 patients. As a second-line regimen, 2 systemic cases and 1 adjuvant case were enrolled in clinical trials. Our analysis exhibited extremely poor prognosis under mitotane-based regimens, and further treatment strategies are warranted to improve outcomes.

BACKGROUND Eribulin is widely used for the treatment of breast cancer and soft-tissue sarcoma (STS). Previous studies identified the pre-treatment absolute lymphocyte count, baseline neutrophil-to-lymphocyte ratio (NLR) and C-reactive protein concentration as potential prognostic markers in patients with breast cancer treated with eribulin. However, prognostic factors for eribulin treatment in patients with STS have not been identified. PATIENTS AND METHODS This was a retrospective analysis of data collected prospectively from 53 patients who were treated with eribulin for recurrent or metastatic STS between March 2016 and August 2019. Univariate and multivariate analyses were performed to determine the predictive factors of durable clinical benefit, progression-free survival, and overall survival. RESULTS L-Sarcoma histology [hazard ratio (HR)=28.20, 95% confidence intervaI (CI)=1.67-476.00; p=0.021] and pre-treatment NLR

Background/aim In the CheckMate-141 trial regarding head and neck cancer (HNC), nivolumab conferred a survival benefit to patients. However, the best treatment sequence of chemotherapy and anti-PD-1/PD-L1 therapy in these cancers is unclear. Patients and methods This was an observational study using data collected prospectively from 97 HNC patients treated with nivolumab at our institutions. Twenty-two HNC patients who received paclitaxel-based chemotherapy before (pre-PTX, n=12) and after (post-PTX, n=10) nivolumab were evaluated. Results The median follow-up time was 15.9 months (range=6.9-35.9 months). There was a significant difference in the overall response rate (ORR) between pre-PTX (17%) and post-PTX (70%) (p=0.027). Similarly, time to progression (TTP) was significantly longer after nivolumab than before nivolumab (post-PTX, 7.4 months; pre-PTX, 4.9 months, p=0.020). Conclusion Paclitaxel-based chemotherapy had a better ORR and TTP after nivolumab than before nivolumab for HNC. The sequential administration of anti-PD-1 therapy followed by paclitaxel-based chemotherapy could be a better strategy for HNC.

Background: Large prospective studies of chemotherapy for metastatic or recurrent adenoid cystic carcinoma (ACC) of the head and neck are lacking due to the rarity of ACC. The aim of this study is to evaluate the efficacy of carboplatin plus paclitaxel toward ACC and perform an exploratory investigation of the prognostic factors to investigate the optimal strategy for metastatic or recurrent ACC.Methods: We retrospectively analyzed recurrent or metastatic ACC patients treated with carboplatin plus paclitaxel between April 2007 and September 2019 in our hospital. Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS) were evaluated, and an exploratory analysis of the prognostic factors including tumor growth rate (TGR) was conducted.Results: A total of 26 ACC patients were enrolled. ORR and DCR were 11.5% and 76.9%; the median PFS and OS were 8.1 and 22.3 months, respectively. From the results of the multivariate analysis, higher (≥ 6%/month) TGR was associated with worse PFS (hazard ratio [HR] 7.00, 95%CI 1.34–36.53, p = 0.02) and OS (HR 29.33, 95%CI 3.38–254.80, p Conclusions: Carboplatin plus paclitaxel showed modest efficacy for recurrent or metastatic ACC patients. Watchful waiting may be optimal for ACC patients with lower TGR. Systemic chemotherapy should be considered when TGR increases during active surveillance.

Background In the CheckMate-141 trial, nivolumab conferred a survival benefit in patients with recurrent or metastatic refractory squamous cell carcinoma (SCC) head and neck cancer (HNC). Here, we examined the efficacy of nivolumab in patients with histological subtypes or primary sites of HNC not included in the CheckMate-141 trial. Methods This was a retrospective analysis of data collected prospectively from 97 patients who were treated with nivolumab for recurrent or metastatic HNC at our institution. The patients were assigned to three groups based on HNC primary site: 1) oral cavity, pharynx, and larynx, which were included in CheckMate-141 (n = 68), 2) nasopharynx (excluded in CheckMate-141, n = 7) and 3) other primary sites excluded in CheckMate-141 (n = 22) and assigned to two groups according to histological subtype: 1) SCC (included in CheckMate-141, n = 83) and 2) non-SCC (all sites excluded in CheckMate-141, n = 14). Survival outcomes and nivolumab treatment response were compared between the primary site and histological subgroups. Results The median number of nivolumab treatments was 7 cycles (range, 1-53 cycles) and the median follow-up time was 9.1 months (range, 0.66-33.0 months). There were no significant differences in response rates between the three primary site subgroups (CheckMate-141 sites 22%, nasopharynx 43%, others 18%; p=0) or the two histological subtype subgroups (SCC 25%, non-SCC 7%, p=0). Similarly, overall survival and progression-free survival were comparable for patients stratified by primary site or histological subtype. Conclusion No significant difference in response rates or survival outcomes was detected between nivolumab-treated HNC patients with primary sites and histological subtypes that were included versus excluded in the CheckMate-141 trial. These data provide a potential rationale for nivolumab therapy for all HNC patients in clinical practice.

Introduction Drug repositioning (DR) is defined as determining new therapeutic applications for existing drugs. This approach is advantageous over de novo drug discovery in accelerating clinical development, in terms of lower costs, a shortened development period, a well-known action mechanism, a feasible dosage, and an acceptable safety profile. Areas covered This work was aimed at reviewing agents with successful DR in hematology. Expert opinion Thalidomide and plerixafor have been successfully repositioned for treating multiple myeloma and harvesting peripheral blood stem cells, respectively. The former was originally developed as a sedative and the latter as an anti-HIV drug. Currently, the feasibility of repositioning various agents is being explored (e.g., an anti-influenza virus drug oseltamivir for primary immune thrombocytopenia, an anti-HIV drug abacavir for adult T-cell leukemia, and a macrolide antibiotic clarithromycin for multiple myeloma). Furthermore, bosutinib for chronic myeloid leukemia or the antiplatelet drug cilostazol have been suggested to have clinical benefits for the management of amyotrophic lateral sclerosis and ischemic stroke, respectively. To promote DR, effective application of artificial intelligence or stem cell models, comprehensive database construction shared between academia and pharmaceutical companies, suitable handling of drug patents, and wide cooperation in the area of specialty are warranted.

Objectives: This retrospective observational study is conducted to evaluate the association between cancer cachexia and prognosis in head and neck cancer patients treated with chemoradiotherapy using skeletal muscle mass index at the level of the third lumbar vertebra with computed tomography.Methods: Two hundred forty-two patients were enrolled and categorized into the following four groups based on cancer cachexia criteria and treatment setting: definitive chemoradiotherapy with cachexia, definitive chemoradiotherapy without cachexia, adjuvant chemoradiotherapy with cachexia, and adjuvant chemoradiotherapy without cachexia. Progression-free survival (PFS) and overall survival (OS) between cachexia and non-cachexia groups were compared by treatment setting using the long-rank test. Prognostic factors were evaluated using the Cox proportional hazards model.Results: Fifty patients were diagnosed with cancer cachexia (20.7%). In the definitive setting, both PFS and OS were significantly shorter in the cachexia group (median PFS, 15.5 months vs. not reached, p < 0.01; median OS, 48.4 months vs. not reached. p < 0.01). Conversely, there was no significant difference between the two groups in the adjuvant setting. UICC Stage IV, base of albumin of Conclusion: Cancer cachexia was negatively related with prognosis in patients with head and neck squamous cell carcinoma who received definitive chemoradiotherapy. Nutritional intervention during chemoradiotherapy may improve survival in these patients. Further research is warranted.

Introduction: Transformation is a multi-step event wherein indolent lymphomas, such as follicular lymphomas, are converted into an aggressive subtype, such as diffuse large B-cell lymphoma. This process progresses not only through mutations in several of the causative genes, such as TP53, CDKN2A/B, or MYC, but also through epigenetic or micro-environmental changes. Excisional biopsy is recommended when transformation is clinically suspected.Areas covered: The authors summarized the current knowledge regarding the clinicopathological and molecular features of transformed lymphomas and discussed the relevance of re-biopsy in the diagnosis of transformation, comparing it with noninvasive diagnostic tools [fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) and circulating tumor DNA (ctDNA) analysis].Expert opinion: Pathological confirmation by biopsy is considered the golden standard for diagnosis and is indispensable for determining subsequent treatment strategies. The potential weakness of this approach is its invasiveness and the unavailability of pathological findings outside the biopsied areas. In the context of relapse, PET/CT is used mainly for the selection of the best suitable biopsy site, while ctDNA has the potential for detecting systemic genomic changes associated with relapse before clinical presentation. Future investigations should be focused on combining biopsies with new technologies for an early and accurate diagnosis of transformation.

Introduction: Angioimmunoblastic T-cell lymphoma (AITL) is a type of peripheral T-cell lymphomas harboring aggressive biological behaviors and presenting unique immunologic hyperactivation. Gene expression profiling has revealed that AITL cells derive from follicular T helper (Tfh) cells. The prognosis is poor under CHOP-like regimen, and salvage chemotherapy is mostly ineffective. Thus, novel therapies are required in patients with AITL. NCCN Guidelines for peripheral T-cell lymphoma refer to cyclosporin (CyA) as one therapeutic option in second- or later lines especially for AITL cases unfeasible for hematopoietic stem-cell transplantation (HSCT). The clinical data of AITL are based on small-scale case series, and prospective trials are scarce.Areas covered: In this article, the authors reviewed published articles or conference abstracts, and extracted total 26 patients with AITL receiving CyA.Expert opinion: The overall response rate in above 26 patients was outstanding (86% in second or later lines), suggesting the utility in heavily treated cases including those who underwent HSCT. Meanwhile, publication bias is the most serious limitation in this literature review. Larger case series or prospective data with CyA alone or in combination with other drugs are warranted to establish the position in the treatment strategy of patients with AITL.

Background/Aim: Trabectedin and eribulin are widely used for the treatment of soft-tissue sarcoma (STS). Previously it was shown that the baseline neutrophil-to-lymphocyte ratio (NLR) predicts the efficacy of eribulin for STS. However, prognostic factors for trabectedin on STS have not been identified to date. Patients and Methods: We conducted a retrospective study of data collected prospectively from 39 patients treated with trabectedin for recurrent or metastatic STS between October 2012 and December 2019. To determine the predictive factors of overall survival (OS) and progression-free survival (PFS), univariate and multivariate analyses were performed. Results: Age ≥40 (HR=0.33, 95% CI=0.15-0.71; p=0.0050) and changes in NLR (ΔNLR)

Cytotoxic chemotherapy, including cyclophosphamide, vincristine, and dacarbazine (CVD) therapy, is widely used to treat metastatic pheochromocytoma and paraganglioma. Because these diseases are rare, studies are needed to establish treatment strategies. This was a single-center and retrospective study to analyze the efficacy of chemotherapy for patients with metastatic pheochromocytoma and paraganglioma diagnosed in 1983-2020. Clinical characteristics, tumor volume response, biochemical response based on catecholamine level, overall survival, and progression-free survival were evaluated. Patients with a complete response or partial response in tumor volume or catecholamine level were classified as responders. Sixteen patients were administered chemotherapy for a median of 16.5 cycles (interquartile range, 10-42). The tumor volume response was classified as follows: partial response (N = 4), stable disease (N = 9), and progressive disease (N = 3) (disease control rate = 81%). The biochemical responses were as follows: complete response (N = 2), partial response (N = 5), no change (N = 3), and progressive disease (N = 1) (disease control rate = 91%). The 5-year survival rate was 50% (95% confidence interval [CI], 21-74%) and median overall survival was 4.4 years (95% CI, 2.4 years-not reached). Overall survival and progression-free survival between responders and nonresponders were not statistically different. One patient developed myelodysplastic syndrome during CVD therapy. In conclusion, chemotherapy achieved disease control among more than half of patients, although survival did not differ between responders and nonresponders. Further fundamental research and prospective trials are needed to analyze the efficacy of CVD therapy.

Background Head and neck squamous cell carcinoma (HNSCC) is a geriatric cancer. However, older adult patients are frequently underrepresented in large clinical trials. Aims The aim of this study is to assess the efficacy and safety of the EXTREME regimen (platinum + fluorouracil + cetuximab) in older and younger adult patients with HNSCC. Methods and results Patients with recurrent or metastatic HNSCC treated with the EXTREME regimen were retrospectively analyzed. We compare the efficacy and safety in older (aged ≥70 years) younger (aged

Background/Aim: Lenvatinib is one of the few options for patients with anaplastic thyroid cancer (ATC). However, tumor markers for ATC treated with lenvatinib is lacking. The aim of this study was to explore whether the neutrophil-to-lymphocyte ratio (NLR) can be a tumor marker for ATC treated with lenvatinib. Patients and Methods: We retrospectively analyzed the prognostic significance of the NLR in 13 ATC patients treated with lenvatinib. Results: The disease control rate was better in patients with lower NLR (

Clinical evidence regarding eribulin treatment for patients with soft tissue sarcoma (STS) is limited to those with L-sarcoma (leiomyosarcoma and liposarcoma) who have completed at least two chemotherapies. Whether histological subtypes and treatment lines affect the efficacy and safety of eribulin for patients with STS has yet to be elucidated. The current study retrospectively reviewed patients with STS receiving eribulin at the Cancer Institute Hospital of JFCR and evaluated the prognostic factors affecting its efficacy and safety by histological diagnoses and treatment lines. A total of 41 patients with STS, including 26 with L-sarcoma, underwent eribulin treatment. Additionally, a total of and 14 patients, including 12 with L-sarcoma, received eribulin as a second-line treatment. The results revealed that patients with L-sarcoma demonstrated longer progression-free survival (PFS) rates compared with patients without L-sarcoma (4.5 vs. 2.3 months; P=0.005). Furthermore, differences in treatment line significantly affected PFS (4.5 months in second-line treatment vs. 2.4 months in later lines; P=0.037). A high number of patients with L-sarcoma received eribulin as a second-line treatment. Regarding safety, several adverse events were reported, such as neutropenia, which were more frequently observed in patients with L-sarcoma or other patients receiving eribulin as a second-line treatment. However, most adverse events were tolerable. The clinical efficacy of eribulin was increased in patients with L-sarcoma, which was similar to previous clinical trials. However, treatment lines could also affect its efficacy. When evaluating the clinical value of eribulin to STS, it is important to consider treatment lines.

A specific category termed immunodeficiency-associated lymphoproliferative disorders (LPD) exists in the 2016 revised WHO classification concerning lymphoid neoplasms. This category is defined by etiology and includes LPD developing in association with organ transplantation or immunosuppressive/immunomodulatory agents including methotrexate. The functional mechanism is chiefly explained by the autonomous proliferation of Epstein-Barr virus (EBV)-infected lymphocytes induced by host-immune suppression. This category ranges from reactive lymphocyte hyperplasia to monomorphic lymphoma. Its clinical behavior varies depending on host immunity and pathological features; pathological confirmation by biopsy is thus important for deciding treatment strategies. Owing to the spontaneous regression observed in some patients, uniform chemotherapy is not recommended. The main initial treatment options include the reduction in immunosuppressive drugs, immunotherapy with the anti-CD20 antibody rituximab, chemotherapy, or a combination of these. Other novel treatments such as adoptive immunotherapy with EBV-specific cytotoxic T cells, could be an alternative for relapsed/refractory diseases in clinical trials.

Pancreatic cancer (PC) is one of the most devastating malignancies; it has a 5-year survival rate of only 9%, and novel treatment strategies are urgently needed. While most PC cases occur sporadically, PC associated with hereditary syndromes or familial PC (FPC; defined as an individual having two or more first-degree relatives diagnosed with PC) accounts for about 10% of cases. Hereditary cancer syndromes associated with increased risk for PC include Peutz-Jeghers syndrome, hereditary pancreatitis, familial atypical multiple mole melanoma, familial adenomatous polyposis, Lynch syndrome and hereditary breast and ovarian cancer syndrome. Next-generation sequencing of FPC patients has uncovered new susceptibility genes such as PALB2 and ATM, which participate in homologous recombination repair, and further investigations are in progress. Previous studies have demonstrated that some sporadic cases that do not fulfil FPC criteria also harbor similar mutations, and so genomic testing based on family history might overlook some susceptibility gene carriers. There are no established screening procedures for high-risk unaffected cases, and it is not clear whether surveillance programs would have clinical benefits. In terms of treatment, poly (ADP-ribose) polymerase inhibitors for BRCA-mutated cases or immune checkpoint inhibitors for mismatch repair deficient cases are promising, and clinical trials of these agents are underway.

e18007 Background: Concurrent chemoradiotherapy (CCRT) with cisplatin (CDDP) is a standard treatment for locally advanced head and neck cancer (LAHNC) in the definitive setting. Three cycles of 100 mg/m2 CDDP for every three weeks (Q3W) are now recommended but compliance with CCRT is relatively low due to its severe toxicity. Therefore, the potential de-escalation strategies for LAHNC have been discussed to decrease the therapeutic toxicity. Methods: Patients with LAHNC who underwent definitive CCRT with CDDP between 2012 and 2018 at The Cancer Institute Hospital of Japanese Foundation for Cancer Research were analyzed. Patients were classified into two groups based on the planned CDDP dose: (A) 100 mg/m2 and (B) 80 mg/m2 Q3W for three times. One-to-one propensity score matching was performed to minimize bias between two groups. After patients in two groups were matched by using propensity score, the overall survival (OS), recurrence-free survival (RFS), local recurrence-free survival (LRFS), and metastatic recurrence-free survival (MRFS) were analyzed by the Kaplan-Meier method with the Cox proportional hazards model. The follow-up term was set as two years to evaluate the early survival benefit. The dose and density of CDDP and the objective adverse events were also assessed. Results: A total of 304 patients were included with the median age of 62 (Interquartile range [IQR]: 54-67) years. Among them, 249 patients (82%) were male. Patients were treated with 100 mg/m2 CDDP (n = 145) and 80 mg/m2 CDDP (n = 159) regimens. After the propensity score matching, 119 patients were included in each group, respectively. There were no significant differences in baseline characteristics between two propensity-matched cohorts. The median follow-up time was 24 months in each group. Two-year OS was 93.0% (95% confidence interval [CI]: 88.4-97.8) in group A and 94.9% (91.0-99.0) in group B. Two-year RFS was 86.5% (80.6-92.9) in group A and 83.1% (76.6-90.1) in group B, respectively. No significant difference was observed in OS (Hazard ratio [HR] = 1.42, 95% CI: 0.49-4.08, p = 0.52), RFS (HR = 0.81, 95% CI: 0.42-1.57, p = 0.54), LRFS (HR = 0.57, 95% CI: 0.24-1.36, p = 0.20), and MFS (HR = 1.32, 95% CI: 0.52-3.35, p = 0.56). The median cumulative dose of CDDP was significantly higher in group A (300 mg, interquartile range [IQR]: 240-300) than in group B (240 mg, IQR:160-240) but the frequency of hematological, hepatic, renal, electrolytic, and grade 3-5 any adverse events was not significantly different between two groups. Conclusions: Our study showed no survival difference at 2-year follow-up between 100 mg/m2 and 80 mg/m2 CDDP regimens of definitive CCRT for LAHNC. This result could support the tide of the de-escalation strategy in head and neck cancer treatment. Longer follow-up is necessary and further prospective trials comparing CDDP dosage are warranted.

// Erina Takai 1, * , Shinichi Yachida 1, * , Kyoko Shimizu 2 , Junji Furuse 3 , Emi Kubo 4 , Akihiro Ohmoto 1 , Masami Suzuki 1 , Ralph H. Hruban 5 , Takuji Okusaka 4 , Chigusa Morizane 4 , Toru Furukawa 6 1 Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan 2 Department of Gastroenterology, Institute of Gastroenterology, Tokyo Women’s Medical University, Tokyo, Japan 3 Department of Medical Oncology, Kyorin University School of Medicine, Mitaka, Japan 4 Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan 5 Department of Pathology and Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA 6 Institute for Integrated Medical Sciences, Tokyo Women’s Medical University, Tokyo, Japan * These authors have contributed equally to this work Correspondence to: Toru Furukawa, email: furukawa.toru@twmu.ac.jp Keywords: pancreatic cancer, familial predisposition, BRCA2, ATM, PALB2 Received: July 10, 2016 Accepted: September 29, 2016 Published: October 6, 2016 ABSTRACT Clinicopathologic and genetic features of familial pancreatic cancer (FPC) in Asian countries remain largely unknown. The main purpose of this study was to determine the prevalence of FPC and to define causative FPC-predisposition genes in a Japanese cohort with pancreatic ductal adenocarcinoma (PDAC).We reviewed 1,197 patients with a pathologically proven PDAC and found that 88 (7.3%) were FPC patients who had at least one first-degree relative with PDAC. There were no significant differences between the FPC cases and sporadic cases in terms of gender, age, tumor location, stage, family history of any cancer except PDAC, and personal history of smoking, other cancers, diabetes mellitus and chronic pancreatitis. In the FPC patients, we then investigated the prevalence of germline mutations in 21 genes associated with hereditary predispositions for pancreatic, breast and ovarian cancers by means of the next-generation sequencing using a custom multiple-gene panel. We found that eight (14.5%) of the 54 FPC patients with available germline DNA carried deleterious mutations in BRCA2 , PALB2 , ATM , or MLH1 . These results indicate that a significant fraction of patients with PDAC in Japan have a family history of pancreatic cancer, and some of them harbor deleterious causative mutations in known FPC predisposition genes.

Objectives The median age of patients with pancreatic ductal adenocarcinoma (PDAC) is approximately 70 years, and PDAC rarely affects individuals younger than 40 years. Here, we investigated clinicopathologic features and genetic background of PDAC occurring in young patients (age ≤ 40 years) to determine whether any difference exists in comparison with those of older patients (>40 years). Methods We reviewed 908 patients with pathologically proven PDAC for clinicopathologic characteristics. In addition, we performed targeted sequencing of germline variants for 49 genes that are associated with a hereditary predisposition for cancer in 9 young patients with available DNA. Results Among the 908 patients, a total of 17 were diagnosed at age younger than 40 years. There were no significant differences between young and old groups in terms of sex, smoking history, tumor location, Union for International Cancer Control stage, family histories of any cancer and PDAC in first-degree relatives, and medical history of other cancer. Targeted sequencing analysis demonstrated no definite "pathogenic" variants. Conclusions The clinicopathologic features in young patients were generally similar to those in older patients. The rarity of family history of PDAC and the sequencing analysis for germline variants suggest that hereditary factors might have a weak, if any, relationship with early-onset PDAC.

The risk of malignancy in inflammatory myopathy patients is well recognized. However, the incidence of germ cell tumor (GCT) with inflammatory myopathy is low, and most reported cases of GCT also exhibit testicular tumors. Therefore, a case of extragonadal GCT with dermatomyositis (DM) is reported in the current study to better understand this paraneoplastic syndrome. A 53-year-old man presented with bilateral cervical lymph node enlargement. A lymph node biopsy showed embryonal carcinoma, and computed tomography showed multiple lymph node and lung metastases. A period of one month after bleomycin, etoposide and cisplatin (BEP) chemotherapy, this patient developed an erythematous eruption over the extensor surfaces of bilateral fingers, or Gottron's sign and facial erythema. The patient was diagnosed with DM with a positive anti-TIF-1γ-antibody result. High-dose prednisolone was effective, and there has been no evidence of cancer recurrence for over one year. The literature review identified 17 cases of GCT with inflammatory myopathy that have been reported so far, and it was indicated that this is the first case of extragonadal GCT with DM following chemotherapy. This case highlights the importance of monitoring after the completion of cancer treatment, as distinctive dermal and muscular symptoms should cause us to consider the possibility of paraneoplastic inflammatory myopathy.

Pancreatic cancer (PC) is categorized as a neoplasm associated with Lynch syndrome; however, the precise proportion of PC patients harboring DNA mismatch repair genes (MMR genes) remains unclear, especially in the Asian population. Among 304 Japanese patients with pathologically proven pancreatic ductal adenocarcinoma, we selected 20 (6.6%) patients with a personal or family history involving first- or second-degree relatives fulfilling the revised Bethesda guidelines (RBG), defined as RBG-compatible cases. We analyzed germline variants in 21 genes related to a hereditary predisposition for cancer as well as clinical features in all 20 cases. The RBG-compatible cases did not show any unique clinicopathological features. Targeted sequencing data revealed three patients carrying deleterious or likely deleterious variants. Specifically, these three patients harbored a nonsense variant in ATM, a frameshift variant in ATM, and a concurrent nonsense variant in PMS2 and missense variant in CHEK2 (double-mutation carrier), respectively. Although an MMR gene mutation was identified in only one of the 20 patients, up to 15% of the RBG-compatible PC cases were associated with germline deleterious or likely deleterious variants. These findings showed that these guidelines could be useful for identifying PC patients with DNA damage repair genes as well as MMR genes.

Detection of immunoglobulin light chain restriction (LCR) by flow cytometry (FCM) is a useful tool for B-cell non-Hodgkin lymphoma (B-NHL) diagnosis. Here, we identified B-NHLs without LCR by FCM and investigated the pathological causes for lack of LCR. A total of 89/471 cases (19%) of B-NHL were LCR-negative. The incidence of lack of LCR was 30% both in diffuse large B-cell lymphoma (DLBCL) and marginal zone lymphoma (MZL), and was 6% in follicular lymphoma (FL). In DLBCL cases, low expression of surface membrane light chain (33%), low proportion of lymphoma cells (11%), CD45 negativity (9%), and destruction or sampling error were suggested as reasons for lack of LCR. In MZL cases, the low proportion of lymphoma cells owing to admixture of many reactive germinal centres, and non-detection of plasmacytoid lymphoma cells by CD45 gating might be the reasons. Based on pathological subtypes, the frequency and reasons for lack of LCR by FCM varied.

Our objective was to appraise bronchial hyperresponsiveness in Sjogren’s syndrome (SS) and to analyze the clinical aspects of those patients. Forty-five patients with primary and secondary SS underwent examination with chest X-ray, spirometry and directly writing of the dose-response curve of respiratory resistance (Rrs) during the continuous inhalation of methacholine in stepwise incremental concentrations (astograph). Thirty-one patients (68.9%) had bronchial hyperresponsiveness. Ten out of 12 (83.3%) patients with extraglandular involvement had bronchial hyperresponsiveness. The threshold of the increase of Rrs in SS patients was significantly higher than bronchial asthma. This paper shows that some patients with SS have bronchial hyperresponsiveness; especially in patients with extraglandular involvement, it occurs at a high incidence. In addition, the pattern of the dose-response curve with bronchial hyperresponsiveness in SS was similar to that of chronic bronchitis rather than bronchial asthma in the methacholine inhalation test.

66歳の女性 (F.T.) はセ・ア膜電気泳動でα2位に2本の明瞭なバンドを示し, いずれもIgA-K型と同定された. ゲル濾過で2峰性の peak として分離された高分子分画 (P1) と低分子分画 (P2) はセ・ア膜電気泳動上の2本のIgAバンドと同じ位置に泳動された. これらのIgAの分子構造, サブクラス, アロタイプの検索をIgA1結合レクチン (jacalin) と細菌由来のIgA 1-protease に対する反応性ならびにSDS-PAGEで行った. P1とP2は同じアイソタイプとKタイプを示しP1を還元処理後, agarose gel 電気泳動でP2と同じ移動度に変換した. P1とP2はともに jacalin との反応性を欠き, さらにA 1-protease に感受性を欠くことからIgA2サブクラスと同定した. 非還元下SDS-PAGEでP1とP2はともに light 鎖の2量体が遊離した. 本IgAはH鎖-L鎖間にS-S結合を欠きL鎖間がS-S結合しているA2m (1) アロタイプの性格と一致する. 本報告は日本人にみられたIgA2, A2m (1) アロタイプ骨髄腫蛋白を詳細に検討した最初のものと考える.

199 Background: The median age of pancreatic ductal adenocarcinomas (PDAC) patients is approximately 70 years. We investigated clinical features of PDAC occurring in young patients (< 40 years) in order to determine if any difference exists in comparison to older patients. Methods: We reviewed a single-institution database of 785 patients with pathologically proven PDAC between 2001 and 2012. We examined the clinical features in patients with PDAC below 40 years of age and compared it to those in older patients (≥ 40 years). Results: Of these 785 patients, a total of 10 patients (1.3%) under the age of 40 were identified, with a range of 28 to 37 years. Clinical features in young and older patients have been summarized (table). There are no differences between groups in terms of sex, smoking, tumor location, UICC stage, a family history of PDAC and a family history of any cancer. In the young patients group, three of them were diagnosed with localized diseases, two others with locally advanced diseases, and five others with metastatic diseases. Two of the three patients with localized diseases underwent curative operation. The five patients with metastatic diseases received chemotherapy, and only one patient achieved a partial response treated with FOLFIRINOX regimen. Two of the patients were long-term survivors, having survived over three years. Six of the patients had a family history of other cancers in first-degree relatives. Unexpectedly and most importantly, only one patient had a family history of PDAC. Conclusions: Cases of patients with PDAC below 40 years of age are rare. The clinical features in young patients were generally similar to those in older patients. Almost all young patients had no family history of PDAC, which suggests that hereditary genetic factors have a weak relationship with cases of onset of PDAC at a young age in Japan. [Table: see text]

We report a case of a 37-year-old man with relapsing polychondritis and IgA nephropathy. He visited our hospital with high fever and the swelling of his ears and eyelids. His symptoms and the results of the biopsy of his right auricle fulfilled the Damiani's criteria. Laboratory examination on admission showed an increase of serum IgA level, a presence of immune complex, remarkable hematuria (grade III) and proteinuria (grade II). Most of his symptoms were improved by the administration of antibiotic and NSAIDs, however, urinary findings still remained unchanged. The biopsy of his right kidney led to a diagnosis of IgA nephropathy (group II). Although relapsing polychondritis is known to associate rarely with renal involvement, it is very rare to associate with IgA nephropathy. This case indicates that immune disorders including IgA nephropathy should be investigated in patients with relapsing polychondritis.

We report a 33-year-old female with nephrotic syndrome associated with Henoch-Schönlein nephritis (HSN) during pregnancy. She presented purpura in the legs at 20 weeks in her third pregnancy. A biopsy of her purpuric skin lesion showed leukocytoclastic vasculitis. After a month she was admitted to Sapporo City General Hospital because of development of a nephrotic syndrome. She was treated with heparin as anticoagulants therapy and delivered of a healthy girl by Cesarean section at 34 weeks. Renal biopsy, carried out beyond a month after delivery, revealed diffuse proliferative glomerulonephritis with prominent IgA deposits, which made the diagnosis of HSN (grade III of classification of the renal histopathology of HSN from the International Study of Kidney Disease in Childhood). Prednisolone 40 mg, dipyridamole 300 mg per day and pulse doses of steroid were administrated. Two months later proteinuria was not detected. A sister of the patient had also Henoch-Schönlein Purpura in her childhood. They shared HLA DR 4, DQ 4 which are known to be associated with IgA nephropathy. Fifty percent of pregnant women with chronic glomerulonephritis shows increased proteinuria. Pregnancy may have influence on the increased proteinuria in this case.

尿細管性アシドーシス(RTA)に基づく偽骨折を呈したシェーグレン症候群(SjS)の1例を経験した.症例は38歳女性で,右大腿部痛と歩行困難により市立札幌病院へ入院した.右大腿骨X線写真にて偽骨折像を認め,骨シンチグラムでは,同部および両側肋骨部に多発異常集積像を認めた.代謝性アシドーシス,低カルシウム血症,低リン血症,高アルカリフォスファターゼ血症を呈した.塩化アンモニウム負荷試験で,尿酸性化能の著明な低下を認め重曹負荷試験で排泄率2.1%であり遠位型RTAと診断した.乾燥性角結膜炎および慢性唾液腺炎を認め, SjSに伴うRTAにより骨軟化症を起こし偽骨折をきたしたと考えられた.重曹と1α-OH-D3の投与にて代謝性アシドーシス,偽骨折の改善をみ,骨痛の消失をみた. SjSに偽骨折を伴う症例は非常に稀であるが注意を要する合併症であり報告する.