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The optimal timing for starting lenvatinib treatment in patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC) has long been controversial because of the relatively slow-growing nature of differentiated thyroid cancer. The aim of this study was to establish a scoring system using known clinical factors to simplify decision-making in when to start lenvatinib in RR-DTC patients.We retrospectively analyzed RR-DTC patients treated with lenvatinib. We developed the clinical indication scoring algorithm on the basis of age, tumor-related symptoms, histology, metastatic sites, neutrophil-to-lymphocyte ratio, size of lung metastases, baseline sum of tumor diameters, and tumor-volume doubling time that was used to categorize patients into low-, intermediate-, and high-risk groups.A total of 59 patients were analyzed; 13 low-risk, 36 intermediate-risk, and 10 high-risk. The respective median progression-free survival from the initiation of lenvatinib was 93.7 months in the low-risk group, 20.3 months in the intermediate-risk group, and 6.2 months in the high-risk group (p 0.02). Patients in the high-risk group had significantly worse overall survival compared with those in the low-risk (hazard ratio [HR] 6.59, 95% confidence interval [CI] 1.25-34.90, p 0.03) or intermediate-risk (HR 2.99, 95% CI 1.03-8.63, p 0.05) group. Using our proposed algorithm, patients in the intermediate-risk group showed treatment outcomes similar to that were observed in the pivotal trial of lenvatinib, and were the optimal patients to start lenvatinib.Our proposed scoring system can separate treatment outcomes and prognosis of RR-DTC patients treated with lenvatinib. This simple algorithm can be helpful for oncologists in deciding whether to start lenvatinib treatment in patients with RR-DTC.

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

Human T-cell leukemia virus type 1 (HTLV-I) associated bronchioloalveolar disorder (HABA) is a chronic and progressive bronchiolar/alveolar disorder related to HTLV-1 infection. Clinical knowledge and guidance are lacking for the diagnosis and management of this condition.This work aimed to review the latest information and challenges regarding HABA diagnosis and treatment.HABA is an immune-mediated state induced by HTLV-1. For diagnosis of HABA, other infectious diseases and pulmonary infiltration of adult T-cell leukemia should be excluded by investigations such as computed tomography (CT), transbronchial biopsy, and bronchoalveolar lavage fluid (BALF) analysis. Typical CT findings in HABA include diffuse panbronchiolitis-like or bronchiectasis patterns, whereas cases with other abnormalities, including interstitial pneumonia, have also been reported. A high rate of polyclonal CD4+ and CD25+ lymphocytes is detected in BALF of patients with HABA, reflecting the infiltration of HTLV-1 infected T-cells in the lung. Current treatment options are not HABA specific, and include corticosteroids, macrolide antibiotics, and pirfenidone. Mitigation of the adverse effects of HTLV-1 infection requires the establishment of diagnostic criteria for the disease, screening programs for HABA in HTLV-1 infected individuals, and the development of effective disease treatment strategies.

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.

Objective The primary objective of this study was to identify novel genes that predispose people in the Japanese population to FPC. Summary of background data Familial history of pancreatic cancer is an important risk factor but, to date, few genes predisposing individuals to increased risk of developing FPC have been identified. Methods We performed whole-exome sequencing of germline DNA from 81 Japanese FPC patients. We also investigated somatic gene alterations in 21 matched tumor tissues through whole-exome sequencing and copy number analysis. Results Our germline variants identified previously known FPC susceptibility genes such as ATM and BRCA2, and several novel tumor suppressor genes with potentially deleterious variants for FPC. Interestingly, somatic whole-exome analysis demonstrated that most tumor samples with suspicious loss of heterozygosity of candidate genes were KRAS wild-types, implying that these cases may not have required KRAS activation as a driver event for carcinogenesis. Conclusions Our findings indicate that FPC patients harbor potentially deleterious causative germline variants in tumor suppressor genes, which are known to acquire somatic mutations in pancreatic cancer, and that somatic loss of heterozygosity of some FPC susceptibility genes may contribute to the development of FPC in the absence of somatic KRAS-activating mutation. Genetic testing for a wider variety of FPC-predisposition genes could provide better screening approach for high-risk groups of pancreatic cancer.

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.

Heart failure (HF) is one of the potential adverse events of pazopanib treatment for soft tissue sarcoma (STS), but detailed reports of such HF cases are scarce. This study determined the incidence and risk factors of HF following pazopanib treatment for STS at our Institute and the clinical outcomes.Methods and Results:This study retrospectively analyzed the cases of STS patients treated with pazopanib (n=151) between 2012 and 2020. HF occurred in 6 patients (3.9%) at the median onset of 137 (range 14-468) days after the treatment initiation. When their HF was diagnosed, pazopanib was interrupted in all 6 patients. No patients experienced HF-related death, and HF development was not a significant factor for poor overall survival. The cumulative doses of anthracyclines (225 mg/mThe study findings highlight the effect of past anthracycline exposure and baseline BNP for pazopanib-associated HF. Although the study patients' clinical outcomes were generally favorable, periodic monitoring of cardiac function using ultrasonic echocardiography or serum markers is essential to detect events early and begin therapeutic intervention appropriately under a cardiologist's instructions.

The efficacy of immunoglobulin replacement therapy (IgRT) has been demonstrated for primary immune deficiency diseases and hematological malignancies such as chronic lymphocytic leukemia (CLL) or multiple myeloma with hypogammaglobulinemia. Clinical development of anti-B cell therapies including a monoclonal antibody, bispecific antibody, or chimeric antigen receptor T-cell therapy which could result in severe hypogammaglobulinemia accelerates the argument of prophylactic use of IgRT. Clinical guidelines for CLL describe immunoglobulin administration in patients with a low IgG who have experienced a severe/repeated bacterial infection. The utility in hematopoietic stem-cell transplantation (HSCT) remains unknown. Although an early randomized trial demonstrated that IgRT decreased infection risk and transplant-related mortality after HSCT, subsequent clinical trials could not validate the benefit. Consequently, a meta-analysis did not show the benefit of IgRT in HSCT. Most of the available data derives from matched-related HSCT using myeloablative regimen, and the impact in haploidentical and cord blood transplantation, or reduced-intensity HSCT remains unknown. One crucial issue is that no studies exist for patients with only hypogammaglobulinemia after HSCT. Other challenges are heterogeneous patient characteristics, or immunoglobulin formulation, dosage, schedule, route and duration of IgRT. Without evidence in HSCT, it would be reasonable to follow the guidelines for other diseases with hypogammaglobulinemia.

In the field of hematological malignancy, we often have the opportunity to use antibodies such as immune checkpoint inhibitors that can alter a patient's immune status before or after allo-HCT. The appropriate use of these novel agents is highly necessary to optimize disease control and reduce the risk of complications associated with adverse allo-immune reactions.Clinical data on several monoclonal antibodies targeting programmed cell death 1 (PD-1) (nivolumab or pembrolizumab), C-C chemokine receptor 4 (CCR4) (mogamulizumab), CD30 (brentuximab vedotin), or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) (ipilimumab) are reviewed, with a focus on the incidence and severity of graft-versus-host disease (GVHD).While previous studies demonstrated a favorable prognosis in patients who received nivolumab prior to transplantation, the pretransplant use of nivolumab increases the incidence of GVHD, partly due to the expansion and activation of preexisting T cells. Mogamulizumab also has a significant impact on GVHD, caused by persistent depletion of regulatory T cells with CCR4 positivity. Regarding brentuximab vedotin, phase 1 trials have demonstrated considerable efficacy for steroid-refractory acute or chronic GVHD. In the future, sophisticated methods will be needed to determine the impact of each agent on immune status after allo-HCT.

Simple Summary Second-line systematic therapy options for soft-tissue sarcoma (STS) have remained unchanged for decades due to the rarity and various histological types associated with STS. Challenges with molecular-targeted treatments for STS led to the approval of pazopanib and its wide use for STS. However, predictive markers of pazopanib treatment for STS have not been identified. Baseline neutrophil-to-lymphocyte ratio (NLR) is known as a candidate biomarker for several cancers. In this retrospective study, we investigated the use of the NLR as a predictor for the efficacy and prognosis of pazopanib in patients with STS. Our findings could be useful for the development of biomarker-targeted therapies for STS. Abstract Pazopanib with trabectedin and eribulin is widely used to treat soft-tissue sarcoma (STS). We have shown that baseline neutrophil-to-lymphocyte ratio (NLR) may predict the efficacy and patient prognosis of eribulin. Changes in NLR, but not baseline NLR, can predict patient prognosis of trabectedin. However, prognostic factors of pazopanib for STS have not been identified. We present a retrospective analysis of 141 patients treated with pazopanib for recurrent or metastatic non-round cell STS. Univariate and multivariate analyses were performed to determine the predictive factors of durable clinical benefit (DCB), overall survival (OS), and progression-free survival. L-sarcoma histology (odds ratio [OR] = 0.31, 95% CI = 0.12–0.79; p = 0.014) and pre-treatment NLR < 3.0 (OR = 2.03, 95% CI = 1.02–6.67; p = 0.045) were independent predictive factors of DCB. Pre-treatment NLR < 3.0 (hazard ratio [HR] = 0.55, 95% CI = 0.36–0.84; p = 0.0057), liposarcoma histology (HR = 1.78, 95% CI = 1.09–2.91; p = 0.022), primary extremity site (HR = 0.48, 95% CI = 0.31–0.75; p = 0.0010), ECOG PS ≥ 1 (HR = 1.62, 95% CI = 1.08–2.42; p = 0.019), and CRP < 0.3 (HR = 0.52, 95% CI = 0.33–0.82; p = 0.0050) were independent predictive factors of OS. These findings indicate that baseline NLR predicts the efficacy and patient prognosis of pazopanib for STS.

Background: The clinical benefit of systemic chemotherapy for recurrent/metastatic retroperitoneal/intra-abdominal soft tissue sarcoma (STS) compared to its benefits for other primary lesions has not been known or sufficiently evaluated. Methods and Patients: We retrospectively reviewed the cases of the STS patients who consulted a department of medical oncology in Tokyo between June 2011 and March 2018, and we extracted the cases of patients with primary sites at the retroperitoneum/intra-abdomen (cohort R) or extremities/trunk (cohort E) who received systemic chemotherapy in a recurrent/metastatic setting, comparing the cohorts’ characteristics, chemotherapy details, and prognoses. Results: Of all 337 STS patients, we enrolled 49 patients in cohort R and 75 patients in cohort E. Liposarcoma was more frequently observed in cohort R (51.0%) than cohort E (22.7%). The median chemotherapy treatment line was two lines (range: 1–6) in cohort R and three lines (range: 1–9) in cohort E. The doxorubicin usage rates differed in recurrent/metastatic settings (90.0% in cohort R and 55.0% in cohort E), due mainly to the higher rate of a perioperative chemotherapy treatment history in cohort E (52.0% vs. 6.1% in cohort R). The median overall survival from the start of salvage chemotherapy was 31.9 months (cohort R; 95% CI: 20.9–42.8) and 27.1 months (cohort E; 95% CI: 21.6–32.5) (p = 0.549). Conclusion: There were differences in the distributions of pathology and antitumor drugs used in a salvage setting between retroperitoneal/intra-abdominal and extremities/trunk STS patients in recurrent/metastatic settings, but the prognoses with salvage chemotherapy were similar in the two cohorts.

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: In the absence of a current standard of care, precision oncology with next-generation sequencing provides an important therapeutic option for patients with rare malignancy. Here, we sought to establish the clinical relevancy of comprehensive genomic profiling (CGP) for patients with rare malignancy. Methods: We reviewed 341 patients who underwent CGP (FoundationOne CDx; OncoGuide NCC OncoPanel System)in our institution between 2019 and 2021. Cases were classified as common or rare malignancy based on the Rare Cancers in Europe (RARECARE) definition (incidence of Results: With the exception of 7 unclassifiable cases, rare malignancy accounted for 149 of the 334 cases (45%), with the most common being female genital cancers (32%), followed by digestive cancers (24%), sarcoma (16%), and others (28%). Many (83%) of the patients with rare malignancy harbored at least one pathogenic/likely-pathogenic variant. The commonly mutated genes were TP53 (41%), PIK3CA (20%), ARID1A (14%), and KRAS (13%). ERBB2amplification was detected in 6% of patients (median copy number, 8). Gene fusion in EWSR1 was found in 4% of patients (sarcoma) and in FGFR2 in 1% (cholangiocarcinoma and salivary duct carcinoma). TMB-high (≥10 mut/Mb) and MSI-high cases were found in 8% and 2% of cases, respectively. Druggable alterations were detected in 36 patients; this percentage was not significantly different to that of common malignancy (24% vs. 17%, P=0.10). The common druggable alterations were BRAF V600E (n=10), ERBB2 amplification (n=9), PIK3CA E542K (n=6), and BRCA1/2 variant (n=6). There was no significant difference in OS between the rare and common malignancy groups (1-year OS rate: 62% vs. 46%, P=0.24). Conclusion: In this study, the ratio of rare malignancy was higher than that typically found in previous epidemiological studies (about 20%-25%). We observed no adverse impact for OS, which might be due to the high number of patients (n=48) with intractable pancreatic cancer. Remarkably, >20% of patients harbored a potential druggable alteration. Our results suggest the clinical relevance of CGP for patients with rare malignancy, and its potential utility to provide clues for future clinical development. Citation Format: Akihiro Ohmoto, Naomi Hayashi, Ippei Fukada, Masumi Yamazaki, Mayu Yunokawa, Akiyoshi Kasuga, Eiji Shinozaki, Arisa Ueki, Akiko Tonooka, Kengo Takeuchi, Seiichi Mori, Kazuma Kiyotani, Shunji Takahashi. Druggable gene alterations in Japanese patients with rare malignancy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5735.

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.

Gastroenteropancreatic neuroendocrine carcinoma (GEP-NEC) is a rare and devastating malignancy, and preclinical studies are needed to evaluate potential therapeutic regimens. Here, we examined the antitumor effects of cisplatin (CDDP), etoposide (ETP) and irinotecan (CPT-11) and their combinations on GEP-NEC using three small-cell GEP-NEC cell lines (pancreatic NEC, A99; esophageal NEC, TYUC-1; duodenum NEC, TCC-NECT-2). In vitro studies were conducted using cell viability assays. In vivo experiments were conducted in mice inoculated with A99 or TCC-NECT-2 and treated with no agent, CDDP, CDDP+ETP (EP) or CDDP+CPT-11 (IP). TYUC-1 was the most susceptible to all agents, whereas A99 was refractory. Classical isobolograms showed synergism in both the EP and IP combinations for the three cell lines. In the TCC-NECT-2 mouse model, the IP regimen showed a significant antitumor effect, and CDDP alone showed a marginal effect compared to the control. In contrast, no effect was detected in the A99 model, probably because A99 was established from a metastatic tumor after chemotherapy with EP. Gene expression analysis of the ATP-binding cassette transporters revealed that ATP binding cassette subfamily B member1 (ABCB1) was conspicuously expressed in A99, and ABCB1 and ATP binding cassette subfamily C member2 (ABCC2) were deficient in TYUC-1, which might explain a part of different CDDP susceptibilities between cell lines. These preclinical models indicate that CDDP is a key agent, and IP regimen might be a reasonable option, although its efficacy is moderate. Our data on the platinum-based regimen will be useful as reference information in developing new agents for GEP-NEC.

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.

Inhibitors of poly(ADP-ribose) polymerases (PARPs), which play a key role in DNA damage/repair pathways, have been developed as antitumor agents based on the concept of synthetic lethality. Synthetic lethality is the idea that cell death would be efficiently induced by simultaneous loss of function of plural key molecules, for example, by exposing tumor cells with inactivating gene mutation of BRCA-mediated DNA repair to chemically induced inhibition of PARPs. Indeed, three PARP inhibitors, olaparib, rucaparib and niraparib have already been approved in the US or Europe, mainly for the treatment of BRCA-mutant ovarian cancer. Clinical trials of various combinations of PARP inhibitors with cytotoxic or molecular-targeted agents are also underway. In particular, expanded applications of PARP inhibitors are anticipated following recent reports that defects in homologous recombination repair (HRR) are associated with mutations in repair genes other than BRCA1/BRCA2, such as ATM, ATR, PALB2, RAD51, CHEK1 and CHEK2, as well as with epigenetic loss of BRCA1 function through promoter methylation or overexpression of the BRCA2-interacting transcriptional repressor EMSY. Current topics of interest include selection of the best agent in each clinical context, identification of new treatment targets for HRR-proficient cases, and development of PARP inhibitor-based regimens that are less toxic and that prolong overall survival as well as progression-free survival. In addition, potential long-term side effects and suitable biomarkers for predicting efficacy and mechanisms of clinical resistance are in discussion. This review summarizes representative preclinical and clinical data for PARP inhibitors and discusses their potential for future applications to treat various malignancies.

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.