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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

Yasuyoshi Sato,1 Naoki Fukuda,1 Xiaofei Wang,1 Tetsuya Urasaki,1 Akihiro Ohmoto,1 Kenji Nakano,1 Mayu Yunokawa,1 Makiko Ono,1 Yukiko Sato,2 Hiroki Mitani,3 Junichi Tomomatsu,1 Shunji Takahashi1 1Department of Medical Oncology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan; 2Pathology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan; 3Head and Neck Oncology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo 135-8550, JapanCorrespondence: Junichi TomomatsuHospital of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-Ku, Tokyo 135-8550, JapanTel +8135200111Fax +81335200141Email junichi.tomomatsu@jfcr.or.jpBackground: 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.Keywords: head and neck cancer, nivolumab, PD-1, immunotherapy, immune checkpoint inhibitor, CheckMate-141

Objective: High levels of human type IIA phospholipase A2 (PLA2-IIA) have been found in the eosinophil-mediated inflammation sites, although the pathophysiological role of PLA2-IIA in the eosinophil activation has remained poorly understood. We investigated the effects of PLA2-IIA on eosinophil activation.¶ Methods: Eosinophils were incubated with recombinant human PLA2-IIA or other stimuli, and then eosinophil peroxidase (EPO) (by colorimetric assay) and leukotriene C4 (by enzyme immunoassay) released in the incubation buffer were measured. Expression of CD11b and CD69 on the cell surface was also measured by flow cytometry (by mean fluorescence intensity (MFI)). EPO, LTC4, and CD11b are thought to be markers for early phase activation (occurred in an hour after stimulation), and CD69 is to be a marker for late phase activation (occurred after several hours).¶ Results: While PLA2-IIA (5 μg/ml) did not induce any early phase activation, it induced significant expression of an activation-related antigen, CD69, on human blood eosinophils. The PLA2-IIA, when enzymatically inactivated by either p-bromophenacyl bromide or EDTA, lost its effect on the CD69 induction. Similarly to PLA2-IIA, several lysophospholipids (1 μg/ml) also induced CD69 on eosinophils significantly (control, 0.71 ± 0.11; PLA2-IIA, 3.29 ± 0.37*; lysophosphatidic acid, 2.57 ± 0.43*; specific MFI ± S.E.M., n = 4, *indicate p < 0.05 vs. control).¶ Conclusions: PLA2-IIA induces CD69 expression on the eosinophils through its catalytic activity at least partly via the enzymatic products such as several lysophospholipids from the eosinophil membrane phospholipids. PLA2-IIA may contribute to the eosinophilic inflammation synergistically with other factors. [ABSTRACT FROM AUTHOR]

Background: The phase 3 CheckMate 274 trial demonstrated superiority of adjuvant nivolumab over placebo after radical surgery in patients with high-risk urothelial carcinoma (UC). However, real-world data on the efficacy and safety profile of adjuvant nivolumab in Japan have not been reported., Methods: This retrospective study enrolled patients with high-risk UC who received adjuvant nivolumab therapy following radical surgery between 2022 and 2024 at our institution. We evaluated immune-related adverse events (irAEs) according to the Common Terminology Criteria for Adverse Events, version 5.0. Kaplan-Meier curves were used to assess disease-free survival (DFS) and overall survival (OS)., Results: Thirty-three patients with high-risk UC receiving adjuvant nivolumab therapy following radical surgery were identified, and median follow-up was 11 months. Three patients experienced grade 3 irAEs, and 8 discontinued adjuvant nivolumab therapy due to irAEs. No grade 4 or 5 irAEs were observed. Eight patients have completed 1 year of treatment, and nine are currently on treatment. Nine patients had recurrences and one died of cancer. Of the nine patients with recurrences, six relapsed while on adjuvant nivolumab therapy, two relapsed after completing 1 year of treatment, and one relapsed after discontinuation of irAE. The 1- and 2-year OS rates were 100% and 90%, respectively, and median OS was not reached. The 1- and 2-year DFS rates were 70% and 60%, respectively, and median DFS was 26 months., Conclusions: Adjuvant nivolumab appears to have some efficacy in Japanese patients. Since this is a postoperative adjuvant therapy, careful patient selection is warranted., (© 2024. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Purpose: Heterotopic ossification (HO) can occur after hemiarthroplasty (HA) for femoral neck fractures (FNF). This study aimed to investigate the frequency and factors contributing to the development of HO after HA., Methods: The study included data from 92 of 183 patients (26 male and 66 female) who sustained FNF and underwent HA between April 2019 and January 2022. HO was identified on postoperative radiographic images. Patient background, operative duration, blood loss, and presence of free bone fragments immediately after surgery were compared between the HO and non-HO groups. Statistical analyses included the independent-sample t-test for continuous variables and the chi-squared test for categorical variables. A multivariate logistic regression analysis was performed using HO as an objective variable., Results: HO occurred in 50 of the 92 (54%) patients. There were no statistically significant differences in patient backgrounds. Univariate analysis revealed significantly longer mean operative duration and greater blood loss in the HO group. Free bone fragments in the immediate postoperative period were observed in 29 of 50 (58%) patients in the HO group and in 3 of 42 (7.1%) patients in the non-HO group, a statistically significant difference. Logistic regression analysis revealed that the presence of free bone fragments was an independent explanatory factor for HO development., Conclusion: The presence of free bone fragments immediately after surgery may be significantly associated with the development of HO. Therefore, it is necessary to sufficiently remove such fragments during surgery because they may trigger HO., (© 2024. The Author(s).)

Proteinuria has been described as a major on-target adverse event of lenvatinib, although its long-term impact on renal function and clinical outcomes remains unclear. We conducted a retrospective observational study to assess renal function and prognosis in patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC) receiving lenvatinib. Overall, 70 patients with RR-DTC treated with lenvatinib were enrolled. When proteinuria was observed, the dose and schedule of lenvatinib were adjusted to achieve a urine protein-to-creatinine ratio (UPCR) of less than 3.5 g/gCre according to the study protocols of recent pivotal trials. In total, 50 (71%) and 25 (36%) patients presented with any-grade and grade 3 proteinuria, respectively. Multivariate analysis revealed that age [>65; odds ratio (OR) 8.24, 95% confidence interval (CI) 1.74-39.00, p < 0.01], history of diabetes mellitus (OR 7.79, 95% CI 1.31-46.20, p = 0.02), and hypertension (OR 4.07, 95% CI 1.22-13.60, p = 0.02) were significantly associated with the development of grade 3 proteinuria. Overall, the median estimating glomerular filtration rate (eGFR) gradually decreased every 3 months during treatment. However, no significant deterioration in eGFR was observed in patients with grade 3 proteinuria compared with patients with grades 0-2 proteinuria until 48 months. Patients who developed proteinuria had better survival outcomes than those without proteinuria. In conclusion, the proteinuria grade was not significantly associated with decreased eGFR under UPCR monitoring in our study. Therefore, lenvatinib can carefully be continued targeting UPCR of less than 3.5 g/gCre.

Background: 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/m 2 ) before pazopanib initiation (83% vs. 37%, P=0.031), pazopanib initiation at age ≥60 years (83% vs. 35%, P=0.026), and the baseline B-type natriuretic peptide (BNP) concentration (≥50 pg/mL) before pazopanib (67% vs. 11%, P=0.002) initiation were predictive factors for post-pazopanib treatment HF., Conclusions: The 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.

Background: Lumbar disc herniation (LDH) is most common in men aged 20-40 at the L4/5 level; however, left-right differences have not been reported. Improving our understanding of left- and right-side LDH may facilitate the estimation of mechanical load on intervertebral discs. Here, we assessed left-right differences in LDH via a retrospective analysis of LDH cases., Methods: Among 10,972 surgical cases of LDH identified in the Nagoya Spine Group database, 2899 in which right- and left-LDH sides were observable in a single vertebral segment were identified (mean age 46.3 ± 16.6 years, 2028 males). The following characteristics of patients with right- and left-LDH were compared: age, LDH level, surgical technique, operative time, blood loss, length of hospital stay, preoperative Japan Orthopaedic Association (JOA) score, and JOA recovery rate., Results: LDH occurred on the right and left sides in 1358 and 1541 patients, respectively, with patients with right-side LDH significantly older than those with left (47.9 ± 16.6 versus 45.0 ± 16.5, respectively; p < 0.001). No between-group differences in sex, age, LDH level, surgical technique, operative time, blood loss, length of hospital stay, preoperative JOA score, or JOA recovery rate were observed. The occurrence of right-side LDH increased with age, occurring in 42.7%, 45.1%, 49.9%, and 54.7% of patients aged 10-29, 30-49, 50-69, and 70-89 years, respectively., Conclusion: Left-side LDH was observed more frequently than right; however, right-side LDH incidence increased with age. No significant between-group differences regarding symptoms, treatments, or outcomes were observed., Competing Interests: Declaration of competing interest The authors have no financial conflicts of interest to report., (Copyright © 2022 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Background: E7130 is a novel anticancer agent created from a total synthetic study of norhalichondrin B. The authors report the E7130 dose-escalation part of a first-in-human study of patients with advanced solid tumors (NCT03444701)., Methods: Japanese patients ≥20 years of age were enrolled. E7130 was administered intravenously in two cycles: day 1 of a 21-day cycle (Q3W) or days 1 and 15 of a 28-day cycle (Q2W). Doses were escalated from 270 to 550 μg/m 2 for the Q3W group or 25-400 μg/m 2 for the Q2W group. The primary end point of the dose-escalation phase was safety and tolerability as assessed by the incidence of dose-limiting toxicities (DLTs) and adverse events. Other end points included determination of the maximum tolerated dose (MTD), pharmacokinetics, and pharmacodynamics., Results: Forty-four patients were enrolled: 15 in the E7130 Q3W group and 29 in the Q2W group. Treatment-emergent adverse events (TEAEs) occurred in all patients; the most common TEAE overall was leukopenia (78.6%). Grade 3-4 TEAEs occurred in 93.3% of patients in the Q3W group and 86.2% of patients in the Q2W group. None had a TEAE resulting in study drug discontinuation, and no treatment-related deaths were reported. Per the DLT evaluation, the MTDs were determined as 480 μg/m 2 Q3W and 300 μg/m 2 Q2W. Significant changes in multiple plasma biomarkers, including vascular endothelial growth factor 3 and matrix metallopeptidase 9, were dose-dependent after initial doses of 350-480 μg/m 2 ., Conclusions: E7130 480 μg/m 2 Q3W was chosen for the dose-expansion part over 300 μg/m 2 Q2W primarily per dose-dependent biomarker results., (© 2023 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Introduction: Concurrent chemoradiotherapy (CCRT) is a standard treatment for locally advanced head and neck cancer (LAHNC) in the definitive setting. The Geriatric Nutritional Risk Index (GNRI) is a screening tool to predict the risk of morbidity and mortality in the older adult. Nutritional management is key during CCRT but the association between prognosis and initial nutritional status in older adults with LAHNC undergoing CCRT remains unknown., Materials and Methods: Patients ≥65 years old with LAHNC who received definitive CCRT with cisplatin (80 mg/m 2 or 100 mg/m 2 , every three weeks, three times) between 2012 and 2018 were included. Patients without completion of radiotherapy were excluded. Patients were stratified into two groups based on the GNRI (≦98 or > 98). Overall survival (OS) and event-free survival (EFS) were analyzed by the Kaplan-Meier method and the log-rank test. The Cox proportional hazards model was adopted to identify prognostic factors. GNRI, sex, T and N categories were prespecified as variables for multivariable analysis., Results: The median age of 111 patients (88 male, 79%) was 69 years (interquartile range: 67-71), among which 23 patients had low GNRI (20 male, 87%) and 88 patients had high GNRI (68 male, 77%). Baseline clinical characteristics were not statistically different between the two groups. OS was significantly worse in the low GNRI group than in the high GNRI group (p = 0.048). There was no statistical difference in EFS between the two groups (p = 0.12). Multivariable analysis revealed that low GNRI (hazard ratio [HR]: 3.17, 95% confidence interval [95%CI]: 1.12-8.96, p = 0.029) and higher N category (HR: 4.37, 95% CI: 1.58-12.06, p = 0.004) were associated with worse OS. For EFS, the higher N category was significantly associated with a worse outcome (HR: 2.54, 95% CI: 1.16-5.59, p = 0.02)., Discussion: Poorer nutritional status before initiation of CCRT was associated with worse OS in older adults with LAHNC in the definitive setting. The GNRI is a convenient tool for predicting OS in older adult patients with LAHNC treated with CCRT., Competing Interests: Declaration of Competing Interest None of the authors have a conflict of interest to report for the submitted work., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background/aim: Immune-related adverse events (irAEs) develop in a subset of patients with metastatic renal cell carcinoma (mRCC) treated with immune-checkpoint-inhibitors (ICIs). Evidence regarding the prognostic impact of irAEs remains limited in these patients., Patients and Methods: Ninety-one consecutive patients with mRCC treated with ICIs were retrospectively analyzed. Overall survival (OS) rates were estimated using the Kaplan-Meier method. In multivariate analysis, predictors of OS were analyzed using the Cox-proportional-hazards-model., Results: Twenty-nine patients were treated with the combination of nivolumab plus ipilimumab. According to International Metastatic RCC Database Consortium risk classification, 27/47/17 patients were classified into favorable/intermediate/poor risk categories. The 1, 3, and 5-year OS-rates were 89, 70, and 57%, respectively. A total of 67 irAEs occurred in 44 patients (48%), including 15 patients with grade 3-4. OS was significantly longer in patients with irAEs (p=0.01). In multivariate analysis, Karnofsky performance status, prior nephrectomy, and irAEs were independent significant predictors of OS., Conclusion: In our study, irAEs were significantly associated with OS in mRCC patients treated with ICIs., Competing Interests: T. Yuasa received remuneration for a lecture from Ono Pharma (Osaka, Japan), Bristol-Myers Squibb Japan (Tokyo, Japan), and MSD Japan (Tokyo, Japan). S. Takahashi received remuneration for a lecture from MSD and Eisai, and grants from Eisai, Novartis, Taiho, MSD, Chugai, Bayer, AstraZeneca, Bristol Myers Squib, and Ono Pharmaceutical. The other Authors have no disclosures or conflicts of interest to report in relation to this study., (Copyright 2023, International Institute of Anticancer Research.)

Trabectedin is a therapeutic option for patients with advanced sarcoma. While a randomized trial demonstrated its prolonged progression-free survival (PFS), the reported PFS was <6 months. Some patients can achieve long-term disease control with this treatment. However, the reference information is insufficient. Herein, we retrospectively reviewed 51 sarcoma patients who received trabectedin. We analyzed the clinicopathological features, trabectedin dose, administration schedule, and clinical outcomes, including the overall response rate (ORR) and PFS. Among them, we assessed the detailed data of patients who achieved long-term disease control (PFS >1 year). The ORR in the 49 evaluable patients was 8%, and the median PFS in 51 patients was 7.5 months. Six patients (12%) achieved PFS of >1 year. Five of the six patients had metastatic lesions at trabectedin initiation. The pathological subtypes were myxoid liposarcoma (n = 2), leiomyosarcoma (n = 2), synovial sarcoma (n = 1), and Ewing sarcoma (n = 1). The final administration dose was the minimum dose (0.8 mg/m2) in two patients who continued the treatment over 20 cycles. The best radiological response was partial response (PR) in two myxoid liposarcoma patients and stable disease in four. The durations from trabectedin initiation to the first response in the two PR cases were 163 and 176 days, respectively. Our results support the validity of continuing trabectedin at a sustainable dose and interval in patients who can tolerate it. These results may be useful when considering the clinical application of trabectedin., Competing Interests: NO authors have competing interests., (Copyright: © 2023 Ohmoto et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: The Geriatric Nutritional Risk Index (GNRI) has been reported as a screening tool to assess the nutrition-related risk with mortality in older patients and those with the various diseases. However, the prognostic value of GNRI in metastatic renal cell carcinoma (mRCC) patients receiving nivolumab therapy remains unclear., Methods: Fifty-six consecutive patients with mRCC receiving nivolumab between September 2013 and August 2020 at our institution were retrospectively analyzed. The survival outcomes and prognostic factors associated with overall survival (OS) were statistically analyzed., Results: Thirteen and forty-three patients were classified with low (GNRI < 92) and high (GNRI ≥ 92) GNRI, respectively. Patients with low GNRI demonstrated significantly shorter OS ( P  = 0.0002) than those with high GNRI. In multivariate analysis, GNRI at the time of nivolumab ( P  = 0.008) was extracted as the predictor for OS in addition to Karnofsky performance status (KPS) ( P  = 0.016). Integration of the GNRI into the International Metastatic Renal Cell Cancer Database Consortium (IMDC) risk classification improved the c-index from 0.761 to 0.833 (combination of GNRI with IMDC risk classification) and to 0.778 (substitution of GNRI with KPS in IMDC risk classification)., Conclusions: GNRI was a significant prognostic biomarker in mRCC patients receiving nivolumab.

Introduction: Although systemic therapy, including multi-kinase inhibitors and cytotoxic chemotherapy, is an option for recurrent or metastatic adenoid cystic carcinoma of the head and neck (HNACC), it is not proven whether these therapies can prolong overall survival (OS). The present study investigated the impact of cytotoxic chemotherapy on survival outcomes compared with observation without chemotherapy., Methods: We retrospectively reviewed the medical records of the patients diagnosed with recurrent or metastatic HNACC. We compared the survival outcomes, including survival time from recurrence/metastasis (OS) patients who received systemic chemotherapy with paclitaxel (200 mg/m2) and carboplatin (area under the curve 6) (TC) on day 1 of a 3-week cycle and observation alone. Subgroup analysis was conducted to identify patients who can get benefit from TC., Results: Seventy-five patients (32 in TC and 43 in observation) were analyzed. There was no difference in median OS between TC and observation (52.2 months vs. 44.0 months, hazard ratio 0.76, 95% confidence interval 0.32-1.30, p = 0.21). Landmark analysis to reduce immortal bias also showed no difference between TC and observation in terms of OS. Subgroup analysis showed nonsignificant trends toward longer OS in asymptomatic patients with pulmonary metastasis and without bone metastasis., Conclusions: In our non-randomized comparison, patients who underwent TC did not show prolonged survival time from recurrence and/or metastasis diagnosis compared with observation alone in patients with recurrent or metastatic HNACC. Although systemic chemotherapy is a possible option for metastatic/recurrent HNACC, initial observation might be a valid strategy for asymptomatic patients without extrapulmonary diseases. Further research is warranted to identify the optimal patients and therapeutic regimens to prolong OS in HNACC., (© 2023 S. Karger AG, Basel.)

The mainstay of medical treatment has been tyrosine kinase inhibitors (TKIs) for renal cell cancer (RCC), cytotoxic chemotherapy for urothelial cancer (UC), and androgen deprivation therapy for prostate cancer. These therapeutic modalities still play important roles in these malignancies. However, immune checkpoint inhibitors (ICIs) that target PD-1/PD-L1 or CTLA-4 are being rapidly introduced for the treatment of metastatic urological cancers, just as they have been for other malignancies. Currently, the paradigm of medical treatment for patients with metastatic urological cancer is dramatically changing. Accordingly, we need to organize and summarize the new therapeutic tools, which include immune checkpoint inhibitors, poly (ADP-ribose) polymerase (PARP) inhibitors, and antibody-drug conjugates (ADCs). This review provides an overview of agents and regimens that have just launched or will be launched in the near future in Japan. Based on the promising anti-tumor efficacy and manageable safety profiles being demonstrated in clinical trials, these new agents and therapies are expected to be rapidly introduced in Japanese clinical practice. Additionally, the newly designed ADC, enfortumab vedotin, which comprises a fully human monoclonal antibody conjugated to an anti-cancerous agent via a protease-cleavable linker, has just been launched in Japan. In order to provide the optimal treatment for our patients, we need to completely understand these new therapeutic tools., Competing Interests: TY received remuneration for a lecture from Astellas (Tokyo, Japan), Sanofi Japan (Tokyo, Japan), Pfizer Japan (Tokyo, Japan), Novartis Pharma Japan (Tokyo, Japan), Ono Pharma (Osaka, Japan), Bristol-Myers Squibb Japan (Tokyo, Japan), MSD Japan (Tokyo, Japan), Jansen Pharmaceutical K.K. (Tokyo, Japan), and Merck (Tokyo, Japan). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yuasa, Urasaki and Oki.)

Background: In order to search for predictive biomarkers of efficacy of pembrolizumab therapy for metastatic urothelial cancer (UC), we investigated the relationship between treatment outcomes and early neutrophil-lymphocyte ratio (NLR), lactate dehydrogenase (LDH), and C-reactive protein (CRP) responses., Patients and Methods: Medical records of 101 patients with metastatic UC who started pembrolizumab as a second-line or later treatment were reviewed. NLR, LDH, and CRP were recorded after 3 weeks of therapy. In addition, we investigated whether these factors had an association with prolonged progression-free (PFS) or overall (OS) survival., Results: The objective response rate, median PFS, and median OS were 25.7%, 6.3 months, and 15.2 months, respectively. PFS and OS were significantly shorter in patients with NLR>3, LDH>upper limit of normal (ULN), and CRP>0.5 mg/dl after 3 weeks of pembrolizumab treatment (p<0.05). A predictive model comprising these factors (favorable risk group: 0 risk factors; intermediate-risk group: 1-2 risk factors; poor-risk group: 3 risk factors) revealed distinct PFS and OS curves (p<0.001). In the favorable risk group, 12-month OS was 79.6%; in the poor-risk group, it was 12.8%. Harrell's C-indices for NLR >3, LDH >ULN, CRP >0.5 mg/dl, and all three combined for predicting OS were 0.656, 0.625, 0.633 and 0.678, respectively. Early responses were also non-significantly associated with ORR (p=0.37)., Conclusion: Pembrolizumab treatment outcomes are associated with early NLR, LDH, and CRP responses in metastatic urothelial cancer., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Purpose: 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., Methods: 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., Results: 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., Conclusion: 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., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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., (© 2022 S. Karger AG, Basel.)

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.

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 paradigm of medical treatment for metastatic urothelial carcinoma is dramatically changing through the introduction of pembrolizumab., Aim: We investigated the treatment effectiveness, the safety profile, and the prognostic factors of pembrolizumab in Japanese real-world clinical practice., Methods and Results: The medical records of 74 consecutive Japanese patients with metastatic urothelial cancer (UC), who started pembrolizumab as a second- or later-line treatment at our institution between January 2018 and March 2020, were reviewed and statistically analyzed. The median follow-up period after initiation of pembrolizumab was 8.5 (interquartile range: 3.5-15.7) months. The objective response rate was 30.2%, the median progression-free survival period was 4.9 months, and the median overall survival (OS) period was 13.3 months. Evaluation revealed that 39 (52.9%) patients experienced adverse events (AEs), among whom eight patients (10.9%) had severe AEs (grade 3 or more), including grade 5 hemophagocytic syndrome. Multivariate analysis indicated that the presence of liver metastasis, worse performance status (≥2), elevated serum lactate dehydrogenase, and increased C-reactive protein were predictive of shorter OS., Conclusion: We studied the effectiveness and safety profile of pembrolizumab therapy in Japanese UC patients. We believe that the data presented here will be useful for clinical physicians., (© 2021 The Authors. Cancer Reports published by Wiley Periodicals LLC.)

Immune checkpoint inhibitors (ICIs) play a significant role in therapy for relapsed or refractory cancers due to their excellent efficacy. ICIs, however, frequently induce immune-related adverse events (irAEs) in various tissues and organs, sometimes leading to severe conditions. Thus, early identification and treatment of irAEs are important. Herein, the authors report two cases of a rare type of irAE, severe keratoconjunctivitis with deterioration of eyesight, induced by ICIs. Characteristically, both cases were accompanied by concurrent severe oral mucositis. The patients were treated successfully with both systemic and topical ophthalmic corticosteroids, resulting in complete remission of severe pseudomembranous conjunctivitis and full recovery of eyesight. ICI-induced keratoconjunctivitis progresses rapidly and can lead to blindness. Thus, prompt diagnosis and treatment are necessary.