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Ubiquitin-dependent proteolysis regulates diverse cellular functions with high substrate specificity, which hinges on the ability of ubiquitin E3 ligases to decode the targets' degradation signals, i.e., degrons. Here, we show that BACH1, a transcription repressor of antioxidant response genes, features two distinct unconventional degrons encrypted in the quaternary structure of its homodimeric BTB domain. These two degrons are both functionalized by oxidative stress and are deciphered by two complementary E3s. FBXO22 recognizes a degron constructed by the BACH1 BTB domain dimer interface, which is unmasked from transcriptional co-repressors after oxidative stress releases BACH1 from chromatin. When this degron is impaired by oxidation, a second BACH1 degron manifested by its destabilized BTB dimer is probed by a pair of FBXL17 proteins that remodels the substrate into E3-bound monomers for ubiquitination. Our findings highlight the multidimensionality of protein degradation signals and the functional complementarity of different ubiquitin ligases targeting the same substrate., Competing Interests: Declaration of interests N.Z. and M.P. are scientific cofounders of SEED Therapeutics with financial interests. They also received research funding from and are shareholders in Kymera Therapeutics. N.Z. serves on the scientific advisory boards of Synthex, Molecular Glue Labs, and Differentiated Therapeutics with financial interests. M.P. is a consultant and/or serves on the scientific advisory boards of CullGen, Sibylla Biotech, and Triana Biomedicines with financial interests. The findings presented in this manuscript were not shared with these companies., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Although treatment outcomes for metastatic colorectal cancer (mCRC) have dramatically improved over the past few decades, drug costs have also significantly increased. This study aimed to investigate which first-line treatment regimens for mCRC are actually used (frequency) in Japanese practice and at what cost., Methods: We collected data on patients with mCRC who received first-line treatment at 37 institutions of the Japan Clinical Oncology Group Colorectal Cancer Study Group from July 2021 to June 2022, and calculated the cost of regimens. The cost per month of each regimen was estimated based on standard usage, assuming a patient with a weight of 70 kg and a body surface area of 1.8 m2. We categorized the regimens into very high-cost (≥1 000 000 Japanese yen [JPY]/month), high-cost (≥500 000 JPY/month), and others (<500 000 JPY/month)., Results: The study included 1880 participants, 24% of whom were ≥ 75 years. Molecular targeted containing regimens were received by 78% of the patients. The most frequently used regimen was the doublet regimen (fluoropyrimidine with either oxaliplatin or irinotecan) plus bevacizumab (43%), followed by doublet plus cetuximab or panitumumab (21%). The cost of molecular targeted drugs-containing regimens (ranging from 85 406 to 843 602 JPY/month) is much higher than that of only cytotoxic drug regimens (ranging from 17 672 to 51 004 JPY/month). About 16% received high-cost treatments that included panitumumab-containing regimens and pembrolizumab (17% of patients aged ≤74 years and 11% of patients aged ≥75 years)., Conclusion: About 16% of mCRC patients received first-line treatment with regimens costing >500 000JPY/month, and molecular targeted drugs being the main drivers of cost., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: FOLFOXIRI plus bevacizumab is a standard first-line chemotherapy for patients with metastatic colorectal cancer (mCRC). However, due to the severe toxicities, this regimen is not widely used. There is limited data on the real-world efficacy and safety., Methods: We conducted a retrospective analysis of clinical data from mCRC patients who received FOLFOXIRI plus bevacizumab as first-line chemotherapy at 31 institutions. The initial dose was standardized according to the TRIBE regimen. Induction therapy was defined as a combination of oxaliplatin, irinotecan, and fluorouracil., Results: Out of 104 patients who met the criteria, the median age was 58 years (range, 16-72). 81% of patients had an eastern cooperative oncology group performance status (PS) of 0. An initial dose reduction was observed in 63% of patients. The median number of preplanned induction therapy cycles was 12 (range, 4-12). The completion of scheduled induction therapy cycles was observed in 45% of patients, with treatment-related toxicities being the main reason for discontinuation (63%). The median progression-free survival and overall survival were 12.8 months (95% CI, 10.6-15.0) and 27.9 months (95% CI 21.6-34.2), respectively. The objective response rate and disease control rate were 63.7% and 98.9%, respectively. The R0 resection rate was 21.2%. The main grade 3 or higher toxicities were neutropenia (51%), febrile neutropenia (10%), and nausea/vomiting (5%). No treatment-related deaths were observed., Conclusion: In a real-world clinical setting, FOLFOXIRI plus bevacizumab demonstrated efficacy and safety comparable to previous clinical trials., (© 2024. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Background: This prospective observational study evaluated the real-world effectiveness of nivolumab monotherapy in previously treated advanced gastric cancer (GC). A preplanned 2-year final analysis was performed to confirm survival and tumor behavior with nivolumab monotherapy., Patients and Methods: The primary endpoint was overall survival (OS). The data regarding tumor size were prospectively collected and evaluated using the RECIST criteria. Exploratory analyses were performed for survival according to the tumor response and depth of response (DpR) in patients with measurable lesions who were receiving nivolumab monotherapy as third- or later-line therapy., Results: In 487 patients, the median OS and progression-free survival (PFS) were 5.8 (95% CI 5.3-6.9) months and 1.8 (95% CI 1.7-2.0) months, respectively. The response rate (RR) was 14.5% in 282 patients with measurable lesions. In 234 patients treated with third- or later-line, the DpR was found to be associated with PFS and OS in the Spearman analysis (r = 0.55 and 0.44, respectively) as well as using a discrete variable. When the DpR was divided into 5 groups (-20%≥DpR; -20%

Cholangiocarcinoma (CCA) is a cancer with a poor prognosis due to difficulties in diagnosis and limited treatment options, highlighting the urgent need for new targeted therapies. In a clinical setting, we found that leukotriene levels in bile were higher than in serum. Immunohistochemical analysis of surgically resected samples also revealed that CysLT receptor 1 (CysLTR1) was more highly expressed in CCA than in normal bile duct tissue, prompting us to investigate leukotriene as a potential therapeutic target in CCA. In vitro studies using CCA cell lines expressing CysLTR1 showed that leukotriene D4, a major ligand of CysLTR1, promoted cell proliferation, with increased phosphorylation of AKT and extracellular signal-regulated kinase 1/2 (ERK1/2). Additionally, treatment with two clinically available anti-allergic drugs-zileuton, an inhibitor of CysLT formation, and montelukast, a CysLTR1 inhibitor-had inhibitory effects on cell proliferation and migratory capacity, accompanied by the reduced phosphorylation of AKT and ERK1/2. Furthermore, the simultaneous administration of both drugs synergistically enhanced the inhibitory effect on cell proliferation. Our study suggests that use of these drugs may represent a novel approach to treat CCA through drug repositioning.

The LAMPdirect Genelyzer KIT allows for the detection of SARS-CoV-2 RNA in saliva samples with a loop-mediated isothermal amplification (LAMP) method and generates results within 20 min. It has been approved by the Pharmaceuticals and Medical Devices Agency in Japan. In this study, the performance of the LAMPdirect Genelyzer KIT was compared with that of the RT-qPCR reference method using 50 nasopharyngeal swabs and 100 saliva samples. In addition, we evaluated the applicability of an alternative reverse transcriptase and the effects of an inactivation buffer. The total agreement rates were 80.0 % and 82.0 % for nasopharyngeal and saliva samples, respectively. When considering samples at the detection limit (50 copies/reaction) that increases the chance of transmission between humans, the total agreement rates were 100% and 94.1% for nasopharyngeal and saliva samples, respectively. The LAMP method is simple, fast, and inexpensive, making it useful for small medical institutions or rural areas., Competing Interests: Declaration of competing interest MK received research grants from Canon Medical Systems Corp. [grant numbers 22C013 and 23C002] for the submitted work. MK received research grants from SB Coronavirus Inspection Center Corp., and Ezaki Glico Co., Ltd.outside the submitted work. KY received research grants from Fujirebio Inc., Mizuho Medy Co. Ltd., VisGene Co. Ltd., Canon Medical Systems Corp., Sanyo Chemical Industries Ltd., CarbGeM Inc., Sysmex Corp., and Toyobo Co. Ltd. outside the submitted work. All other authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier Inc.)

The transcription factor BACH1 regulates heme homeostasis and oxidative stress responses and promotes cancer metastasis upon aberrant accumulation. Its stability is controlled by two F-box protein ubiquitin ligases, FBXO22 and FBXL17. Here we show that the homodimeric BTB domain of BACH1 functions as a previously undescribed quaternary structure degron, which is deciphered by the two F-box proteins via distinct mechanisms. After BACH1 is released from chromatin by heme, FBXO22 asymmetrically recognizes a cross-protomer interface of the intact BACH1 BTB dimer, which is otherwise masked by the co-repressor NCOR1. If the BACH1 BTB dimer escapes the surveillance by FBXO22 due to oxidative modifications, its quaternary structure integrity is probed by a pair of FBXL17, which simultaneously engage and remodel the two BTB protomers into E3-bound monomers for ubiquitination. By unveiling the multifaceted regulatory mechanisms of BACH1 stability, our studies highlight the abilities of ubiquitin ligases to decode high-order protein assemblies and reveal therapeutic opportunities to block cancer invasion via compound-induced BACH1 destabilization., Competing Interests: DECLARATION OF INTERESTS N.Z. and M.P. are scientific cofounders of and have financial interests in SEED Therapeutics. They also received research funding from and are shareholders in Kymera Therapeutics. N.Z. serves as a member of the scientific advisory board of Synthex with financial interests. M.P. is a consultant and a member of the scientific advisory board of CullGen and Triana Biomedicines with financial interests. The findings presented in this manuscript were not discussed with any person in these companies. The authors declare no other competing interests.

Background and Aims: Pivotal phase III trials indicated that the anti-PD-1 inhibitor nivolumab prolongs overall survival in patients with advanced gastric cancer. Nivolumab is currently used in the first- or later-line treatment of patients with advanced gastric cancer in Japan. The efficacy of immune check inhibitor rechallenge after progression has been reported in other cancers. Therefore, this study investigated the clinical outcome of nivolumab rechallenge in patients with advanced gastric cancer who received nivolumab in a previous systemic line., Methods: We retrospectively reviewed the medical records of six patients with advanced or recurrent gastric cancer who received nivolumab rechallenge., Results: During initial nivolumab therapy, three patients experienced partial responses, and one patient achieved stable disease. The reasons for discontinuing initial nivolumab therapy were progressive disease in five patients and immune-related adverse events in one patient. The median interval duration of treatment for patients receiving both nivolumab regimens was 13.7 (range: 5.1-17.8) months. During nivolumab rechallenge, no patients achieved partial responses, whereas two patients had stable disease. Median progression-free survival was 2.5 (95% confidence interval [CI] = 1.6-not available [NA]) months, and median overall survival was 7.4 (95% CI = 2.3-NA) months. Although one patient had discontinued prior nivolumab therapy because of immune-related adverse events, there were no immune-related adverse events associated with nivolumab rechallenge., Conclusions: The benefit of nivolumab rechallenge in patients with advanced gastric cancer was limited. Rechallenge with the same immune check inhibitor might be ineffective in patients with advanced gastric cancer., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Accurate diagnosis of the localization of prostate cancer (PCa) on magnetic resonance imaging (MRI) remains a challenge. We aimed to assess discrepancy between the location of PCa pathologically diagnosed using surgical specimens and lesions indicated as possible PCa by the Prostate Imaging Reporting and Data System on MRI. The primary endpoint was the concordance rate between the site of probable clinically significant PCa (csPCa) identified using biparametric MRI (bpMRI) and location of PCa in the surgical specimen obtained using robot-assisted total prostatectomy. Among 85 lesions identified in 30 patients; 42 (49.4%) were identified as possible PCa on MRI. The 85 PCa lesions were divided into positive and negative groups based on the bpMRI results. None of the patients had missed csPCa. Although the diagnostic accuracy of bpMRI was relatively high for PCas located in the middle of the prostate ( p = 0.029), it was relatively low for PCa located at the base of the prostate, all of which were csPCas. Although current modalities can accurately diagnose PCa, the possibility that PCa is present with multiple lesions in the prostate should be considered, even if MRI does not detect PCa.

Background/aims: Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) using a 19-gauge needle is an efficient sampling method for the diagnosis of lymphadenopathy. This study compared 19-gauge conventional and Franseen needles for the diagnosis of lymphadenopathy and classification of malignant lymphoma (ML)., Methods: Patient characteristics, number of needle passes, puncture route, sensitivity, specificity, and accuracy of cytology/histology for lymphadenopathy were analyzed in patients diagnosed with lymphadenopathy by EUS-FNA using conventional or Franseen needles., Results: Between 2012 and 2022, 146 patients met the inclusion criteria (conventional [n=70] and Franseen [n=76]). The median number of needle passes was significantly lower in the conventional group than in the Franseen group (3 [1-6] vs. 4 [1-6], p=0.023). There were no significant differences in cytological/histological diagnoses between the two groups. For ML, the immunohistochemical evaluation rate, sensitivity of flow cytometry, and cytogenetic assessment were not significantly different in either group. Bleeding as adverse events (AEs) were observed in three patients in the Franseen group., Conclusions: Both the 19-gauge conventional and Franseen needles showed high accuracy in lymphadenopathy and ML classification. Considering sufficient tissue collection and the avoidance of AEs, the use of 19-gauge conventional needles seems to be a good option for the diagnosis of lymphadenopathy.

Introduction: Immune checkpoint inhibitors (ICIs) are being increasingly used to treat advanced malignancies. ICI-induced pancreatic injury (ICI-PI), which is an immune-related adverse event that may be a risk factor of ICI-associated pancreatitis, is not well documented in the literature., Methods: Consecutive patients who received ICIs for advanced malignancies from August 2015 through October 2022 were analyzed for the incidence of ICI-PI based on the Common Terminology Criteria for Adverse Events and ICI-associated pancreatitis. The imaging, clinical, and pathological findings of ICI-associated pancreatitis were also assessed., Results: This study enrolled 843 patients. In multivariable analyses, dual or simultaneous immunotherapy and ≥10 cycles of ICI administration were significant predictive factors for all grades of pancreatic injury, including grade ≥3. Notably, patients who received simultaneous immunotherapy exhibited a higher incidence of grade ≥3 pancreatic injuries compared with those receiving asynchronous immunotherapy in univariable analysis ( P = 0.032). One-fifth of the patients (16/70) with grade ≥3 pancreatic injuries had imaging evidence of pancreatitis similar to mild acute pancreatitis. ICI-associated pancreatitis was observed in 5.7% (48/843) of patients, including 1.8% (15/843) with moderate-to-severe pancreatitis (grade ≥2). Symptomatic cases (0.36%, 3/843) were treated with steroids with favorable outcomes. Immunohistochemistry for CD4 and CD8 revealed greater infiltration of CD8 + than CD4 + lymphocytes., Discussion: Simultaneous immunotherapy and dual immunotherapy are risk factors of ICI-PI. Although most patients diagnosed with ICI-PI and ICI-associated pancreatitis were asymptomatic and had a low mortality likelihood, long-term outcomes, including endocrine and exocrine function, should be carefully monitored., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Background: Trifluridine/tipiracil (FTD/TPI) plus bevacizumab has shown clinical benefit for metastatic colorectal cancer (mCRC) refractory to standard therapy. However, few data have been available for patients with pretreated mCRC who are intolerant of intensive therapy (vulnerable)., Methods: We performed a multicenter retrospective study (WJOG14520G; TWILIGHT) of FTD/TPI plus bevacizumab for vulnerable patients with pretreated mCRC. Eligibility criteria included previous chemotherapy (although patients treated with all key cytotoxic agents, a fluoropyrimidine, oxaliplatin, and irinotecan, were excluded) and intolerance of full-dose combination therapy with oxaliplatin or irinotecan at the start of FTD/TPI plus bevacizumab., Results: The median age of 93 evaluable patients was 79 years (range, 21-90). Intolerance of intensive therapy was attributable to an older age in 60 (65%) patients, serious concomitant disease in 24 (26%) patients, and a poor performance status in 19 (20%) patients. FTD/TPI plus bevacizumab was administered as second-line treatment in 74 (80%) patients and as third- or fourth-line treatment in 19 (20%) patients. The objective response rate was 4.9% (95% confidence interval [CI], 1.4%-12.2%), and the disease control rate was 67.9% (95% CI, 56.6%-77.8%). With a median follow-up time of 21.6 months, median overall survival and progression-free survival were 18.6 months (95% CI, 12.1-23.2) and 6.3 months (95% CI, 5.0-8.3), respectively. Neutropenia of grade ≥3 developed in 50 (54%) patients, whereas 2 (2%) patients experienced febrile neutropenia, and no treatment-related death was observed., Conclusion: Our data show the potential efficacy and acceptable safety profile of FTD/TPI plus bevacizumab for vulnerable patients with pretreated mCRC., (© The Author(s) 2023. Published by Oxford University Press.)

Background: Non-inferiority of trifluridine/tipiracil (FTD/TPI) plus bevacizumab (BEV) to irinotecan/fluoropyrimidine plus BEV in metastatic colorectal cancer was investigated in the phase III TRUSTY study, and we conducted a phase II study of FOLFIRI (5-FU+leucovorin+irinotecan) plus zib-aflibercept (AFL) after FTD/TPI plus BEV. However, the TRUSTY study failed during the recruitment of our patients., Objective: We present the findings of a phase II study on the efficacy of FOLFIRI plus zib-aflibercept (AFL) after FTD/TPI plus BEV, including clinical results with plasma biomarker analyses., Methods: This was a multicenter, single-arm, phase II study in patients with metastatic colorectal cancer refractory or intolerant to oxaliplatin, fluoropyrimidine, BEV, and FTD/TPI. The primary endpoint was progression-free survival. Fifteen plasma angiogenesis-associated biomarkers were analyzed using a Luminex ® multiplex assay U-kit., Results: Between January 2020 and May 2022, 26 patients (median age, 68 years) from 15 sites were enrolled. The median progression-free survival was 4.9 months (85% confidence interval, 3.4 month-not estimated). The overall response and disease control rates were 8% and 62%, respectively. The median levels of vascular endothelial growth factor-A and placental growth factor, both targets of AFL, were below the measurable limit of 30 pg/mL and 16 pg/mL, respectively. Patients were divided into two groups at the median levels of baseline biomarkers. The progression-free survival did not differ between high and low expressers of placental growth factor (p = 0.7), while it tended to be shorter in those with high levels of osteopontin (p = 0.05), angiopoietin-2 (p = 0.07), and tissue inhibitor of matrix metalloproteinases-1 (p = 0.1)., Conclusions: This study did not meet the primary endpoint. Hence, FOLFIRI plus AFL should not be used after FTD/TPI plus BEV for metastatic colorectal cancer. Further studies are needed to determine factors not targeted by AFL that may affect the efficacy of the treatment., Clinical Trial Registration: jRCTs041190100., (© 2024. The Author(s).)

Currently, no established marker exists for predicting peritoneal metastasis progression during chemotherapy, although they are major interruptive factors in sequential chemotherapy in patients with advanced gastric cancer (AGC). This multicenter retrospective study was conducted from June 2015 to July 2019, analyzing 73 patients with AGC who underwent taxane-plus-ramucirumab (TAX/RAM) therapy and had their serum carbohydrate antigen 125 (CA125) concentrations measured. Of 31 patients with elevated CA125 levels above a cutoff of 35 U/mL, 25 (80.6%) had peritoneal metastasis. The CA125 concentrations before TAX/RAM treatment were associated with ascites burden. The overall survival was significantly shorter in the CA125-elevated group. CA125 kinetics, measured at a median of 28 days after chemotherapy, were associated with the ascites response (complete or partial response: -1.86%/day; stable disease: 0.28%/day; progressive disease: 2.33%/day). Progression-free survival in the CA125-increased group, defined by an increase of 0.0067%/day using receiver operating characteristic curve analysis, was significantly poorer among patients with peritoneal metastases. In conclusion, this study highlights that CA125 kinetics can serve as an early predictor for the progression of peritoneal metastasis during TAX/RAM treatment.

Pancreatic neuroendocrine neoplasms (panNENs) are rare pancreatic neoplasms, and descriptions of treatment remain limited. Autotaxin (ATX) is a secreted autocrine motility factor involved in the production of lysophosphatidic acid (LPA), a lipid mediator that promotes the progression of various cancers. The aim of this study was to clarify the importance of the ATX-LPA axis in panNENs and to confirm its contribution to panNEN progression using clinical data, cell lines, and a mouse model. Serum ATX level was higher in patients with panNEN than in patients with other pancreatic diseases (chronic pancreatitis, pancreatic ductal adenocarcinoma [PDAC], intraductal papillary mucinous neoplasm, autoimmune pancreatitis) and healthy controls, and 61% of clinical specimens stained strongly for ATX. In a case we encountered, serum ATX level fluctuated with disease progression. An in vitro study showed higher ATX mRNA expression in panNEN cell lines than in PDAC cell lines. Cell proliferation and migration in panNEN cell lines were stimulated via the ATX-LPA axis and suppressed by RNA interference or inhibitors. An in vivo study showed that intraperitoneal injection of GLPG1690, an ATX inhibitor, suppressed tumor progression in a xenograft model. These findings revealed that ATX expression is significantly elevated in panNEN and is related to the progression of panNEN. We showed the potential of ATX as a novel biomarker and therapeutic target., (© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Adenocarcinomas with enteroblastic differentiation are rare clear cell tumors that are positive for enteroblastic markers. Enteroblastic differentiation is particularly uncommon in colorectal adenocarcinomas. Herein, we report a case of clear cell adenocarcinoma with enteroblastic differentiation in the sigmoid colon of a 38-year-old Japanese woman that metastasized to the lower left ureter. After neoadjuvant chemotherapy, the patient underwent low anterior resection. The tumor consisted of tubular, cribriform, and focal micropapillary proliferation of clear cells immunopositive for spalt-like transcription factor 4 (SALL4), glypican 3, and alpha-fetoprotein. Six months after the colonic resection, a tumor was found in the left lower ureter, which was resected. The ureteral tumor revealed clear cell adenocarcinoma, which was identical to the colonic tumor proliferating in the ureteral mucosa. Metastatic ureteral tumors are rare. We performed a literature search and found only 50 reported cases of ureteral metastases from colorectal cancer. Of these, only 10 metastatic tumors were identified in the ureteral mucosa. No case of ureteral metastasis of clear cell colorectal adenocarcinoma or colorectal adenocarcinoma with enteroblastic differentiation has been reported. Hence, it can be challenging to distinguish them from clear cell adenocarcinoma of the urinary tract and/or clear cell urothelial carcinoma. This paper discussed the differential diagnosis of these tumors and reviewed the clinicopathological features of colorectal carcinomas metastasizing to the ureter., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

During endoscopic ultrasound-guided biliary drainage (EUS-BD), there is a risk for bile leakage until stent deployment, which can result in severe peritonitis, particularly when passing a drainage stent becomes challenging despite tract dilation. There is no established method or dedicated device to optimize EUS-BD. Therefore, we have developed a novel stent deployment technique using the tapered sheath dilator. To address the safety and technical aspects of the EUS-BD technique, we retrospectively analyzed 11 consecutive patients who underwent EUS-BD using the tapered sheath dilator. The procedure involved the insertion of a guidewire, followed by mechanical dilation using the tapered sheath dilator. Subsequently, the inner catheter was removed and drainage stents (up to 6 Fr in diameter) were deployed through the outer sheath. We found a 100% technical success rate for tract dilation and stent deployment; moreover, all patients achieved clinical success. The median time for dilation was 40 s (range, 8-198), whereas the median time from dilation to stent deployment was 10 min (range, 6-19). Notably, no cases of bile leakage or peritonitis were observed. In conclusion, the use of the integrated device for tract dilation and stent delivery system might provide a safe and straightforward technique for drainage stenting during EUS-BD., Competing Interests: None., (© 2023 The Authors. DEN Open published by John Wiley & Sons Australia, Ltd on behalf of Japan Gastroenterological Endoscopy Society.)

Background: Data regarding treatment sequence for vulnerable patients with metastatic colorectal cancer (mCRC) in a real-world setting are lacking., Objective: We aimed to assess treatment outcomes in second-line or later chemotherapy for vulnerable patients with mCRC in a real-world setting., Patients and Methods: Vulnerable patients with mCRC who received less intensive treatment ('vulnerable') regimens, i.e. fluoropyrimidines with or without biologics (FP), reduced-dose doublet regimens with or without biologics (Doublet), and anti-epidermal growth factor receptor monotherapy (Anti-EGFR), as first-line therapy between June 2015 and December 2018 were retrospectively reviewed., Results: A total of 210 patients from 15 hospitals were analyzed. The median age was 78 years (range 28-90), and 44 patients (21%) had an Eastern Cooperative Oncology Group performance status (ECOG PS) score of 2. In the entire population, the median time to treatment failure (TTF) and overall survival (OS) were 7.6 and 21.4 months, respectively. Following the failure of first-line therapy in 195 patients, 74 (38%), 24 (12%), and 13 (7%) patients received vulnerable regimens, full-dose doublet regimens with or without biologics, and other regimens, respectively, whereas 84 (43%) received best supportive care (BSC). In patients receiving vulnerable regimens as second-line therapy, the median TTF and OS were 4.4 and 13.7 months, respectively, while response rate and disease control rate were 18% and 62%, respectively. In 84 patients who received BSC, the median OS was 3.5 months., Conclusions: Second-line chemotherapy for vulnerable patients with mCRC showed clinically meaningful outcomes; however, few patients received second-line therapy, and survival among patients who received BSC was dismal., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: A population of regulatory T cells (Treg), which reside within thymic nurse cell complexes, express adiponectin and abrogate breast cancer development in transgenic mice. In this study, we examined whether adiponectin-expressing Treg could impair triple-negative breast cancer, which is defined by a lack of estrogen receptors, progesterone receptors, and human epidermal growth factor receptor-2., Methods: CD4- and CD25-positive cells were sorted from cultured T lymphocytes of a previously characterized experimental thymic tumor model composed of thymic nurse cells and abundant lymphoid stroma. These sorted cells were examined for FOXP3 and adiponectin immunoreactivity and subsequently exposed to triple-negative breast cancer MDA-MB-157 and -231 cells., Results: Adiponectin-expressing Treg were obtained by CD4- and CD25-positive sorting and cell death was induced in triple-negative breast cancer cells through the cell-in-cell phenomenon., Conclusions: Adiponectin-expressing Treg may be candidates for adoptive cell therapy against triple-negative breast cancer., (© 2023 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Translation initiates when the eIF4F complex binds the 5' mRNA cap, followed by 5' untranslated region scanning for the start codon by scanning ribosomes. Here, we demonstrate that the ASC-1 complex (ASCC), which was previously shown to promote the dissociation of colliding 80S ribosomes, associates with scanning ribosomes to regulate translation initiation. Selective translation complex profiling (TCP-seq) analysis revealed that ASCC3, a helicase domain-containing subunit of ASCC, localizes predominantly to the 5' untranslated region of mRNAs. Ribo-seq, TCP-seq, and luciferase reporter analyses showed that ASCC3 knockdown impairs 43S preinitiation complex loading and scanning dynamics, thereby reducing translation efficiency. Whereas eIF4A, an RNA helicase in the eIF4F complex, is important for global translation, ASCC was found to regulate the scanning process for a specific subset of transcripts. Our results have thus revealed that ASCC is required not only for dissociation of colliding 80S ribosomes but also for efficient translation initiation by scanning ribosomes at a subset of transcripts., (© 2023 The Authors.)

Background: The clinical value of soluble forms of programmed cell death-1 (sPD-1), PD ligand 1 (sPD-L1) and cytotoxic T lymphocyte-associated protein-4 (sCTLA-4) for gastric cancer (GC) patients treated with nivolumab monotherapy has remained unknown., Methods: Blood samples collected before nivolumab treatment from 439 GC patients enrolled in the DELIVER (Japan Clinical Cancer Research Organisation GC-08) trial were analysed for sPD-1, sPD-L1 and sCTLA-4. Corresponding baseline clinical data were also retrieved., Results: Higher plasma levels of sPD-1 (hazard ratio [HR] = 1.27, p = 0.020), sPD-L1 (HR = 1.86, p < 0.001) and sCTLA-4 (HR = 1.33, p = 0.008) were significantly associated with shorter overall survival (OS), whereas only higher sPD-L1 levels was significantly associated with shorter progression-free survival (HR = 1.30, p = 0.008). The sPD-L1 concentration was significantly associated with the Glasgow prognostic score (GPS) (p < 0.001), but both sPD-L1 (HR = 1.67, p < 0.001) and GPS (HR = 1.39, p = 0.009 for GPS 0 versus 1; HR = 1.95, p < 0.001 for GPS 0 versus 2) were independently associated with OS. Patients with a GPS of 0 and low sPD-L1 thus showed the longest OS (median, 12.0 months) and those with a GPS of 2 and high sPD-L1 showed the shortest OS (median, 3.1 months), yielding a HR of 3.69 (p < 0.001)., Conclusion: Baseline sPD-L1 levels have the potential to predict survival for advanced GC patients treated with nivolumab, with the prognostic accuracy of sPD-L1 being improved by its combination with GPS., Competing Interests: Conflict of interest statement H. Kawakami has received consulting fees from Bristol-Myers Squibb Co. Ltd., Eli Lilly Japan K.K., MSD K.K., Ono Pharmaceutical Co. Ltd., Daiichi-Sankyo Co. Ltd., and Taiho Pharmaceutical Co. Ltd.; honoraria from Bristol-Myers Squibb Co. Ltd., AstraZeneca K.K., Eli Lilly Japan K.K., MSD K.K., Ono Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., Daiichi Sankyo Co. Ltd., Takeda Pharmaceutical Co. Ltd., and Taiho Pharmaceutical Co. Ltd.; lecture fees from Bristol-Myers Squibb Co. Ltd., Eli Lilly Japan K.K., MSD K.K., Ono Pharmaceutical Co. Ltd., Daiichi Sankyo Co. Ltd., Chugai Pharmaceutical Co. Ltd., Takeda Pharmaceutical Co. Ltd., and Taiho Pharmaceutical Co. Ltd.; and research funding from Bristol-Myers Squibb Co. Ltd., Chugai Pharmaceutical Co. Ltd., Taiho Pharmaceutical Co. Ltd., and Eisai Co. Ltd. Y. Sunakawa has received consulting fees from Ono Pharmaceutical Co. Ltd., Merck Biopharma Co., Ltd, and Guardant Health Japan Co.; honoraria from Bristol-Myers Squibb Co. Ltd., Bayer Yakuhin Ltd., Eli Lilly Japan K.K., MSD K.K., Ono Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., Daiichi Sankyo Co. Ltd., Takeda Pharmaceutical Co. Ltd., Merck Biopharma Co., Ltd, Guardant Health Japan Co., Sysmex Co., and Taiho Pharmaceutical Co. Ltd.; and research funding from Chugai Pharmaceutical Co. Ltd., Takeda Pharmaceutical Co. Ltd., Eli Lilly Japan K.K., Sanofi, Taiho Pharmaceutical Co. Ltd., and Ohtsuka Pharmaceutical Co. E. Inoue has received consulting fees from Nippontect Systems Co. Ltd. as well as lecture fees from Bristol-Myers Squibb Co. Ltd. and Pfizer Japan Inc. K. R. Matoba is a director of the DNA Chip Research Inc. and holds shares in the company. Noda, T. Sato, C. Suminaka, and M. Yamaki are employees of Sysmex Corporation. Y. Sakamoto has received lecture fees from Eli Lilly Japan K.K., MSD K.K., Ono Pharmaceutical Co. Ltd., Daiichi-Sankyo Co. Ltd., Taiho Pharmaceutical Co. Ltd.; Chugai Pharmaceutical Co. Ltd., Takeda Pharmaceutical Co. Ltd., Yakult Honsha Co. Ltd. Y. Kito has received honoraria from Ono Pharmaceutical Co. Ltd., Daiichi-Sankyo Co. Ltd., and Taiho Pharmaceutical Co. Ltd. A. Makiyama has received honoraria from Eli Lilly Japan K.K., Ono Pharmaceutical Co. Ltd., Daiichi Sankyo Co. Ltd., Taiho Pharmaceutical Co. Ltd., and Bristol-Myers Squibb Co. Ltd. H Hayashi has received honoraria from AstraZeneca K.K., Boehringer Ingelheim Japan Inc., Bristol-Myers Squibb Co. Ltd., Chugai Pharmaceutical Co. Ltd., Eli Lilly Japan K.K., Kyorin Pharmaceutical Co. Ltd., Merck Biopharma Co. Ltd., MSD K.K., Novartis Pharmaceuticals K.K., Ono Pharmaceutical Co. Ltd., Taiho Pharmaceutical Co. Ltd., and Takeda Pharmaceutical Co. Ltd.; consulting fees from AstraZeneca K.K., Boehringer Ingelheim Japan Inc., Bristol-Myers Squibb Co. Ltd., Chugai Pharmaceutical Co. Ltd., Eli Lilly Japan K.K., Pfizer Japan Inc., Shanghai Haihe Biopharma, Takeda Pharmaceutical Co. Ltd., and Merck Biopharma Co. Ltd.; and research funding from AstraZeneca K.K., Astellas Pharma, MSD K.K., Ono Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Novartis Pharma K.K., grants, Pfizer Japan Inc., Bristol Myers Squibb Company, Eli Lilly Japan K.K., Chugai Pharmaceutical Co.,Ltd., Daiichi Sankyo Co., Ltd., Merck Serono Co., Ltd./Merck Biopharma Co., Ltd., Takeda Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., SymBio Pharmaceuticals Limited, AbbVie Inc, inVentiv Health Japan, ICON Japan K.K., GRITSONE ONCOLOGY.INC, PAREXEL International Corp., Kissei Pharmaceutical Co., Ltd., EPS Corporation, Syneos Health, Pfizer R&D Japan G.K., A2 Healthcare Corp., Quintiles Inc./IQVIA Services JAPAN K.K., EP-CRSU CO., LTD., Linical Co., Ltd., Eisai Co., Ltd., CMIC Shift Zero K.K., Kyowa Hakko Kirin Co., Ltd, Bayer Yakuhin, Ltd, EPS International Co., Ltd., Otsuka Pharmaceutical Co., Ltd. T. Honjo received a research grant from Sysmex Corporation and Ono Pharmaceutical Co. Ltd. related to this study. K. Nakagawa has received consulting fees from Eli Lilly Japan K.K., Ono Pharmaceutical Co., Ltd., KYORIN Pharmaceutical Co., Ltd., Pfizer Japan Inc., Patents from Daiichi Sankyo Co., Ltd. Honoraria from Ono Pharmaceutical Co., Ltd., Merck Biopharma Co., Ltd., Amgen Inc., Kyowa Kirin Co., Ltd., Nippon Kayaku Co., Ltd., Takeda Pharmaceutical Co., Ltd., AstraZeneca K.K., 3H Clinical Trial Inc., Chugai Pharmaceutical Co., Ltd., Care Net, Inc., Eli Lilly Japan K.K., Medical Review Co., Ltd., MSD K.K., Medical Mobile Communications co., Ltd, Pfizer Japan Inc., YODOSHA CO., LTD., Nippon Boehringer Ingelheim Co., Ltd., Nikkei Business Publications, Inc., Taiho Pharmaceutical Co., Ltd., Japan Clinical Research Operations Bayer Yakuhin, Ltd., CMIC Co., Ltd., CMIC ShiftZero K.K., Novartis Pharma K.K., Life Technologies Japan Ltd., TAIYO Pharma Co., Ltd., Neo Communication KYORIN Pharmaceutical Co., Ltd., Roche Diagnostics K.K., Bristol-Myers Squibb K.K., AbbVie Inc. Research Funding from PAREXEL International Corp., Eisai Co., Ltd., PRA HEALTHSCIENCES, AstraZeneca K.K., EPS Corporation, Mochida Pharmaceutical Co., Ltd., Kissei Pharmaceutical Co., Ltd., Covance Japan Inc., EPS International Co., Ltd., Japan Clinical Research Operations,Daiichi Sankyo Co., Ltd., Takeda Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., GlaxoSmithKline K.K., MSD K.K., Sanofi K.K., Ono Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., PPD-SNBL K.K., Nippon Boehringer Ingelheim Co., Ltd., SymBio Pharmaceuticals Limited,Sysmex Corporation, IQVIA Services JAPAN K.K., Medical Research Support,SYNEOS HEALTH CLINICAL K.K., Eli Lilly Japan K.K., Nippon Kayaku Co., Ltd.,Amgen Inc., EP-CRSU Co., Ltd., Novartis Pharma K.K., Mebix, Inc., Otsuka Pharmaceutical Co., Ltd., Bristol-Myers Squibb K.K., SRL, Inc.,Janssen Pharmaceutical K.K.,Pfizer R&D Japan G.K., AbbVie Inc., A2 Healthcare Corp., Bayer Yakuhin, Ltd., Pfizer Japan Inc. W. Ichikawa has received honoraria from Taiho Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., Daiichi Sankyo Co. Ltd., Eli Lilly Japan K.K., Takeda Pharmaceutical Co.,Ltd., Shionogi & Co., Ltd., AstraZeneca K.K., Merck Biopharma Co., Ltd., Bristol-Myers Squibb Co. Ltd., Bayer Yakuhin Ltd., Nippon Kayaku Co., Ltd. All remaining authors declare no conflicts of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Currently, there is no surgical assistance system that can perform a three-dimensional (3D) planned total hip arthroplasty (THA) by methods other than surgical assistance navigation or robots. However, they are expensive, cumbersome, and subject to additional invasiveness, so there is a need for a simpler and less expensive 3D surgical support system. In this study, THA was performed using the anterolateral approach (Watson-Jones) in the supine position in 23 subjects to examine the efficacy and safety of a patient-specific femoral guide linked to 3D surgery support software. In 48% of the subjects, the difference in anterior torsion angle from the preoperative plan was within ±5 degrees, while in 83% of the subjects, the difference was within ±10 degrees. The 95% confidence interval (4.61-8.70) of the absolute difference did not fall below the pre-defined threshold of 7.2 degrees (p = 0.293). No adverse events were observed other than 2 cases (8.7%) of hemorrhage that required a blood transfusion. We confirmed the efficacy and safety of the patient-specific femoral guide in anterolateral supine approach THA.

Alzheimer's disease (AD) is a progressive neuropsychiatric disease affecting many elderly people and is characterized by progressive cognitive impairment of memory, visuospatial, and executive functions. As the elderly population is growing, the number of AD patients is increasing considerably. There is currently growing interest in determining AD's cognitive dysfunction markers. We used exact low-resolution-brain-electromagnetic-tomography independent-component-analysis (eLORETA-ICA) to assess activities of five electroencephalography resting-state-networks (EEG-RSNs) in 90 drug-free AD patients and 11 drug-free patients with mild-cognitive-impairment due to AD (ADMCI). Compared to 147 healthy subjects, the AD/ADMCI patients showed significantly decreased activities in the memory network and occipital alpha activity, where the age difference between the AD/ADMCI and healthy groups was corrected by linear regression analysis. Furthermore, the age-corrected EEG-RSN activities showed correlations with cognitive function test scores in AD/ADMCI. In particular, decreased memory network activity showed correlations with worse total cognitive scores for both Mini-Mental-State-Examination (MMSE) and Alzheimer's Disease-Assessment-Scale-cognitive-component-Japanese version (ADAS-J cog) including worse sub-scores for orientation, registration, repetition, word recognition and ideational praxis. Our results indicate that AD affects specific EEG-RSNs and deteriorated network activity causes symptoms. Overall, eLORETA-ICA is a useful, non-invasive tool for assessing EEG-functional-network activities and provides better understanding of the neurophysiological mechanisms underlying the disease., (© 2023. The Author(s).)

Pathophysiological difference of depression in patients with and without autistic spectrum disorder (ASD) has not been investigated previously. Therefore, we sought to determine whether there were differences between non-ASD and ASD groups on resting-state functional magnetic resonance imaging (rs-fMRI) in patients with depression. We performed 3T MRI under resting state in 8 patients with depression and ASD and 12 patients with depression but without ASD. The ASD group showed increased functional connectivity in the cerebellar network of the left posterior inferior temporal gyrus and anterior cerebellar lobes compared to the non-ASD group in an analysis of covariance. Adding antipsychotics, antidepressants, benzodiazepines, nonbenzodiazepines, anxiolytics, hypnotics, or age as covariates showed a similar increase in functional connectivity. Thus, this study found that depressive patients with ASD had increased functional connectivity in the cerebellar network. Our findings suggest that fMRI may be able to evaluate differences in depressed patients with and without ASD., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Introduction: Zoledronic acid (5 mg; ZOL), a once-yearly bisphosphonate, reduces osteoporotic fractures and increases bone mineral density (BMD). This 3-year post-marketing surveillance examined its real-world safety and effectiveness., Materials and Methods: This prospective, observational study included patients who started ZOL for osteoporosis. Data were assessed at baseline, 12, 24, and 36 months for safety and effectiveness. Treatment persistence, potentially related factors, and persistence before and after the COVID-19 pandemic started were also investigated., Results: The safety analysis and effectiveness analysis sets included 1406 and 1387 patients, respectively, with mean age of 76.5 years. Adverse reactions (ARs) occurred in 19.35% of patients, with an acute-phase reaction in 10.31, 1.01, and 0.55% after the first, second, and third ZOL infusions. Renal function-related ARs, hypocalcaemia, jaw osteonecrosis, and atypical femoral fracture occurred in 1.71, 0.43, 0.43, and 0.07% of patients, respectively. Three-year cumulative fracture incidences were 4.44% for vertebral, 5.64% for non-vertebral, and 9.56% for clinical fractures. BMD increased by 6.79, 3.14, and 1.78% at the lumbar spine, femoral neck, and total hip, respectively, after 3-year treatment. Bone turnover markers remained within reference ranges. Treatment persistence was 70.34% over 2 years and 51.71% over 3 years. Male, age ≥ 75 years, no previous medicines for osteoporosis, no concomitant medicines for osteoporosis, and inpatient at the first infusion were related to discontinuation. There was no significant difference in the persistence rate between before and after the COVID-19 pandemic (74.7% vs. 69.9%; p = 0.141)., Conclusion: This 3-year post-marketing surveillance confirmed the real-world safety and effectiveness of ZOL., (© 2023. The Japanese Society Bone and Mineral Research.)

We herein report a 64-year-old man with concomitant pancreatic ductal adenocarcinoma (PDAC) and type 1 autoimmune pancreatitis (AIP). An endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB) from the pancreatic head mass revealed level 2 histology of AIP and atypical glands. We diagnosed definitive focal AIP using the clinical diagnostic criteria. Computed tomography revealed that the pancreatic mass had not been reduced by steroid therapy. Surgery was performed after a histological PDAC diagnosis was made via a transpapillary biliary biopsy. The resected specimen revealed PDAC associated with AIP. It is important to consider the cooccurrence of PDAC and AIP even if the histological diagnosis via an EUS-FNB is AIP.

Background: Endoscopic transpapillary gallbladder drainage (ETGBD) has been reported as an alternative procedure for acute cholecystitis but remains a challenging procedure., Aims: To elucidate the efficacy of a strategic approach for ETGBD that utilizes a four-step classification system and the optional use of 'Three-pillar' assistance with the following devices: cholangioscopy (SpyGlass DS, SG), a flex-type guidewire (Flex-GW), and a 3-Fr microcatheter (3-Fr Micro)., Methods: A total of 115 patients undergoing ETGBD were studied retrospectively. Characteristics and technical outcomes were compared between conventional ETGBD technique (Classical ETGBD, N = 50) and strategic ETGBD with optional Three-pillar assistance (Strategic ETGBD, N = 65)., Results: SG-assistance (15/65, 23.1%) was as an excellent troubleshooter in Category 1 (failure to identify the cystic duct [CD] orifice) and Category 2 (failure to advance the GW across the CD takeoff due to unfavorable angle). Flex-GW (19/65, 29.2%) worked for Category 3b (failure of GW access to the GB due to multiple tortuosities). 3-Fr Micro (11/65, 16.9%) was effective for Category 3a (failure of GW access to the GB due to CD obstruction) and Category 4 (failure of drainage stent insertion to the GB). The overall technical success rate was significantly higher for Strategic ETGBD (63/65, 96.9%) compared with Classical ETGBD (36/50, 72.0%) (p = 0.0001)., Conclusions: Strategic ETGBD, which includes the Three-pillar assistance options of SG in the initial steps, Flex-GW for tortuous CD, and 3-Fr Micro for stenotic CD, achieved a significantly higher success rate than for Classical ETGBD., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Yoshida 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: Micronodular thymic neoplasm with lymphoid stroma (MNT), a subtype of thymic tumor, is histopathologically characterized by micronodular thymic epithelial cell nests with lymphoid stroma. Despite the distinct histopathology of MNT, its pathogenesis remains unclear., Methods: In this study, we aimed to examine a thymic tumor harboring thymic epithelial and lymphoid cells in a nonobese diabetic/severe combined immunodeficiency mouse., Results: The excised tumor cells were cultured in vitro and comprised epithelial tumor cells and lymphoid cells. During a three-dimensional cell culture, the epithelial tumor cells formed micronodular cell nests surrounded by lymphoid stroma. Notably, the lymphoid cells underwent apoptosis when they were separated from the epithelial tumor cells. Cutaneous transplantation of the cultured epithelial cells with splenocytes from BALB/c mice led to tumor formation, and these cells demonstrated a histopathology similar to that of human MNT in a nonobese diabetic/severe combined immunodeficiency mouse., Conclusion: Given its overlapping features with human MNT, the transplanted tumor could serve as an experimental model of this disease., (© 2022 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Sampling of bile juice during endoscopic retrograde cholangiopancreatography (ERCP) has potential benefit of being amenable to the identification of novel biomarkers in liquid biopsy. This study reports the results of a global investigation of exosomal microRNAs (miRNAs) in bile to identify potential biomarkers for biliary tract cancers (BTCs). Eighty-eight bile samples collected during ERCP (45 BTC and 43 noncancer control samples) were enrolled in this study. Eleven BTC samples and nine control samples were assigned as the discovery set. Exosomes in bile and serum samples were collected using a glass membrane column with size-controlled macroporous glass (MPG), and exosomal miRNA expression profiles were evaluated using comprehensive miRNA microarray analysis (3D-Gene). For validation, exosomal miRNA in the bile samples of 34 BTCs and 34 controls were comprehensively evaluated using 3D-Gene. In the discovery set, eight exosomal miRNAs in bile were identified as significant aberrant expression markers, while no miRNA with aberrant expression in serum was identified. In a comparison of the discovery and validation sets, miR-451a and miR-3619-3p were identified as reproducible upregulated markers, and the combination of the two bile miRNAs showed an excellent area under the curve (0.819) value for diagnosing BTCs. In addition, high miR-3619-3p expression in bile reflects poorer prognosis of BTCs (hazard ratio = 2.89). The MPG-extracted exosomal miRNAs in bile aspirated during ERCP provide a convenient new approach for diagnosing biliary diseases. Bile-derived miRNA analysis with miR-451a and miR-3619-3p represents a potentially valuable diagnostic strategy for identifying BTCs as well as a predictive indicator of BTC prognosis., (© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Accelerated tumor growth during immunotherapy in pre-existing measurable lesions, hyperprogressive disease (HPD), has been reported. However, progression of non-measurable lesions and new lesions are frequently observed in patients with advanced gastric cancer (AGC)., Methods: This retrospective study involved AGC patients at 24 Japanese institutions who had measurable lesions and received nivolumab after ≥ 2 lines of chemotherapy. HPD was defined as a ≥ two-fold increase in the tumor growth rate of measurable lesions. The pattern of disease progression was classified according to new lesions in different organs and ascites appeared/increase of ascites., Results: Of 245 patients, 147 (60.0%) showed progressive disease (PD) as the best response and 41 (16.7%) showed HPD during nivolumab monotherapy. There was no significant difference in overall survival (OS) between patients with HPD and those with PD other than HPD (median OS 5.0 vs 4.8 months; hazard ratio [HR] 1.0, 95% confidence interval [CI] 0.6-1.5; p = 1.0). Fifty-three patients developed new lesions in different organs and 58 had appearance/increase of ascites; these patients showed shorter OS than those without each of these features (median OS 3.3 vs 7.1 months, HR 1.8, 95% CI 1.2-2.7, p = 0.0031 for new lesions, and 3.0 vs 7.8 months, HR 2.6, 95% CI 1.8-3.8, p < 0.0001 for ascites). Thirty-one patients who had both features showed the worst prognosis (median OS 2.6 months)., Conclusions: New lesions in different organs and appearance/increase of ascites, rather than the original definition of HPD, are the patterns of disease progression associated with poor prognosis in AGC patients receiving nivolumab whose best response was PD., (© 2022. The Author(s).)

Background: The real-world survival benefit of FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) plus anti-VEGF therapy (Triplet) over doublet chemotherapy (Doublet) remains controversial in patients with BRAF V600E mutant metastatic colorectal cancer (mCRC)., Patients and Methods: WJOG13219G was a multicenter, retrospective, registry-based study of patients with BRAF V600E mutant mCRC who received first-line triplet or doublet chemotherapy from January 2014 to December 2019 in Japan. Inverse probability of treatment weighting (IPTW) was used to adjust for patient background., Results: The analysis included 79 and 91 patients in the Triplet and Doublet groups, respectively. The Triplet group was significantly younger and had better performance status. No statistical difference was noted in progression-free survival (PFS; HR, 0.82; 95% CI, 0.60-1.13; P = .22) and overall survival (OS; HR, 0.88; 95% CI, 0.62-1.25; P = .48) between both groups. IPTW analysis also showed no difference between the 2 groups in PFS (HR, 0.86; 95% CI, 0.69-1.08; P = .20) and OS (HR, 0.93; 95% CI, 0.73-1.20; P = .59). The Triplet and Doublet groups had an objective response rate of 53% and 41%, respectively (P = .10). At least one grade 3 or 4 adverse event was seen in 51 (65%) and 43 (47%) patients in the Triplet and Doublet groups, respectively, with the incidence of neutropenia being significantly higher in the former., Conclusion: Triplet therapy had no survival benefit versus doublet therapy in the overall and IPTW cohorts or specific subgroups for real-world patients with BRAF V600E mutant mCRC., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Competing Interests: The authors declare that they have no conflict of interest.

Objectives: To examine the differences in antimicrobial selection outcomes in nursing and healthcare-associated pneumonia (NHCAP) patients with and without risk factors for drug-resistant pathogen (RDRP) infection, and to identify the cause of in-hospital death after improvement of NHCAP., Methods: We conducted a retrospective analysis of the medical records of hospitalized adult patients with NHCAP. NHCAP patients were divided into the RDRP and non-RDRP groups. The RDRP group was further classified into the narrow and broad subgroups according to the type of empirical antimicrobial agent selected. The difference in mortality between these subgroups was then examined. The cause of all in-hospital deaths was also evaluated., Results: e evaluated 220 patients with NHCAP. There was no difference in mortality between the narrow and broad subgroups (11.8% vs. 15.4%, p=0.655). Among the group with improved NHCAP, 11.3% (n=23/203) died in hospital before discharge. Although the causes of death in patients who improved after NHCAP were diverse, the most common was recurrence of pneumonia., Conclusions: Empirical antimicrobial therapy for NHCAP may not always require selection of broad-spectrum antimicrobial agents, as has been previously reported. Patients with NHCAP may die from other causes, even after NHCAP has improved., Competing Interests: The authors declare no conflicts of interest associated with this manuscript.

Urolithin A (UA; 3,8-dihydroxybenzo[c]chromen-6-one), a metabolite generated by intestinal bacteria during the biotransformation of ellagitannins, has gained considerable attention in treating several cancers. Cholangiocarcinoma (CCA) remains one of the most lethal cancers; it grows in a special environment constantly exposed to both blood and bile. Since UA is known to undergo enterohepatic recirculation, we hypothesized that UA might have significant antitumor effects in CCA. Here, we investigated the therapeutic potential of UA in CCA and aimed to elucidate its mechanisms, including autophagy. UA treatment inhibited cell proliferation and induced G2/M phase cell cycle arrest in CCA cells. UA also suppressed cell migration and invasion, but did not cause apoptosis. Furthermore, Western blotting and immunocytochemistry demonstrated increased LC3-II accumulation, while electron microscopy demonstrated induced autophagosomes after UA treatment, suggesting that UA upregulated autophagy in CCA cells. In xenograft mice treated with UA, tumor growth was inhibited with increased LC3-II levels. On the other hand, phospho-kinase array demonstrated downregulation of the AKT/WNK1 pathway. LC3-II expression was elevated in WNK1 knocked down cells, indicating that WNK1 is the key signal for regulating autophagy. Thus, UA exerted antitumor effects by suppressing the AKT/WNK1 signaling pathway and inducing autophagy. In conclusion, UA, a natural, well-tolerated compound, may be a promising therapeutic candidate for advanced CCA., Competing Interests: The 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 Sahashi, Kato, Yoshida, Hayashi, Naitoh, Hori, Natsume, Jinno, Kachi, Asano, Toyohara, Kito, Ammanamanchi and Kataoka.)

The humoral and cellular immune responses against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) upon the coronavirus disease 2019 (COVID-19) vaccination remain to be clarified. Hence, we aimed to investigate the long-term chronological changes in SARS-CoV-2 specific IgG antibody, neutralizing antibody, and T cell responses during and after receiving the BNT162b2 vaccine. We performed serological, neutralization, and T cell assays among 100 hospital workers aged 22-73 years who received the vaccine. We conducted seven surveys up to 8 months after the second vaccination dose. SARS-CoV-2 spike protein-specific IgG (IgG-S) titers and T cell responses increased significantly following the first vaccination dose. The highest titers were observed on day 29 and decreased gradually until the end of the follow-up period. There was no correlation between IgG-S and T cell responses. Notably, T cell responses were detected on day 15, earlier than the onset of neutralizing activity. This study demonstrated that both IgG-S and T cell responses were detected before acquiring sufficient levels of SARS-CoV-2 neutralizing antibodies. These immune responses are sustained for approximately 6 to 10 weeks but not for 7 months or later following the second vaccination, indicating the need for the booster dose (i.e., third vaccination)., (© 2022. The Author(s).)

We describe a case of unclassifiable T/NK-cell lymphoma with concomitant acute myeloid leukemia (AML). A 73-year-old Japanese man was diagnosed with AML by bone marrow smear, but the presence of splenomegaly and liver tumor was incompatible with AML. Splenectomy and hepatic resection were performed to resolve the thrombocytopenia and define the diagnosis. The pathological findings showed sinusoidal involvement of abnormal lymphoid cells that were CD3-positive but negative for T-cell receptor (TCR) rearrangement. Our case could not be categorized as hepatosplenic T-cell lymphoma because of the lack of immunohistological expression of TCR, despite the clinical similarity., Competing Interests: The authors declare they have no conflicts of interest., (© 2022 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Background: As mesothelioma generally has an unfavorable prognosis, further advances are needed to improve the outcomes in patients with mesothelioma. In the present study, we generated and characterized a monoclonal antibody that could inhibit mesothelioma cell proliferation in a xenotransplantation mouse model., Methods: We generated monoclonal antibodies by immunizing mice with cultured mesothelioma cells. These antibodies were then characterized by immunofluorescence staining, immunohistochemical staining, secondary antibody-drug conjugate assay, antibody inoculation in a xenotransplantation mesothelioma mouse model, and mass spectrometry followed by small interfering RNA (siRNA) analysis. 5' rapid amplification of complementary DNA ends followed by sequencing was performed to deduce the amino acid sequences of the variable regions of the light and heavy chains of AX10., Results: An IgG2b κ-type AX10 antibody against the cell surface membrane of sarcomatoid mesothelioma cells was generated. AX10 immunoreactivity was detected in 12 out of 22 different mesothelioma tissue specimens, but there was little AX10 immunoreactivity in a normal human tissue array. AX10 decreased Matrigel invasion by MPM-1 cells but did not affect cell proliferation. Notably, AX10 significantly inhibited the proliferation of MPM-1 cells xenotransplanted into Severe combined immunodeficiency-Nonobese diabetic mice. Matrix-assisted laser desorption ionization time-of-flight mass spectrometry followed by siRNA silencing indicated that AX10 reacted to a unique alternatively spliced isoform of sarcolemma-associated protein. AX10 is composed of as yet unregistered amino acid sequences in its variable region., Conclusions: AX10 could have therapeutic potential for patients with sarcomatoid mesothelioma., (© 2022 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Histological evidence is essential for diagnosing malignant biliary strictures. However, conventional brush cytology remains the primary method used worldwide, despite its low diagnostic sensitivity and accuracy, as it is technically easy, rapid, and cost-effective. The aim of this study was to evaluate the diagnostic performance of a recently introduced endoscopic scraper, the simplicity of which is comparable to that of a conventional brush, by comparing diagnostic yields and the number of collected cells. The sensitivity of the endoscopic scraper when using the cell block technique was significantly higher than when using brush cytology or a brush with the cell block technique (53.6% vs. 30.9%, p < 0.001; 53.6% vs. 31.6%, p = 0.024, respectively). Quantitative digital image analysis of cell block sections revealed that the median number of cells obtained with the endoscopic scraper was significantly higher than when using the brush (1917 vs. 1014 cells, p = 0.042). Furthermore, seven cases (8.3%; 7/84) were diagnosed by immunohistochemical analysis of the cell block section obtained from the endoscopic scraper. Given its simplicity and greater capacity for sample acquisition, use of the endoscopic scraper in conjunction with the cell block technique could replace brush cytology for the histological diagnosis of malignant biliary strictures.

Objectives: To determine whether the prevalence of gram-negative bacilli (GNB; Pseudomonas aeruginosa , Klebsiella pneumoniae , and Escherichia coli ) in sputum and urine specimens from outpatients and inpatients differed by season and according to temperature and humidity changes., Methods: In this retrospective study, microbiologic data for adult patients from 2008 to 2019 were retrieved from the electronic database of a hospital in Japan. Data were categorized by specimen type (sputum and urine) and specimen collection (outpatient and inpatient). Associations between variables were assessed using Spearman's rank correlation coefficients. Differences between groups were assessed using Pearson's chi-square test and analysis of discrete variance., Results: Among inpatients, the frequencies of P. aeruginosa and K. pneumoniae isolation from sputum specimens were higher in summer and autumn. The frequency of P. aeruginosa isolation from urine specimens was higher in autumn. These seasonal trends were observed in specimens from both outpatients and inpatients. No seasonal trend was observed in the frequency of E. coli isolation. Mean monthly temperature was positively correlated with the frequency of isolating P. aeruginosa (r=0.2198, p=0.0081) and K. pneumonia e (r=0.3443, p=0.00002) from sputum as well as with the frequency of isolating K. pneumoniae (r=0.1905, p=0.0222) from urine. Mean monthly humidity was positively correlated with the frequency of isolating K. pneumoniae (r=0.2602, p=0.0016) from sputum., Conclusions: GNB were isolated more frequently in summer and autumn than in other seasons. These seasonal trends were observed for both outpatient and inpatient specimens. Seasonality should be considered for optimal infection control of GNB in hospitals., Competing Interests: The authors declare no conflicts of interest associated with this manuscript.

Background: A platinum-containing anti-cancer agent, oxaliplatin (L-OHP), is known to induce peripheral neuropathy, including erectile dysfunction (ED) as a side effect, while Gosha-jinki-gan (GJG) is a traditional Japanese herbal medicine mainly used for peripheral neuropathy., Aim: To investigate the effect of GJG on L-OHP-induced ED in rats., Methods: Twelve-week-old male Wister/ST rats were categorized into the following groups: Sham, Sham+GJG, L-OHP, and L-OHP+GJG (each n = 10). The L-OHP and L-OHP+GJG groups were injected intravenously with L-OHP (4 mg/kg) for 2 consecutive days in the first week. Statistical significance was determined using Bonferroni's multiple comparison test., Outcomes: At the end of the study period, erectile function was evaluated by measuring intracavernosal pressure (ICP) and mean arterial pressure (MAP) after cavernous nerve stimulation. Western blot analysis was used to assess the neuronal nitric oxide synthase (nNOS) and endothelial nitric oxide synthase (eNOS) levels, and quantitative polymerase chain reaction was used to assess the expression of phosphodiesterase-5 (PDE-5) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-1., Results: The ICP/MAP ratio of L-OHP rats (0.34 ± 0.06) was significantly lower than that of Sham rats (0.67 ± 0.03, P < .01), however, the ICP/MAP ratio of L-OHP+GJG rats (0.55 ± 0.01) was significantly higher than that of L-OHP rats (P < .01). There were no significant differences in the nNOS and eNOS protein expression between both groups (P > .05). GJG administration significantly decreased PDE-5 and NADPH oxidase-1 messenger RNA expressions in the L-OHP+GJG group., Clinical Translation: This animal model study suggests that GJG might be effective for erectile function in cancer survivors., Strengths & Limitations: Our study identified that GJG had no notable side effects in the treated group. Further investigation of the cavernous nerve would also help elucidate the mechanism of GJG effect, which is a limitation of this study., Conclusion: We found that GJG administration improved L-OHP-induced ED by improving transcriptional PDE-5 expression. Kataoka T, Kawaki Y, Kito Y, et al. Gosha-Jinki-Gan Improved Erectile Dysfunction Caused by Anti-Cancer Agent Oxaliplatin by Decreasing Transcriptional Expression of Phosphodiesterase-5 in Rats. Sex Med 2022;10:100484., (Copyright © 2021 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

To improve component-placement accuracy in total knee arthroplasty, we developed two devices: an original extramedullary patient-specific guide for the femur and an original extramedullary universal guide for the tibia (EM-TIBIA). We also developed a new function in ZedView, a three-dimensional surgical assistive software, that provides the parameters necessary to install the EM-TIBIA. Compared with conventional manual methods based on X-ray two-dimensional images or ZedView, these newly developed devices function as an extramedullary intraoperative support guide in conjunction with ZedView, simplifying surgical procedures. We conducted a study to evaluate the efficacy and safety of the surgery using the new guides and software function. Nineteen patients underwent surgery. On the femoral side, the mean absolute difference of the installation alignment was within 3° for all parameters. On the other hand, on the tibial side, the mean absolute difference from the preoperative plan for the rotation was 5.26±5.30°. The proportion of patients whose difference fell within ±3° was 52.6% (95% confi dence interval: 28.9 to 75.6%), and did not meet the pre-specified criteria for efficacy (P=0.261). No serious adverse events were reported, and no excessive bleeding, thrombosis, infections, or intraoperative or postoperative fractures were noted. The two new guides can easily reproduce the preoperative plan as 3D intraoperative support jigs, but errors can occur on the tibia side due to soft tissue that is not recognized by CT, creating problems in installation accuracy.

With the development of newer devices and technical innovations, pancreaticobiliary endoscopy is expanding to assume more advanced therapeutic roles. As with other devices, slimmed-down "3-Fr microcatheters" are considered to be opening new windows toward entirely new therapeutic techniques for various purposes. Our practical experience with a total of 34 consecutive patients in whom 3-Fr microcatheters were applied during pancreaticobiliary endoscopic procedures clarified the potential roles of this instrument in pancreaticobiliary endoscopy. The major benefits of 3-Fr microcatheters involve their slimness and flexibility. Applications of 3-Fr microcatheters could be categorized into three groups according to the characteristics of usage: (1) utilization as a cannulation catheter for peroral digital cholangioscopy (n = 15); (2) selective advancement through deep flexures or severely stenotic ducts (n = 11); or (3) two-devices-in-one-channel technique (n = 8). The microcatheter worked successfully for cannulation of cholangioscopy in all but one case (14/15, 93.3%). For selective advancement, the microcatheter worked for troubleshooting in 9 of 11 cases (81.8%). With the two-devices-in-one-channel technique, the microcatheter proved satisfactory in all cases (8/8, 100%). In total, the microcatheter was successfully maneuvered in 31 of 34 cases (91.1%), following the failure of procedures using conventional endoscopic techniques. In terms of adverse events, cystic duct injury was only observed in two cases (5.8%), who recovered under conservative observation, because its slimness could minimize the damage. We believe that 3-Fr microcatheters offer effective and safe salvage troubleshooting during various endoscopic pancreaticobiliary procedures that face troublesome situations with conventional strategies., (© 2021 Japan Gastroenterological Endoscopy Society.)

Background: SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4-deficient thoracic sarcoma (SMARCA4-DTS) is a rare disease that has recently been described as an entity. It is characterized by an aggressive clinical course and specific genetic alterations. As an immunohistological feature, the tumors are deficient in SMARCA4 and SMARCA2 and express sex-determining region Y (SRY)-box 2 (SOX2). Occasionally, there are cases that are less frequent and difficult to distinguish from SMARCA4-deficient non-small cell lung carcinoma (SMARCA4-dNSCLC). Therefore, the 5th edition of the World Health Organization (WHO) classification describes thoracic SMARCA 4-deficient undifferentiated tumors (SMARCA4-UT). In contrast, Carney's triad is a syndrome that combines three rare soft tissue tumors: gastric leiomyosarcoma, pulmonary chondroma, and extra-adrenal paraganglioma. Protein kinase cAMP-dependent type I regulatory subunit alpha (PRKAR1A) has been proposed as the causative gene. Both diseases are valuable cases; moreover, there have been no previous reports of their coexistence., Case Presentation: A 43-year-old man visited our hospital because of respiratory distress. Computed tomography revealed a large mass measuring 55 mm in the upper lobe of the right lung and front mediastinum, with metastases in the surrounding lymph nodes. Needle biopsy was performed for diagnosis, and histological examination of the samples revealed monotonous epithelioid-like cells with loose binding and sheet-form proliferation. The tumor cells had distinct nuclei with some rhabdoid-like cells. Immunohistochemical analysis revealed that the tumor cells were positive for AE1AE3, SOX2, CD34, and p53 and negative for SMARCA4 and SMARCA2. The patient died 6 months after admission, without any treatment. Autopsy revealed ganglioneuroma and enchondroma suggestive of an incomplete Carney complex., Conclusion: SMARCA4-UT is a rare and recently established disease. While it is difficult to diagnose, it is necessary to distinguish undifferentiated carcinoma, large cell carcinoma, Ewing sarcoma, and epithelioid sarcoma when diagnosing tumors involving the mediastinum. Moreover, cases of SMARCA4-UT with ganglioneuroma and enchondroma are very rare. We discuss and report a case of SMARCA4-UT in which we also examined ARID1A and SLC7A11expression., (© 2022. The Author(s).)

Background: There is no large real-world data regarding efficacy and safety of immunotherapy in gastric cancer (GC). Although some tumors can grow rapidly after immunotherapy, the patient proportions and survival outcomes are unclear in GC., Methods: A multicenter, prospective observational study was performed to evaluate clinical outcomes including survival time, safety, and tumor behavior of nivolumab treatment for patients with advanced GC. Primary endpoint was overall survival (OS), and secondary endpoints included response rate (RR), disease control rate (DCR), progression-free survival (PFS), tumor growth rate (TGR) at first evaluation, and safety., Results: Of 501 enrolled patients, 487 were evaluable (median age 70 years, 71% male, performance status 0/1/2 [42%/44%/14%], 21% HER2-pos, 42% patients with ascites). Median OS was 5.82 months (95% CI 5.29-7.00) with a 1-year survival rate of 30% and median PFS of 1.84 months (95% CI 1.71-1.97). The DCR was 39.4% and the RR was 14.2% (95% CI 10.3-18.8) in 282 patients with measurable lesions. In 219 patients evaluable for TGR, 20.5% were identified as hyperprogressive disease (HPD). OS from the first evaluation of patients with HPD was shorter compared with non-HPD (HR 1.77, 95% CI 1.25-2.51, P = 0.001), but it was not worse than that of patients with progression and non-HPD (HR 1.05, 95% CI 0.72-1.53, P = 0.8). A multivariate analysis revealed the presence of peritoneal metastasis was a prognostic factor for OS and PFS., Conclusions: Our real-world data demonstrated the comparable survival time to a previous clinical trial and revealed the frequency and prognosis of patients with HPD in advanced GC treated with nivolumab., (© 2021. The International Gastric Cancer Association and The Japanese Gastric Cancer Association.)

Background & Aims: Platelet-derived growth factor receptor α (PDGFRα)-positive interstitial cells (PIC) are interposed between enteric nerve fibers and smooth muscle cells (SMCs) in the tunica muscularis of the gastrointestinal tract. PIC have robust expression of small conductance Ca 2+ activated K + channels 3 (SK3 channels) and transduce inhibitory inputs from purinergic and sympathetic nerves in mouse and human colon. We investigated whether PIC also express pituitary adenylate cyclase-activating polypeptide (PACAP) receptors, PAC1 (PAC 1 R), and are involved in mediating inhibitory regulation of colonic contractions by PACAP in mouse and human colons., Methods: Gene expression analysis, Ca 2+ imaging, and contractile experiments were performed on mouse colonic muscles. Ca 2+ imaging, intracellular electrical recordings, and contractile experiments were performed on human colonic muscles., Results: Adcyap1r1 (encoding PAC 1 R) is highly expressed in mouse PIC. Interstitial cells of Cajal (ICC) and SMCs expressed far lower levels of Adcyap1r. Vipr1 and Vipr2 were expressed at low levels in PIC, ICC, and SMCs. PACAP elicited Ca 2+ transients in mouse PIC and inhibited spontaneous phasic contractions via SK channels. In human colonic muscles, PAC 1 R agonists elicited Ca 2+ transients in PIC, hyperpolarized SMCs through SK channels and inhibited spontaneous phasic contractions., Conclusions: PIC of mouse and human colon utilize PAC 1 R-SK channel signal pathway to inhibit colonic contractions in response to PACAP. Effects of PACAP are in addition to the previously described purinergic and sympathetic inputs to PIC. Thus, PIC integrate inhibitory inputs from at least 3 neurotransmitters and utilize several types of receptors to activate SK channels and regulate colonic contractile behaviors., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Oxidative stress serves an important role in carcinogenesis. The present study investigated the clinical significance of oxidative stress as a prognostic factor for diffuse large B-cell lymphoma (DLBCL). The participants comprised 55 consecutive patients with DLBCL. A commercially available derivatives of reactive oxygen metabolites (d-ROMs) test kit was used to assess oxidant levels. Similarly, a commercially available biological antioxidant potential (BAP) test was used to assess antioxidant levels. The antioxidative/oxidative stress ratio was calculated as d-ROMs/BAP. The median serum concentration of d-ROMs was 425 µM. The levels of d-ROMs were significantly higher in patients with DLBCL than in healthy volunteers (P<0.01). The complete remission (CR) rates in patients with d-ROMs <425 and ≥425 µM were 81.5 and 85.7%, respectively [not significant (NS)]. The 3-year overall survival (OS) rates for patients with d-ROMs <425 and ≥425 µM were 67.2 and 72.0%, respectively (NS). The median BAP was 2,002 µM. The CR rates of patients with BAP <2,002 and ≥2,002 µM were 77.8 and 88.9%, respectively (NS). The 3-year OS rates of patients with BAP <2,002 and ≥2,002 µM were 60.9 and 75.9%, respectively (NS). No significant difference in the d-ROMs/BAP ratio was observed between groups. Multivariate analysis revealed that d-ROMs were an independent prognostic factor for progression-free survival., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2020, Spandidos Publications.)

The purpose of this study was to demonstrate the preparation of spherical submicron YAG:Ce particles with controllable particle outer diameters and crystallite sizes and their photoluminescence (PL) properties, which were produced using a flame-assisted spray-pyrolysis method followed by the annealing process. The correlation of particle outer diameter, crystallite size, and PL performance of the prepared particles was also investigated. Experimental results showed that the increases in the particle outer diameters have an impact on the obtainment of higher PL performance. Large particle outer diameters permitted the crystallites to grow more, whereas this is in contrast to the condition for small particle outer diameter having limitations in crystallite growth. This study also found that too large outer diameter (>557 nm) was not effective since crystallites cannot grow anymore and it permits possible scattering problems. This study provides significant information for optimizing synthesis parameters for controlling particle outer diameters and crystallite sizes, which could be relevant to other functional properties, especially for lens, solar cell, and LED applications., Competing Interests: We certify that all authors agree for publishing this work, and we have no conflict of interest to declare. We warrant that the article is the authors' original work., (This journal is © The Royal Society of Chemistry.)

Background: Chemotherapeutics, one of the standard treatment options for cancer worldwide, have various adverse effects, including erectile dysfunction (ED)., Aim: To investigate erectile function in an animal model after administration of the anticancer agent oxaliplatin (L-OHP)., Methods: Male Wistar/ST rats were divided into 2 groups: L-OHP rats (n = 21), which were intravenously administered L-OHP (4 mg/kg; twice a week for 4 weeks), and Control rats (n = 21), which were injected with the same volume of 5% glucose solution, using the same dosing schedule. At the end of the study period, erectile function was evaluated by measuring intracavernous pressure (ICP) and mean arterial pressure (MAP) after cavernous nerve stimulation (n = 9-10). Endothelial function was evaluated with an isometric tension study using corpus cavernosum strips (n = 11). Western blot analysis was used to assess neuronal nitric oxide (nNOS) and endothelial NO synthase (eNOS) protein levels (n = 7). Real-time quantitative polymerase chain reaction (qRT-PCR) was used to assess the expression of inflammation- and oxidative stress-related markers (nicotinamide adenine dinucleotide phosphate oxidase-1, p22 phox , interleukin [IL]-6, and nuclear factor-kappa B) (n = 6). Statistical significance was determined using the Student's t-test., Outcomes: The L-OHP group had a significantly lower ICP:MAP ratio than the control group (P < .05). Compared to the Control group, the L-OHP group exhibited significantly lower responses to ACh and eNOS protein levels and significantly higher inflammatory biomarker levels., Clinical Translation: The results based on this animal model indicate that use of the anticancer agent L-OHP should be considered as a risk factor for ED occurring via reduction of NO bioavailability in humans; our results provide possible treatment strategies for maintaining the erectile function of cancer survivors., Strengths and Limitations: Our study showed that the anticancer agent L-OHP has the propensity to cause ED in rats. A major limitation of this study is the lack of an established cure for ED associated with L-OHP and the lack of clinical evidence., Conclusions: L-OHP causes ED in rats via reduction of NO bioavailability caused by endothelial dysfunction. Kataoka T, Mori T, Suzuki J, et al. Oxaliplatin, an Anticancer Agent, Causes Erectile Dysfunction in Rats due to Endothelial Dysfunction. J Sex Med 2021;18:1337-1345., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)