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It is important to regulate the oxygen concentration and scavenge oxygen radicals throughout the life of animals. In mammalian embryos, proper oxygen concentration gradually increases in utero and excessive oxygen is rather toxic during early embryonic development. Reactive oxygen species (ROS) are generated as by-products in the respiratory system and increased under inflammatory conditions. In the pathogenesis of a variety of adult human diseases such as cancer and cardiovascular disorders, ROS cause an enhancement of tissue injuries. ROS promote not only the development of atherosclerosis but also tissue injury during the reperfusion process. The thioredoxin (TRX) system is one of the most important mechanisms for regulating the redox balance. TRX is a small redox active protein distributed ubiquitously in various mammalian tissues and cells. TRX acts as not only an antioxidant but also an anti-inflammatory and an antiapoptotic protein. TRX is induced by oxidative stress and released from cells in response to oxidative stress. In various human diseases, the serum/plasma level of TRX is a well-recognized biomarker of oxidative stress. Here we discuss the roles of TRX on oxygen stress and redox regulation from different perspectives, in embryogenesis and in adult diseases focusing on cardiac disorders. reactive oxygen species; oxidative stress doi:10.1152/ajpheart.01316.2006

Background: Although recent advances in systemic therapies for hepatocellular carcinoma (HCC) have led to prolonged patient survival, the high costs of the drugs place a heavy burden on both patients and society. The objectives of this study were to examine the treatment regimens used as first-line systemic treatment for patients with advanced HCC in Japan and to estimate the treatment costs per regimen., Methods: For this study, we aggregated the data of patients who had received first-line systemic treatment for advanced HCC between July 2021 and June 2022. The treatment cost per month of each regimen was estimated based on standard usage, assuming an average weight of 60 kg for male patients. The data were categorized by the treatment regimen, and the treatments were categorized based on the cost into very high-cost (≥1 000 000 Japanese yen [JPY]/month), high-cost (≥500 000 JPY/month) and other (<500 000 JPY/month) treatments., Results: Of the total of 552 patients from 24 institutions whose data were analyzed in this study, 439 (79.5%) received atezolizumab plus bevacizumab, 98 (17.8%) received lenvatinib and 15 (2.7%) received sorafenib as the first-line treatment. The treatment cost per month for each of the above regimens was as follows: atezolizumab plus bevacizumab, 1 176 284 JPY; lenvatinib, 362 295 JPY and sorafenib, 571 644 JPY. In total, 82.2% of patients received high-cost regimens, and the majority of these patients received a very high-cost regimen of atezolizumab plus bevacizumab., Conclusions: Advances in systemic therapies for HCC have led to prolonged patient survival. However, the treatment costs are also increasing, imposing a burden on both the patients and society., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Undifferentiated carcinoma (UC) of the pancreas is a rare subtype of pancreatic cancer displaying no definitive direction of differentiation. UC has been reported as a highly aggressive malignant neoplasm, with a median overall survival of <1 year, except for several surgical series. On the other hand, UC tissue sometimes contains non-neoplastic osteoclast-like giant cells (OGCs), and such cases have been reported to have relatively longer survival. Thus, the World Health Organization (WHO) classification histologically distinguishes UC with OGCs (UCOGCs) from UC, and UCs were subclassified into three subtypes: anaplastic UC, sarcomatoid UC and carcinosarcoma. However, still less is known about UC due to its rarity, and such situations lead to further difficulties in treatment for UC. To date, only surgical resection can offer curative treatment for patients with UC, and no clear evidence for chemotherapy exists for them. However, a retrospective cohort study and case reports showed that relatively promising results paclitaxel-containing regimens for treatment of patients with unresectable UC. Furthermore, high programmed cell death protein 1 expression has been reported in sarcomatoid UCs and UCOGCs, and promising responses to anti-programmed death-ligand 1 therapy have been described in case reports of UCOGCs. Recent advances in chemotherapeutic agents and molecular technologies are opening up the possibilities for expanded treatments., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

We report the different properties of two types of red fluorescent proteins (RFP), undescribed species, extracted from two octocorals, Scleronephthya sp. 1 (S. sp. 1) and S. sp, 2 (Alcyonacea, Nephtheidae). S. sp. 1, named Alc-Orange, emits strong green emission at 492 nm and weak red emission at 590 and 630 nm when excited at 449 and 574 nm, respectively. S. sp. 2, LS-Red, emits strong deep red at 642 nm and weak green at 480 and 510 nm when excited at 574 nm and 434 nm, respectively. LS-Red has a very large Stokes shift of about 208 nm emitting at 642 nm when excited at 434 nm. Interestingly, LS-Red shows some emissions at 480 (blue emission), 514 (green emission), 563 (orange emission), and 642 nm (deep red emission) continuously at pH 7.5, which means multicolored fluorescence protein by one excitation at 434 nm. In pH dependence of fluorescence of Alc-Orange (pH 13 to 3.5), no relation between 'green and red FPs' was observed, whereas LS-Red showed the interconversion between 'green and red forms' depending on pH (11.5 to 4.5)., (© 2022 John Wiley & Sons Ltd.)

Background/objectives: Pancreatic adenosquamous carcinoma (PASC) is a rare variant of pancreatic ductal adenocarcinoma (PDAC). The usual treatment for metastatic or recurrent PASC is systemic chemotherapy in accordance with the PDAC treatment strategy. This study aimed to investigate the efficacy of chemotherapy, especially the benefit of recent combination therapies, in patients with metastatic or recurrent PASC., Methods: We conducted a multicenter retrospective analysis of 116 patients with metastatic or recurrent PASC treated with first-line chemotherapy between April 2001 and December 2017 at 24 Japanese institutions., Results: Combination chemotherapies included gemcitabine + nab-paclitaxel (GnP, n = 28), fluorouracil/leucovorin + irinotecan + oxaliplatin (FFX, n = 10), gemcitabine + S-1 (GS, n = 10), and others (n = 9). Monotherapies included gemcitabine (n = 51) and S-1 (n = 8). The median overall survival (OS) was 6.5, 7.3, and 4.3 months for the whole cohort, the combination therapy group, and the monotherapy group, respectively. Multivariate analysis indicated that combination therapy showed a better trend in OS than monotherapy (hazard ratio = 0.68; 95% confidence interval, 0.38-1.20). GnP or FFX were selected in 58.7% of patients after FFX was approved in Japan, and revealed a median OS, median progression-free survival, and objective response rate of 7.3 months, 2.8 months, and 26.9% in GnP and 7.2 months, 2.3 months, and 20.0% in FFX respectively., Conclusions: This study suggests that combination therapy may be more effective than monotherapy. GnP and FFX showed similar and clinically meaningful efficacy for patients with metastatic or recurrent PASC., (Copyright © 2022 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Background: Gemcitabine plus nab-paclitaxel (GnP) has been a standard treatment for unresectable pancreatic cancer (uPC); however, the current treatment status and usefulness in older adults with uPC remain unclear. Therefore, we aimed to investigate the patient background and compare the efficacy and safety of GnP versus other treatments in older adults with uPC., Patients and Methods: In this prospective observational study, we enrolled 233 eligible patients aged ≥76 years with pathologically proven, clinically uPC, and no history of chemotherapy from 55 Japanese centers during September 2018-September 2019. The main endpoints were overall survival (OS), progression-free survival (PFS), and safety. Geriatric assessments were performed upon registration and after 3 months. To adjust for confounders, we conducted propensity score-matched analyses., Results: GnP, gemcitabine alone (Gem), best supportive care, and other therapies were administered to 116, 72, 16, and 29 patients, respectively. In the propensity score-matched analysis, 42 patients each were selected from the GnP and Gem groups. The median OS was longer in the GnP group than in the Gem group (12.2 vs. 9.4 months; hazard ratio [HR], 0.65; 95% CI, 0.37-1.13). The median PFS was significantly longer in the GnP group than in the Gem group (9.2 vs. 3.7 months; HR, 0.38; 95% CI, 0.23-0.64). The incidence of severe adverse events was higher with GnP than with Gem; however, the difference was not significant., Conclusion: GnP is more efficacious than Gem in patients aged ≥76 years with uPC despite demonstrating a higher incidence of severe adverse events., (© The Author(s) 2022. Published by Oxford University Press.)

Objectives: Endoscopic ultrasound-guided tissue acquisition (EUS-TA) plays a crucial role in the diagnosis of pancreatic tumors. The present study aimed to investigate the current status of needle tract seeding (NTS) after EUS-TA of pancreatic tumors based on a nationwide survey in Japan., Methods: Patients who underwent surgical resection of primary pancreatic tumors after EUS-TA performed between April 2010 and March 2018 were surveyed. The incidence rates of NTS were determined, and compared in patients with pancreatic ductal adenocarcinomas (PDACs) and other tumors, and in patients who underwent transgastric and transduodenal EUS-TA of PDACs. The detailed features and prognosis of patients with NTS were also assessed., Results: A total of 12,109 patients underwent surgical resection of primary pancreatic tumors after EUS-TA. The overall incidence rate of NTS was 0.330%, and the NTS rate was significantly higher in patients with PDAC than in those with other tumors (0.409% vs. 0.071%, P=0.004). NTS was observed in 0.857% of patients who underwent transgastric EUS-TA, but in none of those who underwent transduodenal EUS-TA. Of the patients with NTS of PDACs, the median time from EUS-TA to occurrence of NTS and median patient survival were 19.3 and 44.7 months, respectively, with 97.4% of NTS located in the gastric wall and 65.8% of NTS resected. The patient survival was significantly longer in patients who underwent NTS resection than in those without NTS resection (P=0.037)., Conclusions: NTS appeared only after transgastric not after transduodenal EUS-TA. Careful follow-up provides an opportunity to remove localized NTS lesions by gastrectomy., (This article is protected by copyright. All rights reserved.)

Living cells and organelles are separated by a lipid membrane bilayer. It is possible to induce morphological changes in this membrane by disturbing the order of the membrane using external stimuli and understanding the details of this mechanism is expected to be applicable to intracellular transport. DBA (DBAB-BODIPY-aminopropyl), which contains (1) a DBAB (4-[di(biphenyl-4-yl)amino]azobenzene) moiety that undergoes photo-isomerization under visible light irradiation, and (2) a BODIPY (borondipyrromethene) fluorophore was synthesized. The π-π* transition absorptions of both the azo moiety and that of BODIPY moiety in DBA were observed, independently. The photo-isomerization rate constant of the DMSO solution of DBA at 299K is 5.5 ×10 -3 /s. The structure of the fluorescent group in DBA did not readily influence the isomerization. Upon introducing DBA into the lipid bilayer membranes of a vesicle suspension and irradiating the vesicles with visible light to isomerize the azo group, a morphological change in of the vesicles was observed due to the disturbance of the membrane order. Thus, DBA is a useful molecule for artificial modulation of the lipid membrane morphology.

Background/aim: We aimed to evaluate pancreatic cancer (PC) with positive peritoneal lavage cytology (CY1) outcomes following a change in adjuvant therapy., Patients and Methods: The clinicopathological data of patients with pancreatic adenocarcinoma with CY1 at 14 institutions, between 2007 and 2015, were collected and analyzed., Results: Of the 124 eligible patients, 114 underwent macroscopically curative resection. Of the 114 patients, 80 (70%) did not have early recurrence and received postoperative chemotherapy that was S-1 in 43 (54%), gemcitabine in 31 (39%), and others in six (7%). The median overall survival was 21.0 months in S-1 and 19.2 in gemcitabine therapy (p=0.23), whereas the median relapse-free survival was 10.2 and 7.1 months (p=0.03), respectively., Conclusion: Following the change in adjuvant therapy, most PC patients with CY1 who underwent macroscopically curative resection received S-1; however, it was insufficient. Further development of postoperative chemotherapy is required., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

In the FUGA-BT trial (JCOG1113), gemcitabine plus S-1 (GS) showed non-inferiority to gemcitabine plus cisplatin (GC) in overall survival (OS) with good tolerance for patients with advanced biliary tract cancer (BTC). We performed a subgroup analysis focused on the elderly cohort of this trial. All 354 enrolled patients in JCOG1113 were classify into two groups; < 75 (non-elderly) and ≥ 75 years (elderly) group. We investigated the influence of age on the safety analysis, including the incidence of chemotherapeutic adverse events and the efficacy analysis, including OS. There were no remarkable differences in OS between the elderly (n = 60) and the non-elderly groups (n = 294). In the elderly group, median OS was 12.7 and 17.7 months for those who received GC (n = 20) and GS (n = 40), respectively. The prevalence of all-grade adverse events was similar between the elderly and the non-elderly groups. However, among the elderly group, Grade ≥ 3 hematological adverse events were more frequently observed in the GC arm than in the GS arm. The clinical outcomes of combination chemotherapy in elderly patients with advanced BTC were comparable to non-elderly patients. GS may be the more favorable treatment for elderly patients with advanced BTC., (© 2022. The Author(s).)

Objective: The treatment result of the uncovered metallic stent (uncovered MS) and covered metallic stent (covered MS) for unresectable malignant distal biliary obstruction is controversial. This time, we conducted this study to compare the efficacies and complication rates of uncovered MS and covered MS in unresectable malignant distal biliary obstructions at a prospective randomized multicenter trial., Materials and Methods: From April 2014 to September 2018, patients with unresectable malignant distal biliary obstruction were randomly assigned to 2 groups: the uncovered MS group and the covered MS group., Results: 92 treatment results patients were discussed. 48 patients were assigned to the uncovered MS group and 44 cases were assigned to the covered MS group. Both groups showed a drainage effect. No significant difference was found in the drainage effect between the 2 groups. The number of stent occlusion was significantly greater ( p  = .0467) in uncovered MS (43.8%) comparing with those in covered MS (22.7%). As the cause of stent occlusion, tumor ingrowth was significantly greater ( p  < .001) in the uncovered MS group (35.4%) than in the covered MS group (2.3%). The median stent patency period was significantly longer ( p  = .0112) in the covered MS group (455 days) than that of the uncovered MS group (301 days). A significant difference in the median survival period was not found between the 2 groups., Conclusions: Covered MS showed the possibility of extending the stent patency period by suppressing tumor ingrowth more than uncovered MS does. The UMIN Clinical Trial Registry number is UMIN000015093.

JCOG1113 is a randomized phase III trial in patients with advanced biliary tract cancers (BTCs) (UMIN000001685), and gemcitabine plus S-1 (GS) was not inferior to gemcitabine plus cisplatin (GC). However, poor renal function often results in high toxicity of S-1. Therefore, we examined whether GS can be recommended for patients with low creatinine clearance (CCr). Renal function was classified by CCr as calculated by the Cockcroft-Gault formula: high CCr (CCr ≥ 80 ml/min) and low CCr (80 > CCr ≥ 50 ml/min). Of 354 patients, 87 patients on GC and 91 on GS were included in the low CCr group, while there were 88 patients on GC and 88 patients on GS in the high CCr group. The HR of overall survival for GS compared with GC was 0.687 (95% CI 0.504-0.937) in the low CCr group. Although the total number of incidences of all Grade 3-4 non-haematological adverse reactions was higher (36.0% vs. 11.8%, p = 0.0002), the number of patients who discontinued treatment was not different (14.1% vs. 16.9%, p = 0.679) for GS compared with GC in the low CCr group. This study suggests that GS should be selected for the treatment of advanced BTC patients with reduced renal function.

Background: Undifferentiated carcinoma (UC) of the pancreas has been considered a highly aggressive malignancy. However, only a few studies have systematically described the clinical course of UC patients. The aim of this study was to clarify the prognosis and construct a prognostic model for patients with unresectable UC., Methods: This study was conducted at 17 institutions in Japan, and a total of 55 patients were analyzed., Results: The median overall survival (OS) of patients with unresectable UC was 3.95 months. In the multivariate Cox proportional hazards (CPH) model, age ≥65 years, Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2, and C-reactive protein (CRP) >10 mg/L were independent prognostic factors for OS (age ≥65 years: hazard ratio [HR], 2.732; 95% confidence interval [CI], 1.353-5.515; ECOG PS ≥ 2: HR, 7.866; 95% CI, 1.981-31.241; CRP >10 mg/L: HR, 1.956; 95% CI, 1.013-3.775). Based on the β coefficients from the CPH model, the prognostic scores were defined as follows: age ≥65 years (3 points), ECOG PS ≥ 2 (6 points), and CRP >10 ml/L (2 points). The final prognostic model was the sum of the points. The derived prognostic model stratified patients into high-risk (score ≥4) and low-risk (score 0-3) groups, with significant differences in OS (1.45 vs. 8.19 months, respectively; p < 0.001)., Conclusions: The prognostic model stratified patients into high-risk and low-risk groups. These findings suggest that this model can serve as a tool for patient information and decision-making with regard to the therapeutic strategy for UC., Competing Interests: Declaration of competing interest Hiroshi Imaoka has received research funding from Ono Pharmaceutical; honoraria from Yakult Honsha, AstraZeneca, and Nihon Servier; and is a member of advisory board for Nihon Servier. Masafumi Ikeda has received research funding from Yakult Honsha, Ono Pharmaceutical, Bristol-Myers Squibb, NanoCarrier, Novartis, Bayer, Eisai, Eli Lilly Japan, MSD, Chugai Pharma, AstraZeneca, J-Pharma, Pfizer, ASLAN Pharmaceuticals, Merck Serono, and Takeda; honoraria from Taiho Pharmaceutical, Yakult Honsha, Novartis, Bayer, Eisai, Eli Lilly Japan, Sumitomo Dainippon Pharma, Teijin Pharma, MSD, Mylan, Chugai Pharma, Astellas Pharma, EA Pharma, Gilead, Otsuka, and Nihon Servier; and is a member of advisory board for Nihon Servier, Novartis, Bayer, Eisai, Eli Lilly Japan, Chugai Pharma, AstraZeneca, Shire, ASLAN Pharmaceuticals, and NanoCarrier. Satoshi Kobayashi has received research funding from Taiho Pharmaceutical, and Yakult Honsha; honoraria from Taiho Pharmaceutical, Kyowa Hakko Kirin, Bayer, Teijin Pharma, and Eisai. Makoto Ueno has received research funding from Taiho Pharmaceutical, Yakult Honsha, AstraZeneca, Merck Serono, MSD, Daiichi Sankyo, Astellas Pharma, Eisai, Ono Pharmaceutical, Sumitomo Dainippon Pharma, Incyte, and ASLAN Pharmaceuticals; honoraria from Taiho Pharmaceutical, Yakult Honsha, AstraZeneca, Merck Serono, Nipro Corporation, MSD, and Daiichi Sankyo. Chikusa Morizane has received research funding from Ono Pharmaceutical, Yakult Honsha, Eisai, J-Pharma, AstraZeneca, Merck Serono, and Taiho Pharmaceutical; and honoraria from Yakult Honsha, Eisai, MSD, Teijin Pharma, Taiho Pharmaceutical, and Novartis; and is a member of advisory board for Yakult Honsha, MSD, J-Pharma, AstraZeneca, Teijin Pharma, Taiho Pharmaceutical, and Novartis. Junji Furuse has received research funding from Ono Pharmaceutical, MSD, Sumitomo Dainippon Pharma, J-Pharma, Yakult Honsha, AstraZeneca, Daiichi Sankyo, Eisai, Bayer, Pfizer, NanoCarrier, Kyowa Hakko Kirin, Taiho Pharmaceutical, Chugai Pharma, Sanofi, Takeda, Mochida Pharmaceutical, Astellas Pharma, and Eli Lilly Japan; and honoraria from Eisai, Bayer, Taiho Pharmaceutical, Ono Pharmaceutical, Novartis, Yakult Honsha, Teijin Pharma, Shionogi, EA Pharma, Eli Lilly Japan, Takeda, Chugai Pharma, Mochida Pharmaceutical, Nihon Servier, Sanofi, Fujifilm Toyama Chemical, Nobel pharma, Pfizer, Sawai Pharmaceutical, Daiichi Sankyo, Sumitomo Dainippon Pharma, Merck Serono, Nippon Kayaku, MSD, Shire, and Kyowa Hakko Kirin. The other authors have no conflict of interest., (Copyright © 2021 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Background: UGT1A1 *28 and *6 polymorphism is associated with reduced enzyme activity and severe toxicities of irinotecan, especially in patients with homozygous or heterozygous for UGT1A1*28 or *6 polymorphism for both UGT1A1*28 and *6 (double-variant-type of UGT1A1 polymorphism, UGT1A1-DV). FOLFIRINOX is one of the standard treatments for metastatic pancreatic cancer (PC). The optimal dose of irinotecan as a component of the FOLFIRINOX has not been established yet for patients with UGT1A1-DV., Patients and Methods: Advanced PC patients with UGT1A1-DV who had received at least one cycle of FOLFIRINOX from December 2013 to March 2016 were collected retrospectively conducted at multicenter in Japan. We evaluated the patient characteristics, efficacy and safety of FOLFIRINOX and investigate the optimal initial dose of irinotecan in Japanese advanced PC patients with UGT1A1-DV., Results: A total of 31 patients were enrolled. Grade 4 neutropenia was seen more frequently (67%; 4/6) in patients who had received irinotecan at an initial dose of  ≥ 150 mg/m 2 than in those who had received the drug at an initial dose of  ≤ 120 mg/m 2 (20%; 5/24). The response rate (RR) and progression-free survival (PFS) in patients given irinotecan of  ≤ 120 mg/m 2 were 21.4% and 8.1 months, respectively, which were consistent with previous report for patients without UGT1A1-DV., Conclusion: Based on our findings, we recommend that in Japanese advanced PC patients with UGT1A1- DV treated with FOLFIRINOX, irinotecan be administered at an initial dose of  ≤ 120 mg/m 2 .