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The KEAP1-NRF2 system induces the expression of antioxidant genes in response to various types of oxidative stress. Some cancer cells activate this system, which increases their malignancy through genetic mutations. We performed a retrospective cohort study using the C-CAT database, which contains the gene-panel sequence data from 60,056 cases of diagnosed solid tumors. We analyzed somatic mutations in NRF2 and KEAP1 genes and their associations with clinical outcomes. Variants in the NRF2 gene were clustered in exon 2, which encodes the DLG and ETGE motifs essential for KEAP1 interaction. The NRF2 variants were frequently observed in esophageal and lung squamous cell carcinoma with frequencies of 35.9% and 19.6%, respectively. Among these mutations, the NRF2 variants in the ETGE motif were indicators of a worse prognosis. KEAP1 variants were found in 2.5% of all cases. The variants were frequent in lung cancer and showed a worse prognosis in lung and other types of adenocarcinomas. We then conducted gene expression analysis using TCGA data. While cancers with DLG and ETGE variants were similar in terms of gene expression profiles, there were significant differences between cancers with KEAP1 and NRF2 variants. Our results indicate that genetic alteration of the KEAP1-NRF2 pathway is a major factor in patient prognosis for each cancer type and its genetic variant. Variants in NRF2 and KEAP1 genes can characterize the biological basis of each cancer type and are involved in carcinogenesis, resistance to therapy, and other biological differences., (© 2024 The Author(s). Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

In this study, we determined the temperature-dependent viscosities, glass transition temperatures, and fragilities of tetraalkylphosphonium docusate ionic liquids (ILs) and their equimolar mixtures with alkanes to elucidate the effects of the alkyl groups on the phosphonium cation. The target ILs were the docusate salts with tributylheptylphosphonium ([P 4447 ][doc]), tributyltetradecylphosphonium ([P 444,14 ][doc]), butyltrihexylphosphonium ([P 4666 ][doc]), trihexylheptylphosphonium ([P 6667 ][doc]), and trihexyltetradecylphosphonium cations ([P 666,14 ][doc]). The comparable IL/alkane mixtures were equimolar mixtures of IL and alkane with the same carbon numbers of the target ILs: [P 4447 ][doc]/hexane to [P 6667 ][doc]; [P 4447 ][doc]/heptane to [P 444,14 ][doc]; [P 444,14 ][doc]/hexane to [P 666,14 ][doc]; [P 4666 ][doc]/decane to [P 666,14 ][doc]; and [P 6667 ][doc]/heptane to [P 666,14 ][doc]. The viscosities and glass transition temperatures of the neat ILs were higher than those of their respective IL/alkane mixtures. Based on the analysis of temperature-dependent viscosities, including a viscosity value of 10 13 mPa·s at the glass transition temperature using the Vogel-Fulcher-Tammann equation, the neat ILs were stronger liquids than the corresponding IL/alkane mixtures. By comparing several combinations of the neat ILs and IL/alkane mixtures, we found that the larger the alkane, the more fragile the mixture., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Objective Many vascular endothelial growth factor (VEGF) pathway inhibitors are used in the treatment of patients with various advanced cancers; however, treatments induce cardiovascular adverse events (CVAEs), such as hypertension, heart failure, arrhythmia, arterial or venous embolism, and hemorrhage. Some studies have suggested a correlation between efficacy and CVAEs; however, further evidence is required. This study evaluated real-world data concerning the frequency and degree of CVAEs and possible associations between CVAEs and efficacy in such patients. Methods and Patients We analyzed CVAEs observed in 294 patients with advanced cancer who were treated with ramucirumab, regorafenib, pazopanib, sunitinib, or sorafenib. Results CVAEs of any grade and proteinuria within 8 weeks after the initiation of VEGF pathway inhibitors (early) or during the treatment period (total period) were observed in 72%-85% and 77%-92% of the patients, respectively. The progression-free survival (PFS) of patients with a CVAE of grade ≥1 in the early period was favorable compared with the PFS of those who had no CVAE (median, 4.9 vs. 3.5 months, P = 0.016, log-rank test). Furthermore, the PFS of patients with a CVAE grade ≥3 in the early period was favorable compared to that of those with CVAEs of grades 0-2. Taken together, a higher degree of CVAE was correlated with favorable patient outcomes. Conclusion This study revealed the frequency and degree of CVAEs in patients with solid cancers who received VEGF pathway inhibitors in a real-world setting and added evidence regarding the correlation between CVAEs and efficacy of VEGF pathway inhibitors.

Purpose: The genome-wide DNA methylation status (GWMS) predicts of therapeutic response to anti-epidermal growth factor receptor (EGFR) antibodies in treating metastatic colorectal cancer. We verified the significance of GWMS as a predictive factor for the efficacy of anti-EGFR antibodies in the second-line treatment of metastatic colorectal cancer., Methods: Clinical data were obtained from a prospective trial database, and a genome-wide DNA methylation analysis was performed. GWMS was classified into high-methylated colorectal cancer (HMCC) and low-methylated colorectal cancer (LMCC). The patients were divided into subgroups according to the treatment arm (cetuximab plus irinotecan or irinotecan alone) and GWMS, and the clinical outcomes were compared between the subgroups., Results: Of the 112 patients, 58 (51.8%) were in the cetuximab plus irinotecan arm, and 54 (48.2%) were in the irinotecan arm; 47 (42.0%) were in the HMCC, and 65 (58.0%) were in the LMCC group regarding GWMS. Compared with the LMCC group, the progression-free survival (PFS) was significantly shortened in the HMCC group in the cetuximab plus irinotecan arm (median 1.4 vs. 4.1 months, p = 0.001, hazard ratio = 2.56), whereas no significant differences were observed in the irinotecan arm. A multivariate analysis showed that GWMS was an independent predictor of PFS and overall survival (OS) in the cetuximab plus irinotecan arm (p = 0.002, p = 0.005, respectively), whereas GWMS did not contribute to either PFS or OS in the irinotecan arm., Conclusions: GWMS was a predictive factor for the efficacy of anti-EGFR antibodies in the second-line treatment of metastatic colorectal cancer., (© 2024. The Author(s).)

In this study, we investigated the water concentration dependence of the intermolecular vibrations of two hydrated ionic liquids (ILs), cholinium dihydrogen phosphate ([ch][dhp]) and cholinium bromide ([ch]Br), using femtosecond Raman-induced Kerr effect spectroscopy (fs-RIKES). The anions of the former and latter hydrated ILs are kosmotropic and chaotropic, respectively. We found that the spectral peak of ∼50 cm -1 shifted to the low-frequency side in hydrated [ch][dhp], indicating the weakening of its intermolecular interactions. In contrast, no change in the peak frequency of the low-frequency band at ∼50 cm -1 was observed with increasing water concentration in hydrated [ch]Br. The vibrational density of states (VDOS) spectra generated from molecular dynamics (MD) simulations were in qualitative agreement with the experimental results. Decomposition analysis of the VDOS spectra for each component revealed that the red shift of the low-frequency band in the hydrated [ch][dhp] upon water addition was essentially due to the contributions of anions and water rather than that of the cholinium cation. We also found from the low-frequency spectra of the two hydrated ILs that they differed in the concentration dependence of the 180 cm -1 band, which is assigned as a hindered translational motion of water molecules combined to form O···O stretching motions. From the relationship between the peak frequency of the low-frequency band and the bulk parameter, which is the square root of the surface tension divided by the density, we found that the peak frequency in the hydrated IL with kosmotropic [dhp] - depends on the bulk parameter, similar to the case for an aqueous solution of the typical deep eutectic solvent reline. However, the peak frequency of the hydrated IL with chaotropic Br - is constant with the bulk parameter.

In Japan, comprehensive genomic profiling (CGP) tests have been reimbursed under the national health care system for solid cancer patients who have finished standard treatment. More than 50,000 patients have taken the test since June 2019. We performed a nation-wide questionnaire survey between March 2021 and July 2022. Questionnaires were sent to 80 designated Cancer Genomic Medicine Hospitals. Of the 933 responses received, 370 (39.7%) were web based and 563 (60.3%) were paper based. Most patients (784, 84%) first learned about CGP tests from healthcare professionals, and 775 (83.1%) gave informed consent to their treating physician. At the time of informed consent, they were most worried about test results not leading to novel treatment (536, 57.4%). On a scale of 0-10, 702 respondents (75.2%) felt that the explanations of the test result were easy to understand (7 or higher). Ninety-one patients (9.8%) started their recommended treatment. Many patients could not receive recommended treatment because no approved drugs or clinical trials were available (102/177, 57.6%). Ninety-eight patients (10.5%) did not wish their findings to be disclosed. Overall satisfaction with the CGP test process was high, with 602 respondents (64.5%) giving a score of 7-10. The major reason for choosing 0-6 was that the CGP test result did not lead to new treatment (217/277, 78.3%). In conclusion, satisfaction with the CGP test process was high. Patients and family members need better access to information. More patients need to be treated with genomically matched therapy., (© 2024 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: BRAF V600 mutations are common in melanoma, thyroid, and non-small-cell lung cancers. Despite dabrafenib and trametinib being standard treatments for certain cancers, their efficacy across various solid tumours remains unelucidated. The BELIEVE trial assessed the efficacy of dabrafenib and trametinib in solid tumours with BRAF V600E/R or non-V600 BRAF mutations., Methods: Between October 1, 2019, and June 2022, at least 50 patients with measurable and seven without measurable diseases examined were enrolled in a subcohort of the BELIEVE trial (NCCH1901, jRCTs031190104). BRAF mutated solid tumour cases other than BRAF V600E mutated colorectal cancer, melanoma, and non-small cell lung cancer cases were included. Patients with solid tumours received dabrafenib (150 mg) twice daily and trametinib (2 mg) once daily until disease progression or intolerable toxicity was observed. The primary endpoint was overall response rate (ORR), and secondary endpoints included progression-free survival (PFS), 6-month PFS, and overall survival (OS). Bayesian analysis was performed using a prior distribution with a 30% expected response rate [Beta (0.6, 1.4)]., Findings: Fourty-seven patients with measurable disease, mainly with the BRAF V600E mutation (94%), and three others with non-V600E BRAF mutations (V600R, G466A, and N486_P490del) were enrolled. The primary sites included the thyroid gland, central nervous system, liver, bile ducts, colorectum, and pancreas. The confirmed ORR was 28.0%; the expected value of posterior distribution [Beta (14.6, 37.4)] was 28.1%, although the primary endpoint was achieved, not exceeding an unexpectedly high response rate of 60% obtained using Bayesian analysis. The disease control rate (DCR) was 84.0%. The median PFS was 6.5 months (95% confidence interval [CI]; 4.2-7.2 months, 87.8% at 6 months). Responses were observed across seven tumour types. Median OS was 9.7 months (95% CI, 7.5-12.2 months). Additional patients without measurable diseases had a median PFS of 4.5 months. Adverse events (AEs) were consistent with previous reports, with 45.6% of patients experiencing grade ≥3 AEs., Interpretation: This study reported promising efficacy against BRAF V600-mutant tumours. Dabrafenib and trametinib would offer a new therapeutic option for rare cancers, such as high-grade gliomas, biliary tract cancer, and thyroid cancer., Funding: This study was funded by the Japan Agency for Medical Research and Development (22ck0106622h0003) and a Health and Labour Sciences Research Grant (19EA1008)., Competing Interests: Dr. Tahara reports personal fees from Novartis, during the conduct of the study; grants and personal fees from Ono Pharmaceutical, grants and personal fees from Bayer, personal fees from MSD, personal fees from BMS, personal fees from Merck Biopharma, personal fees from Pfizer, personal fees from Rakuten Medical, personal fees from Lilly, personal fees from Boehringer Ingelheim, personal fees from Eisai, personal fees from Chugai Pharmaceutical, personal fees from Daiichi-Sankyo, personal fees from Janssen Pharmaceutical, personal fees from Genmab, personal fees from Astra Zeneca, personal fees from Abbvie, personal fees from Astellas, outside the submitted work. Dr. Yamamoto reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Ono Pharmaceutical, Chugai, Daiichi-Sankyo, Eisai, Payment for expert testimony from Eisai, Takeda, Boehringer Ingelheim, Cimic, Chugai, Other financial or non-financial interests from Astellas, Chugai, Eisai, Taiho, BMS, Pfizer, Novartis, Eli Lilly, AbbVie, Daiichi-Sankyo, Bayer, Boehringer Ingelheim, Kyowa-Hakko Kirin, Takeda, ONO, Janssen Pharma, MSD, MERCK, GSK, Sumitomo Dainippon, Chiome Bioscience, Otsuka, Carna Biosciences, Genmab, Shionogi, TORAY, KAKEN, InventisBio, Rakuten Medical., (© 2024 The Author(s).)

Introduction: Patients with the head and neck squamous cell carcinoma (SCC) are often treated with immune checkpoint inhibitors (ICIs). Recently, antibiotic intake was reported to lower the efficacy of ICIs in patients with several types of cancers. However, it is unclear if antibiotics affect the efficacy of ICIs in patients with head and neck SCC. We retrospectively assessed the influence of antibiotics on the treatment efficacy of nivolumab, an ICI, in patients with head and neck SCC., Methods: We reviewed the medical records of patients with head and neck SCC treated with nivolumab at the Department of Medical Oncology, Tohoku University Hospital, between 2017 and 2021. Patients who received oral or intravenous antibiotics from a month before the day of nivolumab initiation to the day of the first imaging evaluation of ICI efficacy were assigned to the antibiotic-treated group. The remaining patients were assigned to the antibiotic-untreated group. The response rate (RR), progression-free survival (PFS), and overall survival time (OS) of both groups were compared., Results: Forty-five patients were assigned to the antibiotic-treated group and 19 to the antibiotic-untreated group. The RR, median PFS, and median OS of the antibiotic-treated group were 23.7%, 3.2 months (95% confidential interval [CI]: 2.0-4.1), and 8.4 months (95% CI: 5.3-15.1) and those of the antibiotic-untreated group were 42.1%, 5.8 months (95% CI: 2.3-16.7), and 18.4 months (95% CI: 6.2-23.1), respectively. The PFS of the antibiotic-untreated group was significantly longer than that of the antibiotic-treated group., Conclusion: Our findings indicate that antibiotic treatment significantly shortens the PFS with nivolumab therapy in patients with head and neck SCC., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Introduction: Neuroendocrine carcinoma (NEC) is characterized by a poor prognosis and is generally treated with platinum and etoposide combination therapy as first-line chemotherapy. However, it remains uncertain whether carboplatin and etoposide combination therapy (CE) and cisplatin and etoposide combination therapy (PE) have comparable treatment efficacy. In this retrospective analysis, we compared the efficacy and safety of CE and PE in patients with NEC., Methods: We retrospectively reviewed the patient's clinical record from 2005 to 2022 at the Department of Medical Oncology, Tohoku University Hospital. Patients who received either CE or PE were included in the study. Statistical analyses were performed using JMP Pro 16.0 (SAS Institute Inc., Cary, NC, USA)., Results: A total of 104 patients were enrolled, with 73 patients assigned to the CE group and 31 patients assigned to the PE group. Statistically, the response rate, progression-free survival time and overall survival time were 42.6%, 5.1 months (95% CI: 3.5-6.3) and 13.6 months (95% CI: 8.9-17.4), respectively, in the CE groups and 44.4%, 5.6 months (95% CI: 3.1-7.0) and 12.5 months (95% CI: 11.2-14.6), respectively, in the PE groups. There was no significant difference in treatment efficacy between the CE and the PE groups. However, the number of patients with elevated creatinine (3.35 mg/dL and 3.88 mg/dL in 2 patients, respectively) was significantly higher in the PE group than in the CE group., Conclusion: The efficacy of CE and PE in patients with NEC is comparable. However, the incidence of renal dysfunction was found to be significantly higher in the PE group than in the CE group., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Background/aim: Urachal carcinoma is a rare cancer, with limited evidence regarding systemic chemotherapy for metastatic urachal carcinoma. This study aimed to evaluate the efficacy and safety of a combination therapy of 5-fluorouracil and irinotecan (FOLFIRI) in patients with metastatic urachal carcinoma., Patients and Methods: Patients with metastatic urachal carcinoma treated with FOLFIRI between March 2008 and April 2023 at the Department of Medical Oncology, Tohoku University Hospital, were retrospectively analyzed using medical records., Results: Six patients with urachal carcinoma received FOLFIRI. The histological type was adenocarcinoma in all patients. The metastatic or recurrent sites were the peritoneum, lungs, lymph nodes, and local relapse sites. Three patients received FOLFIRI as first-line chemotherapy, and the other three received FOLFIRI as second-line chemotherapy. Two patients had only non-measurable lesions as the targets of tumor response. The best response was the stable disease or non-complete response/non-progressive disease in four patients, with a disease control rate of 67%. The median progression-free survival was 7.5 months. In two patients with ascites only as the site of metastasis, the amount of ascites and serum tumor marker levels decreased after FOLFIRI was initiated. Grade 3/4 toxicities included grade 3 neutropenia in one patient and grade 3 diarrhea in one patient., Conclusion: FOLFIRI has modest efficacy and good tolerability for the treatment of metastatic urachal carcinoma., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Neither TP53 mutation nor DNA methylation status has been established as a biomarker alone of metastatic colorectal cancer. We analyzed the association between TP53 mutation functional subtypes and genome-wide DNA methylation status (GWMS) as combined prognostic markers., Methods: Patient clinical data were obtained from the TRICOLORE study, a randomized phase III trial. The TP53 mutations were classified into wild-type, gain-of-function (GOF) mutations, and non-gain-of-function (non-GOF) mutations. GWMS of the tumor tissues classified them into high-methylated colorectal cancer (HMCC) and low-methylated colorectal cancer (LMCC). Overall survival (OS) was compared based on these subgroups., Results: Of the 209 patients, 60 (28.7%) were HMCC and 149 (71.3%) were LMCC, 35 (16.7%) were TP53 wild-type and 174 (83.3%) were TP53 mutants including 79 (45.4%) GOF mutations and 95 (54.6%) non-GOF mutations. The OS of the HMCC group was shorter than that of the LMCC group (median 25.3 vs. 40.3 months, P < .001, hazard ratio 1.87) in the total cohort. The combined subgroup analyses of GWMS and TP53 mutation subtypes showed that the HMCC/GOF group had significantly shorter OS than the HMCC/non-GOF group, the LMCC/GOF group, and the LMCC/non-GOF group (median 17.7; 35.3, 40.3, and 41.2 months, P = .007, P < .001, and P < .001, respectively), regardless of the primary tumor location. By the multivariate analysis, only HMCC (P = .009) was a poor prognostic factor in the GOF mutation group., Conclusions: TP53 GOF with HMCC is a newly identified poorest prognostic molecular subset in metastatic colorectal cancer., Competing Interests: Disclosure Dr. Kota Ouchi reports honoraria from Taiho, Lilly, Asahi Kasei, and Merck, outside the submitted work; Dr. Shin Takahashi reports honoraria from Taiho, Asahi Kasei, Daiichi Sankyo, Chugai Pharma, Yakult, Merck, Ono, and Bristol-Myers Squibb, and research funding from Merck and Ono, outside the submitted work; Prof. Yasuhide Yamada reports honoraria from Taiho, Ono, and Boehringer Ingelheim, and research funding from Chugai, outside the submitted work; Prof. Yoshito Komatsu reports honoraria from Lilly, Taiho, Chugai Pharma, Takeda, Bayer, Bristol-Myers Squibb, Sanofi, Merck, Yakult, Ono, Nipro Corporation, Moroo Co, Asahi Kasei, Mitsubishi Tanabe Pharma, Otsuka, Medical Review Co, and Daiichi Sankyo, and research funding from Merck Sharp & Dohme, Taiho, Yakult, Bayer, Daiichi Sankyo, Ono, NanoCarrier, Sanofi, Sysmex, Shionogi, IQVIA, PAREXEL, Astellas, Mediscience Planning, Sumitomo Dainippon Pharma, A2 Healthcare, Incyte, Lilly, Nipro Corporation, and BeiGene, outside the submitted work; Dr. Ken Shimada reports research funding from Taiho and Chugai Pharma, outside the submitted work; Dr. Tatsuro Yamaguchi reports honoraria from Chugai Pharma, outside the submitted work; Dr. Masanobu Takahashi reports speaker's bureau from Taiho, Bristol-Myers Squibb, and Ono, and research funding from Chugai Pharma and Ono, outside the submitted work; Prof. Ishioka reports honoraria from Daiichi Sankyo, Ono, Taiho, Chugai Pharma, Sanofi, Nippon Kayaku, Takeda, Kyowa Kirin International, Asahi Kasei, Shionogi, Lilly, Otsuka, Yakult, and Tsumura & Co, and research funding from Chugai Pharma, Taiho, Takeda, Yakult, Daiichi Sankyo, Asahi Kasei, Nippon Kayaku, Ono, Kyowa Kirin, Tsumura & Co, Bayer, Shionogi, Otsuka, Sanofi, Lilly, Hitachi and Riken Genesis, outside the submitted work. All remaining authors have declared no conflict of interest., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

This study particularly compares the surface tensions and contact angles for molten bis(fluorosulfonyl)amide salts of imidazolium, ammonium, and phosphonium cations with the pentyl, ethoxyethyl, or ethylthioethyl group. The examined substrate plates for contact angle measurements include silicate glass, platinum, copper, graphene, and polytetrafluoroethylene (PTFE). In addition, quantum chemistry calculations were performed to obtain the optimized structures of the cations and anions of the ionic liquids (ILs) that were studied here along with some typical anions and their dipole moments, mean polarizabilities, and charge distributions. All ILs showed the same order of contact angles with respect to the substrates: PTFE > graphene ≈ copper ≈ platinum > silicate glass. By comparing the three functional groups, i.e., pentyl, ethoxyethyl, and ethylthioethyl, the ILs with the ethylthioethyl group featured a higher work of adhesion than the respective ILs with the pentyl or ethoxyethyl group. The values of the surface tensions of the ILs followed the same trend for the three functional groups. Based on the Fowkes theory, it was found that the larger surface tensions of the ILs with the ethylthioethyl group compared with pentyl and ethoxyethyl groups were because of the increase in both dispersive and nondispersive components. The quantum chemistry calculations of the ions showed a larger dipole moment and mean polarizability for the cations with the ethylthioethyl group as compared with the pentyl and ethoxyethyl groups. This is consistent with the analysis results of the surface tensions based on the Fowkes theory. By comparing other anions, the dispersive component of the surface tension of the ILs with bis(fluorosulfonyl)amide was large, which is attributed to the small dipole moment of the anion.

Background: Pembrolizumab-containing regimens are standards of care for recurrent and metastatic head and neck squamous cell carcinoma (R/M HNSCC). The depth of response (DpR) predicts the survival of patients with several types of solid cancers; however, its association with the survival outcomes of patients with R/M HNSCC treated with pembrolizumab-containing regimens remains unclear., Methods: This study included 66 patients with R/M HNSCC who received a pemblolizumab-containing regimen as a first-line therapy at Tohoku University Hospital, Sendai, Japan. The patients' characteristics, combined positive score, baseline tumor size, tumor response, DpR, overall survival (OS), progression-free survival (PFS), PFS2, and adverse events were reviewed. The associations between DpR and survival outcomes were analyzed., Results: The 1 year-OS and 1 year-PFS rates of pembrolizumab-containing regimens were 69.4% and 24.4%, respectively. The response rate was 28.8%. The mean and median values of tumor change from baseline were 5.1% and -9.0%. In the correlation analysis, a significant negative correlation was observed between tumor change rate from baseline and survival outcomes (OS: r= -0.41, p=0.0017; PFS: r=-0.49, p<0.001). In the multivariate analysis, DpR with tumor change of ≤-45 was associated with better OS and PFS., Conclusion: DpR induced by pembrolizumab-containing regimens may be a predictive factor for OS and PFS in patients with R/M HNSCC., Competing Interests: KSai received research funding from Eisai and Adlai Nortye. MT received research funding from MSD, Ono pharmaceutical, Chugai Pharmaceutical, Merck pharmaceutical, and Boehringer Ingelheim. CI was funded by the Tokyo Cooperative Oncology Group and obtained financial support from Chugai Pharmaceutical, Taiho Pharmaceutical, Daiichi Sankyo Company, Asahi Kasei Pharma, Bayer Yakuhin, Nippon Kayaku, and Takeda Pharmaceutical; CI is a representative of the Tohoku Clinical Oncology Research and Education Society, a specified nonprofit corporation. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Saijo, Imai, Ouchi, Sasaki, Yoshida, Kawamura, Taniguchi, Kasahara, Komine, Shirota, Takahashi and Ishioka.)

Immune cells can recognize tumor-associated antigens released from dead tumor cells, which elicit immune responses, potentially resulting in tumor regression. Tumor cell death induced by chemotherapy has also been reported to activate immunity. However, various studies have reported drug-induced immunosuppression or suppression of inflammation by apoptotic cells. Thus, this study aimed to investigate whether apoptotic tumor cells trigger antitumor immunity independent of anticancer treatment. Local immune responses were evaluated after direct induction of tumor cell apoptosis using a Herpes simplex virus thymidine kinase/ganciclovir (HSV-tk/GCV) system. The inflammatory response was significantly altered at the tumor site after apoptosis induction. The expression of cytokines and molecules that activate and suppress inflammation simultaneously increased. The HSV-tk/GCV-induced tumor cell apoptosis resulted in tumor growth suppression and promoted T lymphocyte infiltration into tumors. Therefore, the role of T cells after inducing tumor cell death was explored. CD8 T cell depletion abrogated the antitumor efficacy of apoptosis induction, indicating that tumor regression was mainly dependent on CD8 T cells. Furthermore, CD4 T cell depletion inhibited tumor growth, suggesting the potential role of CD4 T cells in suppressive tumor immunity. Tumor tissues were evaluated after tumor cell apoptosis and CD4 T cell depletion to elucidate this immunological mechanism. Foxp3 and CTLA4, regulatory T-cell markers, decreased. Furthermore, arginase 1, an immune-suppressive mediator induced by myeloid cells, was significantly downregulated. These findings indicate that tumors accelerate CD8 T cell-dependent antitumor immunity and CD4 T cell-mediated suppressive immunity. These findings could be a therapeutic target for immunotherapy in combination with cytotoxic chemotherapy., (© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Ionic liquid viscosity is one of the most important properties to consider for practical applications. Yet, the connection between local structure and viscosity remains an open question. This article explores the structural origin of differences in the viscosity and viscoelastic relaxation across several ionic liquids, including cations with alkyl, ether, and thioether tails, of the imidazolium and pyrrolidinium families coupled with the NTf 2 - anion. In all cases, for the systems studied here, we find that pyrrolidinium-based ions are "harder" than their imidazolium-based counterparts. We make a connection between the chemical concept of hardness vs softness and specific structural and structural dynamic quantities that can be derived from scattering experiments and simulations.

Comprehensive genomic profiling (CGP) tests have been nationally reimbursed in Japan since June 2019 under strict restrictions, and over 46,000 patients have taken the test. Core Hospitals and Designated Hospitals host molecular tumor boards, which is more time-consuming than simply participating in them. We sent a questionnaire to government-designated Cancer Genomic Medicine Hospitals, including all 12 Core Hospitals, all 33 Designated Hospitals, and 117 of 188 Cooperative Hospitals. The questionnaire asked how much time physicians and nonphysicians spent on administrative work for cancer genomic medicine. For every CGP test, 7.6 h of administrative work was needed. Physicians spent 2.7 h/patient, while nonphysicians spent 4.9 h/patient. Time spent preparing for molecular tumor boards, called Expert Panels, was the longest, followed by time spent participating in Expert Panels. Assuming an hourly wage of ¥24,000/h for physicians and ¥2800/h for nonphysicians, mean labor cost was ¥78,071/patient. On a monthly basis, more time was spent on administrative work at Core Hospitals compared with Designated Hospitals and Cooperative Hospitals (385 vs. 166 vs. 51 h/month, respectively, p < 0.001). Consequently, labor cost per month was higher at Core Hospitals than at Designated Hospitals and Cooperative Hospitals (¥3,951,854 vs. ¥1,687,167 vs. ¥487,279/month, respectively, p < 0.001). Completing a CGP test for a cancer patient in Japan is associated with significant labor at each hospital, especially at Core Hospitals. Streamlining the exchange of information and simplifying Expert Panels will likely alleviate this burden., (© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Cancer treatment is increasingly evolving toward personalized medicine, which sequences numerous cancer-related genes and identifies therapeutic targets. On the other hand, patients with germline pathogenic variants (GPV) have been identified as secondary findings (SF) and oncologists have been urged to handle them. All SF disclosure considerations for patients are addressed and decided at the molecular tumor boards (MTB) in the facility. In this study, we retrospectively summarized the results of all cases in which comprehensive genomic profiling (CGP) test was conducted at our hospital, and discussed the possibility of presumed germline pathogenic variants (PGPV) at MTB. MTB recommended confirmatory testing for 64 patients. Informed consent was obtained from attending physicians for 53 of them, 30 patients requested testing, and 17 patients tested positive for a confirmatory test. Together with already known variants, 4.5 % of the total confirmed in this cohort. Variants verified in this study were BRCA1 (n = 12), BRCA2 (n = 6), MSH2 (n = 2), MSH6 (n = 2), WT1 (n = 2), TP53, MEN1, CHEK2, MLH1, TSC2, PTEN, RB1, and SMARCB1. There was no difference in the tumor's VAF between confirmed positive and negative cases for variants determined as PGPV by MTB. Current results demonstrate the actual number of cases until confirmatory germline test for patients with PGPV from tumor-only CGP test through the discussion at the MTB. The practical results at this single facility will serve as a guide for the management of the selection and distribution of SF in the genome analysis., (© 2023. The Author(s), under exclusive licence to The Japan Society of Human Genetics.)

The microscopic aspects of 1-methyl-3-octylimidazolium tetrafluoroborate ([MOIm][BF 4 ]) mixtures with formamide (FA), N -methylformamide (NMF), and N , N -dimethylformamide (DMF) were investigated using spectroscopic techniques of femtosecond Raman-induced Kerr effect spectroscopy (fs-RIKES), FT-IR, and NMR. Molecular dynamics simulations and quantum chemistry calculations were also performed. According to fs-RIKES, the first moment of the low-frequency spectrum bands mainly originating from the intermolecular vibrations in the [MOIm][BF 4 ]/FA and [MOIm][BF 4 ]/DMF systems changed gradually with the molecular liquid mole fraction X ML but that in the [MOIm][BF 4 ]/NMF system was constant up to X NMF = 0.7 and then gradually increased in the range of X NMF ≥ 0.7. Excluding the contribution of the 2D hydrogen-bonding network due to the presence of FA in the low-frequency spectrum band, the X ML dependence of the normalized first moment of the low-frequency band in the [MOIm][BF 4 for the three mixtures due to the hydrogen bonds. The imidazolium ring C-H band also showed a similar tendency to the amide C═O band. 4 ]/NMF systems revealed that the normalized first moment did not remarkably change in the range of X ML < 0.7 but drastically increased in X ML ≥ 0.7. FT-IR results indicated that the amide C═O band shifted to the low-frequency side with increasing X ML for the three mixtures due to the hydrogen bonds. The imidazolium ring C-H band also showed a similar tendency to the amide C═O band. 19 F NMR probed the microenvironment of [BF 4 ] - in the mixtures. The [MOIm][BF 4 ]/NMF and [MOIm][BF 4 ]/DMF systems showed an up-field shift of the F atoms of the anion with increasing X ML , and the [MOIm][BF 4 ]/FA system exhibited a down-field shift. Steep changes in the chemical shifts were confirmed in the region of X ML > 0.8. On the basis of the quantum chemistry calculations, the observed chemical shifts with increasing X ML were mainly attributed to the many-body interactions of ions and amides for the [MOIm][BF 4 ]/FA and [MOIm][BF 4 ]/DMF systems. Meanwhile, the long distance between the cation and the anion was due to the high dielectric medium for the [MOIm][BF 4 ]/NMF system, which led to an up-field shift.

Background: A paradigm shift has occurred in cancer chemotherapy from tumor-specific treatment with cytotoxic agents to personalized medicine with molecular-targeted drugs. Thus, it is essential to identify genomic alterations and molecular features to recommend effective targeted molecular medicines regardless of the tumor site. Nevertheless, it takes considerable expertise to identify treatment targets from primary-sequencing data in order to provide drug recommendations. The Molecular Tumor Board (MTB) denotes a platform that integrates clinical and molecular features for clinical decisions., Methods: This study retrospectively analyses all the cases of discussion and decision at the MTB in Tohoku University Hospital and summarizes genetic alterations and treatment recommendations., Results: The MTB discussed 1003 comprehensive genomic profiling (CGP) tests conducted in patients with solid cancer, and the resulting rate of assessing treatment recommendations was approximately 19%. Among hundreds of genes in the CGP test, only 30 genetic alterations or biomarkers were used to make treatment recommendations. The leading biomarkers that led to treatment recommendations were tumor mutational burden-high (TMB-H) (n = 32), ERBB2 amplification (n = 24), BRAF V600E (n = 16), and BRCA1/2 alterations (n = 32). Thyroid cancer accounted for most cancer cases for which treatment recommendation was provided (81.3%), followed by non-small cell lung cancer (42.4%) and urologic cancer (31.3%). The number of tests performed for gastrointestinal cancers was high (n = 359); however, the treatment recommendations for the same were below average (13%)., Conclusion: The results of this study may be used to simplify treatment recommendations from the CGP reports and help select patients for testing, thereby increasing the accuracy of personalized medicine., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

This study compared the physical properties, e.g., glass transition temperature, melting point, viscosity, density, surface tension, and electrical conductivity, and the low-frequency spectra under 200 cm -1 of three synthesized ionic liquids (ILs), triethylpentylphosphonium bis(fluorosulfonyl)amide ([P 2225 ][NF 2 ]), ethoxyethyltriethylphosphonium bis(fluorosulfonyl)amide ([P 222(2O2) ][NF 2 ]), and triethyl[2-(ethylthio)ethyl]phosphonium bis(fluorosulfonyl)amide ([P 222(2S2) ][NF 2 ]), at various temperatures using femtosecond Raman-induced Kerr effect spectroscopy (fs-RIKES) and terahertz time-domain spectroscopy (THz-TDS). The [P 222(2S2) ][NF 2 ] had the highest viscosity and glass transition temperature, whereas the [P 222(2O2) ][NF 2 ] had the lowest. Among the three ILs, the [P 222(2S2) ][NF 2 ] had the highest density and surface tension, and the [P 222(2O2) ][NF 2 ] had the highest electrical conductivity. The RIKES and THz-TDS spectral line shapes for the three ILs varied significantly. For the [P 2225 ][NF 2 ], molecular dynamics simulations successfully reproduced the line shapes of the experimental spectra and indicated that the RIKES spectrum was mainly due to the cation and cross-term and their rotational motions, whereas the THz-TDS spectrum was mainly due to the anion and its translational motion. This shows that it is desirable to utilize both fs-RIKES and THz-TDS methods to reveal molecular motions at the low-frequency domain. The [P 222(2S2) ][NF 2 ] had higher frequency peaks and broader bands in the low-frequency spectra via fs-RIKES and THz-TDS than those for the [P 2225 ][NF 2 ] and [P 222(2O2) ][NF 2 ].

Importance: Quality assurance of molecular tumor boards (MTBs) is crucial in cancer genome medicine., Objective: To evaluate the concordance of recommendations by MTBs and centrally developed consensus treatment recommendations at all 12 leading institutions for cancer genomic medicine in Japan using 50 simulated cases., Design, Setting, and Participants: This was a prospective quality improvement study of 50 simulated cancer cases. Molecular tumor boards from 12 core hospitals independently recommended treatment for 50 cases blinded to the centrally developed consensus treatment recommendations. The study's central committee consisted of representatives from all 12 core hospitals in Japan who selected the 50 simulated cases from The Cancer Genome Atlas database, including frequently observed genomic alterations. The central committee recommended centrally developed consensus treatment. The concordance rate for genomically matched treatments between MTBs and centrally developed consensus treatment recommendations was evaluated. Data analysis was conducted from January 22 to March 3, 2021., Exposures: Simulated cases of cancer., Main Outcomes and Measures: The primary outcome was concordance, defined as the proportion of recommendations by MTBs concordant with centrally developed consensus treatment recommendations. A mixed-effects logistic regression model, adjusted for institutes as a random intercept, was applied. High evidence levels were defined as established biomarkers for which the treatment was ready for routine use in clinical practice, and low evidence levels were defined as biomarkers for genomically matched treatment that were under investigation., Results: The Clinical Practice Guidance for Next-Generation Sequencing in Cancer Diagnosis and Treatment (edition 2.1) was used for evidence-level definition. The mean concordance between MTBs and centrally developed consensus treatment recommendations was 62% (95% CI, 57%-65%). Each MTB concordance varied from 48% to 86%. The concordance rate was higher in the subset of patients with colorectal cancer (100%; 95% CI, 94.0%-100%), ROS1 fusion (100%; 95% CI, 85.5%-100%), and high evidence level A/R (A: 88%; 95% CI, 81.8%-93.0%; R:100%; 95% CI, 92.6%-100%). Conversely, the concordance rate was lower in cases of cervical cancer (11%; 95% CI, 3.1%-26.1%), TP53 mutation (16%; 95% CI, 12.5%-19.9%), and low evidence level C/D/E (C: 30%; 95% CI, 24.7%-35.9%; D: 25%; 95% CI, 5.5%-57.2%; and E: 18%; 95% CI, 13.8%-23.0%). Multivariate analysis showed that evidence level (high [A/R] vs low [C/D/E]: odds ratio, 4.4; 95% CI, 1.8-10.8) and TP53 alteration (yes vs no: odds ratio, 0.06; 95% CI, 0.03-0.10) were significantly associated with concordance., Conclusions and Relevance: The findings of this study suggest that genomically matched treatment recommendations differ among MTBs, particularly in genomic alterations with low evidence levels wherein treatment is being investigated. Sharing information on matched therapy for low evidence levels may be needed to improve the quality of MTBs.

About 4 and a half years have passed since"Cancer Genome Medicine"was first mentioned in the Third Phase of the Basic Plan to Promote Cancer Control Programs that started in October 2017. Currently, cancer genomic medicine is being carried out by the cancer gene panel test, which is covered by public insurance, mainly at the 12 Cancer Genome Medicine Core Center Hospital designated nationwide by the Ministry of Health, Labor, and Welfare in Japan. Cancer genomic medicine has come to be positioned as a standard medical treatment. However, there are various challenges in operating an expert panel that professionally examines the results of the gene panel tests and reports treatment recommendations and secondary findings that suggest hereditary tumors. In addition, there is an urgent need to disseminate and educate healthcare professionals and patients about cancer genomic medicine. In this panel discussion on January 14, 2022, 10 panelists discussed how to solve these issues and the prospects for the future.

Genomic profiling assays was covered by Japanese national health insurance in June 2019, and cancer genome medicine has started. Prior to this, the Ministry of Health, Labor and Welfare designated facilities that can provide cancer genome medicine. The designated facilities are entrusted with the mission to test not only their own patients but also those of local hospitals. Therefore, cooperation among hospitals is necessary, and each hospital is devising its own unique approach. In this section, we will introduce the efforts of Tohoku University Hospital as a core hospital for cancer genome medicine in terms of inter-hospital collaboration.

In this study, we investigated the temperature dependence of intermolecular vibrations and orientational dynamics in the aqueous solutions of imidazole hydrochloride, imidazole, sodium triazolide, and triazole using femtosecond Raman-induced Kerr effect spectroscopy (fs-RIKES) and steady-state Raman spectroscopy. The difference low-frequency Raman spectra under 250 cm -1 of the aqueous solutions relative to the neat water showed that the spectral shoulder in the high-frequency region at 60-100 cm -1 , assigned to the libration of an aromatic ring, was higher in frequency for the imidazolium cation but lower for the triazolide anion than those of the respective neutral aromatics. The results of the ab initio quantum chemistry calculations of the clusters of the aromatics and water molecule(s) were consistent with the experimental spectra of the aqueous solutions. Further, the results of the temperature-dependent experiments showed that the signal intensity in the low-frequency region below 50 cm -1 increased for all solutions with an increase in temperature. In contrast, the spectral density in the high-frequency region above 80 cm -1 exhibited almost no shift for the 1.0 M solutions, while a significant red shift was observed for the 5.0 M solutions. In addition, the temperature-dependent densities, viscosities, and surface tensions were characterized for the aqueous aromatic solutions from 293 to 353 K.

Background/aim: This phase II study assessed the efficacy of capecitabine plus cisplatin in patients with advanced gastric cancer refractory to adjuvant S-1., Patients and Methods: This single-arm, open-label, multicenter, phase II study was conducted by Tohoku Clinical Oncology Research and Education Society (T-CORE) in Japan. Patients aged ≥20 years with advanced HER2-negative gastric cancer that was refractory to S-1 were enrolled. Patients received 80 mg/m 2 cisplatin on day 1 intravenously and 1,000 mg/m 2 capecitabine twice daily from day 1 to day 14, in 3-week cycles. The primary endpoint was progression-free survival (PFS). The threshold overall response rate (ORR) was estimated to be 15%. The secondary endpoints were overall survival (OS), time to treatment failure, ORR, and toxicities., Results: In total, 21 patients were enrolled from seven hospitals. The median patient age was 63 years. Nineteen patients received the protocol treatment. Median PFS was 3.7 months [90% confidence interval (CI)=2.7-5.6 months], which did not reach the predefined threshold of 4.0 months. ORR was 5.9% (95%CI=0.0-17.1%). Median OS was 11.9 months (95% CI 6.3-19.4 months). Febrile neutropenia was observed in 5.3% of patients. The most frequently observed grade 3 non-hematologic toxicities were nausea (15.8%) and hyponatremia (15.8%)., Conclusion: The addition of a fluoropyrimidine to a platinum agent after adjuvant therapy is not suitable for gastric cancer., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

We investigated the intermolecular dynamics and static structure in the aqueous solutions of lidocaine hydrochloride (LDHCl) in the concentration range of [LDHCl] = 0-2.00 M using femtosecond Raman-induced Kerr effect spectroscopy (fs-RIKES), small- and wide-angle X-ray scattering (SWAXS), and dynamic light scattering (DLS). For the fs-RIKES experiments, the concentration dependence of the difference low-frequency spectra of the aqueous LDHCl solutions relative to the neat water, which was mainly due to the intermolecular vibrations, was characterized using an exponential function with a characteristic concentration of ∼1 M. For the SWAXS experiments, we observed a manifestation of an excess scattering component centered within a range of 8-10 nm -1 in the aqueous LDHCl solutions. The results of Fourier inversion and further deconvolution analyses unambiguously demonstrated that lidocaines assemble into a nanometer-sized micelle-like structure with the innermost core (∼0.3 nm) and outer shell (∼0.5 nm), respectively. The DLS experiments also found nanometer-sized aggregates and further indicated evidence of the clusters of the aggregates. The results of viscosities, densities, and surface tensions of the solutions and the quantum chemistry calculations supported the unique features of the microscopic intermolecular interaction and the micelle-like aggregation.

The mixing states of two imidazolium-based ionic liquids (ILs) with different anions, 1-methyl-3-octylimidazolium tetrafluoroborate (C 8 mimBF 4 ) and bis(trifluoromethylsulfonyl)amide (C 8 mimTFSA), with three molecular liquids (MLs), methanol (MeOH), acetonitrile (AN), and dimethyl sulfoxide (DMSO), have been investigated on both mesoscopic and microscopic scales using small-angle neutron scattering (SANS), infrared (IR), and 1 H and 13 C nuclear magnetic resonance (NMR) spectroscopy. Additionally, molecular dynamics (MD) simulations have been conducted on the six combinations of ILs and MLs to observe the states of their mixtures on the atomic level. The SANS profiles of the IL-ML mixtures suggested that MeOH molecules only form clusters in both C 8 mimBF 4 and C 8 mimTFSA, whereas AN and DMSO were homogeneously mixed with ILs on the SANS scale. MeOH clusters are more enhanced in BF 4 - -IL than TFSA - -IL. The microscopic interactions among IL cations, anions, and MLs should contribute to the mesoscopic mixing states of the IL-ML mixtures. In fact, the IL cation-anion, cation-ML, anion-ML, and ML-ML interactions observed by IR, NMR, and MD simulations clarified the reasons for the mixing states of the IL-ML binary solutions observed by the SANS experiments. In neat ILs, the imidazolium ring of the IL cation more strongly interacts with BF 4 - than TFSA - due to the higher charge density of the former. The interaction of anions with the imidazolium ring is more easily loosened on adding MLs to ILs in the order of DMSO > MeOH > AN. It does not significantly depend on the anions. However, the replacement of the anion on the imidazolium ring by an ML depends on the anions; the replacement is more proceeded in the order of MeOH > DMSO > AN in BF 4 - -IL, while DMSO > MeOH > AN in TFSA - -IL. On the other hand, the solvation of both anions by MLs is stronger in the order of MeOH > DMSO ≈ AN. Despite the stronger interactions of MeOH with both cations and anions, MeOH molecules are heterogeneously mixed with both ILs to form clusters in the mixtures. Therefore, the self-hydrogen bonding among MeOH molecules most markedly governs the mixing state of the binary solutions among the abovementioned interactions.

This is the first report on low-frequency spectra of ionic liquid (IL)/polymer mixtures using femtosecond Raman-induced Kerr effect spectroscopy. We studied mixtures of 1-methyl-3-octylimidazolium tetrafluoroborate ([MOIm][BF 4 ]) and poly(ethylene glycol) (PEG) with M n = 400 (PEG400) at various concentrations. To elucidate the unique features of the IL/polymer mixture system, mixtures of PEG400 with a molecular liquid, 1-octhylimidazole (OIm), which is a neutral analog of the cation, were also studied. In addition, mixtures of [MOIm][BF 4 ] with ethylene glycol (EG) and poly(ethylene glycol) with M n = 4000 (PEG4000) were also investigated. The first moments of broad low-frequency spectra, mainly due to intermolecular vibrations for the [MOIm][BF 4 ]/PEG400 and OIm/PEG400, increased slightly with increasing concentration of PEG400, indicating that microscopic intermolecular interactions, in general, are slightly enhanced. We also compared the [MOIm][BF 4 ] mixtures with EG, PEG400, and PEG4000 at concentrations of 5 and 10 wt % PEG or EG. The low-frequency spectra of samples with the same concentrations were quite similar, but a comparison of the normalized spectra showed that the spectral intensity in the low-frequency region below ∼50 cm -1 of the [MOIm][BF 4 ] mixtures with PEG400 and PEG4000 is somewhat lower than that of the [MOIm][BF 4 ] mixtures with EG. Although the effect of the polymer is small compared to other polymer solution systems, this feature is attributed to a suppression of translational motion in the mixtures of [MOIm][BF 4 ] with PEG compared to the mixtures of [MOIm][BF 4 ] with EG due to the greater mass of PEG than EG. Density, surface tension, viscosity, and electrical conductivity were also estimated. From Walden plots, it was found that the [MOIm][BF 4 ]/PEG4000 system showed more ideal electrical conductive behavior than the [MOIm][BF 4 ]/PEG400 and [MOIm][BF 4 ]/EG systems.

Purpose: The current study aimed to determine the efficacy of trifluridine/tipiracil for elderly patients with advanced colorectal cancer., Methods: This single-arm, open-label, multicenter, phase II study included elderly patients aged 65 years or more who had fluoropyrimidine-refractory advanced colorectal cancer and received trifluridine/tipiracil (70 mg/m 2 , days 1-5 and 8-12, every 4 weeks). The primary endpoint was progression-free survival (PFS), while secondary endpoints included overall survival (OS), overall response rate (ORR), toxicities, association between efficacy and geriatric assessment scores, and association between toxicity and plasma drug concentrations., Results: A total of 30 patients with a mean age of 73 years were enrolled. Median PFS was 2.3 months (95% confidence interval, 1.9-4.3 months), while median OS was 5.7 months (95% confidence interval, 3.7-8.9 months). Patients had an ORR of 0%, with 57% having stable disease. Grade 4 neutropenia was observed in 13% of the patients. Patients with a higher G8 score (15 or more) showed longer PFS than those with a lower G8 score (median 4.6 vs. 2.0 months; p = 0.047). Moreover, patients with grade 3 or 4 neutropenia showed higher maximum trifluridine concentrations than those with grade 1 or 2 neutropenia (mean 2945 vs. 2107 ng/mL; p = 0.036)., Discussion: The current phase II trial demonstrated that trifluridine/tipiracil was an effective and well-tolerated option for elderly patients with advanced colorectal cancer. Moreover, geriatric assessment tools and/or plasma drug concentration monitoring might be helpful in predicting the efficacy and toxicities in elderly patients receiving this drug., Trial Registration Number: UMIN000017589, 15/May/2015 (The University Hospital Medical Information Network)., (© 2021. The Author(s).)

Epithelial ovarian cancer (EOC) is a fatal gynecologic cancer, and its poor prognosis is mainly due to delayed diagnosis. Therefore, biomarker identification and prognosis prediction are crucial in EOC. Altered cell metabolism is a characteristic feature of cancers, and metabolomics reflects an individual's current phenotype. In particular, plasma metabolome analyses can be useful for biomarker identification. In this study, we analyzed 624 metabolites, including uremic toxins (UTx) in plasma derived from 80 patients with EOC using ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Compared with the healthy control, we detected 77 significantly increased metabolites and 114 significantly decreased metabolites in EOC patients. Especially, decreased concentrations of lysophosphatidylcholines and phosphatidylcholines and increased concentrations of triglycerides were observed, indicating a metabolic profile characteristic of EOC patients. After calculating the parameters of each metabolic index, we found that higher ratios of kynurenine to tryptophan correlates with worse prognosis in EOC patients. Kynurenine, one of the UTx, can affect the prognosis of EOC. Our results demonstrated that plasma metabolome analysis is useful not only for the diagnosis of EOC, but also for predicting prognosis with the variation of UTx and evaluating response to chemotherapy.

Background: Understanding treatment goal is essential for decision-making among patients with unresectable/recurrent solid cancers. However, no previous studies in Japan have examined the association between patients' understanding and physicians' explanations. We aimed to examine agreement between patients' and physicians' reports of communication about palliative care and current health condition among patients with unresectable/recurrent cancer and explore factors associated with optimistic understanding in Japan., Methods: In this cross-sectional, multicenter, observational survey in Japan, 178 patients with unresectable/ recurrent solid cancers and 16 physicians responded to questionnaires. The primary outcome was agreement between patients' and physicians' reports of communication about palliative care and current health condition., Results: Of 56 patients who reported their communication about palliative care, 25/56 (44.6%) agreed with physician reports, and 31/56 (55.4%) were more optimistic than their physicians. Regarding current overall health condition, 45/122 (36.9%) patients gave reports that agreed with physicians' reports, and 77/122 (63.1%) were optimistic relative to physicians. Physicians' general approach about disclosure were not associated with patients' understanding., Conclusions: Fewer than 50% of Japanese patients with unresectable/recurrent cancer agreed with their physicians, whereas most others were more optimistic about palliative care communication and their health condition as compared to physicians. Effective communication is essential to ensure informed decisionmaking.

In this study, we examined the low-frequency spectra of 1-methyl-3-octylimidazolium tetrafluoroborate ([MOIm][BF 4 ]) mixtures with methanol (MeOH), acetonitrile (MeCN), and dimethyl sulfoxide (DMSO), which were obtained by femtosecond Raman-induced Kerr effect spectroscopy (fs-RIKES) and molecular dynamics (MD) simulations. In addition, we estimated the liquid properties of the mixtures, such as density ρ, surface tension γ, viscosity η, and electrical conductivity σ. The line shapes of the low-frequency Kerr spectra of the three [MOIm][BF 4 ] mixture systems strongly depend on the mole fraction of the molecular liquid, X ML . The spectral intensity increases with increasing X ML of the [MOIm][BF 4 ]/MeCN system but decreases for the [MOIm][BF 4 ]/MeOH and [MOIm][BF 4 ]/DMSO systems. These behaviors of the spectral intensities reasonably agree with the vibrational density-of-states spectra when the polarizability anisotropies of MeOH, MeCN, DMSO, and ion species are considered. The characteristic frequencies (first moments, M 1 ) of the low-frequency spectra of the three mixture systems are almost insensitive at X ML = 0-0.6. However, the frequencies vary mildly at X ML = 0.6-0.9 and dramatically at X ML = 0.9-1. The X ML -dependent M 1 in the Kerr spectra are well reproduced by the MD simulations. Plots of M 1 versus bulk parameter, ( γ/ρ ) 1/2 , for the three mixture systems show that the mixtures at X ML = 0-0.6 behave like aromatic cation-based ionic liquids (ILs), those at X ML = 0.9-1 are molecular liquids (MLs), and those at X ML = 0.6-0.9 are transitioning between aromatic cation-based ILs and MLs. MD simulations show that the solvent molecules localized at the interface between the ionic and the alkyl group regions without forming large solvent networks at X ML = 0-0.6. However, solvent networks or regions develop largely at X ML = 0.6-0.9 and the constituent ions of the IL disperse in the MLs at X ML = 0.9-1. The MD simulations corroborate the results obtained by fs-RIKES.

Introduction: Human epidermal growth factor receptor 2 (HER2) gene amplification and mutations have emerged as oncogenic drivers and therapeutic targets not limited to breast and gastric cancers, but also in a variety of cancers. However, even if an actionable gene alteration is found, the incidence of HER2 amplification in these cancers is less than 5%. It is too difficult to conduct a conventional randomized, controlled trial in a rare fraction. Therefore, we have designed a organ-agnostic basket study, which covers a variety of solid cancers harboring HER2 amplification, in 1 study protocol., Methods/design: This trial is a multicenter, single-arm, basket phase 2 study in Japan. Patients with solid cancers harboring HER2 amplification that have progressed with standard treatment, or rare cancers for which there is no standard treatment, will be eligible. Target cancers include bile duct, urothelial, uterine, ovarian, and other solid cancers where HER2 amplification is detected by comprehensive genomic profiling using next-generation sequencing technology. A total of 38 patients will be treated with combination therapy with trastuzumab and pertuzumab every 3 weeks until disease progression, unmanageable toxicity, death, or patient refusal. The primary endpoint is the objective response rate, and secondary endpoints are progression-free survival, overall survival, and duration of response., Discussion: The aim of this trial is to evaluate the safety and efficacy of combination therapy with trastuzumab and pertuzumab in patients with locally advanced or metastatic, solid cancers harboring HER2 amplification. Instead of focusing on 1 organ type, our trial design uses a basket study focusing on HER2 amplification, regardless of the site or origin of the cancer. The results of our study will advance clinical and scientific knowledge concerning the treatment of locally advanced, rare solid cancers harboring HER2 amplification, using the combination of trastuzumab and pertuzumab., Trial Registration: This trial was registered in Japan Registry of Clinical Trials (jCRT) on February 25, 2019, as jRCT2031180150.

Two genomic profiling assays have been approved by Japanese national health insurance in December 2018. Japanese government assigned core hospitals, which can conduct molecular tumor board, called"expert panel"to make a therapeutic recommendation based on the genomic findings and concentrated the function of cancer genomic medicine. The genomic profiling tests under Japanese national health insurance system must be covered for the entire population. To eliminate regional disparities of such an advanced medicine, the infrastructure to spread cancer genomic medicine for collaborating among hospitals should be established. Here, we introduce our efforts to make regional collaboration in Tohoku University Hospital.

Background: Oxaliplatin and irinotecan are generally used to treat advanced colorectal cancer (CRC) patients. Antibiotics improve the cytotoxicity of oxaliplatin but not irinotecan in a colon cancer cell line in vitro . This study retrospectively assessed whether antibiotics improve the treatment efficacy of oxaliplatin- but not irinotecan-based therapy in advanced CRC patients. Patients and Methods . The medical records of 220 advanced CRC patients who underwent oxaliplatin- or irinotecan-based therapy were retrospectively reviewed. The oxaliplatin and irinotecan groups were further divided into antibiotic-treated (group 1) and antibiotic-untreated (group 2) subgroups., Results: In oxaliplatin groups 1 and 2, the response rate (RR) was 58.2% and 30.2%, while the disease control rate (DCR) was 92.5% and 64.2%, respectively; the median progression-free survival (PFS) was 10.5 months (95% confidence interval (CI) = 7.5-12.2) and 7.0 months (95% CI = 17.0-26.0), respectively, and the median overall survival (OS) was 23.8 months (95% CI = 5.1-9.1) and 17.4 months (95% CI = 13.1-24.9), respectively. In irinotecan groups 1 and 2, the RR was 17.8% and 20.0%, while the DCR was 75.6% and 69.1%, respectively; the median PFS was 8.2 months (95% CI = 6.2-12.7) and 7.9 months (95% CI = 12.0-23.0), respectively, and the median OS was 16.8 months (95% CI = 5.9-10.6) and 13.1 months (95% CI = 10.4-23.7), respectively., Conclusion: To improve the treatment efficacy of oxaliplatin-based therapy in advanced CRC patients, adding antibiotics is a potential therapeutic option., Competing Interests: Chikashi Ishioka, the corresponding author, received research funding from the Tokyo Cooperative Oncology Group, received contributions from Chugai Pharmaceutical, Ono Pharmaceutical, MSD, Pfizer, AstraZeneca, Bristol-Myers Squibb, Janssen Pharmaceutical, Taiho Pharmaceutical, Daiichi Sankyo Company, Limited, and Takeda Pharmaceutical, and is a representative of Tohoku Clinical Oncology Research and Education Society, a specified nonprofit corporation. Masanobu Takahashi received research funding from Ono Pharmaceutical., (Copyright © 2020 Hiroo Imai et al.)

Background: Pseudomyxoma peritonei (PMP) is a rare malignancy, and there is insufficient evidence about systemic chemotherapy for this disease., Methods: We retrospectively evaluated the efficacy and safety of a chemotherapeutic regimen with 5-fluorouracil and oxaliplatin (modified FOLFOX6, mFOLFOX6) for patients with unresectable pseudomyxoma peritonei. Patients who received the therapy between April 2000 and February 2019 at the Department of Medical Oncology, Tohoku University Hospital, were enrolled in this study., Results: Eight patients were treated with mFOLFOX6. The sites of primary tumor were appendix in six patients, ovary in a patient, and urachus in a patient. Six patients received surgery. Seven patients had histologically high-grade PMP, and one patient had low-grade PMP. The median follow-up duration was 27.2 months. All the patients had non-measurable regions as the targets of tumor response. Non-complete response or non-progressive disease was observed in seven patients, with a disease control rate of 87.5%. The median progression-free survival and overall survival were 13.0 months and 27.9 months, respectively. An obvious reduction in the symptoms was observed in two patients. Five patients experienced decline in the serum tumor markers, CEA or CA19-9. The grade 3/4 toxicity that was observed was grade 4 neutropenia in one patient and grade 3 neutropenia in two patients., Conclusions: mFOLFOX6 might be an effective and tolerable treatment option for patients with unresectable PMP. To our knowledge, this is the first case series of mFOLFOX6 in patients with unresectable PMP and the first case series of systemic chemotherapy for Asian patients with unresectable PMP.

In this study, the low-frequency vibrational dynamics of polystyrene (PS) in CCl 4 was investigated by femtosecond Raman-induced Kerr effect spectroscopy. Ethylbenzene (EBz) was also investigated as a model monomer of the polymer to elucidate the unique dynamical features of PS in solution. The broadened low-frequency spectrum of the PS/CCl 4 in the frequency region below 150 cm -1 is significantly different from that of the EBz/CCl 4 . Difference spectra between the PS or EBz solutions and neat CCl 4 , normalized to an internal vibrational mode of CCl 4 , clearly show a much lower spectral intensity for the PS/CCl 4 than the EBz/CCl 4 in the low-frequency region below ca. 20 cm -1 . This indicates that translational motions are suppressed in the PS/CCl 4 compared to the EBz/CCl 4 . Moreover, the high-frequency motion at ca. 70 cm -1 , mainly due to phenyl ring librations, occurs at higher frequency in PS (78 cm -1 ) than EBz (65 cm -1 ). In addition, the results of concentration-dependent experiments show that the first moment ( M 1 ) of the low-frequency difference spectra of both PS/CCl 4 and EBz/CCl 4 is almost independent of the concentration. The molecular weight dependence of the low-frequency spectrum in the PS/CCl 4 shows that the M 1 value of the low-frequency spectral band of PS shifts to higher frequencies when the molecular weight of PS increases up to M w = ∼1000, which corresponds approximately to the decamer, and then remains constant upon further increasing the molecular weight.

We developed a reference material (RM) for the determination of hexavalent chromium (Cr(VI)) in tap water. The tap water RM was prepared by adding a Cr(VI) standard solution to the raw material without acidification, i.e., under the original pH conditions of 7.6, because the decrease in the concentration of Cr(VI) was observed when the tap water had been adjusted to pH 1 with HNO 3 . The prepared tap-water RM (2 L) was packed in 10 fluororesin (PFA) bottles with an inside plug (200 mL each). Each PFA bottle (Cr(VI)-containing tap water) was sealed in a reclosable poly bag and then stored at 5°C in a refrigerator. The tap water RM had a Cr(VI) concentration of 51 μg L -1 . The concentration of Cr(VI) was determined by diphenylcarbazide absorptiometry using a 100-mm quartz cell. The detection limit of Cr(VI) in the sample solution corresponding to three-times the standard deviation (n = 5) of blank values was 0.51 μg L -1 . The homogeneity of Cr(VI) in the tap water RM was evaluated by an analysis of the variance after the Cochran test. There was no significant difference between the within-bottle and between-bottle variances of the analytical results, indicating that the tap water RM was sufficiently homogeneous. The stability of Cr(VI) in the tap water RM was investigated by monitoring the Cr(VI) concentration over a period of 6 months. The slope of the regression line of the Cr(VI) concentration versus the storage time did not significantly differ from zero, indicating that the tap water RM was stable for 6 months. The concentrations (50 - 51 μg L -1 ) of Cr(VI) in the tap water RM were in good agreement with the total chromium concentrations (50 - 51 μg L -1 ) obtained by atomic absorption spectrometry.

Various immune cells are recruited in the tumor microenvironment. It is well established that cellular immune responses, such as cytotoxic or suppressive activities, play an important role in regulating tumor growth and metastasis. However, the contribution of humoral immune responses against tumors is poorly understood. Fc receptors constitute critical elements for the up- or downregulation of immune responses through immune complexes. Here, we examined the potential role of the inhibitory Fc receptor, Fcγ receptor IIB (FcγRIIB), in tumor immunity using a mouse model. Our findings indicated that tumor-specific antibodies are induced in tumor-bearing mice and control tumor immunity. FcγRIIB deletion significantly improved both cellular and humoral immunity against tumors and delayed tumor growth. These findings indicated that spontaneous antibodies against tumors create a suppressive tumor microenvironment through FcγRIIB signaling, thus suggesting an attractive therapeutic target for cancer immunotherapy.

The antibodies targeting programmed death 1 (PD-1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) have provided survival benefits in patients with advanced malignant melanoma. The anti-PD-1 antibodies nivolumab and pembrolizumab are considered superior to the anti-CTLA-4 antibody ipilimumab as first-line therapy, suggesting that ipilimumab should be administered to patients with anti-PD-1 antibody-refractory melanoma in the second-line setting. However, there is limited evidence regarding the efficacy and safety of ipilimumab after disease progression on anti-PD-1 antibody therapy. Moreover, in patients with mucosal melanoma, a rare and aggressive subtype, evidence is extremely poor. This study aimed to clarify the efficacy and safety of ipilimumab among Japanese patients with nivolumab-refractory advanced mucosal melanoma. We retrospectively analyzed the seven patients with advanced mucosal melanoma who were treated with ipilimumab after disease progression on nivolumab at our hospital between September 2015 and December 2017. No patient achieved complete response or partial response to ipilimumab therapy. However, six patients achieved stable disease, and of these patients, three achieved a decline in the tumor size. All the three patients with a decline in tumor size developed grade 3 toxicity: two patients developed colitis and one patient experienced alanine aminotransferase elevation. The median progression-free survival (PFS) for prior nivolumab therapy was 148 days. The median PFS for ipilimumab therapy after disease progression with nivolumab was 193 days. The median overall survival was 661 days. In conclusion, although even partial response was undetectable with ipilimumab therapy, ipilimumab could produce additional PFS among nivolumab-refractory advanced mucosal melanoma patients.

In Japan, "Designated Core Hospitals for Cancer Genomic Medicine" as leading hospitals on cancer genomic medicine and "Cooperative Hospitals for Cancer Genomic Medicine" which conduct cancer genomic medicine in each region are working together to promote cancer genomic medicine. Eleven institutions as the former and 135 institutions as the latter are currently designated. It is essential to hold a molecular tumor board, which is called "Expert Panel" in Japan, to provide cancer genomic medicine for patients. In the Expert Panel, the results of tumor sequencing are interpreted with clinical information, then recommended treatment and genetic information to be provided are determined. Holding Expert Panels is a duty of Designated Core Hospitals for Cancer Genomic Medicine and Cooperative Hospitals need to participate in it. In order to facilitate the Expert Panel, it is effective to share patient's information using well-managed Web system. Besides that, there are many tasks to be addressed by cooperation of Designated Core Hospitals and Cooperative Hospitals such as registration of patient's information in the Center for Cancer genomics and Advanced Therapeutics(C-CAT), correspondence to increasing genomic testing and nurturing specialized human resources involved in cancer genomic medicine. Interinstitutional collaboration should be more encouraged to propagate cancer genomic medicine.

We investigated the temperature dependence of the intermolecular vibrational dynamics of pyrrolidinium-based ionic liquids (ILs) with 10 different anion species using femtosecond Raman-induced Kerr effect spectroscopy. The features of the temperature-dependent vibrational spectra vary with the different anions. In the case of the ILs with spherical top anions, such as tetrafluoroborate and hexafluorophosphate, and trifluoromethanesulfonate, the spectral intensity in the low-frequency region below 50 cm -1 increases with rising temperature, while that in the high-frequency region above 50 cm -1 remains almost unchanged. Similar temperature-dependent features were also found in the bis(fluorosulfonyl)amide and bis(perfluoroalkylsulfonyl)amide salts. However, the difference spectra at respective temperature relative to 293 K indicate that the spectra of the bis(fluorosulfonyl)amide and bis(perfluoroalkylsulfonyl)amide salts are more temperature-sensitive in the low-frequency region below 50 cm -1 compared to those of the tetrafluoroborate, hexafluorophosphate, and trifluoromethanesulfonate salts. The spectra of 1-butyl-1-methylpyrrolidinium-based ILs with dicyanamide and tricyanomethide anions show a characteristic temperature dependence; in addition to an increase of the spectral intensity in the low-frequency region below 50 cm -1 , a red shift of the spectra in the high-frequency side above 50 cm -1 was observed with increasing temperature. This implies that the librational motions of planar dicyanamide and tricyanomethide anions contribute substantially to the low-frequency spectra. We also compared the temperature-dependent low-frequency spectra of 1-butyl-1-methylpyrrolidinium- and 1-(2-methoxyethyl)-1-methylpyrrolidinium-based ILs with some anions. Although the spectral shapes are slightly different in the range of 70-150 cm -1 , which can be attributed to the intramolecular vibrational modes of the cations, the temperature dependence of the spectral shapes is quite similar, indicating that the ether substitution in the cation side groups has little effects on the temperature dependence of the low-frequency spectra. The fragilities of the ILs were also estimated from the temperature-dependent viscosities and the glass-transition temperatures. The fragility parameter seems to be correlated with the temperature dependence of the first moment of the low-frequency spectral bands mainly arising from the intermolecular vibrations of the ILs.

Background: Recombinant human soluble thrombomodulin (rTM) has been established and introduced in the clinic as a standard treatment for disseminated intravascular coagulation (DIC). However, the efficacy and safety of rTM for DIC associated with solid tumors (DIC-STs) have not been fully established. Here, we performed a retrospective analysis of the clinical outcomes of rTM for DIC-STs and considered a treatment strategy with rTM for DIC-STs., Methods: Patients with DIC-STs between November 2009 and March 2016 in 2 cancer core hospitals were retrospectively analyzed. Data, including patient background, treatment course, and clinical outcomes of rTM for DIC-STs, were extracted. The clinical outcomes were evaluated by comparing the DIC score, resolution rate, and overall survival (OS) duration., Results: The study included 123 patients with DIC-STs. The median OS in all patients was 41 days. The DIC resolution rate was 35.2%. DIC scores and DIC-related blood test data (fibrin degradation product and prothrombin time-international normalized ratio) significantly improved at the end of rTM administration (P < 0.001). The OS duration was longer in patients who were treated with chemotherapy after DIC onset than in those who were not treated with chemotherapy (median, 178 days vs. 17 days, P < 0.001). In both univariate and multivariate analyses, chemotherapy after DIC onset showed the strongest association with OS., Conclusions: rTM can at least temporarily improve or maintain the state of DIC-STs. It is suggested that prolongation of survival can be expected when control of DIC and treatment of the underlying disease are compatible.

In this study, we have investigated the effects of cation structures on the temperature dependence of the intermolecular vibrational dynamics of ionic liquids using femtosecond Raman-induced Kerr effect spectroscopy. The ionic liquids used in this study are bis(trifluoromethylsulfonyl)amide [NTf 2 ] - salts of the cations 1-butyl-3-methylimidazolium [C 4 MIm] + , 1-butyl-1-methylpyrrolidinium [Pyrr 14 ] + , 1-butylpyridinium [C 4 Py] + , butyldiethylmethylammonium [N 1224 ] + , triethyloctylammonium [N 2228 ] + , and triethyloctylphosphonium [P 2228 ] + . All of the ionic liquids show temperature-dependent low-frequency spectra. A difference in the temperature dependence between the spectra of the aromatic and nonaromatic cation based ionic liquids is especially significant. In the case of the aromatic cation based ionic liquids [C 4 MIm][NTf 2 ] and [C 4 Py][NTf 2 ], the spectral intensities in the low-frequency region below ca. 50 cm -1 increase and the high-frequency components at ca. 80 cm -1 shift to lower frequencies with rising temperature. In contrast, the ionic liquids based on nonaromatic cations only exhibit an increase in the low-frequency region below ca. 50 cm -1 with increasing temperature, while the high-frequency region of the spectra above ca. 50 cm -1 shows little change with variation of the temperature. These results suggest that the presence or absence of aromatic rings is the main factor in determining the temperature-dependent spectral features, particularly in the high-frequency region. We also found that the alkyl chain length and central atoms of the nonaromatic quaternary cations do not have much influence on the temperature-dependent spectral features. The first moments of the aromatic cation based ionic liquids are a little more sensitive to temperature than those of the nonaromatic cation based ionic liquids. The temperature-dependent viscosities and fragilities of the ionic liquids have also been examined.

The combinations of oral fluoropyrimidines and cisplatin such as capecitabine and cisplatin (XP) or S-1 and cisplatin (SP) are regarded as a standard therapy against unresectable, recurrent, or advanced gastric cancer (AGC). Especially, SP is the most common regimen against AGC in Japan. For patients with human epidermal growth factor receptor type 2 (HER2)-positive AGC, trastuzumab, a monoclonal antibody targeting HER2 antibody, is additionally used in combination. Although trastuzumab in combination with XP (trastuzumab-XP) have been widely accepted, the efficacy of trastuzumab in combination with SP (trastuzumab-SP) lacks sufficient verification. The aim of the present study is to validate the comparability of trastuzumab-SP to trastuzumab-XP. Patients with HER2-positive AGC were assigned to the trastuzumab-XP or trastuzumab-SP group. We then retrospectively compared the efficacy and safety between both groups. As a first-line chemotherapy, trastuzumab in combination with XP or SP was administered to 58 patients: 28 with trastuzumab-XP and 30 with trastuzumab-SP. In the trastuzumab-XP group, response rate (RR), disease control rate (DCR), median progression-free survival (mPFS), and median overall survival (mOS) were 39.3%, 89.3%, 7.9 months, and 20.0 months, respectively. In the trastuzumab-SP group, RR, DCR, mPFS and mOS were 50.0%, 86.7%, 6.9 months, and 16.7 months, respectively. No significant difference in efficacy was observed between both groups. Severe hand-foot syndrome was observed more frequently in the trastuzumab-XP group than in the trastuzumab-SP group (14.3% vs. 0%, p = 0.05). Trastuzumab in combination with SP is a potential first-line therapeutic option for patients with HER2-positive AGC.