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Hiroo Imai, Ken Saijo, Keigo Komine, Reio Ueta, Ryunosuke Numakura, Shonosuke Wakayama, Sho Umegaki, Sakura Hiraide, Yoshufumi Kawamura, Yuki Kasahara, Kota Ohuchi, Masahiro Takahashi, Shin Takahashi, Hidekazu Shirota, Masanobu Takahashi, Chikashi Ishioka Department of Medical Oncology, Tohoku University Hospital, Sendai, 980-8575, JapanCorrespondence: Chikashi Ishioka, Department of Medical Oncology, Tohoku University Hospital, 4-1, Seiryo-machi, Aobaku, Sendai, 980-8575, Japan, Tel +81 227178543, Fax +81 227178548, Email chikashi@tohoku.ac.jpPurpose: One of the first-line treatment for gastric cancer patients is oxaliplatin, and the efficacy of this chemotherapeutic can be attenuated by the microbiome. In this study, we retrospectively evaluated whether treatment with antibiotics improved the efficacy of oxaliplatin-based chemotherapy in patients with advanced gastric cancer.Patients and Methods: Fifty-four patients were assigned to the antibiotic-treated group and 35 to the antibiotic-untreated group.Results: The response rate of oxaliplatin-based chemotherapy in the antibiotic-treated and antibiotic-untreated groups was 66.7% and 41.4%, respectively (p = 0.038). The median progression-free survival after oxaliplatin-based chemotherapy in the antibiotic-treated and antibiotic-untreated groups was 8.8 and 5.2 months, respectively (hazard ratio = 0.456, 95% confidence interval = 0.254– 0.819; p = 0.007, Log rank test). Univariate and multivariate analyses revealed that antibiotic treatment was the only clinical parameter that correlated with the response to oxaliplatin.Conclusion: Antibiotic treatment could be used therapeutically to enhance the efficacy of oxaliplatin-based chemotherapy in patients with advanced gastric cancer.Keywords: gastric cancer, chemotherapy, oxaliplatin, antibiotics

Hiroo Imai,1 Ken Saijo,1 Keigo Komine,1 Yasufumi Otsuki,2 Kota Ohuchi,1 Yuko Sato,1 Akira Okita,2 Masahiro Takahashi,1 Shin Takahashi,2 Hidekazu Shirota,1 Masanobu Takahashi,2 Chikashi Ishioka21Department of Medical Oncology, Tohoku University Hospital, Sendai, Japan; 2Department of Clinical Oncology, Institute of Developing, Aging and Cancer, Tohoku University, Sendai, JapanCorrespondence: Chikashi IshiokaDepartment of Medical Oncology, Tohoku University Hospital, 4-1, Seiryo-machi, Aobaku, Sendai 980-8575, JapanTel +81 22 717 8543Fax +81 22 717 8548Email chikashi@tohoku.ac.jpBackground: The addition of antibiotics reportedly augments the efficacy of gemcitabine (GEM) in tumor-bearing mice. However, whether this phenomenon is also observed in cancer patients remains unclear. In the present study, we aimed to assess whether antibiotics for treatment or prevention of infection augments treatment efficacies of GEM-containing regimens in patients with any type of cancer.Methods: Medical records of patients diagnosed with cancer histopathologically and treated with GEM-containing regimens (n=169) were retrospectively reviewed. Patients were assigned into two groups: antibiotics-untreated group (patients who were treated with GEM-containing regimens but without antibiotics) and antibiotics-treated group (patients who were treated with GEM-containing regimens plus antibiotics). Response rates, progression-free survival (PFS) time, and overall survival (OS) time were analyzed for each group.Results: The response rates of the antibiotics-untreated and antibiotics-treated groups with GEM-containing regimens were 15.1% and 27.6%, respectively. The median PFS times of the antibiotics-untreated and antibiotics-treated groups were 2.5 (95% CI: 1.86–3.73) and 4.9 (95% CI: 3.47–6.0) months, respectively. The median OS times of the antibiotics-untreated and antibiotics-treated groups were 7.53 (95% CI: 5.63–9.57) months and 13.83 (95% CI: 10.83–16.43) months, respectively.Conclusion: The addition of antibiotics augments the treatment efficacies of GEM-containing regimens, and it may be a potential therapeutic option to improve treatment efficacies of GEM-containing regimens in patients with advanced cancer.Keywords: antibiotics, bacteria, gemcitabine, multivariate analysis, univariate analysis

Hiroo Imai, Ken Saijo, Keigo Komine, Yoshifumi Kawamura, Sakura Hiraide, Sho Umegaki, Yoshinari Okada, Kota Ohuchi, Yuko Sato, Masahiro Takahashi, Shin Takahashi, Hidekazu Shirota, Masanobu Takahashi, Chikashi Ishioka Department of Medical Oncology, Tohoku University Hospital, Sendai, Japan Purpose: Research has revealed that some patients who develop resistance to the first taxane treatment exhibit a moderate response to the second taxane treatment (incomplete cross-resistance between paclitaxel and docetaxel). However, which patients are most likely to respond to the second treatment remains unclear. The aim of this study was to determine the predictive factors for the efficacy of the second taxane treatment in patients resistant to the first.Patients and methods: We enrolled patients treated with paclitaxel and docetaxel (n=31) in this study. Using univariate and multivariate analyses, we determined the predictive factors for the efficacy of the second taxane treatment. Then, we assigned patients to one of the three groups: 1) those with a partial response (PR) to the first taxane treatment who subsequently became refractory (PR group); 2) those whose response was stable disease (SD) and subsequently became refractory (SD group); and 3) those whose response was the progression of the disease with the first taxane treatment (progression disease [PD] group). Furthermore, the response rates were assessed for each group. All statistical analyses were performed using JMP 11.Results: Responses to the first taxane treatment considerably correlated with the efficacy of the second treatment in patients with a PR to the first taxane treatment (P=0.0061, univariate analysis; P=0.0056, multivariate analysis). In addition, response rates to the second taxane treatment in the PR, SD, and PD groups were 33.3%, 0%, and 0%, respectively.Conclusion: The response to the first taxane treatment was a predictive factor for the efficacy of the second taxane treatment in patients with a PR to the first. Thus, the second treatment is highly recommended for patients who exhibit tumor shrinkage (a PR) by the first treatment. Keywords: taxane, predictive factor, univariate analysis, multivariate analysis

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.