Others

Gut microbiota and efficacy of immune-checkpoint inhibitors (ICIs) in patients (pts) with advanced solid tumor: Nationwide Cancer Genome Screening Project, SCRUM-Japan MONSTAR-SCREEN

Author(s)：: Satoshi Horasawa¹, Kentaro Sawada², Riu Yamashita¹, Takao Fujisawa¹, Ayumu Yoshikawa¹,
Yoshiaki Nakamura¹, Hiroya Taniguti^1,3, Shigenori Kadowaki³, Ken Kato⁴, Taroh Satoh⁵, Yoshito Komatsu⁶, Eigi Oki⁷,
Hisateru Yasui⁸, Kentaro Yamazaki⁹, Takayuki Yoshino¹
Affiliation(s)：: ¹National Cancer Center Hospital East, ²Kushiro Rosai Hospital,³Aichi Cancer Center,⁴National Cancer Center Hospital,⁵Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University,⁶Cancer Center, Hospital, Hokkaido University,⁷Surgery and Science, Graduate School of Medical Sciences, Kyushu University,⁸Kobe City Medical Center General Hospital,⁹Shizuoka Cancer Center

Background
MONSTAR-SCREEN prospectively assesses gut microbiota and circulating tumor DNA in 2,000 pts with advanced solid tumor at 31 Japanese institutions. Here we report an initial analysis of association between alpha diversity index (ADI) of fecal microbiome and efficacy of ICIs from Sep 2019 to Sep 2020.
Method
The 16S rRNA gene sequencing to V3-V4 region was conducted for assessing the ADI, which was represented as an operational taxonomic unit (OTU) score. Objective response rate (ORR) was assessed by RECIST version 1.1 and progression-free survival (PFS) on ICIs was estimated using the Kaplan-Meier method. Microsatellite instability (MSI) and blood tumor mutational burden (bTMB) status were measured by FoundationOneLiquid plus a 1.125Mb bTMB assay at the same time points as the feces collection. In addition, tissue TMB (tTMB) was measured by FoundationOneCDx using pretreatment tissue samples.
Results
A total of 167 pts were included. Most common cancer types were head and neck cancer (N=43), malignant melanoma (N=26) and gastric cancer (N=25). Of these, 136 (81%) pts received ICI alone, while 31 (19%) did chemotherapy combination. We determined the optimal cutoff value of 240 by combined sensitivity with specificity for the ORR. The ORR in high OTU (OTU-H > 240, N=52) was 35%, while that with low OTU (OTU-L < 240, N=115) was 17% (p=0.01). In addition, OTU-H pts had a significantly a longer PFS on ICIs than OTU-L (8.6 vs. 2.6 months; hazard ratio, 0.48; 95% CI, 0.30-0.78; p=0.002). Multivariate analyses for the ORR and PFS demonstrated the OTU was the only significant independent factor beyond MSI, bTMB, and tTMB status.
Conclusion
Diversity of gut microbiota by the OTU was significantly associated with higher ORR and longer PFS on ICIs in pts with advanced solid tumor. These indicated the potential of the OTU as a tumor-agnostic biomarker for the efficacy of ICIs beyond MSI and TMB status. Further study with shotgun and single cell metagenome analyses are ongoing.

Basic research on novel iPS cell-derived dendritic cell vaccine therapy applying the ubiquitin proteasome system

Author(s)：: Shinta Tominaga¹, Toshiyasu Ojima¹, Motoki Miyazawa¹, Hiromitsu Iwamoto¹, Junya Kitadani¹, Shinpei Maruoka¹,
Hiroki Yamaue¹
Affiliation(s)：: ¹Second Department of Surgery, Wakayama Medical University

Dendritic cells (DCs) are the most potent antigen-presenting cells. In clinical application of DC vaccine therapy, however, it is reported that DCs generated from patients with a variety of malignancies are impaired in terms of maturation and antigen-presenting ability. Several apheresis are required to obtain a sufficient amount of dendritic cells. Therefore We have reported significant efficacy of induced pluripotent stem cells (iPSCs) in generating DCs for cancer vaccine therapy. By inducing iPSC-derived DCs (iPSDCs) in mice, our study reported that genetically modified iPSDCs are equivalent to that of bone marrow derived DCs (MoDCs) in a mouse model in terms of functional and antigen-presenting capacity (Int. J. Cancer; 2014: 134, 332-341). We have also demonstrated that genetically modified iPSDCs expressing carcinoembryonic antigen (CEA) - which were induced by transducing CEA cDNA into iPSDCs - exhibited CEA-specific cytotoxicity in mouse and human models (Sci. Rep; 2018: 8, 4569). In our mouse model studies, no mice had tumors disappeared. Further enhancement of antitumor effect is required for clinical application. We are conducting research on iPSDC vaccine therapy targeting the highly immunogenic TAA mesothelin and focusing on the ubiquitin proteasome system as a device to enhance the antigen-presenting ability of DC. We are certain that this is an important basic study for the clinical application of iPSDC vaccine therapy.

Elobixibat effectively relieves chronic constipation in cancer patients, regardless of food intake amount

Author(s)：: Akiko Fuyuki^1,2, Takaomi Kessoku^1,2, Kosuke Tanaka^1,2, Yuki Kasai^1,2, Anna Ozaki², Michihiro Iwaki^1,2, Takashi Kobayashi², Tsutomu Yoshihara², Yasushi Honda², Takuma Higurashi², Masataka Taguri⁴, Shunsuke Oyamada⁵, Noritoshi Kobayashi³, Yasushi Ichikawa^1,3, Atsushi Nakajima²
Affiliation(s)：: ¹Department of Palliative Medicine, Hospital, Yokohama City University, ²Department of Gastroenterology and Hepatology, Yokohama City University,³Department of Oncology, Hospital, Yokohama City University,⁴Department of Data Science, School of Medicine, Yokohama City University,⁵JORTC Data Center, Japanese Organization for Research and Treatment of Cancer (JORTC)

Background:
Cancer patients receiving palliative care often suffer from chronic constipation. Elobixibat is a novel inhibitor of the ileal bile acid transporter which is used for treatment of chronic constipation, and recent clinical trials have reported its effectiveness. However, the effectiveness of elobixibat for cancer patients with constipation has not been clarified. The aim of this study was to investigate the efficacy of elobixibat for the management of constipation in cancer patients.
Methods:
This was a prospective, single-center study, and targeted hospitalized cancer patients diagnosed with chronic constipation using the ROME IV criteria. Each participant started receiving elobixibat administration (5-15 mg) every day within 2 weeks after hospitalization, and instructed to continue their administration until discharge. Spontaneous bowel movements (SBMs), complete spontaneous bowel movements (CSBMs), Bristol stool form scale (BSFS), and the Patient Assessment of Constipation Quality of Life questionnaire (PAC-QOL) scores were assessed before and after elobixibat administration. The relationship between the amount of food intake and SBM frequency were also evaluated.
Results:
Among the 83 participants, the mean pre- and post-treatment frequencies of daily SBMs were 0.3 and 1.2 (P < 0.0001) and those of CSBMs were 0.1 and 0.6 (P < 0.0001), respectively. The mean pre-treatment BSFS score was 1.6, whereas the post-treatment value was 3.5 (P < 0.0001); the mean PAC-QOL score (overall) improved from 1.01 to 0.74 (P = 0.01). There was no significant change in the daily SBM frequency between fasting and feeding states (1.2 vs 1.3, P = 0.8), and there was no correlation between the amount of food intake and the SBM frequency, after elobixibat administration (r = 0.03). Severe adverse events were not observed.
Conclusions:
This study demonstrated that elobixibat is safe and effective for cancer patients with chronic constipation, regardless of the food intake amount.

Association between thiamine decrease and neuropsychiatric symptoms in gastrointestinal and hematological cancer patients receiving chemotherapy

Author(s)：: Yohei Iimura¹, Tomohiro Kurokawa², Shohei Andoh³, Toyotaka Kawamata³, Aki Sato³, Kazuaki Yokoyama³, Yoichi Imai³,
Giichiro Tsurita², Yuka Ahiko^2,4, Susumu Aikou^2,4, Dai Shida^2,4, Masanori Nojima⁵, Arinobu Tojo³, Munetoshi Sugiura⁶,
Seiichiro Kuroda¹
Affiliation(s)：: ¹Department of Pharmacy, The IMSUT Hospital, The Institute of Medical Science, The University of Tokyo, ²The Department of Surgery, The IMSUT Hospital, The Institute of Medical Science, The University of Tokyo,³Department of Hematology/Oncology, The IMSUT Hospital, The Institute of Medical Science, The University of Tokyo,⁴Division of Frontier Surgery, The Institute of Medical Science, The University of Tokyo,⁵Center for Translational Research, The Institute of Medical Science, The University of Tokyo,⁶Department of Drug Safety and Risk Management, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences

Background
Clinical evidence of thiamine-related neuropsychiatric symptoms, including mild or non-specific symptoms induced by mild or severe thiamine deficiency (TD), is limited because serum thiamine levels tend to be evaluated only for patients who develop severe neuropsychiatric symptoms suspected to be related to TD. This study aimed to evaluate the relationship between mild or severe thiamine deficiency and mild or non-specific neuropsychiatric symptoms, and the influence of chemotherapy on thiamine serum levels in gastrointestinal and hematological cancer patients receiving chemotherapy.
Methods
We retrospectively identified patients who were diagnosed with gastrointestinal and hematological cancers at our hospital. We evaluated the risk factors associated with neuropsychiatric symptoms (mild to severe cognitive impairment, attention impairment, and mood or emotional disorder), the relationship between the presence of neuropsychiatric symptoms and thiamine serum levels, and changes in thiamine serum levels after chemotherapy.
Results
A total of 87 patients (gastrointestinal cancer: n=45, hematological cancer: n=42) were enrolled in this analysis. Logistic regression analysis detected thiamine decrease as a significant factor associated with neuropsychiatric symptoms (p < 0.001, odds ratio = 0.040, 95% confidence interval [CI]: 0.010-0.163). The Mann-Whitney U test showed that patients with neuropsychiatric symptoms had significantly lower thiamine serum levels (19.5 ± 5.4 ng/mL, n=39) than patients without neuropsychiatric symptoms (31.9 ± 14.2 ng/mL, n=48) (p=0.001). The Wilcoxon rank-sum test showed that thiamine serum levels after chemotherapy were significantly lower than those before administration of chemotherapy in hematological cancer patients (p=0.001).
Conclusion
Our study showed that a decrease in thiamine serum levels may be a risk factor for neuropsychiatric symptoms, and chemotherapy may lead to a decrease in thiamine serum levels.

Initial Report to Develop Robust Deep Learning Model for Detecting Genomic Status in Gliomas Against Image Differences among Facilities

Author(s)：: Satoshi Takahashi^1,2, Masamichi Takahashi^3,4, Kinoshita Manabu⁵, Mototaka Miyake⁶, Kazuma Kobayashi¹, Jun Sese^7,8,
Koichi Ichimura⁹, Yoshitaka Narita³, Ryuji Hamamoto^1,2, Consortium Of Molecular Diagnosis Of Glioma¹⁰
Affiliation(s)：: ¹Division of Medical AI Research and Development, National Cancer Center Research Institute, ²Cancer Translational Research Team, RIKEN Center for Advanced Intelligence Project,³Department of Neurosurgery and Neuro-Oncology, National Cancer Center Hospital,⁴Division of International Collaborative Research, National Cancer Center,⁵Department of Neurosurgery, Asahikawa Medical University,⁶Department of Diagnostic Radiology, National Cancer Center,⁷Artificial Intelligence Research Center,, , National Institute of Advanced Industrial Science and Technology, Tokyo, Japan,⁸Humanome Lab Inc.,,⁹Department of Brain Disease Translational Research, Faculty of Medicine, Juntendo University,¹⁰Consortium of Molecular Diagnosis of glioma

Background: The importance of detecting genomic status of gliomas is increasingly recognized and IDH (isocitrate dehydrogenase) mutation and TERT (telomerase reverse transcriptase) promoter mutation have a significant impact on treatment decisions. Noninvasive prediction of these genomic status in gliomas is a challenging problem, however, deep learning model using magnetic resonance imaging (MRI) can be a solution. The image differences among facilities causing performance degradation, called domain shift, has been also reported in other tasks such as brain tumor segmentation. We investigated whether the gene status could be predicted by a deep learning model, and if so, to what extent it would be affected by domain shift.

Method: We used the data from the Multimodal Brain Tumor Segmentation Challenge (BraTS) and the Japanese cohort (JC) dataset consisted of brain tumor images collected from 544 patients in 10 facilities in Japan. We focused on IDH mutation and TERT promoter mutation. The deep learning models to predict the status of these genes were trained by the BraTS dataset or the training portion of JC dataset, and the accuracy of the models was evaluated by the test portion of JC dataset.

Results: The IDH mutation predicting model trained by the BraTS dataset showed 80.0% of accuracy with the validation portion of BraTS dataset, however, only 67.3% with the test portion of JC dataset. The TERT promoter mutation predicting model trained by the training portion of JC dataset showed only 49% of accuracy for the test portion of JC dataset.

Conclusion: IDH mutation can be predicted by deep learning models using MRI, but the performance degeneration by domain shift was significant. On the other hands, TERT promoter mutation could not be predicted enough by current deep learning techniques. In both mutations, further studies are needed.

Sexual health problems and unmet needs in cancer survivors

Author(s)：: Chie Watanabe¹, Akiko Ikeda², Megumi Umeda²
Affiliation(s)：: ¹School of Nursing and Rehabilitation Sciences, Showa University, ²Cancer Net Japan

【目的】がん経験者のセクシュアリティ支援プログラム開発の前調査として、がん治療やがんの進行に伴う性生活への影響と支援における課題を明らかにすることを目的にがん経験者を対象に実態調査を行った。
【方法】2021年に認定NPO法人キャンサーネットジャパンのML登録者を対象にWEB調査を行った。主な調査項目は、がん治療後の性生活の変化と性機能障害の有無とその内容、性に関する相談経験の有無と支援に関するニーズとした。
【結果】470名(男性156名、女性314名)のがん経験者より有効回答を得た。回答者のがん種は乳がん36.2%、造血器腫瘍23.6%を占めていた。現在の性生活にとてももしくは満足していると回答者は24.4%に留まっていた。がん治療後の性生活の頻度の変化は、がん治療前に月1回以上性生活があったうちの48.9%(男性55.6%，女性45.7%)は性生活が全くない状況にあった。調査時に月1回以上の性生活のある238名のうち、85名(35.7%)が性欲の低下を感じており、有意な性差は認められなかった。また、女性では性交疼痛が27.2%、男性の29.0%に勃起障害が認められた。性生活への抵抗感として頻度の多いものは、全体では「性的な気持ちになれない」17.0%、性別で有意な差がみられた意見は、女性では「治療後の身体の変化を見られたくない」17.2% (p<0.001)が、男性では「体力がない」13.5% (p=0.002)が多い傾向がみられた。「性行為による感染症・病気への影響が怖い」と回答したものは5.7%であった。これらの抵抗感にAYA世代かどうかの年齢による差はみられなかった。セクシュアリティに関して「相談が誰にもできなかった」と回答したのは34.9%で、8割以上が支援の不十分さを感じていた。支援の在り方については、医療者からの情報提供のみではなく、半数以上が経験者の体験談や情報共有を希望していた。具体的な支援方法については、プライバシーの保護や匿名性が確保されたWEB上での相談、医療者とあたり前に話すことができるようなコミュニケーションや治療開始前からの情報提供の必要性などの意見が多く見られた。
【考察】性生活を継続しているがん経験者の約3割で性機能への影響が生じていることが明らかになった。また、性生活への抵抗感もあり、それらの多くは相談に至らないunmet needsとなっていることが指摘された。今後は医療者のセクシュアリティに関する相談への教育やWEB上での支援ツールの開発が求められる。