Yasuyuki Okada, Yasushi Sato, Ryo Shinomiya, Takanori Miyake, Taku Takahashi, Reiko Yokoyama, Yasuhiro Mitsui, Tetsu Tomonari, Koichi Okamoto, Masahiro Sogabe, Hiroshi Miyamoto, Yutaka Kawano and Tetsuji Takayama : Conditions for effective use of liposomal irinotecan with fluorouracil and leucovorin in unresectable pancreatic cancer after FOLFIRINOX treatment., International Journal of Clinical Oncology, Online ahead of print., 2025.
(Summary)
Liposomal irinotecan + fluorouracil/leucovorin (nal-IRI + 5FU/LV) is commonly used as a second- or later-line treatment for pancreatic ductal adenocarcinoma (PDAC) and offers survival benefits. However, its efficacy and safety in patients previously treated with FOLFIRINOX, which includes irinotecan, remain unclear. We evaluated the efficacy and safety of nal-IRI + 5FU/LV in patients with unresectable PDAC who received previous FOLFIRINOX therapy and those who did not. This retrospective observational study included 42 patients with PDAC who were treated with nal-IRI + 5FU/LV (October 2020-November 2023). Patients were grouped based on prior FOLFIRINOX treatment. The progression-free survival (PFS) in patients who previously received modified FOLFIRINOX (mFFX) therapy was shorter than that in patients who did not (2.5 vs. 3.5 months, P = 0.07). When patients with greater than- and less than the cut-off value of irinotecan-free interval (IFI) were classified into the long and short IFI groups, respectively, PFS was significantly longer in the long-IFI group than that in the short IFI group (4.0 vs. 2.1 months, P = 0.01). Moreover, the C-reactive protein/albumin ratio (CAR) was also a significant predictor of PFS (P = 0.03). Furthermore, both factors were found to be independent factors influencing PFS in the univariate Cox regression analysis (P = 0.02 and P = 0.04). Nal-IRI + 5FU/LV therapy may be a safe and effective option as a second- or later-line treatment, particularly for patients who have not previously received mFFX therapy. For patients who received prior mFFX exposure, a longer IFI and lower CAR may indicate greater potential benefit, thus aiding in more personalized treatment approaches.
Kaizo Kagemoto, Koichi Okamoto, Yasuyuki Okada, Motoko Sei, Shota Fujimoto, Mai Yagi, Takeshi Mitsuhashi, Hiroyuki Ueda, Takanori Yoshimoto, Takanori Kashihara, Tomoyuki Kawaguchi, Yoshifumi Kida, Yasuhiro Mitsui, Yutaka Kawano, Masahiro Sogabe, Hiroshi Miyamoto, Yasushi Sato, Naoki Muguruma and Tetsuji Takayama : Clinicopathological evaluation of the efficacy of endoscopic treatment for sessile serrated lesions comparing endoscopic mucosal resection, cold snare polypectomy, and underwater endoscopic mucosal resection., DEN Open, 5, 1, e70051, 2024.
(Summary)
Recently, various endoscopic treatments for colorectal polyps have been reported, including cold snare polypectomy (CSP) and underwater endoscopic mucosal resection (UEMR), in addition to EMR. However, a precise treatment strategy for sessile serrated lesions (SSL) has not been established. In this study, we analyzed the clinicopathological features of SSL resected by EMR, CSP, and UEMR to determine the most suitable treatment for SSL. A total of 92 SSL resected via EMR ( = 11), CSP ( = 36), and UEMR ( = 45) were retrospectively enrolled between February 2021 and October 2022. To evaluate pathological findings, we examined SSL samples, which were stretched before formalin fixation and sectioned at 2-mm intervals. Primary outcomes were the R0 resection rate and thickness of submucosal (SM) tissue specimens for each treatment. In addition, we evaluated SSL with dysplasia (SSLD) and the inverted growth pattern which may affect the vertical margin. The R0 resection rate significantly differed among the three groups (EMR, 73%; CSP, 42%; UEMR, 87%, = 0.001). The median thickness of SM tissue resected by CSP (0 µm) was significantly less than that by EMR (362 µm) and UEMR (325 µm; < 0.001). All four SSLDs were diagnosed endoscopically. Five SSLs with inverted growth patterns were pathologically diagnosed. Of these, two SSLs with inverted growth patterns could not be diagnosed endoscopically. UEMR is considered to be a suitable treatment option for SSL. CSP results were pathologically insufficient. Therefore, surveillance to evaluate local recurrence is important, and the results of further multicenter prospective studies should be referred.
Tetsu Tomonari, Joji Tani, Yasushi Sato, Hironori Tanaka, Aasahiro Morishita, Koichi Okamoto, Yutaka Kawano, Masahiro Sogabe, Hiroshi Miyamoto and Tetsuji Takayama : Initial treatment efficacy and safety of durvalumab plus tremelimumab combination therapy in unresectable hepatocellular carcinoma in clinical practice., JGH Open, 8, 10, e70033, 2024.
(Summary)
We aimed to evaluate the efficacy and safety of durvalumab plus tremelimumab (Dur + Tre) combination therapy in patients with unresectable hepatocellular carcinoma (uHCC) in clinical practice. We retrospectively evaluated 37 patients with uHCC from our institutions between April 2023 and January 2024. Patients were divided into first- and later-line groups for analysis of antitumor efficacy, adverse events (AEs), and transition rate to second-line treatment according to the Response Evaluation Criteria in Solid Tumors (RECIST). The disease control rate (DCR) for the first-line group was 80.9%, which was significantly higher than that for the later-line group (50%). The incidence of immune-related AEs (irAEs) was 24.3%, with grade 3 or higher irAEs including increased transaminase (8.1%), diarrhea (8.1%), and adrenal insufficiency (2.7%). The rates of drug withdrawal and discontinuation owing to AEs were 23.8% and 19%, respectively, in the first-line treatment and 31.2% and 12.5%, respectively, in the later-line treatment, with no significant difference. Analysis of changes in liver reserve using the albumin-bilirubin (ALBI) score showed no obvious loss of liver reserve for up to 12 weeks. The transition rate from first- to second-line therapy after progressive disease (PD) was as high as 94.7%. The efficacy and safety of Dur + Tre in clinical practice were comparable to those reported in a recent phase III trial. The first-line Dur + Tre therapy had a higher DCR than that of the later lines, and the transition rate to second-line therapy was considerably high, suggesting that Dur + Tre therapy would be more beneficial in first-line treatment.
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer. Recent studies indicated that cancer-associated adipocytes (CAAs) play crucial roles in tumor progression; however, the precise mechanism remains unknown. Here, we analyzed specific exosomal microRNAs (miRNA) signatures derived from pancreatic CAAs to investigate their role in cancer progression. CAAs were generated by co-culturing human adipocytes with human pancreatic cancer cells, and exosomes were isolated from the CAA-conditioned medium (CAA-CM). Small RNA-seq analysis was used to identify differentially expressed miRNAs in these exosomes. The effects of miRNAs on cell proliferation, migration/invasion, and drug sensitivity were examined. Luciferase reporter assays, real-time polymerase chain reaction, and western blotting were performed to investigate the molecular mechanisms of the miRNAs. The clinical relevance of the miRNAs was investigated using publicly available data and our cohort of patients with PDAC. miR-199a-3p expression was significantly increased in CAA-CM-derived exosomes. CAA-derived exosomes transferred miR-199a-3p to pancreatic cancer cells. Transfection with miR-199a-3p increased the proliferation, invasion, migration, and drug resistance of pancreatic cancer cells by downregulating SOCS7, increasing STAT3 phosphorylation, and upregulating SAA1 expression. High tissue miR-199a-3p expression is correlated with poor prognosis in patients with PDAC. Liquid biopsies revealed that exosomal miR-199a-3p could accurately differentiate patients with PDAC from healthy controls. Multivariate survival analysis indicated that miR-199a is an independent prognostic factor for PDAC. miR-199a-3p in CAA-derived exosomes contributes to the malignant transformation of pancreatic cancer via the SOCS7/STAT3/SAA1 pathway, suggesting its potential as a biomarker and therapeutic target for PDAC.
Masahiro Sogabe, Toshiya Okahisa, Miwako Kagawa, Takanori Kashihara, Ryo Shinomiya, Takanori Miyake, Tomoyuki Kawaguchi, Reiko Yokoyama, Kaizo Kagemoto, Yoshifumi Kida, Yasuyuki Okada, Tetsu Tomonari, Yutaka Kawano, Yasushi Sato, Masahiko Nakasono and Tetsuji Takayama : The association between alcohol consumption and cardiometabolic factors and liver fibrosis in metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction and alcohol-associated liver disease., Alimentary Pharmacology & Therapeutics, 60, 11-12, 1587-1598, 2024.
(Summary)
The relationships between alcohol consumption, cardiometabolic factors, and liver fibrosis in patients with metabolic dysfunction-associated steatotic liver disease and those with metabolic dysfunction and alcohol-associated liver disease remain unclear. To investigate the longitudinal associations among alcohol consumption, cardiometabolic factors, and liver fibrosis in patients with these two liver diseases. This observational cohort study included 1866 patients with metabolic dysfunction-associated steatotic liver disease and 521 patients with metabolic dysfunction and alcohol-associated liver disease who underwent > two health checkups over >2 years. The associations of both liver diseases with worsening non-invasive liver fibrosis scores were assessed using the Cox regression analysis. Both liver diseases independently worsened liver fibrosis in both sexes. However, the hazard ratio for worsening liver fibrosis in females was significantly higher with metabolic dysfunction and alcohol-associated liver disease than with metabolic dysfunction-associated steatotic liver disease. Worsening liver fibrosis was not associated with alcohol consumption. Among males with metabolic dysfunction-associated steatotic liver disease, the hazard ratio for worsening liver fibrosis was significantly higher in those with multiple cardiometabolic factors compared to those with a single cardiometabolic factor. Although both metabolic steatotic liver disease and metabolic alcohol-associated liver disease were correlated with liver fibrosis progression in both sexes, the impact of alcohol consumption and cardiometabolic factors on fibrosis progression differed by sex. Cardiometabolic factors may have a stronger impact on liver fibrosis than alcohol consumption in males with metabolic dysfunction-associated steatotic liver disease.
Masahiro Sogabe, Toshiya Okahisa, Miwako Kagawa, Motoko Sei, Hiroyuki Ueda, reiko yokoyama, Kaizo Kagemoto, Hironori Tanaka, Yoshifumi Kida, Fumika Nakamura, Tetsu Tomonari, Koichi Okamoto, Yutaka Kawano, Hiroshi Miyamoto, Yasushi Sato, Masahiko Nakasono and Tetsuji Takayama : Association of metabolic dysfunction-associated steatotic liver disease with erosive esophagitis development: a longitudinal observational study., Journal of Gastroenterology and Hepatology, 39, 6, 1107-1114, 2024.
(Summary)
Although erosive esophagitis (EE) is associated with fatty liver and metabolic dysregulation, the association between EE and metabolic dysfunction-associated steatotic liver disease (MASLD) remains unclear. Thus, this study aimed to investigate the longitudinal association between MASLD and EE. We included 1578 patients without EE at baseline who underwent more than two health checkups over 2 years. Generalized estimation equations were used to analyze associations between MASLD and EE according to repeated measures at baseline and most recent stages. EE development rates in men and women were 14.5% and 7.2%, respectively. After adjusting for lifestyle habits, the odds ratios of MASLD for EE development in men and women were 1.907 (95% confidence interval [CI]: 1.289-2.832, P < 0.005) and 1.483 (95% CI: 0.783-2.811, P = 0.227), respectively. In the subgroup analysis, after adjusting for lifestyle habits, among men and women aged 50 years with more than three MASLD components, the odds ratios for EE development were 2.408 (95% CI: 1.505-3.855, P < 0.001) and 2.148 (95% CI: 1.093-4.221, P < 0.05), respectively. After adjusting for various factors, the significant risk factors for EE development were different between men and women. The influence of MASLD and other factors on EE development differed by sex and age. Particularly, patients aged 50 years with MASLD and with an increased number of MASLD components should be considered at increased risk for EE.
Masahiro Sogabe, Toshiya Okahisa, Miwako Kagawa, Takanori Kashihara, shota Fujimoto, Tomoyuki Kawaguchi, Reiko Yokoyama, Kaizo Kagemoto, Hironori Tanaka, Yoshifumi Kida, Tetsu Tomonari, Yutaka Kawano, Yasushi Sato, Masahiko Nakasono and Tetsuji Takayama : Impact of alcohol consumption on metabolic dysfunction-associated fatty liver disease development and remission: A longitudinal cohort study., European Journal of Clinical Investigation, 54, 9, e14221, 2024.
(Summary)
The influence of alcohol intake on metabolic dysfunction-associated fatty liver disease (MAFLD) development and remission remains unclear; thus, we aimed to investigate their longitudinal associations. This observational cohort study included 6349 patients who underwent more than two health check-ups over >2 years between April 2013 and March 2021. Generalized estimation equations were used to analyse the longitudinal associations between changes in alcohol intake and MAFLD according to repeated measures at baseline and the most recent stage. The MAFLD development and remission rates were 20.4 and 5.1 and 9.1 and 4.7% in men and women, respectively. Although alcohol consumption was not a significant factor for MAFLD development, consuming 0.1-69.9 g/week (odds ratio [OR]: 0.672, 95% confidence interval [CI]: 0.469-0.964, p < .05) and 280 g/week were significant factors for MAFLD development in males (OR: 1.796, 95% CI: 1.009-3.196, p < .05) and females (OR: 16.74, 95% CI: 3.877-72.24, p < .001). Regardless of quantity and frequency, alcohol consumption was not a significant factor for MAFLD remission. Several noninvasive liver fibrosis scores were significantly associated with alcohol intake quantity and frequency in males with MAFLD development and remission (p < .05). The nonalcoholic fatty liver disease fibrosis score differed significantly between males with and without reduced alcohol intake (p < .05) who showed MAFLD remission. Although the influence of alcohol intake on MAFLD development and remission differed, alcohol consumption was not beneficial for MAFLD remission in either sex. Alcohol intake reduction or cessation is recommended to prevent liver fibrosis, even in those who achieve MAFLD remission.
Ryo Shinomiya, Yasushi Sato, Takanori Yoshimoto, Tomoyuki Kawaguchi, Akihiro Hirao, Koichi Okamoto, Yutaka Kawano, Masahiro Sogabe, Hiroshi Miyamoto and Tetsuji Takayama : A case of treatmentresistant advanced gastric cancer with FGFR2gene alteration successfully treated with pemigatinib., International Cancer Conference Journal, 13, 240-244, 2024.
Yutaka Kawano, Maki Tanaka, Yasushi Sato, Shigekazu Sugino, Jun Suzuki, Masaki Fujishima, Eri Okumura, Hideo Takekoshi, Osamu Uehara, Shintaro Sugita, Yoshihiro Abiko, Tetsu Tomonari, Hironori Tanaka, Hidekatsu Takeda and Tetsuji Takayama : Acanthopanax senticosus ameliorates steatohepatitis through HNF4 alpha pathway activation in mice., Scientific Reports, 14, 1, 110, 2024.
(Summary)
Non-alcoholic fatty liver disease is a common liver disease worldwide, and is associated with dysregulation of lipid metabolism, leading to inflammation and fibrosis. Acanthopanax senticosus Harms (ASH) is widely used in traditional medicine as an adaptogen food. We examined the effect of ASH on steatohepatitis using a high-fat diet mouse model. Mice were fed a choline-deficient, L-amino acid-defined, high-fat diet with ASH extract (ASHE). After 6 weeks, liver RNA transcriptome sequencing (RNA-Seq) was performed, followed by Ingenuity Pathway Analysis (IPA). Our findings revealed that mice fed a high-fat diet with 5% ASHE exhibited significantly reduced liver steatosis. These mice also demonstrated alleviated inflammation and reduced fibrosis in the liver. IPA of RNA-Seq indicated that hepatocyte nuclear factor 4 alpha (HNF4 alpha), a transcription factor, was the activated upstream regulator (P-value 0.00155, z score = 2.413) in the liver of ASHE-fed mice. Adenosine triphosphate binding cassette transporter 8 and carboxylesterase 2, downstream targets of HNF4 alpha pathway, were upregulated. Finally, ASHE-treated HepG2 cells exposed to palmitate exhibited significantly decreased lipid droplet contents. Our study provides that ASHE can activate HNF4 alpha pathway and promote fat secretion from hepatocytes, thereby serving as a prophylactic treatment for steatohepatitis in mice.
Tetsu Tomonari, Joji Tani, Yasushi Sato, Hironori Tanaka, Takahiro Tanaka, Tatsuya Taniguchi, Yutaka Kawano, Asahiro Morishita, Koichi Okamoto, Masahiro Sogabe, Hiroshi Miyamoto, Tsutomu Masaki and Tetsuji Takayama : Clinical Features and Outcomes of Conversion Therapy in Patients with Unresectable Hepatocellular Carcinoma., Cancers, 15, 21, 5221, 2023.
(Summary)
<jats:p>This retrospective multicenter study analyzed 244 patients with unresectable hepatocellular carcinoma treated with lenvatinib (LEN) and atezolizumab + bevacizumab (Atezo + Bev) to examine the characteristics, treatment courses, and prognoses. The cases of patients who could achieve HCC downstaging from Barcelona Clinic Liver Cancer (BCLC) stage B or C to A or zero indicated the need for conversion therapy. The patients' prognoses with and without conversion therapy were compared. Of the 244 patients, 12 (4.9%) underwent conversion therapy, six out of 131 (4.6%) were treated with LEN, and six out of 113 (5.3%) were treated with Atezo + Bev. Eleven patients (91.7%) with a modified albumin bilirubin (mALBI) grade 1 or 2a and BCLC-B stage showed significantly higher rates of transition during conversion therapy (p < 0.05). The patients undergoing conversion therapy had a significantly longer median overall survival rate than those receiving chemotherapy alone (1208 [1064–NA] vs. 569 [466–704] days, p < 0.01). A comparison of the patients who achieved a partial response with and without conversion was evaluated using propensity score matching to reduce the confounding factors, showing a significant survival benefit in the conversion group (1208 [1064–NA] vs. 665 days, p < 0.01). Among the patients with u-HCC who were treated with LEN and Atezo + Bev, those with mALBI 1 + 2a and BCLC-B were likely to achieve conversion therapy with downstaging.</jats:p>
Reiko Yokoyama, Yasushi Sato, Fumika Nakamura, Kaizo Kagemoto, Yasuhiro Mitsui, Koichi Okamoto, Yutaka Kawano, Masahiro Sogabe, Hiroshi Miyamoto and Tetsuji Takayama : Efficacy of immune checkpoint inhibitors in patients with anorectal melanoma in association with immune-related adverse events: a case series., Clinical Journal of Gastroenterology, Online ahead of print., 2023.
(Summary)
Anorectal melanoma (AM) is a rare subtype of mucosal melanoma with a poor prognosis. Given its rarity compared to its cutaneous counterpart, the benefits and side effects of immune checkpoint inhibitor (ICI) therapy and the relationship between side effects and prognosis remain unclear. Herein, we describe the clinical presentation of five patients with AM treated with ICI as well as their relationship to the treatment course and the development of immune-related adverse events (irAEs). Three patients received sequential or concurrent administrations of nivolumab and ipilimumab, one received nivolumab alone, and one received ipilimumab alone. The response rate (RR) and disease control rate (DCR) were 40% and 80%, respectively. Pituitary and hepatic dysfunctions were the most common irAEs observed (40% each), followed by thyroid, diarrhea, and renal dysfunctions (20% each). The RR was 67% in patients with irAEs while no response was observed in patients without irAEs. DCR was 100% and 50% in patients with and without irAEs, respectively. Overall survival was 34 months in irAE and 8.75 months in non-irAE cases, with a longer survival trend in irAE cases. ICI therapy was effective and well-tolerated by AM patients, with potentially better outcomes for those who experienced irAEs compared to those who did not.
Yasushi Sato, Koichi Okamoto, Yutaka Kawano, Akinari kasai, Tomoyuki Kawaguchi, Tamotsu Sagawa, Masahiro Sogabe, Hiroshi Miyamoto and Tetsuji Takayama : Novel Biomarkers of Gastric Cancer: Current Research and Future Perspectives., Journal of Clinical Medicine, 12, 4646, 2023.
(Summary)
Gastric cancer is a heterogeneous disease with diverse histological and genomic subtypes, making it difficult to demonstrate treatment efficacy in clinical trials. However, recent efforts have been made to identify molecular biomarkers with prognostic and predictive implications to better understand the broad heterogeneity of gastric cancer and develop effective targeted therapies for it. HER2 overexpression, HER2/neu amplification, MSI-H, and PD-L1+ are predictive biomarkers in gastric cancer, and a growing number of clinical trials based on novel biomarkers have demonstrated the efficacy of targeted therapies alone or in combination with conventional chemotherapy. Enrichment design clinical trials of targeted therapies against FGFR2b and claudin 18.2 have demonstrated efficacy in unresectable advanced gastric cancer. Nonetheless, it is essential to continuously validate promising molecular biomarkers and introduce them into clinical practice to optimize treatment selection and improve patient outcomes. In this review, we focused on established (PD-L1, HER2, MSI) and emerging biomarkers (FGFR2, CLDN18.2) in gastric cancer, their clinical significance, detection methods, limitations, and molecular agents that target these biomarkers.
Tamotsu Sagawa, Yasushi Sato, Hiroyuki Nagashimia, Kohichi Takada, Mamoru Takahashi, Masahiro Hiarakawa, Kyoko Hamaguchi, Fumito Tamura, Koshi Fujikawa, Koichi Okamoto, Yutaka Kawano, Masahiro Sogabe, Hiroshi Miyamoto and Tetsuji Takayama : Hilar/mediastinal and cutaneous drug-induced sarcoidosis-like reaction associated with immune checkpoint inhibitors in metastatic colorectal cancer: a case report., Frontiers in Immunology, 14, 1203621, 2023.
(Summary)
Immune checkpoint inhibitors (ICIs) are the standard treatment for metastatic colorectal cancer (mCRC) with high microsatellite instability (MSI-H). Among immune-related adverse events (irAEs), drug-induced sarcoidosis-like reactions (DISR) are often difficult to differentiate from cancer progression. This is a case of a woman in her mid-60s, with mCRC (RAS wild/BRAF mutant/MSI-H) and abdominal lymph node metastasis, treated with four courses of ipilimumab + nivolumab every 3 weeks, followed by nivolumab every 2 weeks as third-line treatment. After treatment, the original lymph node metastases shrank, but hilar/mediastinal lymph nodes appeared. Endoscopic ultrasound-guided fine-needle aspiration of these lymph nodes revealed multiple epithelioid granulomas without necrosis, indicating a sarcoidosis-like reaction. Fluorodeoxyglucose-positron emission tomography scan showed abnormal subcutaneous accumulation in bilateral forearms and bilateral knee joints. Biopsy of the cutaneous lesions was also performed, which revealed epithelioid granulomas. As the patient had no symptoms in other organs, no specific therapeutic intervention was administered. After the discontinuation of immunotherapy, the sarcoidosis-like reaction regressed without cancer relapse. Clinicians should be aware of the possibility of DISR as an irAE during the ICI treatment of mCRC. In suspected cases of DISR following ICI therapy, it is important to differentiate between cancer progression and DISR through histological diagnosis for the subsequent strategy, as radiological and serological findings are not definitive.
Tamotsu Sagawa, Yasushi Sato, Masahiro Hirakawa, Kyoko Hamguchi, Fumito Tamura, Hiroyuki Nagashima, Koshi Fujikawa, Koichi Okamoto, Yutaka Kawano, Masahiro Sogabe, Hiroshi Miyamoto and Tetsuji Takayama : Case Report: Longitudinal monitoring of clonal evolution by circulating tumor DNA for resistance to anti-EGFR antibody in a case of metastatic colorectal cancer., Frontiers in Oncology, 13, 1203296, 2023.
(Summary)
Treatment with anti-EGFR antibody has been shown to prolong survival in patients with RAS wild-type metastatic colorectal cancer (mCRC). However, even patients who initially respond to anti-EGFR antibody therapy, almost without exception, develop resistance to the therapy and then fail to respond. Secondary mutations in the mitogen-activated protein (MAPK) signaling pathway (mainly in NRAS and BRAF) have been implicated in anti-EGFR resistance. However, the process by which resistant clones develop during therapy has not been elucidated, and considerable intrapatient and interpatient heterogeneity exists. Circulating tumor DNA (ctDNA) testing has recently allowed the noninvasive detection of heterogeneous molecular alterations that underlie the evolution of resistance to anti-EGFR. In this report, we describe our observation of genomic alterations in and in a patient with acquired resistance to anti-EGFR antibody drugs by tracking clonal evolution using serial ctDNA anaylsis. A 54-year-old woman was initially diagnosed with sigmoid colon cancer with multiple liver metastases. After receiving first-line mFOLFOX + cetuximab, second-line FOLFIRI + ramucirumab, third-line trifluridine/tipiracil + bevacizumab, fourth-line regorafenib, and fifth-line CAPOX + bevacizumab, she was rechallenged with CPT-11 + cetuximab. The best response to anti-EGFR rechallenge therapy was a partial response. in the ctDNA was assessed during treatment. The status changed from wild type to mutant type, back to wild type, and again to mutant type ( codon 61) during the course of treatment. In this report, tracking of ctDNA allowed us to describe clonal evolution in a case in which we observed genomic alterations in and in a patient who acquired resistance to anti-EGFR antibody drugs during treatment. It is reasonable to consider repeat molecular interrogation during progression in patients with mCRC by using ctDNA analysis, which could help to identify patients who may benefit from a rechallenge strategy.
Tetsu Tomonari, Hironori Tanaka, Takahiro Tanaka, Tatsuya Taniguchi, Masahiro Sogabe, Yutaka Kawano, Koichi Okamoto, Hiroshi Miyamoto, Yasushi Sato and Tetsuji Takayama : A case of complete response with rechallenge-lenvatinib plus transcatheter arterial chemoembolization for unresectable hepatocellular carcinoma refractory to multiple molecular-targeted agent treatments., Clinical Journal of Gastroenterology, 16, 3, 438-443, 2023.
(Summary)
The efficacy of lenvatinib (LEN) plus transcatheter arterial chemoembolization (LEN-TACE) has been reported, but its effect on unresectable hepatocellular carcinoma (HCC) refractory to LEN therapy has not been demonstrated. We report a case of HCC refractory to multiple molecular-targeted agents (MTA) treatments, including LEN, that was successfully treated with LEN-TACE. A 59-year-old man was referred to our department with multiple HCCs and a background of hepatitis B virus infection. TACE was the initial treatment. However, he was determined to be TACE-refractory, and multitargeted therapy was initiated. LEN was started at 12 mg/day but resulted in progressive disease (PD) after 13 months of the administration. The response to second-line sorafenib was PD after 2 months. Third-line therapy with atezolizumab + bevacizumab was stopped after one course because of an immune-related adverse event (i.e., dermatitis). The response to fourth-line regorafenib was PD at 2 months, and the response to fifth-line cabozantinib was PD after 6 months. The efficacy of LEN-TACE was recently reported; therefore, we decided to attempt LEN-TACE therapy as a salvage line. After obtaining the patient's consent to repeat LEN and TACE, treatment was initiated. The tumor markers levels markedly reduced after LEN-TACE therapy. After three additional TACE treatments with continued LEN administration, the tumor marker levels normalized, and complete response was determined based on RECIST guidelines. LEN-TACE therapy may effectively treat unresectable advanced HCC in the LEN-rechallenge setting and may be a treatment option as a last-line therapeutic option.
Tetsu Tomonari, Joji Tani, Chikara Ogawa, Akihiro Deguchi, Tomonori Senoh, Akio Moriya, Hiroshi Shibata, Hiroshi Fukuno, Hironori Tanaka, Takahiro Tanaka, Tatsuya Taniguchi, Masahiro Sogabe, Yutaka Kawano, Akihiro Morishita, Koichi Takaguchi, Hiroshi Miyamoto, Yasushi Sato, Tsutomu Masaki and Tetsuji Takayama : Multicenter retrospective study of Initial treatment outcome and feasibility of initiating dose reduction of cabozantinib in unresectable hepatocellular carcinoma., Hepatology Research, 53, 2, 172-178, 2023.
(Summary)
Cabozantinib (CAB), a multiple kinase inhibitor, has been approved for use in patients with previously treated unresectable hepatocellular carcinoma (uHCC). However, real-world clinical data are lacking, particularly clinical data regarding dose modifications of CAB. We analyzed the clinical outcomes of CAB in uHCC and compared treatment outcomes between the full- and reduced-dose groups. This multicenter, observational study included patients with uHCC who were treated with CAB from March 2021 to April 2022. Patient characteristics, efficacy, and safety were compared between the full- and reduced-dose groups. Twenty-six patients from eight institutes were analyzed. Cabozantinib was administered as a third-line or later treatment in 25 (96.2%) patients and postimmunotherapy in 21 (80.5%) patients. There were 15 patients in the full-dose group (60 mg CAB) and 11 in the reduced-dose group (40 or 20 mg CAB). The objective response rate (ORR) and disease control rate (DCR) were not significantly different between the two groups. The ORR was 6.7% for the full-dose group and 9.1% for the reduced-dose group, and the DCR was 53.4% and 81.8%, respectively. Progression-free survival analysis showed no significant differences between the two groups. The incidence of decreased appetite, fatigue, and diarrhea, and the rate of discontinuation and dose reduction, was significantly higher in the full-dose group. Our study suggests that the efficacy and safety of CAB in real-world clinical practice are comparable to those of the phase III trial (CELESTIAL), and that dose reduction of CAB may be a safer treatment option.
Yasushi Sato, Yasuyuki Okada, Yasuteru Fujino, Tomoyuki Kawaguchi, Yoshifumi Kida, Yasuhiro Mitsui, Hironori Tanaka, Tetsu Tomonari, Shinji Kitamura, Koichi Okamoto, Yutaka Kawano, Hiroshi Miyamoto, Masahiro Sogabe and Tetsuji Takayama : Clinical Outcomes of Comprehensive Genomic Profiling Tests for Gastrointestinal Cancers: Experience from Tokushima University Hospital., The Journal of Medical Investigation : JMI, 70, 1.2, 154-159, 2023.
(Summary)
In Japan, cancer genome profiling (CGP) for cancer patients without standard treatment has been covered by public insurance since June 2019. This study analyzed data of 122 patients with gastrointestinal tumors who underwent CGP to clarify cancer genome medicine's current status and possible problems at the Tokushima University Hospital. The major types of cancer included pancreatic (n=30), colorectal (n=25), biliary tract (n=15), gastric (n=11), and hepatocellular carcinoma (n=8). CGP tests included F1CDx in 70 patients (57%), F1LCDx in 36 (30%), TSO500 in 14 (11%), and NCC Oncopanel in 2 (2%). Actionable gene alterations were identified in 72 patients (59%), but only 5 patients (4%) were treated for pancreatic (n=1), colorectal (n=3), and small bowel cancers (n=1). The main reasons for not receiving genotype-matched therapy included the lack of appropriate drugs or clinical trials that matched the actionable gene alterations (n=40) and the inability to participate in clinical trials (n=10). There is still not a sufficient number of patients receiving genotype-matched treatment for gastrointestinal cancers. To promote cancer genome medicine in regional areas, attempts to improve access to genotype-matched therapies are required, as well as to promote the development of new molecular-targeted drugs and clinical trials for these drugs. J. Med. Invest. 70 : 154-159, February, 2023.
Yutaka Kawano : Alterations in the oral microbiome of individuals with a healthy oral environment following COVID-19 vaccination, BMC Oral Health, 22, 1, 2022.
(Summary)
Several reports suggest that the microbiome of the digestive system affects vaccine efficacy and that the severity of coronavirus disease (COVID-19) is associated with decreased diversity of the oral and/or intestinal microbiome. The present study examined the effects of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine on the oral microbiome. Forty healthy Japanese oral healthcare personnel were recruited, and unstimulated saliva was collected before vaccination, after the 1st vaccination, and after the 2nd vaccination. Genomic DNA was extracted from saliva samples, and PCR amplicons of the 16S rRNA gene were analyzed using next-generation sequencing. Microbial diversity and composition were analyzed using Quantitative Insights into Microbial Ecology 2. In addition, alterations in microbial function were assessed using PICRUSt2. SARS-CoV-2 mRNA vaccination significantly increased oral bacterial diversity and significantly decreased the proportion of the genus Bacteroides. The SARS-CoV-2 mRNA vaccine alters the oral microbiome; accordingly, vaccination might have beneficial effects on oral health.
Yutaka Kawano, Nanae Watanabe, Masahiro Nishiyama, Tousei Ohmura, Hiroyoshi Mihara, Kaoru Ono, Maki Tanaka, Yasushi Sato, Tetsu Tomonari, Hidekatsu Takeda and Tetsuji Takayama : <Brief Reports>Feasibility and Safety of Food Containing Acanthopanax senticosus for Treating Patients with Cancer-Related Fatigue., Palliative Medicine Reports, 5, 1, 381-386, 2024.
(Summary)
Cancer-related fatigue (CRF) is a major obstacle to quality of life. Harms (ASH) is available as a botanical adaptogen food worldwide. This study aimed to assess the feasibility and safety of ASH in patients with CRF. Fifteen patients with CRF consumed ASH drink for 28 days. The primary endpoint was the completion rate of the study, and the secondary endpoints were changes in brief fatigue inventory (BFI), oxidative stress markers, and adverse events. Seven patients successfully completed the study. Four patients who had BFI <5.5 at enrollment revealed a decrease in BFI. The biological antioxidant potential/diacron-reactive oxygen metabolites ratio, potential antioxidant capacity, was increased but not significant ( = 0.063). No adverse events attributable to ASH were observed. Approximately 50% patients were successful in consuming ASH for 28 days. Patients with mild CRF showed improvement by using ASH. However, further investigations are needed to validate these findings.
Yasushi Sato, Koichi Okamoto, Yoshifumi Kida, Yasuhiro Mitsui, Yutaka Kawano, Masahiro Sogabe, Hiroshi Miyamoto and Tetsuji Takayama : Overview of Chemotherapy for Gastric Cancer., Journal of Clinical Medicine, 12, 4, 1336, Feb. 2023.
(Summary)
Gastric cancer (GC) is one of the most clinically challenging cancers worldwide. Over the past few years, new molecular-targeted agents and immunotherapy have markedly improved GC prognosis. Human epidermal growth factor receptor 2 (HER2) expression is a key biomarker in first-line chemotherapy for unresectable advanced GC. Further, the addition of trastuzumab to cytotoxic chemotherapy has extended the overall survival of patients with HER2-positive advanced GC. In HER2-negative GC, the combination of nivolumab, an immune checkpoint inhibitor, and a cytotoxic agent has been demonstrated to prolong the overall survival of GC patients. Ramucirumab and trifluridine/tipiracil, which are second- and third-line treatments for GC, and trastuzumab deruxtecan, an antibody-drug conjugate for HER2-positive GC, have been introduced in clinics. New promising molecular-targeted agents are also being developed, and combination therapy comprising immunotherapy and molecular-targeted agents is expected. As the number of available drugs increases, it is important to understand the target biomarkers and drug characteristics and select the optimal therapy for each patient. For resectable disease, differences in the extent of standard lymphadenectomy between Eastern and Western countries have led to different standard treatments: perioperative (neoadjuvant) and adjuvant therapy. This review aimed to summarize recent advances in chemotherapy for advanced GC.
Hironori Tanaka, Tetsu Tomonari, Ryo Shinomiya, Mai Yonezawa, Yutaka Kawano and Tetsuji Takayama : Usefulness of shear wave elastography for evaluation of HCC recurrence after ablation., APASL2024, Kyoto, Mar. 2024.
2.
Yutaka Kawano, Maki Tanaka, Yasushi Sato, Tetsu Tomonari, Hironori Tanaka, Takeshi Mitsuhashi and Tetsuji Takayama : Activation of HNF4α pathway by treatment with botanical plant, Acanthopanax Senticosus, ameliorates steatohepatitis in high-fat fed mice model., AASLD2023, Boston, Nov. 2023.
3.
Yasushi Sato, Kazuyoshi Noda, Yasuyuki Okada, Kensei Nishida, Yutaka Kawano, Toshihito Tanahashi, Masanori Takehara, Yasuteru Fujino, Koichi Okamoto, Hiroshi Miyamoto and Tetsuji Takayama : Exosomal miR-199a-3p secreted from cancer-associated adipocytes promote pancreatic cancer progression., DDW2023, Chicago, May 2023.
4.
Yutaka Kawano, Maki Tanaka, Yasushi Sato, Tetsu Tomonari, Hironori Tanaka, Takeshi Mitsuhashi and Tetsuji Takayama : Activation of HNF4α pathway by treatment with botanical plant, Acanthopanax senticosus, ameliorates steatohepatitis in high-fat fed mice model., DDW2023, Chicago, May 2023.