Gastric Cancer最新文献

{"title":"Survival outcomes of patients with gastric cancer treated with first-line nivolumab plus chemotherapy based on claudin 18.2 expression.","authors":"Hyung-Don Kim, Jinho Shin, Jaewon Hyung, Hyungeun Lee, Meesun Moon, Jeongeun Ma, Young Soo Park, Min-Hee Ryu","doi":"10.1007/s10120-024-01566-7","DOIUrl":"https://doi.org/10.1007/s10120-024-01566-7","url":null,"abstract":"<p><strong>Background: </strong>Claudin 18.2 has emerged as a viable therapeutic target in gastric cancer; however, its clinical relevance in the context of immune checkpoint inhibitor-based chemotherapy is not known. This study aimed to investigate the efficacy of nivolumab plus chemotherapy according to claudin 18.2 expression in patients with gastric cancer.</p><p><strong>Methods: </strong>This single-center study included patients with advanced gastric cancer who were treated with first-line nivolumab plus chemotherapy (n = 204) or chemotherapy alone (n = 183) whose claudin 18.2 immunohistochemistry results were available. Claudin 18.2 positivity (moderate-to-strong expression in ≥ 75% by the 43-14A clone) was analyzed in terms of efficacy outcomes.</p><p><strong>Results: </strong>Among patients treated with nivolumab plus chemotherapy, 96 (47.1%) were assessed to have claudin 18.2-positive tumors. Between patients with claudin 18.2-positive and -negative tumors, objective response rate with nivolumab plus chemotherapy was comparable. Progression-free survival (PFS) and overall survival (OS) with nivolumab plus chemotherapy were comparable between those with claudin 18.2-positive and -negative tumors. For both subgroups with PD-L1 combined positive score ≥ 5 and < 5, PFS and OS with nivolumab plus chemotherapy were also comparable between patients with claudin 18.2-positive and -negative tumors. A consistent trend of favorable PFS and OS was observed with nivolumab plus chemotherapy compared to that of chemotherapy alone in both claudin 18.2-positive and -negative subgroups.</p><p><strong>Conclusion: </strong>The efficacy of nivolumab plus chemotherapy did not vary according to claudin 18.2 positivity. The clinical benefit of nivolumab plus chemotherapy over chemotherapy was consistently observed in claudin 18.2-positive and -negative gastric cancer cases.</p>","PeriodicalId":12684,"journal":{"name":"Gastric Cancer","volume":" ","pages":""},"PeriodicalIF":6.0,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142618668","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Short-term outcomes of a phase II trial of perioperative capecitabine plus oxaliplatin therapy for advanced gastric cancer with extensive lymph node metastases (OGSG1701).","authors":"Yutaka Kimura, Naotoshi Sugimoto, Shunji Endo, Ryohei Kawabata, Jin Matsuyama, Atsushi Takeno, Masato Nakamura, Hiroki Takeshita, Hironaga Satake, Shigeyuki Tamura, Daisuke Sakai, Hisato Kawakami, Yukinori Kurokawa, Toshio Shimokawa, Taroh Satoh","doi":"10.1007/s10120-024-01564-9","DOIUrl":"https://doi.org/10.1007/s10120-024-01564-9","url":null,"abstract":"<p><strong>Background: </strong>The prognosis of advanced gastric cancer (GC) with extensive lymph node (LN) metastasis treated with surgery alone remains poor. We conducted a multicenter phase II study to evaluate the efficacy and safety of perioperative capecitabine plus oxaliplatin (CapeOx) therapy in patients with advanced GC with extensive LN metastases.</p><p><strong>Patients and methods: </strong>Patients with histologically proven HER2-negative or unknown gastric adenocarcinoma with paraaortic LN (PALN) metastases and/or bulky LN metastases located at the celiac axis, common hepatic artery, and/or splenic artery were included in the study. Patients received three cycles of preoperative CapeOx every 3 weeks, followed by five cycles of postoperative CapeOx after gastrectomy with D2 or D2 + including PALN dissection. The primary endpoint was the response rate (RR) according to the RECIST v1.0 criteria.</p><p><strong>Results: </strong>Thirty patients from 14 institutions were enrolled from September 2017 to June 2022. Complete response, partial response, stable disease, and progressive disease occurred in zero, 20, eight, and one patient, respectively. One patient was not evaluated. The RR was 66.7% (90% confidence interval, 50.1-80.7%; one-sided P = 0.049). The preoperative chemotherapy completion rate and the curative resection rate were 96.7% and 93.3%, respectively. The minor (grade ≥ 1b) pathological RR was 66.7%. Grade 3 adverse events of preoperative chemotherapy included neutropenia in 3.3%, anemia in 6.7%, and anorexia in 10.0%. One treatment-related death occurred due to postoperative complications.</p><p><strong>Conclusion: </strong>Preoperative CapeOx chemotherapy showed a favorable RR, curative resection rate, and acceptable adverse events in patients with advanced GC with extensive LN metastasis.</p><p><strong>Registration number: </strong>UMIN000028749 and jRCTs051180186.</p>","PeriodicalId":12684,"journal":{"name":"Gastric Cancer","volume":" ","pages":""},"PeriodicalIF":6.0,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142618666","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Predictors of tolerability for postoperative adjuvant S1 plus docetaxel chemotherapy for gastric cancer: a multicenter retrospective study.","authors":"Kazuhiro Toyota, Kazuaki Tanabe, Mikihiro Kano, Toshiaki Komo, Ryuichi Hotta, Senichiro Yanagawa, Yoshihiro Saeki, Hirofumi Tazawa, Masahiro Ikeda, Masayuki Shishida, Keisuke Okano, Ryuta Ide, Yasuhiro Imaoka, Shinya Takahashi, Hideki Ohdan","doi":"10.1007/s10120-024-01563-w","DOIUrl":"https://doi.org/10.1007/s10120-024-01563-w","url":null,"abstract":"<p><strong>Background: </strong>Adjuvant docetaxel plus S1 (DS) chemotherapy after gastrectomy with D2 lymph node dissection is the standard treatment for stage III gastric cancer in Japan; however, some patients are unable to receive adequate drug administration because of the deterioration of their conditions. This study aimed to investigate the correlation between tolerability for postoperative adjuvant DS chemotherapy and prognosis, and the factors affecting tolerability.</p><p><strong>Methods: </strong>This retrospective study involved patients with stage III gastric cancer who underwent curative resection between 2018 and 2021 from a multicenter database. Patients with a cumulative dose of docetaxel and S1 greater than 120 and 8400 mg/m², respectively, were considered tolerable. The prognostic impact and factors predicting tolerability were analyzed.</p><p><strong>Results: </strong>Of the 103 patients, the tolerable group comprised of 63 (61%) patients and had a significantly better 3-year recurrence-free survival than the intolerable group (83% vs. 64%, P = 0.02). Among the preoperative factors, only performance status (PS, P = 0.04) was significantly correlated with tolerability in the univariate analysis. Among the postoperative factors, PS (P = 0.001) and perioperative weight loss rate (P = 0.02) were significantly correlated with tolerability in the univariate analysis. The multivariate analysis showed significant differences in the PS (odds ratio [OR]: 4.94, 95% confidence interval [CI] 1.79-14.98, P = 0.002) and weight loss rate (OR: 1.10, 95% CI 1.01-1.21, P = 0.03).</p><p><strong>Conclusions: </strong>Tolerance to postoperative adjuvant DS chemotherapy has a significant prognostic impact. Postoperative PS and perioperative weight loss rates were independent predictors of tolerability.</p>","PeriodicalId":12684,"journal":{"name":"Gastric Cancer","volume":" ","pages":""},"PeriodicalIF":6.0,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142618664","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Decorin as a key marker of desmoplastic cancer-associated fibroblasts mediating first-line immune checkpoint blockade resistance in metastatic gastric cancer.","authors":"Ki Tae Kim, Min Hee Lee, Su-Jin Shin, In Cho, Jung Cheol Kuk, Jina Yun, Yoon Young Choi","doi":"10.1007/s10120-024-01567-6","DOIUrl":"https://doi.org/10.1007/s10120-024-01567-6","url":null,"abstract":"<p><strong>Background: </strong>Gastric cancer (GC) remains a significant cause of cancer-related mortality worldwide. Despite the transformative impact of immune checkpoint blockade (ICB) therapies across various cancers, only a minority of patients with metastatic GC (mGC) benefit, emphasizing the urgent need for precise biomarkers to predict therapeutic responses and optimize patient selection.</p><p><strong>Methods: </strong>In this multi-omics study, we conducted whole exome and transcriptome sequencing on 12 tumors from mGC patients treated with nivolumab as first-line therapy. To validate our findings, we performed whole transcriptome sequencing on 17 additional tumors and analyzed 45 tumors from public dataset (PRJEB25780) of patients who received ICB therapy as second or third-line treatment. Comprehensive multi-omics analyses were conducted using single-cell RNA sequencing (n = 5, GSE167297) and spatial transcriptome sequencing (n = 2, independent internal dataset).</p><p><strong>Results: </strong>ICB-sensitive tumors exhibited robust activation of the interferon response pathway, while ICB-resistant tumors displayed epithelial-mesenchymal transition signatures. Intriguingly, at the single-cell level, genes associated with ICB sensitivity were predominantly expressed in immune cells, whereas genes associated with resistance were primarily found in cancer-associated fibroblasts (CAFs), particularly the desmoplastic CAF (dCAF) subtype. We identified DCN as a hallmark dCAF marker, and high DCN expression was inversely correlated with PD-L1 levels, ICB resistance, and poor prognosis in mGC (log-rank p = 0.027).</p><p><strong>Conclusion: </strong>This study elucidates the critical influence of the tumor microenvironment, specifically dCAFs, in mediating ICB resistance in mGC. Our findings highlight DCN as a representative marker for dCAF and a promising negative predictive biomarker for ICB response. These findings highlight the complex stromal-immune interactions and open avenues for personalized treatment for mGC.</p>","PeriodicalId":12684,"journal":{"name":"Gastric Cancer","volume":" ","pages":""},"PeriodicalIF":6.0,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142618662","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advantages of adjuvant chemotherapy using S-1 following minimally invasive gastrectomy for gastric cancer versus open surgery: a propensity score-matched analysis.","authors":"Motonari Ri, Naoki Nishie, Manabu Ohashi, Shota Fukuoka, Kensei Yamaguchi, Rie Makuuchi, Masaru Hayami, Tomoyuki Irino, Takeshi Sano, Souya Nunobe","doi":"10.1007/s10120-024-01565-8","DOIUrl":"https://doi.org/10.1007/s10120-024-01565-8","url":null,"abstract":"<p><strong>Background: </strong>It is essential to ensure optimal adherence to adjuvant chemotherapy regimens following gastric cancer surgery. However, treatment intensity for S-1 as adjuvant chemotherapy has not as yet been compared between minimally invasive (MI) and open (Open) surgery.</p><p><strong>Methods: </strong>We retrospectively compared dose modification of adjuvant S-1 between MI and Open surgery in patients undergoing R0 gastrectomy for gastric or esophago-gastric junction cancer at the Cancer Institute Hospital Tokyo, Japan, during the period from 2012 to 2022, and receiving S-1 for pStage II or S-1 plus docetaxel for pStage III as adjuvant chemotherapy. Propensity score matching (PSM) was conducted to adjust for possible confounders.</p><p><strong>Results: </strong>In total, 323 patients were initially included. After PSM, 158 patients remained, 79 in each group. The adjuvant chemotherapy completion rates were similar in the two groups. However, the proportion of patients who required S-1 dose reduction was significantly lower in the MI than in the Open group (43.0% vs. 65.8%, p = 0.004). In addition, the MI group had significantly fewer patients requiring suspension of S-1 than the Open group (46.8% vs. 64.6%, p = 0.025). Moreover, the frequency of adverse events of grade ≥ 3 was significantly lower in the MI than in the Open group (17.7% vs. 31.7%, p = 0.042).</p><p><strong>Conclusions: </strong>In adjuvant chemotherapy for gastric cancer, minimally invasive surgery may offer better treatment intensity for oral S-1 administration than open surgery.</p>","PeriodicalId":12684,"journal":{"name":"Gastric Cancer","volume":" ","pages":""},"PeriodicalIF":6.0,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142604159","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Morbidity and quality of life of totally laparoscopic versus laparoscopy-assisted distal gastrectomy for early gastric cancer: a multi-center prospective randomized controlled trial (CKLASS01).","authors":"Yu Zhang, Ziyu Li, Yantao Tian, Jiang Yu, Jieti Wang, Changmin Lee, Kuan Wang, Xianli He, Qing Qiao, Gang Ji, Zekuan Xu, Li Yang, Hao Xu, Xiaohui Du, Xiangqian Su, Jiadi Xing, Zhaojian Niu, Linghua Zhu, Su Yan, Yong Li, Junjiang Wang, Zhengrong Li, Yongliang Zhao, Jun You, Changqing Jing, Lin Fan, Yian Du, Gaoping Zhao, Wu Song, Yi Xuan, Mingde Zang, Jie Chen, Sungsoo Park, Hua Huang","doi":"10.1007/s10120-024-01561-y","DOIUrl":"https://doi.org/10.1007/s10120-024-01561-y","url":null,"abstract":"<p><strong>Background: </strong>There is a paucity of confirmatory randomized controlled trials (RCTs) comparing the effectiveness of totally laparoscopic distal gastrectomy (TLDG) vs laparoscopy-assisted distal gastrectomy (LADG) for early gastric cancer (EGC).</p><p><strong>Methods: </strong>A phase III, prospective, multi-center RCT was conducted, wherein patients (n = 442) with clinical stage I gastric cancer eligible for laparoscopic distal gastrectomy were randomized 1:1 to the TLDG or the LADG group. Postoperative morbidity and quality of life (QoL) were compared.</p><p><strong>Results: </strong>In total, 422 patients were assessed (TLDG, 216; LADG, 206) in the modified intention-to-treat (mITT) analysis. The morbidity rate did not differ significantly between the two groups (TLDG, 6.0%; LADG, 5.8%; P = 0.93). The 90-day mortality rate was comparable between the groups (TLDG, 0.5%; LADG, 0.0%; P > 0.99). TLDG was significantly associated with a lower pain score compared with LADG in patients with a BMI of ≥ 25 kg/m² (P = 0.002) at 24 h postoperatively. Moreover, TLDG significantly improved QoL in terms of C30 social functioning at 3 and 6 months (P = 0.03 and P = 0.04), C30 global health status at 3 months (P = 0.02), and STO22 body image at 3 months (P = 0.01), with differences dissipating at 12 months.</p><p><strong>Conclusions: </strong>TLDG is not superior to LADG in terms of postoperative morbidity and mortality, but it provides better C30 social functioning at 3 and 6 months, C30 global health status and STO22 body image at 3 months, and reduces early postoperative pain for patients with a BMI of ≥ 25 kg/m².</p><p><strong>Trial registration: </strong>ClinicalTrials.gov: NCT03393182.</p>","PeriodicalId":12684,"journal":{"name":"Gastric Cancer","volume":" ","pages":""},"PeriodicalIF":6.0,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582824","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Volume of hepatoid component and intratumor M2 macrophages predict prognosis in patients with hepatoid adenocarcinoma of the stomach.","authors":"Yoshiaki Taniguchi, Daisuke Kiyozawa, Kenichi Kohashi, Shinichiro Kawatoko, Takeo Yamamoto, Takehiro Torisu, Tomoharu Yoshizumi, Masafumi Nakamura, Takanari Kitazono, Yoshinao Oda","doi":"10.1007/s10120-024-01562-x","DOIUrl":"https://doi.org/10.1007/s10120-024-01562-x","url":null,"abstract":"<p><strong>Background: </strong>Hepatoid adenocarcinoma of the stomach (HAS), a subtype of gastric cancer (GC), includes multiple tumor components, such as enteroblastic and tubular adenocarcinoma components. However, which component mostly contributes to the aggressive behavior of HAS remains unclear. Moreover, the role of tumor-associated macrophages (TAMs) has not been explored in HAS. This study evaluated the clinical significance of the proportion of the hepatoid component within the tumor, CD163 + macrophages, and macrophage colony-stimulating factor-1 (CSF-1) in HAS.</p><p><strong>Methods: </strong>In total, 56 cases of primary HAS were analyzed. In each case, hepatoid (HC), enteroblastic (EC), and tubular (TC) components were identified, and the ratio of HC to the entire tumor (hepatoid component ratio, HCR) was assessed to examine the correlation between HCR and clinicopathological features. Immunohistochemical staining for CD163 and CSF-1 was performed, and differences in immunohistochemical results among the three tumor components were analyzed. In each tumor component, the prognostic impact of CD163 and CSF-1 was examined.</p><p><strong>Results: </strong>A high HCR was associated with worse overall survival (OS). CD163 + TAMs and CSF-1 immunoreactivity score in HC were significantly higher than those in the other components. High infiltration of CD163 + TAMs and a high CSF-1 immunoreactivity score in HC were associated with an aggressive course and worse OS. Multivariate analysis revealed the proportion of HC in HAS as an independent prognostic factor (HR = 3.176, p = 0.006).</p><p><strong>Conclusions: </strong>The HCR and CD163 + TAMs may be useful prognostic predictors, and TAMs may be novel therapeutic targets of HAS.</p>","PeriodicalId":12684,"journal":{"name":"Gastric Cancer","volume":" ","pages":""},"PeriodicalIF":6.0,"publicationDate":"2024-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564269","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prognostic and predictive factors for the efficacy and safety of trastuzumab deruxtecan in HER2-positive gastric or gastroesophageal junction cancer.","authors":"Amane Jubashi, Izuma Nakayama, Shigehiro Koganemaru, Naoya Sakamoto, Shioto Oda, Yuki Matsubara, Yu Miyashita, Seiya Sato, Shinpei Ushiyama, Akinori Kobayashi, Ukyo Okazaki, Dai Okemoto, Kazumasa Yamamoto, Saori Mishima, Daisuke Kotani, Akihito Kawazoe, Tadayoshi Hashimoto, Yoshiaki Nakamura, Yasutoshi Kuboki, Hideaki Bando, Takashi Kojima, Takayuki Yoshino, Hisamitsu Miyaaki, Kazuhiko Nakao, Kohei Shitara","doi":"10.1007/s10120-024-01560-z","DOIUrl":"https://doi.org/10.1007/s10120-024-01560-z","url":null,"abstract":"<p><strong>Background: </strong>Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate targeting HER2-positive gastric cancer or gastroesophageal junction cancer (GC/GEJC). Although effective, T-DXd has notable toxicities, including interstitial lung disease (ILD). This study evaluated the efficacy, safety, and prognostic factors associated with T-DXd for GC/GEJC.</p><p><strong>Methods: </strong>A retrospective observational study was conducted at our institution by reviewing medical records of patients treated with T-DXd until September 2023. Eligible patients had unresectable advanced or recurrent GC/GEJC, HER2 status of IHC 3 + or IHC 2 + /ISH-positive, and prior treatment with trastuzumab-containing regimen.</p><p><strong>Results: </strong>Among the 101 patients analyzed, the initial T-DXd dose was 6.4 mg/kg in 77 patients and 5.4 mg/kg in 24 patients. The objective response rate was 54.3%, with a median PFS of 5.4 months and a median OS of 11.4 months. The significant prognostic factors for shorter PFS and OS included ECOG PS ≥ 1, presence of primary lesion, and peritoneal metastasis but not the initial T-DXd dose. ILD occurred in 14.9% of patients. Notably, higher T-DXd dose and smaller tumor burden were associated with a higher incidence of ILD.</p><p><strong>Conclusions: </strong>Several factors were associated with prognosis after T-DXd treatment in patients with GC/GEJC. Tumor burden is a potential risk factor for T-DXd-related ILD. Further studies are needed to optimize dosing based on tumor burden and to improve the therapeutic index.</p>","PeriodicalId":12684,"journal":{"name":"Gastric Cancer","volume":" ","pages":""},"PeriodicalIF":6.0,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564265","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comment on \"a machine learning model for predicting the lymph node metastasis of early gastric cancer not meeting the endoscopic curability criteria\".","authors":"Muhammad Irfan, Misaal Fatima, Maryam Shehzadi","doi":"10.1007/s10120-024-01533-2","DOIUrl":"10.1007/s10120-024-01533-2","url":null,"abstract":"","PeriodicalId":12684,"journal":{"name":"Gastric Cancer","volume":" ","pages":"1344-1345"},"PeriodicalIF":6.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141544737","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preclinical toxicological assessment of amido-bridged nucleic acid-modified antisense oligonucleotides targeting synaptotagmin XIII for intra-abdominal treatment of peritoneal metastasis of gastric cancer.","authors":"Mitsuro Kanda, Nao Takano, Hiroshi Miyauchi, Kohei Ueda, Masaaki Mizuno, Yuuya Kasahara, Yasuhiro Kodera, Satoshi Obika","doi":"10.1007/s10120-024-01548-9","DOIUrl":"10.1007/s10120-024-01548-9","url":null,"abstract":"<p><strong>Background: </strong>Peritoneal metastasis of gastric cancer is closely associated with dismal prognosis. In previous preclinical proof-of-concept studies, an amido-bridged nucleic acid (AmNA)-modified antisense oligonucleotide (ASO), designated ASO-4733 that targets the gene encoding synaptotagmin XIII (SYT13), inhibited cellular functions required for the formation of peritoneal metastasis of gastric cancer cells. ASO-4733 achieved therapeutic effects when intra-abdominally administered to mouse xenograft models. Here, we conducted an analysis of Syt13-deficient mice to determine the pharmacokinetics and toxicity of intra-abdominal administration of ASO-4733.</p><p><strong>Methods: </strong>The effects of Syt13-deficiency in mice were determined. Good Laboratory Practice toxicity tests and the toxicokinetics of intra-abdominal administration of ASO-4733 were conducted in cynomolgus monkeys and rats. The pharmacokinetics of ASO-4733 administered intravenously or intra-abdominally to rats were investigated.</p><p><strong>Results: </strong>Syt13-deficient mice exhibited normal reproduction, organ functions, and motor functions. Weekly intra-abdominal administration of ASO-4733 (125 mg/kg), corresponding to a 50-fold increase of the estimated clinical dose for 4 weeks, was well tolerated by cynomolgus monkeys. In rats, off-target toxicity (not attributable to hybridization) was observed after weekly intra-abdominal administration of ASO-4733. Blood concentrations of ASO-4733 were lower and rose more slowly after intra-abdominal administration compared with intravenous administration.</p><p><strong>Conclusions: </strong>The preclinical profile of intra-abdominal administration of ASO-4733 demonstrated its suitability for entry into clinical trials of patients with peritoneal metastasis of gastric cancer.</p>","PeriodicalId":12684,"journal":{"name":"Gastric Cancer","volume":" ","pages":"1229-1241"},"PeriodicalIF":6.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142080107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}