tbuckley/cabot-search huggingface dataset:
Phase II clinical study evaluating the efficacy and safety of disitamab vedotin combined with sintilimab and S-1 in the conversion treatment of HER2-overexpression unresectable gastric cancer.
Authors: Han Liang, Xiaona Wang, Liang Shang, Xiaodong Chen, Xiangdong Cheng, Ziyu Li, Bo Wei, Zhichao Zheng, Guoxin Li, Gang Ji, Zizhen Zhang, Yantao Tian, Qun Zhao, Lin Yang, Heli Liu, Hao Chen, Yanliang Liu
Journal: Journal of Clinical Oncology (2024)

TPS428 Background: Gastric cancer (GC) or gastroesophageal junction adenocarcinoma (GEJA) is the fifth commonest cancer and the fourth leading cause of cancer deaths worldwide. In about 30% to 40% of patients with advanced gastric cancer have lost the opportunity for radical surgery at the first diagnosis, and the overall 5-year survival rate is less than 50%. In recent years, conversion therapy has shown great promise. Disitamab vedotin is an antibody-drug conjugate comprising a novel HER2-directed monoclonal antibody, In previous study C008, RC48 showed a good safety profile and promising activity towards GC, and showed equivalent efficacy for HER2 IHC 2+ or HER2 IHC 3+ tumors. Methods: This study is a single-arm, phase II trial carry out at 16 academic hospitals in China, and will evaluate DV combined with Sintilimab and S-1 in patients with HER2-expressing unresectable gastric cancer. Eligible patients are at ≥ 18 to ≤ 75 years old; histologically confirmed, unresectable stage IV GC or GEJA; Single initial unresectable factor. For example, peritoneal metastasis (P1), Intraperitoneal free cancer cells positive (CY1), Paraaortic lymph node metastasis, liver metastasis (≤ 3 lesions, and ≤ 5 cm for a single lesion), ovarian metastasis; and documented histologically confirmed HER2 IHC 3+ or 2+; ECOG 0-1; at least one unresectable, measurable tumor lesion according to the RECIST version 1.1; adaptable function of the heart, liver, and kidney. 30 patients will be enrolled in this trial and receive Disitamab Vedotin(2.5mg/kg, IV, Q3W), Sintilimab (200 mg, IV, Q3W) and S-1 (twice daily on D1-14 are given at a dose calculate according to the body surface area and repeated every 3 weeks), until patients assessed by MDT to meet the criteria for surgical resection undergo gastrectomy. And the patients with peritoneal dissemination will combine with intraperitoneal administration of paclitaxel (60mg / m2, Q3W). The primary endpoint is R0 resection rate, Secondary endpoints include cORR, OS, RFS and safety. Seven patients have been enrolled in this study. Clinical trial information: NCT05627414 .
Recurrence-free survival as a surrogate for overall survival in esophageal squamous cell carcinoma: Nationwide real-world data from Japan.
Authors: Jun Okui, Kengo Nagashima, Satoru Matsuda, Yasunori Sato, Akihiko Okamura, Hirofumi Kawakubo, Manabu Muto, Yoshihiro Kakeji, Koji Kono, HIROYA TAKEUCHI, Masayuki Watanabe, Yuichiro Doki, Takeo Bamba, Takashi Fukuda, Hitoshi Fujiwara, Shinsuke Sato, Kazuhiro Noma, Hiroshi Miyata, Takeo Fujita, Yuko Kitagawa
Journal: Journal of Clinical Oncology (2024)

269 Background: One of the limitations of the established gold standard, overall survival (OS), is that it requires an extended follow-up period. Addressing this challenge involves investigating appropriate statistically and clinically relevant surrogate endpoints. However, there is a paucity of studies using real-world data (RWD) to explore surrogacy in patients with esophageal squamous cell carcinoma (ESCC). Our study aims to investigate whether recurrence-free survival (RFS) is a valid surrogate endpoint for OS in surgically resectable advanced ESCC patients, utilizing a comprehensive nationwide database in Japan. Methods: The ESCC patients who received neoadjuvant CF (cisplatin and 5-fluorouracil) or DCF (docetaxel, cisplatin and 5-fluorouracil) at 58 Japanese esophageal centers certified by the Japan Esophageal Society were retrospectively reviewed. Kendall's tau between RFS and OS was used at the individual level, and the coefficient of determination was used at the institutional level to assess surrogacy. Additionally, surrogacy between each short-term postoperative endpoint (pathological complete response [pCR] or pathological grade) and OS was investigated using novel statistical methods. Results: Our study encompassed 3154 ESCC patients who underwent subtotal esophagectomy from 2010 to 2015. The cStage I/II/III/IVA/IVB (due to supraclavicular lymph node metastasis) was 224 (7.1%), 1008 (32.0%), 1664 (52.8%), 117 (3.7%), and 140 (4.4%), respectively. The 5-year OS and RFS rate for the entire cohort was 56.6% and 47.7%, respectively. In the primary analysis, a strong correlation between RFS and OS was found (Kendall's tau = 0.797, 95% confidence interval [CI]: 0.782 to 0.812) at the individual level. Subgroup analysis revealed that the better the pathological response, the higher the tau value. An adjusted R 2 of 100.0% (95% CI: 40.2 to 100.0) was obtained with the meta-regression model at the institutional level. The surrogate threshold effect was 0.703. Tau between pCR or pathological grade and OS were -0.025 (95% CI: -0.335 to 0.285) and 0.062 (95% CI: -0.086 to 0.209), respectively. Conclusions: The present study was the first nationwide RWD investigation to demonstrate a strong correlation between RFS and OS in surgically resectable ESCC patients who underwent neoadjuvant chemotherapy (NAC). Notably, this correlation was more pronounced in patients who had a more effective response to NAC. These findings hold promise for expediting the development of novel neoadjuvant treatment by shortening the duration of clinical trials.
Gastric microbiome signature to predict metachronous recurrence after endoscopic resection of gastric neoplasms.
Authors: Hokyoung Lee, Cheol Min Shin, Young Hoon Chang, Hyuk Yoon, Young Soo Park, Nayoung Kim, Dong Ho Lee
Journal: Journal of Clinical Oncology (2024)

399 Background: It is well-established that the gastric microbiota undergoes significant alterations during the process of gastric carcinogenesis. This study aimed to identify gastric mucosa-associated microbiome (MAM) for the prediction of metachronous recurrence after endoscopic resection of gastric neoplasms. Methods: Subgroup analyses were conducted for 81 patients (early gastric cancer: dysplasia = 55:26) from a prospective cohort (Clinical Trials No. NCT04830618). Demographic data, and history of Helicobacter pylori eradication therapy, endoscopic and histologic findings were incorporated. The profile of Gastric MAM obtained from non-cancerous corporal biopsy specimens and was analyzed by 16S rDNA sequencing. Results: Over a median follow-up duration of 53.8 months, 16 metachronous gastric neoplasms (10 adenomas and 6 adenocarcinomas) developed. Baseline gastric MAM varied with H. pylori infection status, but was unaffected by the presence of atrophic gastritis, intestinal metaplasia or synchronous lesions. The group with metachronous recurrence did not exhibit distinct phylogenetic diversity compared with the group devoid of recurrence. β-diversity analysis showed significant difference between the two groups (weighted UniFrac distance, PERMANOVA p = 0.006). In the LEfSe analysis, metachronous recurrence group had an increased abundance of Corynebaceriaceae, Comamonadaceae, Corynebacterium, Curvibacter, and a decreased abundance of Helicobacteraceae, and Helicobacter. The total study population were classified into two distinct gastrotypes by baseline Gastric MAM (gastrotype 1: Helicobacter-dominant, gastrotype 2: Akkermansia-abundant). MAM of gastrotype 1 had higher abundance of Helicobacter pylori, and lower abundance of Akkermansia¸ Comamodaceae, Muribaculacae , Streptococcus, Corynebacteriaceae , Cutibaterium. Patients in gastrotype 2 showed higher risk of metachronous recurrence than gastrotype 1 (hazard ratio = 4.621 by Cox proportional hazard model, p-value = 0.0185). Conclusions: Gastric cancer patients can be classified into two distinct gastrotypes by their MAM profiles, which were associated with different risk of metachronous recurrence. MAM profiling of gastric cancer patients is expected give insight into their risk of metachronous recurrence. Clinical trial information: NCT04830618 .
The expanded indications of HER2-targeted therapies by monitoring of circulating tumor cells.
Authors: Yasuaki Kimura, Koichi Suzuki, Sawako Tamaki, Iku Abe, Yuhei Endo, Kosuke Ichida, Yuta Muto, Masaaki Saito, Toshiki Rikiyama
Journal: Journal of Clinical Oncology (2024)

385 Background: Despite success in the HER2 targeted therapies for metastatic gastric cancer patients, the conventional assessment of HER2 status in tumor tissue specimens is still under debate. Methods: Twenty-seven patients with metastatic gastric cancer were treated according to histological HER2 status. On-chip sorting system was used for the isolation of circulating tumor cells (CTCs) before treatments. Epithelial mesenchymal transition (EMT) was assessed by the vimentin and cytokeratin. DNA was extracted from CTCs and applied to the gene panel with 409 cancer related genes. The fluorescence signal intensity &gt; 50 is set to be a threshold value for distinguishing between positive and negative HER2 on CTCs. Results: Thirteen patients (48%) with HER2 positive in tumor tissues (Group A) were treated with cytotoxic agents and trastuzumab (anti HER2 antibody) while 14 patients (52%) were negative and treated with cytotoxic agents. In these 14 patients, 8 patients (30%) showed HER2 positive (Group B) and 6 patients (22%) displayed HER2 negative (Group C) on CTCs. Increased expression of EMT was seen in Group A and B, indicating they are likely to have metastasis. Group B showed worse PFS than others (13.8 M in A, 7.0 M in B and not reached in C, p=0.012), suggesting Group B could be a candidate for expand indication of Trastuzumab. Genomic analysis showed some mutated genes involved in the PI3K signaling pathway which associated with drug resistance. Conclusions: Monitoring of circulating tumor cells leads to the expand indication of the HER2 targeted therapies in patients with metastatic gastric cancer.
Impact of time-of-day on nivolumab monotherapy infusion in patients with metastatic gastric cancer.
Authors: Yasunobu Ishizuka, Yukiya Narita, Tomoki Sakakida, Munehiro Wakabayashi, Hiroyuki Kodama, Kazunori Honda, Toshiki Masuishi, Hiroya Taniguchi, Shigenori Kadowaki, Masashi Ando, Masahiro Tajika, Kei Muro
Journal: Journal of Clinical Oncology (2024)

268 Background: Nivolumab monotherapy, an immune checkpoint inhibitor, is a standard of care for patients with metastatic gastric cancer (mGC) as a later-line treatment. Several studies have suggested that the circadian rhythm is essential in immune system function, including anti-cancer immunity. This study evaluated whether the time-of-day patterns of nivolumab infusion alter the efficacy of mGC treatment. Methods: This study retrospectively analyzed 298 consecutive mGC patients who received nivolumab monotherapy at a single institution between December 2014 and December 2022. Patients were divided into early (EA)- and late (LA)-nivolumab infusion groups: EA group = ≥70% of their infusions before 14:00, and LA group = &lt;70% of their infusions before 14:00. Treatment efficacy (overall response rate [ORR], disease control rate [DCR], progression-free survival [PFS], and overall survival [OS]) was evaluated. Multivariate analyses included variables with P values &lt;0.1 in univariate analyses. Results: A total of 248 patients were eligible; 140 were classified as having EA, and 108 as having LA. Most baseline characteristics were similar between EA and LA. In contrast, the median infusion time was earlier in EA than in LA (11:50 vs. 14:22). The median follow-up time was 9.0 months (range, 1.2–64.7 months). ORR and DCR were significantly higher in the EA than in the LA among 149 patients with measurable lesions (ORR, 16.9% vs. 3.3%, P=0.01; DCR, 47.2% vs. 20.0%, P&lt;0.01). Patients with EA had significantly better prognoses than those with LA in terms of PFS (median PFS, 2.3 vs. 1.6 months.; hazard ratios [HR], 0.65; P&lt;0.01) and OS (median OS, 7.6 vs. 3.9 months.; HR, 0.64; P&lt;0.01). EA patients received the subsequent chemotherapy more frequently than those in LA (54% vs. 32%; P&lt;0.01). Multivariate analyses, including factors such as age, ECOG performance status, histological type, ascites, modified Glasgow Prognostic Score, and timing of nivolumab infusion, showed that EA was an independent prognostic factor for PFS (adjusted HR, 0.66; P&lt;0.01) and OS (adjusted HR, 0.62; P&lt;0.01). Conclusions: Our data suggest that efforts to schedule nivolumab infusions before mid-afternoon could be considered in daily practice.
Genomic characterization of cholangiocarcinoma with autoimmune etiologies.
Authors: Xin Wang, Oumaima Hamza, Michelle Chan-Seng-Yue, Amy Zhang, Gun Ho Jang, Ayelet Borgida, Manny Kapur, Anna Dodd, Roxana Bucur, Julie Wilson, Arndt Vogel, Steven Gallinger, Faiyaz Notta, Grainne M. O'Kane, Gonzalo Sapisochin, Jennifer J. Knox, Robert C. Grant
Journal: Journal of Clinical Oncology (2024)

531 Background: Chronic inflammation from autoimmune conditions is a well-recognized risk factor for cholangiocarcinoma in the Western world. Cholangiocarcinomas in the setting of autoimmune disease have earlier age-of-onset and worse prognosis. Currently, their biology is inadequately understood, and the risks and benefits of immunotherapy approaches in this population are unknown. We describe the clinical and genomic characteristics of a cohort of cholangiocarcinoma patients with autoimmune etiologies. Methods: In a prospective cohort of 43 patients with mismatch repair proficient cholangiocarcinoma, we performed whole-genome sequencing (WGS, n=43) and total RNA sequencing (RNA-seq, n=28). Among this cohort, 15 patients had cholangiocarcinoma with autoimmune etiologies, including primary sclerosing cholangitis (PSC, n=10), ulcerative colitis (UC, n=6), ankylosing spondylitis (AS, n=1), and Crohn’s disease (CD, n=3). Results: Patients with autoimmune conditions had a 6.46-fold higher Tumour Mutational Burden (TMB) ( P = 0.0010), characterized by higher load of indels ( P = 0.0006). TMB was greater than 10 mutations per megabase in 4 of 15 patients with autoimmune conditions and 0 of 28 patients in those without ( P = 0.0111). Autoimmune patients exhibited an enrichment in mutational signatures 5 ( P = 0.0154), 17 ( P = 0.0004), 28 ( P = 0.028) and 30 ( P = 0.0164). Despite a higher TMB, autoimmune tumours have similar patterns of driver mutations. Differential gene expression of bulk RNA-seq analysis revealed comparable transcriptional markers of immunogenicity, but autoimmune cancers are enriched in pathways involved with cell proliferation and cell-cycle checkpoints. One patient with PSC/UC was treated with gemcitabine, cisplatin, and durvalumab with a partial response, while another with Crohn’s disease had durvalumab added to gemcitabine and cisplatin at progression and experienced stable disease with a decreased CA19-9. Neither experienced immune-related adverse events. Conclusions: Cholangiocarcinoma with autoimmune etiologies have unique genomic features characterized by elevated TMB. Chemo-immunotherapy may be a novel therapeutic option in this subgroup of patients and warrants further study.
A multi-institutional prospective study to compare postoperative quality of life of patients who undergo proximal or total gastrectomy for early gastric cancer (CCOG1602).
Authors: Yumiko Hojo, Mitsuro Kanda, Yoshinari Mochizuki, Chie Tanaka, Seiji Ito, Takuya Watanabe, Satoshi Sueoka, Akiharu Ishiyama, Takanobu Yamada, Takashi Oshima, Masashi Hattori, Shinya Koike, Kiyoshi Ishigure, Hitoshi Teramoto, Kenta Murotani, Yasuhiro Kodera
Journal: Journal of Clinical Oncology (2024)

296 Background: Proximal gastrectomy (PG) has become an increasingly preferred procedure for treating early cancer in the upper third of the stomach when oncological safety is ensured, with expectation for improvement of nutritional status and quality of life (QOL) attributable to the remnant stomach. Although few studies compare postoperative outcomes of patients who undergo total gastrectomy (TG) and PG based on questionnaires, their significant limitations include the retrospective design, use of a questionnaire not specific to a postgastrectomy setting, and observation at a fixed time or after a short postoperative period. Methods: A multi-institutional prospective study (CCOG1602) of patients who undergo PG or TG for cStage I gastric cancer was conducted. We used the Post-Gastrectomy Syndrome Assessment Scale (PGSAS)-37 and The European Organization for Research and Treatment of Cancer quality of life questionnaire (EORTC-QLQ-C30) to evaluate the changes in body weight and QOL over a 3-year postoperative period. The primary endpoint was the weight loss rate 3 years after surgery. Results: We enrolled 109 patients from 18 institutions and selected 65 and 19 patients for inclusion in the TG and PG groups, respectively. There were no differences in age, sex, or preoperative body mass index between the TG and PG groups. Mean postoperative weight loss rates were 16.0% and 11.7% for the TG and PG groups, respectively (Cohen's D 0.656) during postoperative year 1 and 15.0% and 10.8% for TG and PG (Cohen's D 0.543), respectively, during postoperative year 3, indicating that the PG group achieved a better trend with a moderate effect size. According to the PGSAS-37, the PG group experienced a better trend in the indigestion subscale (Cohen's D –1.085) and total symptom score (Cohen's D –0.59) during postoperative year 3 compared with the TG group. In contrast, the EORTC-QLQ-C30 identified no difference between the groups at any time point during the 3-year postoperative period. Conclusions: The CCOG1602 demonstrates that PG tended to be more favorable compared with TG with respect to postoperative weight loss and QOL, particularly regarding indigestion. Clinical trial information: UMIN000020070 .
Prediction of lymph node status in stage T1 esophageal squamous cell carcinoma.
Authors: Yongshun Chen, Xiangli Fan, Honglei Chen
Journal: Journal of Clinical Oncology (2024)

263 Background: With the development of endoscopic therapy and the introduction of immunotherapies, it is more important for preserving the esophagus and uninvaded lymph nodes to avoid the damages involving the long-term quality of life and normal immune function caused by esophagectomy with radical lymphadenectomy. Methods: We collected patients with T1 ESCC who underwent endoscopic resection or esophagectomy from 2014 to 2021 in three cancer centers. The primary end point was presence of lymph node metastasis (LNM) in surgical resection specimens or detection of metastases during follow-up. Univariate and multivariate logistic regression were used to screen the clinicopathological features related to LNM. Using the function 'lrm' constructed the prediction model. The area under the curve (AUC) of receiver operating characteristic and calibration graphs were used to assess the performance of the model. An external validation was conducted to evaluate the generalization of the model. We then prospectively collected 28 surgically resected tissue samples of T1 ESCC to further supplement the model from the cellular and molecular level, and used 6 markers (CK, CD34, D2-40, CD4, CD8, FOXP3) and DAPI dye to process multiple immunofluorescence (mIF) staining. Afterwards, we analyzed the density, spatial distribution of microvessels, lymphatic capillaries and tumor-associated immune cells and the interaction between them and malignant cells in the tumor microenvironment of T1 ESCC to explore the relationship between tumor microenvironment and risk of LNM. Results: 1109 patients with T1 ESCC were included. 653 patients from two centers constituted the training cohort, and 456 patients from the third center served as the validation cohort. Multivariate logistic regression based on the training cohort showed that tumor invasion into the submucosa, poor histological grade, and lymphovascular invasion were risk factors for LNM in T1 ESCC. Subsequently, we constructed a model based on three variables to predict the risk of LNM in T1 ESCC. The model demonstrated good discriminative ability (AUC 0.858, 95%CI 0.826-0.890). After mIF staining of 28 prospectively collected T1 ESCC tissue samples, we observed that microvessels and lymphatic capillaries were abundant in the mucosa in lymph node-positive samples but not in lymph node-negative samples. In addition, the average density of FOXP3 + T cells in samples with and without metastasis was 253/mm 2 and 26/mm 2 (P &lt; 0.001), and the average density of CD8 + T cells was 112/mm 2 and 432/mm 2 (P &lt; 0.001) in quantitative analysis, respectively. Conclusions: This study (RENMIN-237) developed a well-performing LNM risk stratification model of T1 ESCC to reduce both overtreatment and undertreatment, and we found that FOXP3 + T cells in the tumor microenvironment are a risk factor for LNM, while CD8+ T cells can serve as a protective factor against LNM.
Do patients benefit from omega-3 fatty acids?
Authors: Samuel C R Sherratt, R Preston Mason, Peter Libby, Ph Gabriel Steg, Deepak L Bhatt
Journal: Cardiovascular Research (2023)

Abstract Omega-3 fatty acids (O3FAs) possess beneficial properties for cardiovascular (CV) health and elevated O3FA levels are associated with lower incident risk for CV disease (CVD.) Yet, treatment of at-risk patients with various O3FA formulations has produced disparate results in large, well-controlled and well-conducted clinical trials. Prescription formulations and fish oil supplements containing low-dose mixtures of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have routinely failed to prevent CV events in primary and secondary prevention settings when added to contemporary care, as shown most recently in the STRENGTH and OMEMI trials. However, as observed in JELIS, REDUCE-IT, and RESPECT-EPA, EPA-only formulations significantly reduce CVD events in high-risk patients. The CV mechanism of action of EPA, while certainly multifaceted, does not depend solely on reductions of circulating lipids, including triglycerides (TG) and LDL, and event reduction appears related to achieved EPA levels suggesting that the particular chemical and biological properties of EPA, as compared to DHA and other O3FAs, may contribute to its distinct clinical efficacy. In vitro and in vivo studies have shown different effects of EPA compared with DHA alone or EPA/DHA combination treatments, on atherosclerotic plaque morphology, LDL and membrane oxidation, cholesterol distribution, membrane lipid dynamics, glucose homeostasis, endothelial function, and downstream lipid metabolite function. These findings indicate that prescription-grade, EPA-only formulations provide greater benefit than other O3FAs formulations tested. This review summarizes the clinical findings associated with various O3FA formulations, their efficacy in treating CV disease, and their underlying mechanisms of action.