bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exploratory analysis of biomarkers of response to durvalumab in advanced HER2-negative oesophago-gastric adenocarcinoma within a phase 2 clinical trial.
Authors: Lote Hazel , Giota Eleftheria , Fong Caroline , Gordon Anderley , Begum Ruwaida , Satchwell Laura , Kidd Shannon , Cromarty Susan , Fribbens Charlotte Victoria , Starling Naureen , Rao Sheela , Chau Ian , Cunningham David , Zapata Luis 
Published: January 2024

384 Background: Advanced oesophago-gastric cancers have showcased varied responses to immunotherapy based on biomarkers such as tumour mutational burden, microsatellite instability, and PD-L1 expression. However, these markers may not fully capture tumour heterogeneity and evolutionary dynamics. Hence, understanding the intricate relationship between immune selection, specifically immune dN/dS,1 and tumour evolution is vital for devising personalized therapeutic strategies. Methods: In our phase 2 open label, multicentre, randomised PLATFORM trial (NCT02678182), patients received maintenance durvalumab post first-line chemotherapy. A survival advantage was not seen with maintenance durvalumab compared to surveillance and exploratory analysis of PD-L1 expression was not associated with improved survival outcomes.2 However, a subset of patients treated with durvalumab experienced durable responses and some experienced incremental radiological responses. A pilot substudy on a selected cohort (n=24) of these patients was designed to explore the potential of immunogenomics evolutionary-based metrics, notably dN/dS, as predictive biomarkers. DNA and RNA from FFPE baseline tumour samples underwent analysis, examining genomic factors including tumour mutational burden, indel signatures, PDL1 status, and immune evasion mechanisms. Furthermore, the evolutionary metric, immune dN/dS, which has implications in tumour immunoediting and its response to immunotherapies, was scrutinized. Results: A dominant indel mutational signature emerged from the analysis. The majority of patients displayed a significantly higher number of indel variants, compared to non-synonymous and synonymous single-nucleotide variants. A recurring observation was dN/dS values consistently above 1, indicating positive selection for non-synonymous somatic variants. Additionally, hypermutation in driver genes, notably TP53 and XIRP2, was detected. One patient, with a unique dN/dS < 1, showcased survival beyond four years without liver metastases. Immune dN/dS > 1 and no evidence of liver metastases displayed the best prognosis after treatment in contrast with those that have immune dN/dS < 1 with or without liver metastases. Conclusions: Immune dN/dS emerges as a promising tool to decode tumour evolutionary mechanisms, providing profound insights into the dynamics of tumour evolution in advanced HER2 negative oesophago-gastric cancer patients receiving durvalumab immunotherapy. This pilot study underscores the potential of this novel immunogenomic approach in improving patient stratification and tailoring therapeutic strategies in cancer immunotherapy. 1. Zapata et al, Nature Genetics, 2023. 2. Fong et al, J Clin Oncol, 2021. Clinical trial information: NCT02678182 .
The expanded indications of HER2-targeted therapies by monitoring of circulating tumor cells.
Authors: Kimura Yasuaki , Suzuki Koichi , Tamaki Sawako , Abe Iku , Endo Yuhei , Ichida Kosuke , Muto Yuta , Saito Masaaki , Rikiyama Toshiki 
Published: January 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 > 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.
Relationship between the number of positive MSI markers and the efficacy of NIVO+IPI therapy in MSI-H gastric cancer: A subgroup analysis of NO LIMIT study (WJOG13320G/CA209-7W7).
Authors: Hirata Kenro , Kawakami Hisato , Kadowaki Shigenori , Makiyama Akitaka , Tsuda Masahiro , Sugimoto Naotoshi , Machida Nozomu , Hara Hiroki , Hirano Hidekazu , Esaki Taito , Komatsu Yoshito , Hironaka Shuichi , Chiba Yasutaka , Muro Kei 
Published: January 2024

386 Background: Although high instability of microsatellite lesion (MSI-H) is an established biomarker for response to immune checkpoint inhibitors, the relationship between the number of MSI markers and the efficacy of immune checkpoint inhibitors in MSI-H tumors has not been well elucidated. NO LIMIT (WJOG13320G/CA209-7W7) is a phase II trial of nivolumab plus low-dose ipilimumab (NIVO+IPI) for MSI-H advanced gastric or esophagogastric junction cancer (GC) in the first-line setting.1 Here, we investigated the relationship between the number of positive MSI markers and the efficacy of NIVO+IPI in NO LIMIT study. Methods: Eligible patients were unresectable advanced, recurrent, or metastatic GC with confirmed as MSI-H with the MSI-IVD Kit (FALCO), where two or more of the five MSI markers are defined as positive. Nivolumab (240 mg) biweekly and ipilimumab (1 mg/kg) every six weeks were given until disease progression or unacceptable toxicity. The primary endpoint was the objective response rate (ORR) assessed by a blinded independent central review. Secondary endpoints included progression-free survival (PFS), overall survival (OS), safety, and the association between number of positive MSI markers and clinical efficacy (ORR, PFS, OS). The analysis was performed 18 weeks after the first dose in the last patient, with a median follow-up of 9 months (range, 4.0-18.0). Results: The breakdown of MSI markers in the 29 patients enrolled in NO LIMIT was as follows: BAT-26 (26/26, 100%), NR-21 (25/29, 86.2%), BAT-25 (25/29, 86.2%), MONO-27 (29/29, 100%), NR-24 (27/29, 89.4%). Since most of the cases were positive for all five of them (the number of cases with 2, 3, 4, and 5 positive markers was 2, 2, 1, and 24, respectively), we dichotomized cases into group A (all five positive) and group B (the others). Response rates in groups A vs. B were 62.5% (15/24) vs. 60.0% (3/5), respectively. There was no difference in PFS or OS between the two groups. Conclusions: The number of MSI markers is not related to the efficacy of NIVO+IPI in NO LIMIT study. Further follow-up is needed to confirm the relationship between survival. 1. Muro K, et al. ESMO Congress 2023. Clinical trial information: jRCT2080225304 . [Table: see text]
Total neoadjuvant therapy (TNT) for locally advanced rectal cancer (LARC): Real-world experience from a tertiary Asian cancer center.
Authors: Wang Meng , Gwee Yong Xiang , Lin Zhaoting , Yong Wei Peng , Sundar Raghav , Tan Hon Lyn , Choo Joan RE , Tan Ker Kan , Lieske Bettina , Cheong Wai Kit , Tan Teng Hwee , Tey Jeremy Chee Seong , Chee Cheng Ean , Chan Gloria Hui Jia 
Published: January 2024

39 Background: Multiple studies of TNT for LARC have shown improved pathological complete response (pCR) rate and disease-free survival (DFS). However, real-world data in Asia is limited. Methods: Patients (pts) diagnosed with LARC at National University Cancer Institute, Singapore were discussed at a multidisciplinary tumor board. Patients were eligible for TNT if they had cT2/3N+ or cT4Nany, threatened circumferential resection margin (CRM) and adequate organ function. TNT protocol was systemic chemotherapy with 5-6 cycles of mFOLFOX6 (5-fluorouracil, leucovorin, oxaliplatin) or 3-4 cycles of XELOX (capecitabine, oxaliplatin) followed by short- or long-course chemoradiation (CRT), then 3 cycles of mFOLFOX6 or 2 cycles of XELOX. Clinical outcomes included rates of clinical complete response (cCR), pCR, surgery type, R0 resection and DFS. Baseline pt demographics, laboratory results and tumor characteristics were analyzed against these outcomes. Results: 173/205 pts who were diagnosed with rectal cancer between February 2020 and November 2022 had LARC and 47 received TNT. Median age was 65 (range: 33-79), 68.1% male, 78.7% were Chinese, 19.2% had cT4 tumors, 87.2% node positive and 80.9% had CRM involvement. Median tumor distance from anal verge was 6cm (range: 1-15cm) on colonoscopy and 5cm (range: 2-12cm) on magnetic resonance imaging. 95.7% received XELOX, 87.0% had long-course CRT and 83.0% completed all cycles of systemic chemotherapy and CRT. 44.7% had dose reduction of systemic therapy and 4.3% required emergent surgery due to local complications during TNT. After TNT completion, 7 pts did not pursue surgery – 3 achieved cCR (6.4%) and adopted a watch-and-wait approach, 2 had disease progression (PD), and 2 declined. Of those who underwent surgery, 75.0% had sphincter-preserving surgery and 85.0% achieved R0 resection. 2.1% (n =1) achieved pCR. Rates of tumour regression grade (TRG) 0, 1, 2, 3 were 7.5%, 15.0%, 67.5% and 10.0%, respectively. After a median follow up of 21.7 months (range: 9.3 – 41.6 months), 21.3% (n = 10) had disease recurrence and 14.9% (n=7; 5 from PD, 1 from surgery-related complication, 1 unrelated to treatment) passed away. 1-year DFS rate was 88.7% (95% CI 75.0% - 95.2%). Conclusions: This is the first Asian study reporting real-world data of TNT for LARC since its wide-scale adoption. pCR rates appear lower than reported studies. Understanding the limitation of retrospective studies, further analysis is ongoing to determine if factors other than sequence of modality can contribute to the observed findings.
Impact of PD-L1 expression on survival in patients with unresectable/recurrent gastric cancer receiving first-line chemotherapy without immune checkpoint inhibitors.
Authors: Hirano Hidekazu , Yamada Yasuhide , Nagashima Kengo , Hiraoka Nobuyoshi , Sekine Shigeki , Takahashi Naoki , Azuma Mizutomo , Iwasa Satoru , Kanato Keisuke , Machida Nozomu , Kinoshita Takahiro , Hata Hiroaki , Kawakami Hisato , Takahari Daisuke , Ojima Toshiyasu , Kadowaki Shigenori , Boku Narikazu , Kurokawa Yukinori , Terashima Masanori , Yoshikawa Takaki 
Published: January 2024

391 Background: Although high PD-L1 expression predicts a favorable response of advanced solid tumors to immune checkpoint inhibitors (ICIs), its impact on survival in patients with unresectable/recurrent gastric cancer (GC) has remained unclear. We investigated the prognostic value of PD-L1 expression for survival in unresectable/recurrent GC patients receiving first-line chemotherapy without ICIs. Methods: JCOG1013, a phase 3 randomized trial, demonstrated the addition of docetaxel to cisplatin and S-1 as first-line chemotherapy was of no benefit to patients with unresectable/recurrent GC (N=741) either for overall survival (OS) or progression-free survival (PFS). Tumor specimens prior to chemotherapy were collected for assessing PD-L1 expression for this ancillary study. PD-L1 expression was determined using immunohistochemistry (Dako, 28-8 pharmDx) and used to derive the PD-L1 combined positive score (CPS) and PD-L1 tumor proportion score (TPS). As with the CheckMate 649 study, the cutoff values for PD-L1 CPS and PD-L1 TPS were set at 5 and 1%, respectively. Multivariable analyses were performed using Cox proportional hazard models to evaluate the prognostic significance of PD-L1 CPS and PD-L1 TPS as predictors of OS and PFS. All p values were 2-sided; values <0.05 were considered statistically significant. Results: We analyzed 427 patients with unresectable/recurrent GC. The prevalence of PD-L1 CPS≥5, and PD-L1 TPS≥1% was 33% and 24%, respectively. There was no significant difference in OS and PFS between the PD-L1 CPS ≥5 group and the PD-L1 CPS <5 group (Table). The PD-L1 TPS ≥1% group had superior OS and PFS compared to the PD-L1 TPS <1% group (Table). In multivariable analyses for OS, PD-L1 TPS ≥1% was a significant favorable prognostic factor (hazard ratio (HR) = 0.64 [95% CI: 0.50–0.83], p<0.001), but PD-L1 CPS≥5 was not (HR = 0.82 [95% CI: 0.65–1.02], p = 0.073). In multivariable analyses for PFS, PD-L1 TPS ≥1% was a significant favorable prognostic factor (HR = 0.67 [95% CI: 0.52–0.84], p<0.001), but PD-L1 CPS≥5 was not (HR = 0.83 [95% CI: 0.67–1.03], p = 0.090). Conclusions: PD-L1 TPS≥1% is significantly correlated with longer OS and PFS in patients with unresectable/recurrent GC receiving first-line chemotherapy without ICIs. PD-L1 TPS should be considered as a stratification factor in randomized clinical trials for unresectable/recurrent GC. Clinical trial information: UMIN000007652 . [Table: see text]
Role of heat shock protein 90 in hypoxia-induced angiogenesis and epithelial-mesenchymal transition for esophageal squamous cancer cells.
Authors: Tzao Ching , Wang Jin-Kun 
Published: January 2024

395 Background: Hypoxia is known as an important trigger for the development and progression of human cancers. Heat shock proteins (Hsps) may be up-regulated in response to cellular stressors including hypoxia. To date, the functional role of Hsps within hypoxic tumor microenvironment for esophageal squamous cell cancer (ESCC) remains poorly defined. Methods: CoCl2 was used to induce hypoxia that mimics a hypoxic tumor microenvironment in cultured ESCC cells. Successful induction of hypoxia was confirmed by 2’,7’ –dichlorofluorescein diacetate (DCFDA) assay by detection of cellular reactive oxygen species (ROS). 7-Dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), a selective Hsp90 inhibitor, was used to treat 2 ESCC cell lines, KYSE-170 and -510 cells pretreated with or without CoCl2, an agent to induce a hypoxic tumor microenvironment. Cytotoxicity (MTT) and migration assays were conducted in KYSE-17 and -510 ESCC cells in response to different concentrations of CoCl2, followed by protein expression of Hsp 90, vascular endothelial growth factor (VEGF), hypoxia-inducible factor-1a (HIF-1a), mTOR as well as markers related epithelial-mesenchymal transition (EMT) such as snail or E-cadherin, by immunoblot or ELISA. In parallel, cell proliferation and migration assays of ESCC cells were analyzed. Results: CoCl2 induced hypoxia was supported by an induction of reactive oxygen species (ROS). CoCl2 (200 mM) significantly suppressed cell viability and proliferation with a concomitant up-regulation of VEGF and HIF-1a in a dose-dependent fashion. In contrast, cell migration was significantly increased in response to CoCl2, while down-regulating E-cadherin with concomitant increase in Snail expression. 17-DMAG decreased expression of VEGF and HIF-1a. In addition, it inhibited cell migration and invasion of ESCC cells were analyzed. Conclusions: Our data have shown that CoCl2 induced hypoxia promotes EMT and angiogenesis, which are inhibited by 17-DMAG, suggesting that hypoxia induced EMT and angiogenesis is Hsp 90 dependent in ESCC.
Prognostic role of platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR) in advanced gastric cancer treated with immunotherapy: A systematic review and meta-analysis.
Authors: Matsas Silvio , Aguiar Junior Pedro N. , Del Giglio Auro 
Published: January 2024

397 Background: Recent advances in the treatment of Gastric Cancer (GC) have introduced immunotherapy as a promising approach for advanced disease. In this context, potential biomarkers such as the platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR) have gained attention for their roles in predicting treatment outcomes. In this meta-analysis, we explore the clinical significance of PLR and NLR as predictors of Overall Survival (OS) and Progression-Free Survival (PFS) in advanced GC patients undergoing immunotherapy. Methods: Two independent reviewers systematically searched electronic databases, including PubMed, Embase and Scopus. The search incorporated controlled vocabulary (MeSH terms) and keywords related to Gastric Cancer, immunotherapy, platelet-to-lymphocyte ratio (PLR), and neutrophil-to-lymphocyte ratio (NLR). Eligible studies were selected based on predefined criteria, including HR availability, and were assessed for quality and bias using the Newcastle-Ottawa Scale. Data extraction was independently performed by two reviewers, and discrepancies in study selection and data extraction were resolved by a third reviewer. Subgroup analyses were performed to explore potential variations in the study outcomes. All analyses were conducted with RevMan 5.4 and employed random-effects model. Results: In total, 16 studies encompassing 1176 patients for NLR and 8 studies covering 766 patients for PLR were included in this systematic review and meta-analysis. The studies spanned the years between 2018 and 2023. Our analysis revealed significant associations between high NLR and poor OS (HR: 2.11, 95% CI: 1.70-2.62, p < 0.00001) and PFS (HR: 1.76, 95% CI: 1.43-2.17, p < 0.00001). Similarly, elevated PLR was significantly associated with worse OS (HR: 1.77, 95% CI: 1.44-2.17, p < 0.00001) and PFS (HR: 1.61, 95% CI: 1.33-1.96, p < 0.00001). In all conducted subgroup analyses, high NLR and PLR were consistently associated with poor survival outcomes. Conclusions: Our analysis supports the significance of NLR and PLR as accessible and cost-effective biomarkers for predicting survival outcomes in the context of immunotherapy for advanced GC. These findings underscore their potential significance in guiding clinical decisions. Further investigation should be carried out to validate our findings.
Treatment development targeting Hippo pathway for scirrhous type gastric cancer.
Authors: Miki Yuichiro , Yoshii Mami , Kuroda Kenji , Miyamoto Hironari , Tamura Tatsuro , Toyokawa Takahiro , Lee Shigeru , Maeda Kiyoshi 
Published: January 2024

398 Background: Treatment outcome of gastric cancer (GC) has been improved by minimally invasive surgery, and development of new drugs including immune checkpoint inhibitors. However, survival for patients with scirrhous type (SGC, Type4) gastric cancer is dismal. Methods: We collected miRNAs form exosomes released from cancer associated fibroblasts which is developed from resected gastric cancer tissue. Pathway enrichment analysis (PEA) of top miRNAs showed that they are significantly associated with Hippo signaling pathway (Hippo pathway). The molecules relating Hippo pathway was evaluated by Western blotting in cell line, and IHC of tissue array. Results: PEA using top miRNAs showed the significant relationship to Hippo pathway. Yap is a final effector in this pathway, and we found that YAP is not expressed in MKN45 cells (diffuse type), which is supposed to be degraded in cytoplasm. On the contrary, MKN74 cells express both YAP and pYAP. IHC showed that YAP translocation to nucleus is significantly associated with CTGF expression. CTGF low expression is significantly associated with worse prognosis especially in diffuse type GC (Log rank p = 0.022). This trend is similar in the analysis of patients with SGC. Conclusions: The role of Hippo pathway is different between intestinal type and diffuse type of GC. YAP activator could be effective for the treatment of SGC, and we are focusing on the treatment development.
International real-world study of TOTAL neoadjuvant therapy (TNT) for locally advanced rectal cancer (LARC).
Authors: Audisio Alessandro , Velenik Vaneja , Meillat Hélène , Ruiz-Garcia Erika , Riesco Martinez Maria Carmen , Dekervel Jeroen , Carvalho Carlos Torres , Suárez Francisco Javier , Kirac Iva , Hernando Jorge , Artac Mehmet , O'Connor Juan Manuel , Braam Pètra , Shamseddine Ali , Borelli Beatrice , Paez Lopez-Bravo David , Dulskas Audrius , De Felice Francesca , Vanden Bulcke Alexander , Sclafani Francesco 
Published: January 2024

40 Background: TNT has recently emerged as a standard treatment for LARC. However, use and outcome of the different TNT regimens in real-world practice are largely unknown. Methods: This is an international, multicentre, retrospective study sponsored by the Institut Jules Bordet, Brussels. Eligibility was limited to newly diagnosed LARC patients treated with TNT between March 2013 and May 2023 and outside the context of a clinical trial. The primary objective was to describe real-word practice across international centres. Secondary objectives included treatment safety and efficacy. Data were collected into a central electronic database, and remotely monitored. Descriptive statistics were used, and survival outcomes were estimated with Kaplan-Meier curves. Results: 1,272 eligible patients were included from 47 centres across four continents (Europe, Asia, North America and South America). Baseline characteristics were as follows: 63% males, median age 60 years (range 21-88), 47% low rectum, 26% cT4, 47% cN2, 49% EMVI+, 59% CRM+. In the overall population, 21% of the resected patients had a pathological complete response (pCR), while 11.3% were managed according to a watch-&-wait (w&w) strategy. Median follow-up was 24.1 months (IQR 23.7). Local and distant recurrences after curative-intent surgery occurred in 5.5% and 16.2% of patients, respectively. 3-year event-free survival (EFS) was 68.3%, while 3-year overall survival (OS) was 89%. Serious adverse events were reported in 4.3% of patients during radiotherapy, and in 14.7% during chemotherapy. Patient distribution according to the TNT sequence/regimen, and respective efficacy outcomes are reported in the table. Conclusions: This is the largest real-world study of TNT for LARC. Our findings show substantial variation in the choice of TNT sequence and regimen. Efficacy and safety results are overall in line with those reported in clinical trials, and confirm feasibility of TNT in a real-world setting. Patient recruitment is ongoing, and updated results with propensity score matching analyses will be reported at the meeting. [Table: see text]