bluuebunny/crossref_metadata_2025_split huggingface dataset:
Concurrent TP53 mutations and association with outcomes within the SMAD4 mutated subgroup of metastatic colorectal cancer.
Authors: Wang Chongkai , Sandhu Jaideep Singh , Tsao Amber , Fakih Marwan 
Published: June 2022

e15578 Background: SMAD4 mutations have been associated with poor prognosis in patients with metastatic colorectal cancer. However, results have been inconsistent between studies. This study aimed to determine the impact of coexisting mutations with SMAD4 on overall survival (OS) in patients with metastatic colorectal cancer. Methods: This is a retrospective, single institute study. Patients with metastatic colorectal cancer treated at City of Hope between 2013 and 2020 and with available Clinical Laboratory Improvement Amendment (CLIA) certified next-generation tumor sequencing (NGS) results were included. Overall survival was measured from the date of diagnosis of metastatic colorectal cancer. Differences in OS between groups were compared using Kaplan–Meier curves, with p-values calculated via log-rank test. Both univariate and multivariate Cox regression models were applied to estimate the hazard ratios and confidence intervals of survival based on mutation status and other clinical factors. Results: 433 patients with metastatic colorectal cancer were identified. SMAD4 mutation was found in 16.2% (70/433) of tumors. A systemic univariate and multivariate survival analysis model including age, gender, sidedness of primary tumor, RAS, BRAFV600E, APC, TP53 and SMAD4 status showed SMAD4 mutation alone was not associated with worse prognosis (multivariate HR = 1.25, 95% CI 0.90-1.73, p = 0.18). We then investigated SMAD4 mutation in combination with each of the top 4 most frequently associated oncogenes or tumor suppressor genes ( TP53-80%, n = 56; APC- 59%, n = 41; RAS-54%, n = 38; BRAFV600E-11%, n = 8) as a predictive biomarker of survival in patients with metastatic colorectal cancer. Coexisting mutations in SMAD4 and TP53 were significantly associated with worse overall survival (multivariate HR = 2.51, 95% CI 1.46-4.30, p = 0.001). The median overall survival of patients with coexisting SMAD4 and TP53 mutation was 24.2 months compared to 42.2 months for the rest of the population (p = 0.002). Conclusions: SMAD4 mutation status alone is not sufficient for predicting poor prognosis in patients with metastatic colorectal cancer. Coexisting mutations in SMAD4 and TP53 were significantly associated with worse overall survival in patients with metastatic colorectal cancer.
Real-world outcomes among patients with metastatic colorectal cancer treated first line with bevacizumab-awwb.
Authors: Jin Ran , Ogbomo Adesuwa S. , Accortt Neil A. , Lal Lincy S. , Bishi Geetanjali , Sandschafer Darcie , Goldschmidt Jerome H. 
Published: June 2022

e15581 Background: Bevacizumab-awwb (MVASI) was the first FDA-approved biosimilar to Avastin (reference product, RP). Real-world data on effectiveness and safety remain limited and may help address barriers to utilization. Methods: Adult patients who had a confirmed diagnosis of metastatic colorectal cancer (mCRC) (initial presentation on or after 1 January 2018) and initiated bevacizumab-awwb between 19 July 2019 and 30 April 2020 were identified in the ConcertAI Definitive Oncology EMR Dataset. A retrospective medical chart review was conducted to evaluate patient clinical characteristics and outcome data. The current analysis focused on the subset of patients who initiated first-line (1L) bevacizumab-awwb containing therapy (with no prior use of RP) to evaluate incidence of events of interest (EOIs) (Table) and overall survival (OS) probability using Kaplan-Meier analysis. Patients were followed from the initiation of 1L therapy until death, end of record, or end of study period (June 2021), whichever occurred first. Results: A total of 129 patients who initiated bevacizumab-awwb as 1L treatment in combination with chemotherapy were included in this analysis. Majority of patients (78.3%) were treated at clinical oncology practices in a community setting (median age: 60.5 years, 53.5% male). 34.9% of patients had non-metastatic disease (stage of I/II/III) at the initial diagnosis and 38.8% had undergone surgical resection. Median duration of available follow-up data was 10.7 (range: 0.69-22.4) months. During the study period, 100 out of 129 patients had disease progression of which 46 patients had a record of death. The Kaplan-Meier analysis showed that 12-month OS probability was 71.4% (95% CI: 61.0%-79.5%). During treatment with bevacizumab-awwb, 20 EOIs were reported in 18 patients (14.0%). Distribution of events and their management are presented in the Table. None of these EOIs resulted in death. Conclusions: Biosimilar bevacizumab-awwb appeared to be well tolerated, with observed EOIs being manageable, and 12-month OS probability of > 70% for treating patients with mCRC in the real-world setting.[Table: see text]
Total neoadjuvant treatment approach and carcinoembryonic antigen level in locally advanced rectal cancer.
Authors: Sethi Ashish , Abel Stephen , Wegner Rodney E. , Renz Paul , Kirichenko Alexander V. , Wagner Patrick , McCormik James , Finley Gene Grant , Raj Moses S. 
Published: June 2022

e15595 Background: Total Neoadjuvant therapy (TNT) has gained acceptance in the treatment of locally advanced rectal cancer, although the optimal sequencing of therapy chemoradiation (CRT) followed by consolidation chemotherapy (cChT) or induction chemotherapy followed by chemoradiation (iChT), remains a subject of ongoing debate. The effect of TNT sequencing and carcinoembryonic antigen (CEA) level on progression free survival (PFS) is uncertain. We conducted a retrospective analysis to examine these issues. Methods: Patients (n = 44) with locally advanced rectal cancer from June 2016 to December 2020 were reviewed. CEA level was compared against the primary outcome of response to TNT approaches. We categorized patients into 3 groups based on pre-TNT and post-TNT (i.e. pre-surgical) CEA: normal CEAPRE/normal CEAPOST, elevated CEA PRE/normal CEA POST, elevated CEA PRE/elevated CEA POST. 3-Year PFS was calculated using Kaplan-Meier method. Univariable and multivariable logistic regression analyses identified characteristics predictive of PFS and clinicopathologic variables associated with TNT sequencing. Results: The study cohort had a median age of 61 years and was predominantly male (70%) and Caucasian (94%). Pre-treatment stage was either II (27%) or III (72%), with the majority (65%) undergoing iChT. Downstaging occurred in 42/44 (95%). Baseline CEA was elevated in 40.9% of patients. On multivariable, logistic regression variable associated with receipt of CRT followed by cChT included: Age > 61 years clinical T4 disease and lack of T downstaging (p < 0.05 for all).There was no difference in 3-year PFS between patients receiving iChT versus patients receiving cChT (p = 0.53). When patients were stratified according to pretreatment CEA level, no difference in 3 year PFS were noted (p = 0.46). On multivariable analysis, lack of nodal downstaging following neoadjuvant treatment was associated with higher likelihood of progression (p = 0.02). Similarly, pretreatment CEA > 4.25 ng/ml (p = 0.08) and failure of CEA to decrease by >2 ng/ml following TNT (p = 0.07) trended toward higher likelihood of progression. Conclusions: Neither TNT sequencing, nor baseline CEA predicted the PFS although the power of our study was limited. Lack of nodal downstaging was identified as a predictor of worse PFS. Further areas of study should include plasma-based assays to quantitate circulating tumor DNA and next generation sequencing to assess prognosis with different sequencing of TNT.
Outcomes in high-grade neuroendocrine carcinomas (HG-NEC) of the gastrointestinal (GI) tract with modern therapies.
Authors: Belmont Erika , Paydary Koosha , Liao Chih-Yi , Polite Blase N. , Kindler Hedy L. , Setia Namrata , Shergill Ardaman 
Published: June 2022

e15609 Background: HG-NEC of the GI tract are rare and aggressive neoplasms with poor prognosis. Approximately 37.5% of extra-pulmonary NEC are of the GI origin and are most commonly located in esophagus, stomach, pancreas and colon (1,2). Median survival of 7.5 months, with range of 5.7 months to 25.1 months has been reported (2). However, data regarding response to immunotherapy, as well as response to molecularly directed therapies are sparse. In this study, we conducted a retrospective review of GI tract HG-NEC with objective to assess role of modern diagnostics and therapies in clinical outcomes. Methods: We identified 14 patients with GI tract HG-NEC who received care at University of Chicago Medical Center (UCMC). Electronic medical records were reviewed for disease stage, treatments and clinical course. We reviewed available next generation sequencing (NGS) and circulating tumor DNA (ct-DNA) test results. In this cohort, UCMC’s NGS panel: Oncoplus was available and Guardant 360 results were reviewed for liquid biopsy. Results: In our initial review, site of origin included right side of colon (46%), left sided colon (46%), and anus/anorectal (15%). Median overall survival (mOS) ranged from 1.3 months to 81.3 months, and notably the median response to chemo-immunotherapy (IO) was 7.9 months (table 1). Notably one patient received maintenance therapy with immunotherapy alone with progression of disease (POD) in 3 weeks. Six patients had NGS results of which three (50%) had therapeutic targetable alterations (Table). Two patients had liquid biopsy done, of which one had targetable alterations and the other had no tumor related alterations detected. Of the two patients with targetable lesions, one patient has received targeted therapy with POD in 1.2 months and median OS 8.8 months; the other is in the process of initiating targeted therapy. Conclusions: To our knowledge, this is the first report to show a response to combination chemo-immunotherapy and targeted therapies in HG-NEC of GI tract. We are collaborating with other institutions to collate outcomes to similar therapy approaches in this patient cohort. With our study, we hope to inform future therapies and innovation in this important disease.
Different gene mutations among gastric cancer patients with MSS and MSI-H types in China.
Authors: Zheng Jianyong , Du Kunli , Ren Guangming , Xie Zhenyu , Li Ruikai , Zheng Gaozan , Feng Fan , Duan Weiming , Huang Depei , Zhang Hushan 
Published: June 2022

e16018 Background: Gastric cancer is one of the leading causes of cancer-related deaths worldwide, although the incidence has gradually decreased in many Western countries. The status of microsatellites is an important biomarker of gastric cancer immunotherapy, but not all patients with MSI-H have excellent curative effect. Therefore, this study of the molecular background of MSS and MSI-H, which is helpful for the development of gastric cancer immunotherapy in Chinese patients. Methods: The formalin-fixed paraffin-embedded (FFPE) tissues of 6603 patients with CRC who have underwent next-generation sequencing (NGS) from Jan, 2019 to Apr, 2021 in 3DMed Clinical Laboratory Inc. were investigated in this study. These patients are still being followed up. Statistical analysis was performed using Microsoft Office Excel (2013). Results: 7.0% (139/1997) patients with MSI-H status, MSI-H and MSS tumors showed striking gene mutation differences. Among the 10 genes with the highest mutation rate, TP53 ERBB2 CDH1 PIK3CA mutations appear in both MSI-H and MSS patients. But the mutation rates of these genes vary greatly (32.3% VS 53.7%, 19.4% VS 13.0%,12.2% VS 8.2%, 34.5% VS 8.2%, respectively). Among the top 10 mutated genes, ARID1 (70.5%), mutation with the highest rate is only mutated in MSI-H patients. There are other gene mutations, including KMT2C (68.3%), RNF43 (59.7%), TGFBR2 (58.3%), RNF43 (34.5%), MSH3 (46.8%), RAD50(41.0%), MSH6(31.7%), ATR (30.2％), which have hugely higher mutation rates than MSS patients. It is worth noting that the mutation rate of TP53, BCL2L11, CYP2C19, MYC, CCNE1 and UGT1A1 in MSS patients is absolutely higher than that in MSI-H. Conclusions: There are completely differences in gene mutations between MSI-H and MSS gastric cancer patients in the Chinese population, especially TP53, ERBB2, CDH1, PIK3CA KMT2C, RNF43, TGFBR2, RNF43, MSH3, RAD50, MSH6 and ATR, which are of great significance for accurate patient stratification and treatment.
Prediction of peritoneal cancer index and prognosis in peritoneal metastasis of gastric cancer using NLR-PLR-DDI score.
Authors: Jiang Zhihui , Pengfei Yu , Yu Pingyuan , Cao Yang , Ye Zeyao , Chai Tengjiao , Du Yian 
Published: June 2022

e16022 Background: Peritoneal metastasis is the most common metastatic mode of advanced gastric cancer, which is prone to poor prognosis and is also one of the common causes of death in patients with distant gastric cancer metastasis.The purpose of this paper was to establish a new hematologic scoring (an NPD scoring) by the neutrophil-lymphocyte ratio (NLR) and platelet- lymphocyte ratio (PLR) A and D-dimer (DDI), and its association with the peritoneal cancer index (PCI) was evaluated, and the ability of NPD scoring system to judge the prognosis of peritoneal metastasis of gastric cancer. Methods: This was a single-center, nonrandomized, retrospective, cohort study.102 patients with peritoneal metastasis of gastric cancer who underwent diagnostic staging laparoscopy (DSL) were enrolled and assessed with PCI scores.. According to the first PCI (PCI < 15), the patients were divided into low PCI group (n = 67) and high PCI group (n = 35). Through univariate analysis and multivariate analysis, it was found that NLR, PLR and DDI were related to high PCI (≥ 15), and NPD scoring system was established. Chi-square test was used to evaluate the relationship between NPD score, PCI and prognosis. Results: The cohort study found that the differences of NLR, PLR and DDI between low PCI group (n = 67) and high PCI group (n = 35) were statistically significant (P < 0.05). Univariate and multivariate analysis showed that NLR, PLR and DDI were independent risk factors for high PCI (P < 0.05). The NPD score of patients in the high PCI group was significantly higher than those in the low PCI group (P = 0.001). The survival rate of patients in high-risk group (NPD ≥ 2 points) was significantly lower than that in low-risk group (NPD < 2 points) (P = 0.003). Multivariate analysis showed that PCI and NPD score ≥ - 2 were independent predictors of OS. Conclusions: NPD score can be used as a blood marker to predict PCI and prognosis in patients with peritoneal metastasis of gastric cancer, and to guide clinical treatment. This new scoring system is an economic and convenient tool for predicting PCI and judge the prognosis of peritoneal metastasis.
Comparison of surgical resection combined with chemotherapy and palliative chemotherapy for synchronous hepatic metastases from gastric cancer.
Authors: Yu Pingyuan , Pengfei Yu , Jiang Zhihui , Cao Yang , Ye Zeyao , Chai Tengjiao , Du Yian 
Published: June 2022

e16041 Background: Hepatic metastases of gastric cancer(HMGC) are an important factor affecting the prognosis of gastric cancer patients, and 3-14% of gastric cancer cases were diagnosed with synchronous hepatic metastases of gastric cancer (SHMGC). However, there remains much unidentified about the therapy effect of surgical resection on SHMGC. Here, we investigated the associations of surgical resection with the overall survival of SHMGC, which might develop more effective therapy strategies for patients of HMGC. Methods: Patients diagnosed with SHMGC from January 2010 to December 2015 were selected in the study. Kaplan-Meier analysis and multivariable analysis based on the Cox proportional hazards model were performed to compare the effects of surgical resection (including gastrectomy and metastasectomy) combined with chemotherapy (surgical resection group, SR group) and palliative chemotherapy (palliative chemotherapy group, PC group) on survival. Results: A total of 132 patients were enrolled in this study. Overall, 57 (43.2%) were treated with surgical resection/chemotherapy and 75 (56.8%) palliative chemotherapy. Overall survival (OS) was significantly prolonged in the SR group compared with the PC group (33.6 vs. 12.4 months, P < 0.001). In the SR group, the R0 resection (68.4%, 39/57) contributed to markedly prolonged OS compared with the non-R0 resection subgroup (45.1 vs. 13.5 months, P < 0.001). Surgical resection and single hepatic metastasis were independent predictors of OS in multivariate analysis with hazard ratio (HR) of 0.453 (95% confidence interval [CI] 0.276-0.813, p = 0.009) and 0.540 (95%CI 0.315-0.796, p = 0.043), respectively. Conclusions: For patients with synchronous hepatic metastases of gastric cancer, radical surgical resection combined with appropriate chemotherapy may be more beneficial than palliative chemotherapy. Moreover, single hepatic metastasis might achieve better survival after aggressive surgical resection.
Addition of anti-PD1 antibodies to chemotherapy (CT) in first-line treatment of advanced esophageal cancer (EC): A systematic review and meta-analysis.
Authors: Rice Anastasia , Fedyanin Mikhail , Ignatova Ekaterina , Polyanskaya Elizaveta , Dinaeva Elmira , Besova Natalia , Tryakin Alexey 
Published: June 2022

e16055 Background: The addition of anti-PD-1 antibodies to first-line CT is the new standard of care for pts with advanced EC. However, available data on the efficacy of such therapy in different clinical subgroups is still lacking. Therefore, we performed a meta-analysis to determine the efficacy of combination anti-PD1 and systemic CT in terms of overall survival (OS) in pts with advanced EC. Methods: We searched PubMed, proceedings of ASCO, and ESMO conferences up to February 2022. We included prospective randomized phase III trials comparing the combination of anti-PD1 and CT with CT alone as the first-line treatment option for pts with advanced EC. The primary outcome was OS. Meta-analysis was conducted by Review Manager (Ver. 5.3) software. Results: Five trials with a total of 3163 pts were included, of which 1576 received anti-PD1+CT and 1587 received CT alone. There was a significant improvement in PFS (HR, 0.62; 95% CI, 0.56-0.67; p < 0.00001; I2 = 45%, p for heterogeneity 0.12), OS (HR, 0.69; 95% CI, 0.63-0.76; p < 0.00001; I2 = 0%) and ORR (OR, 2.07; 95% CI, 1.76-2.43; p < 0.00001; I2 = 21%) in pts received anti-PD1+CT. OS was improved in pts regardless of age, race, CT regimen, presence of liver metastases, ECOG PS, or histology. Subgroup analysis suggested that the addition of anti-PD1 have a better effect in pts with PDL expression on tumor cells > 1, ≥ 10, and < 10 and in pts with CPS ≥ 10, but not in pts with PDL < 1. We found a tendency towards survival advantage in pts with CPS < 10. No survival benefit was observed in women (tab). Conclusions: Improved OS was found to be associated with addition of anti-PD1 antibodies to systemic CT in different patient subgroups with advanced EC, except for female and in pts with low PDL expression. Despite of meta-analysis results we need prospective randomized trial for pts with CPS < 10.[Table: see text]
Development of combination strategies for focal adhesion kinase inhibition in diffuse gastric cancer.
Authors: Peng Ke , Bass Adam Joel 
Published: June 2022

e16057 Background: Diffuse gastric cancer (DGC) is an aggressive and frequently lethal pathological subtype of gastric cancer (GC). Since DGC often lacks genomic aberrations that indicate clear candidate therapeutic targets, it has been challenging to develop target therapies for this GC subtype. Our previous study highlighted the contribution of focal adhesion kinase (FAK) in the tumorigenesis of DGC, and the potential for small molecule FAK inhibitors to have efficacy in DGC. Currently, FAK inhibitors are under active clinical evaluation in several tumor types. To date, FAK inhibitor monotherapy has been tolerated in the clinic, but has shown only modest clinical efficacy in cancer treatment, which inspired us to explore targets for the combination with FAK inhibitors in DGC. Methods: We constructed the engineered murine DGC model of Cdh1-/- RHOAY42C/+ organoids, with Cdh1 (E-Cadherin) loss and RHOA Y42C mutation, in our previous study. Using this DGC organoids model, we performed genome-scale libraries of open reading frames (ORF) screen to identify candidate mechanisms of resistance to FAK inhibitors (defactinib or PF-573228). For the top hits found in ORF screen, further validations were performed in Cdh1-/- RHOAY42C/+ organoids and human DGC cell lines of NUGC4 and SNU668 to check whether they could function as candidates for the combination with FAK inhibitors. Besides, we used Digiwest, a high-throughput protein analysis assay, to investigate pathway alterations of Cdh1-/- RHOAY42C/+ organoids treated with FAK inhibitors (defactinib or PF-573228). We then explored whether the activated pathways were the candidates for the drug combination. Zero Interaction Potency (ZIP) model was used to measure the synergistic effect between the drugs. The combination strategies were also tested in vivo. Results: We identified that cyclin-dependent kinase 6 (CDK6) promotes FAK inhibitors (defactinib and PF-573228) resistance according to ORF screen, and CDK4/6 inhibitor, Palbociclib, enhances the efficacy of defactinib for DGC models. Furthermore, we demonstrated that FAK inhibitors (defactinib and PF-573228) treatment in DGC models leads to compensatory activation of MAPK pathway in DGC, and the RAF/MEK dual inhibitor VS-6766 effectively enhances the antitumor efficacy of FAK inhibitors in vitro and in vivo. Conclusions: These data suggest that combinations of FAK inhibitors with MAPK inhibitors or CDK4/6 inhibitors are promising treatment strategies for DGC that warrant further testing in clinical trials.