bluuebunny/crossref_metadata_2025 huggingface dataset:
Predicting treatment response for the safe non-operative management of patients with rectal cancer using an MRI-based deep-learning model.
Authors: Selby Heather M. , Liu Charles , Sheth Vipul , Napel Sandy , Wagner Todd , Morris Arden M.
Published: June 2023

e15648

Background: Neoadjuvant chemoradiotherapy (CRT) followed by total mesorectal excision (TME) surgery has been the standard treatment for patients with locally advanced rectal cancer. Surgery, while effective in treating rectal cancer, can lead to significant long-term morbidity, such as bowel, urinary, and sexual dysfunction, and potential dependence on a colostomy for evacuation. A pathologic complete response (pCR) to neoadjuvant CRT suggests that TME surgery may not be necessary, as the tumor may have been effectively treated with CRT alone. However, the only definitive determination of pCR is based on a pathologic exam, which requires a surgical specimen. By comparing pre- and post-CRT images, clinical complete response (cCR) is a surrogate for pCR that does not require surgery. However, cCR is a poor proxy for pCR, with sensitivity and positive predictive values of 34.1% and 30.6% respectively1. Purpose: Our aim is to develop a multiparametric longitudinal MRI-based 3D deep-learning model to predict pCR in patients with locally advanced rectal cancer. Methods: We identified 360 patients with rectal cancer who had neoadjuvant CRT followed by surgical resection between January 2012 and December 2021 in an academic medical center. We have classified patients into two groups based on the presence or absence of pCR in their resected tumor specimen. We will train and validate a multiparametric longitudinal MRI-based 3D deep-learning model to predict pCR. Our model will use T1-weighted, T2-weighted with and without contrast, and/or diffusion-weighted MRIs before and after neoadjuvant CRT to predict pCR. Using multiparametric MRIs offers a comprehensive understanding of the tumor and surrounding tissue, and including longitudinal MRIs will provide valuable information on the impact of treatment. To assess the performance of the model, we will use receiver operating characteristic (ROC) analysis as well as positive and negative predictive values to evaluate its ability to predict pCR. Preliminary Results: Among 360 patients, 227 (63.1%) were male, 187 (51.9%) were Non-White, and the average age was 58.7 (SD of 13.3) years. The surgical pathology reports showed that 44 (12.2%) patients had achieved a pCR, while the visual assessment of post-CRT MRIs revealed that 49 (13.6%) had achieved a cCR. 1. Liu, C. et al. Predictive Value of Clinical Complete Response after Chemoradiation for Rectal Cancer. J. Am. Coll. Surg. 235, S51–S52 (2022).
Consensus molecular subtypes and orphan non-coding RNAs in colorectal cancer.
Authors: Wang Jeffrey , Karimzadeh Mehran , Cavazos Taylor B. , Barzi Afsaneh , Wang Kathleen , Hanna Rose , Arensdorf Patrick , Chau Kimberly H. , Li Helen , Goodarzi Hani , Fish Lisa , Hormozdiari Fereydoun , Alipanahi Babak
Published: June 2023

e15651

Background: Colorectal cancer (CRC) is a highly heterogeneous disease with variable response to different treatment strategies. The consensus molecular subtype (CMS) classification system has been proposed as a gene expression-based framework aimed at capturing the genetic and molecular heterogeneity in CRCs and potentially stratifying patients into clinically relevant subgroups for treatment selection. We previously demonstrated that orphan non-coding RNAs (oncRNAs), a novel class of cancer enriched small non-coding RNAs (smRNA), exhibit cancer-specific expression. We also showed that oncRNAs can be used in a liquid biopsy assay for accurate early-stage detection of CRCs. We hypothesize that oncRNAs may be informative of CRC subtype-specific transcriptional signatures as defined by the CMS groups. Methods: To assess the effectiveness of oncRNAs for categorization of CMS group, we examined smRNA-seq data from The Cancer Genome Atlas (TCGA) for colon and rectal adenocarcinoma tumors ( n= 504), consisting of 77 CMS1, 216 CMS2, 71 CMS3, and 140 CMS4 tumors. CRC-specific oncRNA expression profiles were generated for all tumors in the TCGA cohort. We then trained a machine learning model on oncRNA expression profiles to predict CMS groups using a 5-fold cross validation setup. For our validation cohort, we applied our model to an independent CRC cohort ( n= 348) consisting of 56 CMS1, 101 CMS2, 59 CMS3, and 132 CMS4 CRC samples. Final CMS predictions for the validation cohort were made by averaging across the five training models. Results: Within TCGA testing folds, the model micro-averaged ROC-AUC for CMS classifications were 0.879 (95% CI: 0.86–0.90). In the validation cohort, micro-averaged AUC remained high at 0.915 (0.90–0.93). Sensitivities and AUCs for each subtype are provided in Table 1. The highest model-predicted likelihood for each CMS subtype had an accuracy of 73.6% (68.6%–78.1%), and the two most probable predictions had an accuracy of 91.1% (87.6%–93.9%). Conclusions: This study demonstrates the utility of oncRNA expression profiling to predict CMS for colorectal cancer. The generalizability of our machine learning model suggests that oncRNAs are informative of the biological differences across distinct CMS groups and may be used as a proxy for gene expression signatures to stratify colorectal cancers. Because smRNAs are more likely to be secreted into blood, we posit that an oncRNA-based liquid biopsy may open new opportunities to monitor patients and track changes in their tumor biology in real-time throughout their course of disease and treatment. [Table: see text]
Long-term follow-up results of ipilimumab and nivolumab for the treatment of mismatch repair deficient locally advanced rectal cancer.
Authors: Trotier Danny , Uboha Nataliya Volodymyrivna , Matkowskyj Kristina A. , Zhang Wei , Kratz Jeremy D. , Carchman Evie , Lawson Eilse , Sanger Cristina , Heise Charles , Lubner Sam Joseph , Patel Monica Arun , LoConte Noelle K. , Bassetti Michael F. , Deming Dustin A.
Published: June 2023

e15652

Background: Mismatch repair deficient (dMMR) colorectal cancers have unique biology and responses to therapy. In the advanced setting, first line immunotherapy has superior activity compared to chemotherapy. Recent studies have demonstrated improved responses with neoadjuvant anti-PD1 therapy for dMMR locally advanced rectal cancer (LARC). In this study, we review our experience with the combination of ipilimumab (ipi) and nivolumab (nivo) for the treatment of dMMR LARC. Methods: Patients (pts) with dMMR LARC treated with ipi/nivo at the University of Wisconsin Carbone Center were identified under an IRB-approved protocol. Baseline demographics, molecular testing, treatment history, clinical imaging, and pathological evaluations were collected and summarized. Pts were followed with serial imaging (CT/MRI), endoscopic evaluations, and ctDNA MRD assays. Results: Fours pts (median age: 63 [range: 59-68]; 50% female) with dMMR LARC treated with ipi/nivo were identified. 3 pts had T4 tumors and were node positive. 1 patient had a mutation in MSH6, 1 patient had 2 mutations in MSH2, another had loss of MLH1/PMS2 on IHC, and the last patient had loss of MSH2/MSH6 on IHC. None of the patients have known germline variants. 2 patients were treated initially with FOLFOX chemotherapy and had progressive disease prior to conversion to ipi/nivo. Median follow-up is 25.5 months [range: 9-42] and 1 pt continues on nivo treatment. Pts were treated with 1-4 infusions of ipi and 2-24 months of nivolumab. All patients achieved a complete clinical/pathologic response and remain without evidence of disease recurrence. None of the pts required additional surgery or radiation therapy for cancer recurrence/progression. 3 of the 4 patients developed grade 3/4 immune-related adverse events, including 2 patients with adrenal insufficiency and 1 patient with immune hepatitis. 1 pt developed a fibrotic stricture at the site of the prior cancer requiring resection. Conclusions: dMMR LARC is a unique subtype of rectal cancer sensitive to combination immunotherapy with high potential for complete responses and organ preservation. The use of ipi/nivo in this cohort of pts resulted in complete pathogenic responses for all that remain durable over an extended period of time, though with increased immune-related adverse events compared to anti-PD1 therapies alone. This regimen is currently being studied further in prospective studies.
Effect of TFF2-MSA on tumor growth and survival in anti-PD-1 treated MC38 and CT26.wt colorectal cancer models by targeting MDSCs.
Authors: Daugherty Bruce L , Boohaker Rebecca J , Johnstone Rebecca , Stinson Karr , Qian Jin , Wang Timothy C. , Lederman Seth M.
Published: June 2023

e15654

Background: Myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment are potential therapeutic targets in immune checkpoint cancer therapy, particularly for cancers that are unresponsive to anti-PD-1 therapy. It has previously been demonstrated that trefoil factor family 2 (TFF2), a secreted anti-inflammatory peptide, can partially suppress MDSC expansion and partially activate tumor immunity through agonism of the CXCR4 receptor. We investigated whether a novel fusion protein, TFF2-murine serum albumin (TFF2-MSA), has single agent activity and can improve on the therapeutic effects of anti-PD-1 in the MC38 and CT26.wt syngeneic mouse models of advanced colorectal cancer (CRC). Methods: Two syngeneic colon carcinoma mouse models were developed using the MC38 and CT26.wt CRC cell lines grafted subcutaneously into C57BL/6 and BALB/C mice, respectively. We generated a recombinant fusion protein, designated TFF2-MSA, which contains murine TFF2 fused to murine serum albumin (MSA), for the purpose of increasing half-life and reducing the frequency of dosing. Mice subsequently received TFF2-MSA, anti-PD-1 antibody (clone 29F.1A12) or combination TFF2-MSA/anti-PD-1. Tumor volume, and survival were measured. At the endpoint, flow cytometry was performed on the draining and axillary lymph nodes, to examine treatment-induced effects on cellular immune profiles. Results: In the MC38 model, on Day 49 of treatment, tumor growth was suppressed (TGI) by TFF2-MSA alone, anti-PD-1 alone, and by combination TFF2-MSA/anti-PD-1 by 50%, 82% and 87% TGI, respectively. The survival rates at 50 days of mice treated with vehicle, TFF2-MSA, anti-PD-1, or combination TFF2-MSA/anti-PD-1 were 20%, 50% and 80%, and 90%, respectively. In the combination TFF2-MSA/anti-PD-1 treated mice, 40% demonstrated a complete response. In the CT26.wt model, tumor growth was suppressed by TFF2-MSA, anti-PD-1 and by combination TFF2-MSA/anti-PD-1 by 17%, 43% and 67%, respectively. Survival in the CT26.wt model at Day 30 treated with vehicle, TFF2-MSA, anti-PD1 and the combination of TFF2-MSA/anti-PD-1 was 0%, 40%, 60% and 60%, respectively. The percentage of exhausted CD8+ T cells was markedly reduced in the draining lymph node by the combination TFF2-MSA/anti-PD-1 treatment, as measured by flow cytometry using antibodies against LAG3, TIM3, and PD-1. Conclusions: TFF2-MSA has single agent activity and is additive to anti-PD-1 antibody checkpoint inhibition in treating syngeneic mouse models of advanced CRC. In a separate abstract, additive effects between TFF2-MSA and anti-PD-1 antibody were also demonstrated in a separate ACKP (Atp4b-Cre; Cdh1-/-; LSL-KrasG12D; Trp53-/-) gastric cancer model, suggesting combination therapy may also be applicable to gastric cancer.
Combination polypectomy or excisional biopsy with interventional radiology local tumor destruction versus polypectomy or excisional biopsy for colon cancer: A SEER database analysis.
Authors: Legenza Ashton , Burdyny Michael , Silberstein Peter T. , Tupper Connor
Published: June 2023

e15657

Background: Colon cancer is one of the most common forms of cancer, affecting millions of individuals worldwide. Despite advances in surgical and systemic therapies, a significant proportion of patients still present with locally advanced or metastatic disease. Interventional radiology has emerged as a crucial tool in the management of colon cancer, offering a number of minimally invasive treatments aimed at locally destroying the tumor. This study aims to assess the effectiveness and prognostic impact of various interventional radiology treatments for colon cancer. Methods: We queried the Surveillance, Epidemiology, and End Results (SEER) database for patients diagnosed with primary colon cancer from the cecum to the sigmoid (primary site codes C180-189), including the appendix, diagnosed between 2000-2019. Patients were included if management of the primary tumor included either excisional biopsy, polypectomy, and/or local tumor destruction (LTD) via photodynamic therapy, electrocautery, cryosurgery, or laser ablation (surgical codes 21-24). Variables included for Kaplan-Meier, Chi-square, and Cox Regression analyses were age at diagnosis, sex, race, stage, and surgical management subtype status. Results: A total of 18164 patients were collected from this search of which 775 patients underwent a combination polypectomy or excisional biopsy with LTD, 6997 patients underwent polypectomy alone, 1619 patients underwent excisional biopsy alone, 7959 patients underwent endoscopic polypectomy alone, 814 patients underwent a surgical excision polypectomy alone. On Kaplan-Meier, the combination polypectomy or excisional biopsy with LTD showed better survival than excisional biopsy alone (p < 0.001). The combination treatment showed similar survivability to polypectomy NOS, endoscopy polypectomy alone, and surgical excision polypectomy alone. The one-, three-, and five-year survival rates of combination treatment were 97.0%, 94.7%, and 93.4%, respectively, which is significantly greater than excisional biopsy at all time points (p’s < 0.001) and within 1% of all other treatments at all time points. On Cox regression, no differences in survival were observed between groups. Of note the demographics of older age (p < 0.001), black race (p < 0.001), American Indian/Alaska Native (p = 0.044), regional spread of tumor ( < 0.001), and distant spread of tumor (p < 0.0001) were all associated with worse survival outcomes. Conclusions: Combination polypectomy or excisional biopsy with interventional radiology LTD procedures are associated with improved survival compared to excisional biopsy alone for the treatment of colon cancer. Our results suggest these interventional radiology procedures may be effective additional management options for the management of primary colon tumors.
Polypectomy or excisional biopsy versus combination polypectomy or excisional biopsy with interventional radiology local tumor destruction for rectal cancer: A SEER database analysis.
Authors: Legenza Ashton , Burdyny Michael , Silberstein Peter T. , Tupper Connor
Published: June 2023

e15658

Background: Rectal cancer is a common and potentially debilitating form of gastrointestinal cancer. Despite advances in surgical and systemic therapies, a significant proportion of patients present with locally advanced or recurrent disease. Interventional radiology (IR) has emerged as a crucial tool in the management of rectal cancer, offering a number of minimally invasive treatments aimed at locally destroying the tumor. This study aims to evaluate the efficacy and prognostic significance of combining IR treatments with polypectomy or excisional biopsy in the management of rectal cancer, compared to polypectomy or excisional biopsy alone. Methods: We queried the Surveillance, Epidemiology, and End Results (SEER) database for patients diagnosed with primary rectal cancer from the cecum to the sigmoid (primary site codes C209), including the appendix, diagnosed between 2000-2019. Patients were included if management of the primary tumor included either excisional biopsy, polypectomy, or local tumor destruction (LTD) via photodynamic therapy, electrocautery, cryosurgery, or laser ablation (surgical codes 21-24). Variables included for statistical analyses were age at diagnosis, sex, race, stage, and surgical management subtype status. Results: A total of 24309 patients were collected from this search of which 1437 patients were selected that had undergone a combination polypectomy or excisional biopsy with LTD, 15005 patients underwent polypectomy alone, 7481 patients underwent excisional biopsy alone, 386 patients underwent curette and fulguration. On Kaplan-Meier, combination treatment showed a worse mean survival than polypectomy alone (p < 0.01). Combination treatment showed better mean survival than excisional biopsy alone ( < 0.001). The combination treatment showed similar survivability to curette and fulguration. The one-, three-, and five-year survival rates of combination treatment were 98.5%, 95.8%, and 94.8%, respectively, which is significantly greater than excisional biopsy at all points but significantly worse than polypectomy alone at all time points (p’s < 0.001). On Cox regression, combination treatment showed no difference in survival to polypectomy alone and curette fulguration. Combination treatment survival was significantly better than excisional biopsy alone (p < 0.001). Additionally, older age (p < 0.001), regional spread of tumor (p < 0.001), and distant spread of tumor (p < 0.0001) were all associated with worse survival outcomes. Conclusions: Combination polypectomy or excisional biopsy with IR LTD procedures are associated with improved survival compared to excisional biopsy alone for the treatment of rectal cancer. Our findings suggest that IR procedures may serve as an effective adjunct treatment option for primary rectal tumor management.
Associating patient perceptions to poor uptake of aspirin (ASA) chemoprevention in a single-center cohort of patients with Lynch syndrome (LS).
Authors: Singhal Sachi , Chertok Yana , Riggs Emma D , Daly Mary Beryl , Kim Dong , Hall Michael J.
Published: June 2023

e15662

Background: LS is among the most common hereditary cancer (CA) syndromes, underlying 3% cases of colorectal CA (CRC) and 8% of CRC < 50 yrs. Pts with LS have a very high lifetime risk of CRC, which has been shown to be decreased by intensive colonoscopy (COLO) surveillance. However, interval LS CRCs can still develop, and adjunctive therapies like ASA have been recognized for their chemoprev benefits, with 35% risk reduction associated with sustained ( > 2 yrs) use. Existing data are scarce on uptake of ASA chemoprev in LS pts, as well as pt-level factors that may impact uptake. Methods: PREVENTLynch recruited LS participants in the Fox Chase Cancer Center (FCCC) Risk Registry, who were invited to complete a one-time e-survey after providing informed consent (1/2020-6/2020; IRB 20-8014). Demographic/personal/familial CA history were collected. Inconvenience (INC), side effects (SEs), prevention reassurance (PR), and likelihood of recommending (LoR) available and emerging CA prevention modalities were measured on 9-point scales (low = 1 vs high = 9). Results: 116 LS pts completed the survey. Mean age was 53 yrs [range 23-76 ]. 24.7% (33/116) reported being on ASA, with 24.2% (8/33) taking it for an unrelated cardiac indication. 96.6% (112/116) had completed COLO, with 60.5% getting annual screening and 39.5% getting screening in 2-3 yrs. No significant difference was noted among ASA users and non-users based on age, race and underlying genetic LS subtype. A majority of pts (61.6%) were on ASA 81 mg/day, while 24.3% and 12% reported taking 325 and 650 mg/day, respectively. LS pts both taking and not taking ASA perceived it to be convenient (mean INC: 1.18 ASA users vs 2.11 non-users, p = 0.01). Concern for SEs was lower in ASA users than non-users (mean 1.09 vs 2.30, p = 0.003) while PR of the protective benefits was higher in the ASA users (mean PR 5.94 vs 3.23, p < 0.001). When comparing ASA to COLO, COLO was seen as more INC than ASA by both ASA users and non-users (mean COLO INC 3.0 and 3.1, p = 0.0001 and 0.017 compared to ASA INC, respectively). ASA users were more likely to recommend ASA to others (8.13 vs 4.09, p < 0.001). Conclusions: ASA uptake is low among LS pts. ASA is perceived as a favorable modality of chemoprev in only a fraction of LS pts, with perceived SEs and low PR as barriers to uptake. There is a critical need to address negative perceptions of chemoprev in LS patients as more options are developed. [Table: see text]
Homologous recombination-related (HRR) gene mutation profiling and the association with TMB in Chinese patients with esophageal and gastric cancer.
Authors: Wang Da , Yi Huan , Yu Yangyang , Xiao Mingzhe , Qi Chuang
Published: June 2023

e16000

Background: Homologous recombination deficiency (HRD) is associated with tumorigenesis and could predict the response of PARP inhibitor (PARPi) therapy and immunotherapy. Loss of function or deleterious mutations in homologous recombination-related (HRR) genes contribute to HRD phenotype. Methods: Tumor tissue samples from 1237 Chinese patients with esophageal and gastric cancer were sequenced with 551 cancer-related genes. Based on the clinical evidence, 15 HRR genes ( ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, RAD54L, PPP2R2A) were selected. 623 patients with WES data from the TCGA datasets were included for analysis. Results: In the Chinese cohort, 25.1% (62/247) esophageal cancer (EC) patients and 20.71% (205/990) gastric cancer (GC) patients exhibited somatic HRR (sHRR) gene mutations. The most frequently mutated genes were CHEK2 (7%) in EC and ATM (8%) in GC. The germline HRR (gHRR) gene mutations were identified in 48.16% (118/245) EC patients and 50.66% (498/983) GC patients. BRCA2 was the most common mutant gene (22% in EC and 9% in GC). 4.84% EC patients and 4.14% GC patients carried both germline and somatic HRR gene mutations. The sHRR-Mut patients had a higher median TMB compared to the sHRR-WT patients (EC, 8.09 vs 4.41, p < 0.001; GC, 8.09 vs 4.26, p < 0.001). However, the median TMB was similar between the gHRR-Mut and the gHRR-WT patients (EC, 5.67 vs 5.67, p = 0.903; GC, 4.96 vs 4.41, p = 0.356). In the TCGA cohort, 15.68% (29/185) EC patients and 23.97% (105/438) GC patients exhibited sHRR gene mutations. The most common mutant gene was ATM (5% in EC and 10% in GC). The sHRR-Mut patients had a higher median TMB compared to the sHRR-WT patients (EC, 4.78 vs 2.75, p < 0.001; GC, 21.23 vs 2.65, p < 0.001). For the TCGA gastric cancer cohort, the patients with sHRR-Mut had a significantly better median overall survival compared to the ones with sHRR-WT (46.9 months vs 26.5 months, p = 0.043). Conclusions: Our data reported the genetic landscape of HRR genes in Chinese esophageal and gastric cancer patients. Patients with somatic HRR gene mutations had a significantly elevated TMB level. In gastric cancer, patients carried somatic HRR gene mutations had a significantly prolonged OS.
Clinicogenomic analysis of rare histologic variants of pancreatic carcinoma: Undifferentiated carcinomas with and without osteoclast-like giant cells.
Authors: Mills Jamie , Gunchick Valerie , Shi Jiaqi , Udager Aaron M. , Frankel Timothy , Sahai Vaibhav , Zalupski Mark
Published: June 2023

e16001

Background: Undifferentiated carcinoma (UC) is a rare subtype of pancreatic carcinoma and can present with or without osteoclast-like giant cells (OGC). This 2010 delineation complicates interpretation of prior studies comparing UC to pancreatic ductal adenocarcinomas (PDAC). Limited retrospective data suggest UC-OGC tumors correspond to younger age, larger size, and worse prognosis compared to UC. The role of OGC is hypothesized to alter the immune microenvironment of tumors, leading to different response to therapy compared to PDAC. Methods: The aim of the study was to assess the clinical outcomes, histology (H&E), targeted genomics panel, transcriptomics (RNA panel and CIBERSORT-X), and multiplex immunofluorescence (mIF) to assess the tumor immune milieu in a cohort of adult patients with UC or UC-OGC compared to PDAC. Results: We identified 32 patients with UC and 15 with UC-OGC treated at Michigan Medicine between 2005 and 2021. The demographics, presenting symptoms, tumor size, and CA 19-9 were similar between cohorts. In patients with advanced cancers, median survival was 2.6 months (N = 22) vs 8.13 months (N = 2) for UC and UC-OGC, respectively (p = 0.27). R0 resection was completed in 10 (31%) patients with UC compared to 13 (87%) with UC-OGC; median survival was 17.0 months vs 145.0 months, respectively (p = 0.03). Genomic landscape of UC and UC-OGC was similar to PDAC (TCGA; N = 159), with KRAS and TP53 mutations at similar rates. However, the transcriptome revealed significantly increased M2 macrophages and CD4-8- (γδ) T-cells with significantly decreased regulatory T-cells (Tregs) in UC/UC-OGC (N = 10) compared to PDAC (p < 0.05). These data were corroborated by mIF with significantly reduced Tregs (p < 0.046) and trend toward increased M2 macrophages (p < 0.055) in UC/UC-OGC (N = 17), but not CD8+ T cells, which were significantly enriched in PDAC (p < 0.0001; N = 17). Conclusions: Overall, this study demonstrates significantly longer survival in patients with UC-OGC compared to UC in both advanced and resected patients. Increased pro-tumorigenic M2 macrophage infiltration and decreased Tregs in the tumor immune milieu of UC/UC-OGC suggests a potential role of macrophage inhibitors and other immune-modulatory therapies in combination with chemotherapy for these rare variants of pancreatic cancer.
Association of enhanced epithelial-mesenchymal transition signature with tumor microenvironment, angiogenesis, and survival in gastric cancer.
Authors: Oshi Masanori , Yan Li , Kunisaki Chikara , Endo Itaru , Takabe Kazuaki
Published: June 2023

e16002

Background: Among the hallmarks of cancer, epithelial-mesenchymal transition (EMT) that epithelial cancer cells gain the characteristics of mesenchymal cells, is one of the key mechanisms of cancer cell metastasis. On the other hand, the clinical relevance of EMT that occurs in gastric cancer patients has not been clearly shown. Methods: To measure the level of EMT in gastric cancer, gene set variation analysis was used to score total of 807 gastric cancer patient samples from two independent large cohorts; TCGA and GSE84437. Results: EMT high gastric cancer was significantly associated with worse overall survival (hazard ratio (HR)=1.74, p=0.011 in the TCGA, and HR=2.01, p<0.001 in the GSE84437), and the association was stronger with EMT signature score compared to expressions of each EMT-related genes, CDH1, CDH2, VIM, or FN1. EMT signature levels were not significantly different among gastric cancer, hepatocellular carcinoma, colorectal cancer, breast cancer, and pancreatic ductal adenocarcinoma, and high level of EMT signature was associated with survival only in gastric cancer. Among the histological types, mucinous and diffuse type had high EMT level compared to tubular, papillary, or signet gastric cancer ( p<0.001). EMT signature level was significantly correlated with tumor depth and AJCC stage (all p<0.001), but not consistently with lymphatic metastasis. Interestingly, the EMT score was independent factor for patient survival including clinicopathological features, not only for overall survival but also disease-specific survival in the TCGA cohort (multivariate; p=0.006 and 0.032, respectively). EMT high gastric cancer was associated with low fraction of Th1 cells and high fraction of dendritic cells and M1 macrophages (all p<0.001 in both cohort), but not with interferon-gamma immune response. EMT high gastric cancer tended to be inversely correlated with cell proliferation-related gene sets, and significantly associated with high infiltration fraction of stromal cells, including fibroblasts, adipocytes (all p<0.001). On the other hand, they significantly enriched multiple pro-cancerous gene sets, such as TGF-β signaling, hypoxia, and angiogenesis, consistent with infiltration of angiogenesis-related stromal cells such as microvascular and lymphatic endothelial cells, and pericytes (all p<0.001). These results were shown consistently in two large cohort; TCGA and GSE84437. Conclusions: EMT signature in a bulk tumor was associated with cancer aggravating pathways such as TGF-β signaling, hypoxia, and angiogenesis, as well as with worse survival in gastric cancer patients.
Liquid biopsy effectiveness of esophageal cancer-related genes and their correlation in clinical research.
Authors: Jiang Bo , Lin Yangui , Hui Hongliang , Li Huaming , Zhou Yujun , Chen Yaru , Zhang Weishuang , Cheng Shaochen , Zhang Yiqian
Published: June 2023

e16004

Background: Esophageal cancer ranks as the sixth most common cause of cancer-related deaths worldwide. The occurrence and development of esophageal cancer is a complex process that involves multiple genetic variants, including changes in gene function, which could be a crucial factor in its development. Hence, studying the molecular genetic changes specific to esophageal cancer is essential for understanding its mechanism and guiding clinical treatment. In this study, we analyzed and documented genetic variations and clinical information of 82 esophageal cancer patients to provide new insights into the correlation between genes and clinical symptoms. Methods: The tissue and blood-based DNA samples from 82 patients were analyzed using 680-gene targeted capture sequencing for CNV, fusion, SNV, indel, MSI, and TMB. Coverage of tissue with 2200X, cfDNA 20000X, and control gDNA 10000X. Additionally, the level of PD-L1 expression was assessed in the tissue samples. TMB was classified as TMB-H ( > 10 mutations/megabase) and TMB-L ( < 10). MSI-H was determined with instability ≥20% of 117 sites for detection, while < 20% was determined as MSS. Results: The analysis revealed 786 SNV/indel mutations in 82 patients, of which 346 (44.02%) mutations were detected in both tissue and plasma, 296 (37.66%) only found in tissue, and 144 (18.32%) only found in plasma. 378 mutations were detected in CNV, with 181 mutations (47.88%) in tissue and blood, 186 mutations only found in tissue (49.21%), and 11 mutations only in plasma (2.91%). The high-frequency mutation genes identified in this study were TP53, CCND1, FGF19, FGF3/4, NOTCH1, and PIK3CA, which are also listed as high frequency mutated genes in the IntoGen database (7 cohorts, 945 samples). However, the genes CCND1, FGF19, FGF3/4, and PIK3CA in the CNV results were not in the IntoGen high frequency mutated gene list. The results of tTMB vs bTMB were consistent in 80 out of 82 patients (97.56%). Among the 82 samples, 79 had low expression of PD-L1, while 3 had high PD-L1 expression and TMB-L, MSS. Conclusions: Fibroblast growth factor (FGF) signaling system may plays an important role in tumorigenesis and progression. Increase in the expression of FGFs and fibroblast growth factor receptor genes, might lead to genetic alterations in their protein structures and activation of the FGFs-FGFR signaling pathway, which may contribute to the onset of esophageal cancer. In conclusion, the results of our study suggest that the detection of tissue mutations in the blood of esophageal cancer patients is challenging and cannot be reliably determined by a single blood sample. The incidence of PD-L1 expression was low in all esophageal cancer tissues. Further investigation into the correlation between CCND1, FGF19, FGF3/4, and PIK3CA genes and esophageal cancer is warranted.
Effect of system analysis of reactive oxygen species on prognosis and treatment decisions for patients with esophageal squamous carcinoma.
Authors: Lu Qiang , Yang Qi , Zhao Jinbo , Li Guizhen , Zhang Jipeng , Jia Chenghui , Ji Gang , Wan Yi , Chen Yan
Published: June 2023

e16005

Background: The prevalence of esophageal cancer has recently grown, particularly esophageal squamous cell carcinoma (ESCC). Combining conventional treatment with targeted therapy and immunotherapy has shown unexpectedly positive results in improving the prognosis of patients with ESCC. More study is needed to determine the prognosis for patients with ESCC and establish the appropriate course of treatment. ROS controls different aspects of cell death from signaling to death, and ROS also regulates the tumor environment, affecting various stromal cells that provide metabolic support, blood supply, and immune response to tumors. Although reactive oxygen species (ROS) play an important role in tumorigenesis, it is difficult to reliably predict the effects of ROS-modulating therapies. Methods: This study aimed to establish a ROS-related score (ROSS) model to individually predict the overall survival and therapeutic effects for ESCC patients. Clinical data were derived from the TCGA-ESCA cohort through "UCSC", as well as the whole genome data. The driver ROS genes were identified based on univariate Cox regression. Following that, ROSS was created via a systematic machine-learning pipeline. The association of ROS with immune infiltration and biological function was subsequently assessed by systematic bioinformatics analysis. Finally, we evaluated the predictive efficacy of ROSS for immunotherapy sensitivity using predictive algorithms and real-world immunotherapy cohorts. Results: Patients with significant ROSS had fewer favorable outcomes, according to the data. The proliferation of ESCA cells treated with core ROS gene knocked down was also detected by CCK8. Both univariate and multivariate Cox regression indicated ROSS to be an independent prognostic factor for ESCC patients; however, subgroup analysis eliminated this finding. The functional assay revealed that immune response and cytotoxicity pathways are associated with ROSS, as the subgroup with low ROSS has an active immune microenvironment. Furthermore, patients with low ROSS responded better to chemotherapy, targeted therapy, and immunotherapy. Conclusions: In this study, we systematically analyzed the ROS-related genes in ESCC and developed a ROSS model to assess prognosis and provide guidelines for treatment decisions. This discovery gave rise to a fresh concept for novel therapeutic procedures for the clinical treatment of ESCC.
Identification of novel actionable SNVs via targeted comprehensive genome profiling in patients with gallbladder and cholangiocarcinoma cancer.
Authors: Raut Nirmal Vivek , Bhonde Mandar , Bose Chirantan , Chopra Rakesh , Kad Trupti , Prajapati Sangeeta , Hariramani Kanchan , Mobeen Fauzul , Basavalingegowda Madhura , Haldar Sumit , Mehra Vatsal , Kumaran Manoj Kumar , Jadhav Vikas Balasaheb Leelavati , Joshi Sujit Krishnarao , Shah Mithun , Shah Pankaj Manubhai , Vasudevan Aravindan , Khandare Jayant , Shafi Gowhar
Published: June 2023

e16006

Background: Liquid biopsy approach has paved the way for selecting targeted therapies. When the tissue is absent, the advent of comprehensive Next Generation Sequencing (NGS) using CcfDNA has further allowed significant advances in precision oncology by pinpointing rare, novel, and actionable alterations in oncogenes, tumor suppressor genes, and cellular signaling pathways. Methods: Retrospective NGS-based genome profiling was performed on ccfDNA (circulating cell-free DNA) samples from 11 patients using OncoIndx proprietary gene panel that targets exonic regions of 600 cancer-related genes. Illumina-compatible libraries were prepared by the target hybridization method and sequenced on Nextseq 2000 platform in a pair-end fashion. Variant calling was performed using an in-house developed bioinformatics pipeline. The 11 cases comprised 5 gallbladder and 6 cholangiocarcinoma patients. Results: We uncovered several novel mutations such as MTORK1452N, ERBB2H878Y, JAK1A634T, SMAD3R287W, IDH1R132C, PRKNK161N and FGFR2Y105C. Although ERBB2H878Y and IDH1R132C are known in cholangiocarcinoma, this is the first report of gallbladder cancer. In addition to SMAD3 and PARKIN, alterations were also observed in tumor suppressor proteins APC, BARD1, BRCA1/2, and GATA2. High genomic instability as demonstrated by HRD and LOH correlated with FGFR2, PRKN, and IDH1 mutations. FAT domain mutations in mTOR such as MTORK1452N are known to be responsive to rapamycin. Similarly, ERBB2H878Y is known to respond to rapamycin as well as a TKI. The FGFR2Y105C activating mutation has previously been reported in one case of atypical Crouzon Syndrome but has never been reported in cancer. This could have potential implications for the use of FGFR2 targeting agents in cholangiocarcinoma. IDH1R132C mutation is known in ~11% of cholangiocarcinoma patients, however, this alteration has not been reported in gallbladder cancer. This observation has therapeutic implications for the use of IDH1 inhibitors in gallbladder cancer based on its promising data in cholangiocarcinoma. Conclusions: We report, for the first-time novel and actionable SNVs in key oncogenes and tumor suppressors related to critical signaling pathways in a population of gallbladder and cholangiocarcinoma patients. The data strongly underscores the importance of comprehensive NGS-based in-depth assessment in gaining clinically viable therapeutic insights for patients.
Expression profiles of MUC5AC glycoforms in neoplastic and non-neoplastic pancreatic tissue.
Authors: Manne Ashish , Cheng Xiang , Tsung Allan , Esnakula Ashwini K
Published: June 2023

e16008

Background: MUC5AC, secretory mucin, exists in two major glycoforms, heavily-glycosylated mature (MM) and less-glycosylated immature (IM) isoforms. Prior IM-based tissue expression studies could not establish the clinical significance of MUC5AC in pancreatic ductal adenocarcinoma (PDA). Despite having strong pre-clinical evidence of MM’s role in local invasion, metastasis, and drug (gemcitabine) resistance, its impact on PDA outcomes is unclear. In this study, for the first time, we examined the differential expression of MM and IM by immunohistochemistry in primary PDA (pPDA), metastatic PDA (mPDA), normal pancreatic tissue adjacent to tumor (NAJ), neuroendocrine tumors (NET), Pancreatitis (P), normal pancreas (N) using tissue microarrays (TMA). Methods: Commercially available TMA (PA2081c, tissuearray.com, Derwood, MD) constructed from 96 patients, including 38 pPDA (14-stage 1, 22-Stage 2, and 2-stage 3), 5 mPDA, 24 NAJ, 11 NET, 8 P and 10 N was used in this study. Two separate 1 mm cores represented each case. Immunohistochemistry for MUC5AC was performed using CHL2 clone (ab77576, abcam, Boston, MA) for the IM isoform and 45M1 clone (ab369, abcam, Boston, MA) for the MM isoform. The immunostains were optimized as per the manufacturer's recommendations using appropriate controls. The sections are evaluated for the intensity of expression (0-3) and the percentage of reactive cells, and an H-score is derived from the product of these measurements. Cases are categorized as having negative/weak (score <10) or positive (score >10) expression. For every positive case, the pattern of expression in terms of Apical (Ap), cytoplasmic (Cy), and extracellular (EC) expression was recorded. Results: MUC5AC (MM and IM) is not expressed in N, NAJ, and P. MM expression is only noted in 44% of PDAs (19/43; 18 pPDA and 1 omental mPDA lesion). Three different expression patterns were noted, including Ap (63%), Cy (84%), and EC (47%). IM expression was detected in 60% of PDAs (26/43, 25 pPDA and omental mPDA lesion) and 18% NET (2/11). IM expression was noted in cases with EC MM expression (9/43, 21%), suggesting that IM was further glycosylated to MM and expressed extracellularly in some patients. MM and MM were co-expressed in 40% of PDA (17/43). Liver and abdomen metastatic lesions in the TMA did not express IM or MM. Pertinent clinical information was not available to study the impact of MM’s expression on PDA outcomes. Conclusions: Our study shows that MUC5AC is primarily expressed in PDAs and can be a useful biomarker. Larger studies are ongoing to correlate tissue expression patterns in PDAs for evidence of any association with early recurrence or treatment failure. Preliminary data suggests that only MM isoform is expressed extracellularly and could be detected in patient serum and serve as a potential non-invasive biomarker for treatment selection (for gemcitabine resistance) and monitor the response in certain cases.
Influence of high COL19A1 expression on the effectiveness of neoadjuvant immunotherapy plus chemotherapy and long-term survival in patients with esophageal squamous cell carcinoma.
Authors: Liu Jianhua , Zhang Jia-Tao , Zhu Changbin , Li Weiwei , Li Qian , Huang Zhan , Qiao Guibin , Wu Yi-Long
Published: June 2023

e16013

Background: Neoadjuvant immunotherapy plus chemotherapy may enhance the resectability rate in locally advanced Esophageal Squamous Cell Carcinoma (ESCC). Nevertheless, due to the complex nature of the tumor immune microenvironment, an unmet need remains for biomarkers to identify NPC patients used to identify patients who benefit most from this neoadjuvant treatment strategy. Methods: Two independent cohorts of ESCC patients were enrolled in the study., including retrospective cohort (N=66) and prospective cohort (N=37). A total of 103 NPC FFPE samples were subjected to RNA sequencing. Single sample GSEA (ssGSEA) were performed to explore the Tumor microenvironment (TME). Differential genes associated with survival were analyzed using logistic regression and Kaplan-Meier methods. To reveal the expression of biomarker and TME, immunohistochemistry and multiplex immunofluorescence were used. Results: We demonstrated that COL19A1 high expression facilitates anti-PD-1 therapy [ COL19A1 high, OR (95% CI): 0.31 (0.1−0.97), p = 0.044]. COL19A1high patients could benefit more from neoadjuvant immunotherapy (p < 0.01), high mortality (63.3%, p < 0.01), and have a trend towards a better RFS (p = 0.13) and OS (p = 0.056). Further analyses confirmed increased B cells infiltration and COL19A1 high expression could be seen in the immune-activated subgroup, which resulted in favorable survival and response to neoadjuvant immunotherapy plus chemotherapy. Conclusions: This study revealed an ESCC subpopulation presenting high COL19A1 expression, which responded well to neoadjuvant immunotherapy plus chemotherapy and was associated with good prognosis. It provided a convincing basis for designing biomarker-guided individual treatment.
Genomic alterations of cerebrospinal fluid cell-free DNA in leptomeningeal metastases of gastric cancer.
Authors: Chen Xin , Bai Kaixuan , Zhang Yu , Xu Yang , Huo Yinghao , Wang Sha , Zou Yueli , Qi Xuejiao , Guo Rongyun , Ou Qiuxiang , Zhu Minyi , Liu Dengxiang , Yin Shaohua , Chen Shubo , Bu Hui
Published: June 2023

e16022

Background: Leptomeningeal metastases (LM) were rare in gastric cancer (GC), and GC patients with LM (GCLM) generally suffer from poor prognosis. Nevertheless, the clinical utility of cerebrospinal fluid (CSF) circulating tumor DNA (ctDNA) was under-investigated in GCLM. Methods: We retrospectively studied 15 GCLM patients, and all patients had paired primary tumor tissue samples and post-LM CSF samples while 5 patients also had post-LM plasma samples. All samples were analyzed using next-generation sequencing (NGS), and the molecular and clinical features were correlated with clinical outcomes. Results: CSF had higher mutation allele frequency ( P=0.015), more somatic mutations ( P=0.032), and more copy-number variations ( P<0.001) than tumor or plasma samples. Multiple genetic alterations and aberrant signal pathways were enriched in post-LM CSF, including CCNE1 amplification and cell cycle-related genes, and CCNE1 amplification was significantly associated with patients’ overall survival ( P=0.0062). More potential LM progression-related markers were detected in CSF samples than in tumor samples, including PREX2 mutation ( P=0.014), IGF1R mutation ( P=0.034), AR mutation ( P=0.038), SMARCB1 deletion ( P<0.001), SMAD4 deletion ( P=0.0034), and TGF-beta pathway aberration ( P=0.0038). Additionally, improvement in intracranial pressure ( P<0.001), improvement in CSF cytology ( P=0.0038), and relatively low levels of CSF ctDNA ( P=0.0098) were significantly associated with better PFS. Lastly, we reported a GCLM case whose CSF ctDNA dynamic changes were well correlated with his clinical assessment. Conclusions: CSF ctDNA could more sensitively detect molecular markers and metastasis-related mechanisms than tumor tissues in GCLM patients, and our study sheds light on utilizing CSF ctDNA in prognostic estimation and clinical assessment in GCLM.
Phase 2 study of bavituximab (bavi), a first-in-class antibody targeting phosphatidylserine (PS), plus pembrolizumab (P) in advanced gastric or gastroesophageal junction (GEJ) cancer.
Authors: Lee Jeeyun , Shergill Ardaman , Park Haeseong , Lee Keun-Wook , Arkenau Hendrik-Tobias , Kang Yoon-Koo , Olowokure Olugbenga Olanrele , Kim Jong Gwang , Oh Sung Yong , Oh Do-Youn , Costin Dan , Pippas Andrew William , Chen Jen-Shi , Chaney Marya F. , Koustenis Andrew , Youssoufian Hagop , Makris Lukas , Culm Kerry , Mockbee Colleen M. , Chau Ian
Published: June 2023

e16023

Background: Bavi, a monoclonal antibody designed to inhibit the immunosuppressive effects of PS through interaction with TIM/TAM receptor family members in the tumor microenvironment (TME), was evaluated in combination with P in patients with advanced gastric and GEJ cancer. Methods: ONCG100 was a phase 2, multicenter, open-label, two-cohort global study designed to assess the safety, tolerability, and antitumor activity of bavi (3 mg/kg, QW) plus P (200 mg, Q3W) in advanced gastric or GEJ cancer patients who progressed on ≥1 prior standard therapy (NCT04099641). Patients were checkpoint inhibitor (CPI) naive (Grp 1) or CPI relapsed (Grp 2); known MSI-H patients were excluded. RNA expression was analyzed in pre-treatment tumor tissue using the Xerna TME Panel, an RNA-based diagnostic, to prospectively test hypothesis that tumors with high immune or immune-suppressed TME subtypes (B+) are more likely to respond to bavi plus P than high angiogenic/immune-desert TME subtypes (B-). Results: A total of 80 patients enrolled (Grp 1 n=61, Grp 2 = 19). The most frequently reported Grade ≥ 3 treatment emergent adverse events (occurring in ≥10% of patients overall) were anaemia and gastric cancer progression (n= 10/AE). Key efficacy parameters for Grp 1 patients (2L 57.4%) are summarized in Table 1. In Grp 2, the ORR was 5.3% (95% CI: 0.1, 26.0), whereby 0 patients achieved a complete response and only 1 (5.3%) patient achieved a partial response as the best overall response (BOR). In the remaining patients, BOR was stable disease in 9 (47.4%) patients, progressive disease in 8 (42.1%) patients, and not evaluable in 1 (5.3%) patient. Conclusions: The combination of Bavi and P was well tolerated; observed AEs were consistent with known profiles for each agent. Higher ORRs were observed in CPI-naïve patients with B+ status and baseline NLR<4, and of note, in patients with PD-L1 CPS <1. Future studies may be planned to confirm the activity of Bavi in combination with P with patient selection based on a particular genetic signature. Clinical trial information: NCT04099641 . [Table: see text]