bluuebunny/crossref_metadata_2025_split huggingface dataset:
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.