tbuckley/cabot-search huggingface dataset:
Tumor microbiota, consensus molecular subtype and survival in colon adenocarcinoma.
Authors: Nuria Rodriguez Salas, Lucía Trilla-Fuertes, Angelo Gámez-Pozo, Pedro Lalanda-Delgado, Daniel Matamala-Luengo, Rocio Lopez Vacas, Antje Dittmann, Ana Custodio, Ismael Ghanem, Daniel Martinez-Perez, Juan Angel Fresno-Vara, Jaime Feliú
Journal: Journal of Clinical Oncology (2024)

3607 Background: Microbiota can contribute to inflammation and tumor initiation and progression of colorectal cancer. The aim of this study was the characterization of microbiota proteins in colon adenocarcinoma paraffin samples and the study of the differential microbiota abundances according to survival and Consensus Molecular Subtypes (CMS). Methods: 158 patients with high-risk stage II and stage III colon cancer and treated with surgery and adjuvant chemotherapy were included into the study. Microbiota was studied in the tumor paraffin samples using mass-spectrometry proteomics. Protein isolations were prepared in SDS 2% and digested with trypsin. Then, an analysis of each sample was done using a data-independent acquisition (DIA) mode on an Orbitrap Fusion (Thermo Scientific). Proteomics identification and quantification was done in Spectronaut using Microbiome Database and SwissProt human database as references. Survival analyses were done using BRB Array Tools. Comparisons between CMS were performed using a Kruskal-Wallis test. Results: 158 colon cancer patients (mean age: 67 years, 41% women, 49(31%)-109(63%) stage II-III, 59(37%)-99(63%) right-left colon), were analyzed. Nineteen microbiota proteins and 2,696 human proteins were quantified. After applying quality criteria, 13 microbiota and 1,940 human proteins were used for subsequent analyses. Kaplan-Meier analyses determined three microbiota proteins related to DFS: 1. Firmicutes, Faecalibacterium, p=0.0038; 2. Fusobacteria, Fusobacterium, p=0.0066; 3. Bacteroidetes, Bacteroides, p=0.0099. A microbiota signature combining these three proteins was built, capable to distinguish between patients with low (5 years DFS 80%) and high-risk of relapse (5 years DFS 55%) (p=0.0021, HR= 2.62, 95%CI=(1.45-5.31)). AUC = 0.88. Multivariate analysis showed that the microbiota signature added prognostic value to tumor stage . Additionally, microbiota profiles were different between CMS. CMS1 had a higher expression of proteins from Bacteroidetes. CMS2 showed an enrichment in Prevotella and CMS4 had higher levels of Fusobacterium. Conclusions: Metaproteomics in colon adenocarcinoma paraffin samples were performed, identifying thirteen microbiota proteins after applying quality criteria. The presence of three specific microbiota proteins seems to be related to DFS in colon cancer and a prognostic signature combining them was built. Moreover, CMS had differential microbiota protein profiles, having CMS1 the higher expression of Bacteroidetes proteins, CMS2 had higher levels of Prevotella, and CMS4 presented higher levels of Fusobacterium.
Phase II trial of organ preservation program using short-course radiation and FOLFOXIRI for rectal cancer (SHORT-FOX).
Authors: Erqi L. Pollom, George A. Fisher, Andrew Shelton, Tyler Paul Johnson, Christopher Chen, Scott Jackson, Shagufta Shaheen, Thomas Holden, Jeffrey Bien, Daniel King, Arden M. Morris, Cindy Kin, Aaron Dawes, Natalie Kirilcuk, John Gahagan, Lucas Vitzthum, Vipul Sheth, Eleanor Brown, Aniket Pratapneni, Daniel Tandel Chang
Journal: Journal of Clinical Oncology (2024)

3600 Background: Patients (pts) with rectal cancer who achieve a clinical complete response (cCR) after neoadjuvant therapy may be safely observed and spared the long-term sequela of total mesorectal excision (TME). We hypothesized that a novel neoadjuvant regimen (short-course radiation with boost and FOLFOXIRI chemotherapy) would achieve higher cCR rates than historical controls. Methods: We conducted a single-arm, phase II study of short-course radiation followed by FOLFOXIRI for pts with &gt;T2N0 or low T2N0M0 rectal adenocarcinoma (NCT04380337). Pts underwent radiation (25 Gy/5 fractions + 5 Gy/1 fraction boost) followed by 8 cycles of FOLFOXIRI. Pts were assessed for primary endpoint (cCR) at 8 weeks following chemotherapy. Those who achieved a cCR or near cCR were surveilled. cCR required no tumor on MRI, endoscopy, and if applicable, digital rectal exam. A Simon 2-stage design addressed our primary objective, with interim analyses for futility and toxicity. Assuming a one-sided type 1 error of 0.1, power of 0.9, a null cCR of 0.2 versus an alternate cCR of 0.4, our sample size was 37 pts. Results: Between May 2020 and April 2023, 37 pts enrolled (Table). 25 pts (67.5%) had at least one high risk feature (cT4, extramural vascular invasion [EMVI], N2, threatened circumferential resection margin [CRM], positive lateral node). All pts completed radiation; 32 pts (86.5%) completed all 8 cycles of chemotherapy. Criteria for futility and safety were met at interim analysis. At primary outcome assessment, 9 (24.3%) pts achieved a cCR and 8 (21.6%) pts achieved a near cCR. 3 pts who initially had a cCR developed local regrowth and underwent TME. Of the pts who had a near cCR, 5 developed local regrowth and underwent TME while 3 pts achieved delayed cCR. Serious adverse events occurred in 5 (13.5%) pts; 1 patient had non-hematologic grade 4 toxicity at least possibly related to treatment. There were no treatment-related deaths. The12-month TME-free survival for all patients was 37.2%, and for patients with T3 and T4 tumors was 44.3% and 12.5%, respectively. Conclusions: Short-course radiation followed by FOLFOXIRI was feasible and safe. In this high-risk cohort of pts with rectal cancer, 24.3% of pts had a cCR at time of primary assessment. Clinical trial information: NCT04380337 . [Table: see text]
A study on classifying tumor neoantigens to enhance the accuracy of liquid biopsy in CRC cancer.
Authors: Fenghua Guo, Wenting Liao, Jun Li, Yaru Chen
Journal: Journal of Clinical Oncology (2024)

e15507 Background: Personalized neoantigen vaccines are a promising therapeutic approach in colorectal cancer (CRC). These vaccines are designed based on the identification of specific gene mutations, aiming to evoke an immune response. However, a major challenge arises from the need to distinguish true mutated sites from numerous false positives, particularly in samples of liquid biopsy, where detection rates may be relatively low. To address this issue, we have developed a robust pipeline to enhance the precision and efficiency of detecting target gene mutations, which is crucial during the neoantigen design process. Methods: In this study, an extensive analysis was conducted using tissue and blood samples from a cohort of 859 CRC patients. We identified mutations in the top third most frequently mutated genes (APC, TP53, and KRAS). To design antigenic sequences, the mutations at these gene sites were concatenated with 14 amino acids from both up and down flanking regions. Subsequently, we utilized a similarity scoring algorithm (pairwise2.align from Biopython) to assess the mutation correlation between oncogenes (APC and KRAS) and the suppressor gene TP53. Results: This study observed that mutations within a specific gene tend to generate distinct patterns of new antigens. The majority of APC mutations (90.04%) in the vicinity of the mutation sites led to premature stop codons. Regarding KRAS, the mutation sites with the highest frequency were in the vicinity of the c.35 and c.182 positions, sharing identical neoantigens with NRAS. In contrast, TP53 mutations appeared to be more influenced by other mutations. Neoantigens derived from TP53 were identified, and it was observed that 82.27% of the sequences exhibited more than 40% similarity with other mutations in the same sample.This may be indicative of a co-occurrence mechanism. Conclusions: The classification of neoantigens appears to be similar to the classification of oncogenes and tumor suppressor genes, which may contribute to adjust the minimum detection threshold of liquid biopsy from the perspective of neoantigens. [Table: see text]
Survival and prognosis of anus, anal canal and anorectal carcinoma: Analysis of National Surveillance, Epidemiology, and End Results database from 2000-2020.
Authors: Ashish Guragain, Pugazhendi Inban, Clint Vaz, Urusha Poudel, Pramil Cheriyath, Vinod Nookala, Sajog Kansakar, Shreeja Shikhrakar, Michael Maroules
Journal: Journal of Clinical Oncology (2024)

e15501 Background: Anal cancer comprises about 2.5% of all gastrointestinal malignancies in the USA. The incidence of anal cancer is showing an increasing trend, however studies surrounding its prognostic factors and survival is limited. The aim of our study is to examine the prognostic factors and evaluate survival trends from 2000-2020 using the SEER database. Methods: SEER*Stat Version 8.4.3 software was used to extract anus, anal canal and anorectal carcinoma cases from SEER 17 registries (2000-2020). A total of 32315 patients were included in the study, data with unconfirmed histology were excluded. We analyzed overall mortality, and anal cancer specific mortality (CSM) using a Cox proportional hazards model. The survival analysis was carried out using the Kaplan–Meier method and the log-rank test was used to compare survival curves. Results: Crude analysis revealed a high overall mortality in patients above age 80 (HR = 11.085; 95% CI: 9.9113-13.485), p &lt; 0.001), followed by age 60–79 (HR = 3.665, 95% CI: 3.303- 4.432, p &lt; 0.003. Females were found to have better survival (HR = 0.705; 95% CI: 0.676-0.735). Non-Hispanic blacks were found to have the highest cancer-specific mortality compared to other ethnicities (HR = 1.294; 95% CI: 1.112-1.381). Patients who did not undergo surgical treatment had a significant cancer specific mortality (HR = 1.438; CI: 1.377-1.502). The highest cancer-specific mortality was observed in patients with distant metastases (HR = 2.461, 95% CI: 2.314– 2.616, p &lt; 0.001). Irrespective of surgical status, patients who underwent either chemotherapy or radiation therapy had better survival rates. Multivariate cox proportional hazard regression analyses of CSM also revealed higher mortality among males and Non-Hispanic black patients. The mortality outcomes further become worse with advanced age and lack of application of available treatment options in the form of surgery, chemotherapy or radiotherapy. Conclusions: Our analysis indicated overall increased anal cancer specific mortality in Non-Hispanic blacks. Delayed diagnosis with distant metastasis and those who did not receive any of the available treatment modalities had worse prognosis. We recommend further research to develop better screening strategies for early diagnosis of anal cancer, identifying factors associated with increased mortality in certain ethnicities, and barriers to access available treatment modalities.
Cisplatin and capecitabine as definitive chemoradiation for squamous cell carcinoma of the anal canal (SCCAC): A prospective cohort.
Authors: Abraão Dornellas, Renata Colombo Bonadio, Priscila Muniz Moraes, Denis Galhera, Carolina Ribeiro Victor, Andre Tsin Chih Chen, Carolina Teixeira Muratori, Cinthia Ortega, Henrique Souza Alves, Karim Ibrahim, Caio Nahas, Carlos Frederico Marques, Luciana Bastos Valente Alban, Maria Ignez Braghiroli, Paulo Marcelo Hoff, Camila M Venchiarutti Moniz
Journal: Journal of Clinical Oncology (2024)

e15503 Background: SCCAC is a rare disease. The standard of care treatment with curative intent is chemoradiation (CRT) with mitomycin (MMC) or cisplatin (CDDP) plus infusional 5-Fluoracil (5-FU). Capecitabine may replace 5-FU in MMC doublet. However, MMC and infusional pumps are frequently unavailable in underdeveloped countries. CCDP and capecitabine are widely available, but there is no prospective data about the feasibility and efficacy of this combination in a definitive SCCAC CRT setting. Methods: A Prospective cohort study aimed to evaluate the safety and efficacy of treatment with chemoradiation with CDDP 60mg/m2 D1 and D29 plus Capecitabine 825mg/m2 BID in a population without MMC and infusional pump access. Eligible patients (pts) had T2-4, N0-3, and M0 disease candidates for a full curative CRT regimen. The study data were prospectively collected using REDCap. The primary endpoint was the response by RECIST v.1.1 at 24 weeks(w). The secondary endpoints included toxicity by CTCAE v.5.0, adherence, PFS, and OS. Results: We enrolled 40 consecutive pts between Aug/2019-Dec/2022 in a tertiary cancer center in Brazil. The median age was 61y, the majority were stage III (n = 31, 77.5%) and ECOG 1 (n = 20, 50%). HIV+ serology was observed in 11 pts (27,5%). All patients received CRT, with a median dose of 54Gy in the primary tumor and 45Gy in the elective nodes. At 8w, 35% (n = 14) had a complete response (CR), 50% (n = 20) partial response (PR), and 2.5% (n = 1) progressive disease (PD). At 6 months, CR was observed in 55% (n = 22), PR in 22.5% (n = 9), and PD in 10% (n = 4). 11 pts had disease recurrence, and six died. 1y OS was 94.7% (IC95%: 80.7- 98.6%), and 1y PFS was 75.3% (IC95%:57.8 - 86.3%). Colostomy-free survival at one year was 89.6% (IC95%: 74.7 - 95.9%). Median PFS and OS were not reached with a 2-year median follow-up. Regarding toxicities, radiodermatitis was observed in 94% (n = 36), nausea in 90% (n = 36), and diarrhea in 65% (n = 26). Any grade 3/4 toxicity was present in 27.5% (n = 11), being the majority of radiodermatitis. Four older pts (average age 73y) had definitive suspension of treatment due to toxicity, 06 pts were hospitalized because of a skin infection, and one died due to treatment toxicity. Conclusions: Definitive chemoradiotherapy with cisplatin and capecitabine is feasible; however, older populations require extra attention to early toxicities management.
Mutational landscape and evolutionary pattern of peritoneal metastases in colorectal cancer.
Authors: Yuzhuo Wang, Xianfeng Xu, Jinyu Zheng, Lu Xu, Yuping Zhu, Rui Xu, Yan Shen, Guifang Xu, Weiyou Zhu, Zan Fu, Jing Sun
Journal: Journal of Clinical Oncology (2024)

e15533 Background: Peritoneal metastases occur in approximately 10% of all colorectal cancer (CRC) patients, which are associated with significant morbidity and worse clinical outcome. To date, the evolutionary pattern and molecular mechanisms of peritoneal metastases remains largely unknown, which provided little insights into the prevention and treatment of this subgroup of CRC patients. Methods: We performed whole-exome sequencing (WES) on 49 samples of matched primary tumors, peritoneal metastases, and lymph node metastases from 11 CRC patients. Phylogenetic reconstruction and evolutionary analyses were performed to investigate the mode and route of metastatic dissemination. The timing of metastatic dissemination was inferred using SCIMET. Metastases-associated driver events were analyzed and validated in two independent cohorts. Finally, therapeutic actionability of somatic alterations was assessed. Results: A characterization of metastatic dissemination found that 3 out of 11 patients displayed monoclonal dissemination. Whereas the other 8 patients exhibited polyclonal dissemination, of which 6 were monophyletic and 2 were polyphyletic. In five patients, we observed evidence for the metastasis-seeding-metastasis mode among peritoneal metastases. Additionally, the peritoneal metastases were mainly seeded by the primary tumor rather than the lymph node metastases. Metastatic timing inference found that most (9 out of 11) of the peritoneal metastases occurred early before the primary tumor became clinically detectable. Genetic alterations associated with peritoneal metastases were identified, including somatic mutations in TP53, SMAD4, KRAS, RNF43, and SMARCB1, as well as focal amplifications (8p24) and losses (17p12). Analysis of therapeutic actionability identified potentially targetable oncogenic alterations in all patients. Conclusions: Our results provided important insights into the evolutionary features of peritoneal metastases, which had profound implications for the prediction, prevention, and treatment of peritoneal metastasis in CRC.
Efficacy and safety of nivolumab in pretreated patients with metastatic squamous cell carcinoma of anus: A real-world experience.
Authors: Nicole Conci, Fabiola Lorena Rojas Llimpe, Francesca Di Fabio, Adriana Di Odoardo, Linda Danielli, Renata Seminerio, Carla Tortorella, Alessandra Guido, Dajana Cuicchi, Andrea Laurenzi, Barbara Dalla Via, Maria Lucia Tardio, Karim Rihawi
Journal: Journal of Clinical Oncology (2024)

e15502 Background: Squamous cell carcinoma of the anus (SCCA) is a rare malignancy with limited treatment options for metastatic patients. Immune checkpoint inhibitors (ICI) have been studied on few prospective trials, but its efficacy seems low. Methods: We retrospectively collected clinical, radiological, and laboratory data from patients (pts) diagnosed with metastatic SCCA who received nivolumab as 2 nd or 3 rd line therapy at the Oncology Unit of Bologna University Hospital from October 2017 to November 2023. We analyzed the correlation of clinical-pathological features with the overall response rate (ORR), overall survival (OS), and progression-free survival (PFS). Results: We enrolled 15 pts diagnosed with relapsed/metastatic SCCA; pts characteristics are summarized in Table 1. Nivolumab was administered as a 2 nd line treatment in 13 pts, while 2 pts received ICI in the 3 rd line. Overall, median OS was 8.3 months (mo.) (95% CI 4.37-NA) and median PFS was 4.37 mo. (95% CI 3.67-NA). Of note, ORR was 40%, compared with the 10% ORR seen in the few prospective phase II trials available. Pts with ECOG PS ≥ 2 showed a lower ORR and resulted in worse OS and PFS. ECOG PS 0 pts showed a median OS of 19.17 mo., PFS of 5.17 mo., and ORR of 75%. ECOG PS 1 pts had an OS of 10.73 mo., a PFS of 4.98 mo., and an ORR of 38%, while ECOG PS 2 pts showed 4.37 mo. of OS and PFS with no response seen. The number of metastatic sites at baseline has been shown to be associated with OS. Pts with ≥ 3 metastatic sites showed an OS of 5.17 vs 10.73 mo. for pts with &lt; 3 sites. Overall, no complete response was seen; however, we identified 4 long-responders with a median treatment duration of 15.8 mo. (8.3 - 26.5). All long-responders were HPV-positive and had no liver metastases at the time of treatment initiation. PD-L1 evaluation and molecular characterization is ongoing. Nivolumab was well-tolerated with 5 pts experiencing immune-related adverse events: 4 pts showed G1 toxicities according to the CTCAE, version 5.0 (thrombocytopenia, hypothyroidism and rash) while 1 patient had G4 myopathy caused a treatment discontinuation. Conclusions: ICI is a possible treatment option with a favorable safety profile in pretreated SCCA although a better selection of patients is required. [Table: see text]
Evaluating peripheral myeloid-derived suppressor cells as factor for the diagnosis and treatment efficiency of patients with colorectal cancer.
Authors: Cong Zhou, Lina He, Yi Gu, Bisheng Shi, Xiaojiao Cheng, Ruohan Zhangyuan, Yuguang Shen, Wei Shen, Zheng Wang, Shuiping Tu
Journal: Journal of Clinical Oncology (2024)

e15510 Background: Colorectal cancer (CRC) is one of the most common malignant tumors in the world. As the main immunosuppressive cells in tumor microenvironment (TME), the diagnostic value of myeloid-derived suppressor cells (MDSCs) in periphery of CRC patients and their treatment-related clinical significance are still ambiguous. Methods: Here, blood samples and clinical information were collected from 210 CRC patients and 102 healthy individuals. The frequencies of MDSCs were detected by flow cytometry. Immune-related cytokines were detected by Cytometric Beads Array. Paired blood samples before and after treatment were collected from another 175 CRC patients to assess the effect of therapeutic regimens on MDSCs. Results: Compared with healthy individuals, the proportions of total MDSCs (1.34 vs. 9.20, p&lt; 0.0001), monocyte-MDSCs (Mo-MDSCs) (0.13 vs. 0.60, p&lt; 0.0001) and polymorphonuclear-MDSCs (PMN-MDSCs) (0.87 vs. 7.32, p&lt; 0.0001) were increased, while early-MDSCs (eMDSCs) were decreased (0.02 vs. 0.01, p&lt; 0.0001). The sensitivity, specificity, and AUC of total MDSCs for CRC diagnosis were 80.5%, 90.2% and 0.90. The sensitivity, specificity, and AUC of total MDSCs combined with CEA were 89.5%, 89.0%, and 0.94, respectively. Correlation analysis showed that peripheral MDSCs were significantly correlated with leukocytes (r = 0.24~0.37), immune-related cytokines [especially IL-2 (r = 0.25~0.27), IL-5 (r = 0.26), IL-6 (r = 0.22~0.44), IL-8 (r = 0.18~0.32)], and biomarkers of gastrointestinal tumors (r = 0.24~0.41). Additionally, first-line chemotherapy FOLFOX and XELOX, or chemotherapy plus targeted therapy can effectively reduce total MDSCs (13.30 vs. 2.81, p&lt; 0.001; 15.09 vs. 3.31, p&lt; 0.001) and PMN-MDSCs (13.21 vs. 2.14, p&lt; 0.001; 13.78 vs. 2.22, p&lt; 0.001). Conclusions: This study disclosed that peripheral MDSCs have important diagnostic value and clinical significance for CRC.
Molecular insights into oxaliplatin-induced peripheral neuropathy in colorectal cancer: Unraveling a potential signature.
Authors: Suneeta Modekurty, Michael Iglesia, Katrina Sophia Pedersen, Carolina Salvador, Simon Haroutounian, Kian-Huat Lim, Nikolaos Trikalinos, Rama Suresh, Olivia Aranha, Patrick Grierson, Benjamin R. Tan, Moh'd M. Khushman
Journal: Journal of Clinical Oncology (2024)

e15506 Background: Oxaliplatin (OXA) is a platinum chemotherapy utilized for treating patients with colorectal cancer (CRC). OXA-induced peripheral neuropathy (OXAIPN) stands as the primary non-hematological dose-limiting toxicity. Despite its clinical significance, there exists no reliable molecular predictive biomarker of OXAIPN in current clinical practice. In this study, we delved into the molecular signature associated with OXAIPN in CRC. Methods: OXAIPN-related genes were curated through an extensive literature review. Utilizing publicly available bulk transcriptomic data from the Illumina HiSeq 2500 platform, encompassing tumor and adjacent normal tissues from 18 individuals with CRC, we identified differentially expressed genes (DEGs). Furthermore, single-cell RNA sequencing (scRNA-seq) data from 10X genomics, including normal and tumor tissues from 3 CRC patients, underwent analysis using Seurat and sctype R packages to unveil DEGs associated with cancer cells. Functional and pathway enrichment analysis was performed using the Genecodis4 web-based tool. To validate the inhibition of a curated list of neuropathy-associated genes, RNA-seq data from CRC cell lines (HCT116 and DLD1) treated with Oxaliplatin were processed, and DEGs were determined. Results: A total of 1367 OXAIPN-related genes were identified. Bulk transcriptomic data analysis revealed 715 DEGs, while scRNA-seq analysis uncovered 2,854 DEGs. Noteworthy, upregulated genes from scRNA-seq analysis, including LGALS4, SPINK4, TFF3, REG4, and REG1A, were associated with tumor proliferation through epithelial-mesenchymal transitions, oxidative stress, dysregulated immune system, and inflammation. In CRC cell lines (HCT116 and DLD1), the administration of oxaliplatin resulted in the downregulation of proteins involved in axon excitability (NGF, SOD1, ROBO1, CNTNAP2, and KCNMB1), normal sensory neuron function (SOX10, APOE, SST, S1PR1, and KCND3), voltage-gated sodium (SCNN1B, SCNN1G, SCNN1A, SCN1B, and SCN2B), calcium (CACNA2D2, CACNA1A, CACNA1C, CACNA1E, and CACNA1F), and potassium channels (KCND3, KCNMB1, KCNMA1, KCNJ2, and KCNN4). Conclusions: A molecular signature associated with OXAIPN was identified in patients with CRC and validated in CRC cell lines (HCT116 and DLD1). Further studies to reproduce and evaluate its potential in predicting OXAIPN in CRC patients in the clinic are warranted.