tbuckley/cabot-search huggingface dataset:
Benefits for adjuvant chemotherapy of resected colon carcinoma examined by Artificial Intelligence Laboratory (NCI-Br) through synthetic data and machine learning: A tribute to Prof. Charles George Moertel.
Authors: Rubens Kesley, Leonaldson Dos Santos Castro, José Humberto Simões Correa
Journal: Journal of Clinical Oncology (2024)

e15537 Background: Data is considered the basis of the modern economy and the production of synthetic data can revolutionize the applicability of artificial intelligence in healthcare. However, there are few synthetic databases in biostatistics and few mechanisms capable of generating them. The objective of the study is to develop a synthetic database based on the seminal article by Moertel et al (1990) entitled: Levamisole and Fluoracil for adjuvant therapy of resected colon carcinoma, which revolutionized oncological treatment. Methods: An algorithm with probabilistic and logical methods and specialized knowledge was used to reconstruct the dataset with the variables studied by Moertel et al (1990). Based on the percentages observed in the study and logical programming rules in R language, we propose to create a model capable of simulating the original dataset with the epidemiological (age and sex) and anatomopathological (tumor location, depth of tumor invasion, involvement of adjacent organs, obstruction, perforation, peritoneal implants, number of metastatic lymph nodes and histological differentiation type). Using the decreasing exponential function it was possible to simulate the decay of the probability density function of the original sample for recurrence and survival. The synthesized data was subjected to traditional statistical analysis and machine learning, using decision trees. Results: Statistical analyzes of the independent exploratory variables of relapse (invasion, metastatic lymph nodes, cellular differentiation) and survival (tumor location, invasion, metastatic lymph nodes, cellular differentiation) demonstrated statistical significance (p = 0.001). The behavior of the exploratory variables for recurrence and survival was similar to the recurrence and survival curves observed by the Kaplan-Meier statistical method (p = 0.001). Decision trees were created with amplified samples that demonstrated the importance of the variables number of lymph nodes, tumor invasion and chemotherapy. Conclusions: The proposed algorithm showed that it is possible to recreate a dataset with statistical similarities to the original, based on detailed analysis, knowledge in Data Science and Analytics, mathematical methods and rules determined by the domain expert. The study of synthetic dataset allows evaluating the quality of the article studied, amplifying or reducing the sample, mapping interrelationships between explicative and dependent variables, and analyzing the synthetic dataset according to artificial intelligence, demonstrating that artificial intelligence laboratories are essential for analyzing the health data.
The association of protein-energy malnutrition and in-hospital clinical outcomes among patients with colorectal cancer hospitalized for gastrointestinal bleeding: A nationwide analysis.
Authors: Hilary Elom, Tarfa Verinumbe, Elvis Obomanu, Colton Jones, Ryan Mayo
Journal: Journal of Clinical Oncology (2024)

e15531 Background: Patients with colorectal cancer (CRC) commonly present with gastrointestinal (GI) bleeding and are at risk of developing protein-energy malnutrition (PEM) either due to effects of therapeutic interventions (chemotherapy, immunotherapy, radiation) or primary disease on appetite and caloric intake. There are several existing studies on CRC and gastrointestinal hemorrhage, however the impact of concurrent PEM on in-hospital outcomes for patients with CRC admitted for GI bleeding is unclear. Our study aims to assess the association of PEM and clinical outcomes among patients with CRC hospitalized for GI bleeding. Methods: We analyzed data from the 2020 National Inpatient Survey on patients with CRC who were admitted with GI bleeding. To determine our study sample, we used International Classification of Diseases, 10th Revision (ICD10) codes for CRC (C18.X, C19 and C20), and GI bleeding (K92.2 and K62.5). The primary exposure was a comorbid diagnosis of PEM (defined based on the ICD 10 codes E40 – E46). The clinical outcomes assessed in this study were all-cause mortality, sepsis, septic shock and length of stay in the hospital. A multivariate logistic regression was used to assess the association of comorbid PEM with all-cause mortality and sepsis. A cox proportional hazard regression was used to investigate the association between the PEM and time to discharge. Covariates adjusted for in our final analyses included age, sex, insurance status and number of comorbidities present on the patients record at discharge. Results: Of the 2223 patients with CRC who were admitted for GI bleeding, 55% were male, 64% were White and mean age was 63 years (SD 14.2). A quarter (23%) had comorbid PEM, 14.6% had sepsis and 5.4% had septic shock. About 6.5% died during hospitalization and the mean length of hospital stay was 7.8 days. Comorbid PEM was significantly associated with a two-fold increase in the risk of all-cause in-hospital mortality (aOR 2.05; 95% CI: 1.41 – 3.98), sepsis (aOR 2.33; 95% CI: 1.78 – 3.05) and septic shock (aOR 2.0; 95% CI:1.35 – 3.09). Additionally, compared to patients without PEM, those with concomitant PEM had a lower discharge rate (HR 0.71, 95%CI: 0.64-0.78). Conclusions: Our study demonstrated that comorbid PEM in patients with CRC hospitalized for GI bleeding is associated with increased risk of all-cause in-hospital mortality, sepsis, septic shock and prolonged length of stay. The findings from this study highlight the need for nutritional considerations when managing patients with CRC and GI bleeding to prevent adverse health outcomes and potentially improve survival among these patients.
The treatment outcomes of patients with <i>BRAF<sup>V600E</sup></i>–mutated metastatic colorectal cancer (mCRC): The Polish retrospective cohort study.
Authors: Jolanta Zok, Michał Bieńkowski, Barbara Radecka, Agata Kuchar, Szymon Borowiec, Joanna Streb, Michał Jurczyk, Anna Jakieła-Drąg, Marek Gelej, Patryk Zając, Małgorzata Ploch-Glapińska, Renata Duchnowska
Journal: Journal of Clinical Oncology (2024)

e15535 Background: BRAF V600E mutation is found in approximately 6-11% of metastatic colorectal cancer patients (mCRC). According to the international guidelines in BRAF V600E mutated mCRC, the triplet chemotherapy FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin, irinotecan) with bevacizumab and encorafenib plus cetuximab should be considered in 1 st and 2 nd line treatment setting, respectively. Methods: This retrospective and multicenter study evaluates clinical practices in BRAF V600E mutated mCRC patients treated between 2011 and 2023 in Poland. All patients were tested for BRAF and RAS mutations before starting the 1 st line treatment, using PCR from archival paraffin-embedded tumor tissue. Results: One hundred twenty-six patients (median age 68 years (range 45-85), 55% female and 45% male) from five oncology centers were included. The majority of patients had a right-sided primary tumor 69 (55%). The 1 st line of chemotherapy received 100 patients (79,4%). The majority of patients received doublet chemotherapy: FOLFOX (folinic acid, 5-fluorouracil, oxaliplatin), FOLFIRI (folinic acid, 5-fluorouracil, irinotecan), XELOX (capecitabine, oxaliplatin), FOLFIRI and bevacizumab: 30 (30%), 47 (47%), 5 (5%), 3 (3%), respectively. Only three patients (3%) received FOLFOXIRI, and one patient with bevacizumab. The median duration of 1 st line treatment for the overall population was 5.26 months (95% CI 2 days - 18.9 months). Subsequently, 50 (50%), 20 (20%), 6 (6%), and 1 (1%), patients received 2 nd , 3 rd , 4 th , and 5 th line therapy, respectively. The most frequently used 2 nd chemotherapy regimens were FOLFOX ( n = 8; 16%), FOLFOX plus bevacizumab ( n = 13; 26%), FOLFIRI ( n = 13; 26%), and FOLFIRI plus aflibercept ( n = 7; 14%). During the median follow-up period of 38.5 months (range 32.0 – N/A), 96 (79.3%) patients died. Median OS from mCRC diagnosis was 13.7 months (95% CI: 11.3-17.6). Conclusions: This study highlights the unmet need for effective treatment strategies for patients with BRAF V600E mutated mCRC in Poland.
Use of epigenetic inhibitor screen to identify HDAC1/2 inhibitor as a pro-differentiation therapy in colorectal cancer.
Authors: Pornlada Likasitwatanakul, Zhixin Li, Sandor Spisak, Paul Doan, Pratyusha Bala, Priscilla Liow, Malvina Papanastasiou, Jun Qi, Nilay S. Sethi
Journal: Journal of Clinical Oncology (2024)

e15538 Background: Impaired differentiation is a key mechanism by which neoplastic cells persist and eventually progress to malignancy in the renewing colonic epithelium. Our group recently demonstrated that SOX9 functionally prevents differentiation to promote colorectal cancer (CRC) development; however, we have yet to convert this knowledge for therapeutic gains. Methods: To this end, we developed a discovery platform by genome-engineering SOX9 (stem cell activity) and KRT20 (differentiation) genomic loci of CRC cell lines to express two fluorescent markers simultaneously. Epigenetic modulators play an essential role in intestinal epithelium differentiation, and drug-targeting epigenetic regulators are emerging as a novel therapy class. Hence, we applied a small molecule screen targeting epigenetic regulators to our platform, searching for perturbations that induce differentiation, reduce stem cell activity, and suppress viability, and ultimately converged on a selective HDAC1/2 inhibitor. Results: CRC cell lines, patient-derived organoids, and Apc KO mice treated with selective HDAC1/2 inhibitors illustrated induction of differentiation and suppression of stem cell activity by transcriptional and chromatin accessibility profiling. Streptavidin bead pulldown of a biotinylated HDAC1/2 inhibitor (using an inactive version as a control) followed by mass spectrometry confirmed specific interaction with HDAC1/2, ensuring on-target activity. By testing several HDAC inhibitors in CRC cell lines, we found that HDAC1, 2, and/or 3 inhibition is required for the differentiation phenotype. To identify the mechanism of action, we pursued unbiased global histone modification profiling upon HDAC1/2 inhibitor treatment and observed increased acetylation (ac) of H3K9, H3K27, and H4K8. To elucidate how acetylation of these specific histones induced differentiation, we performed chromatin immunoprecipitation followed by DNA sequencing (ChIP-seq) in CRC cell lines treated with two HDAC1/2 inhibitors. Intriguingly, only regions with increased H3K27ac bound by HDAC1/2 were significantly associated with differentiation transcriptome and chromatin accessibility profiles. Blocking H3K27ac by degrading EP300/CBP reversed the differentiation phenotype induced by HDAC1/2 inhibition, confirming its necessity. Conclusions: Despite HDAC inhibitors being unsuccessful with previous CRC clinical trials, our HDAC1/2 inhibitor demonstrated synergistic killing and differentiation effect with 5-fluorouracil, the backbone of the most common treatment regimens for GI cancers. Romidepsin, an HDAC1/2 inhibitor approved for cutaneous T-cell lymphoma, reproduced similar phenotypes in CRC cell models. These preclinical studies highlight the possibility of using a small molecule HDAC1/2 inhibitor as a pro-differentiation therapy in colorectal cancer.
Types of thromboembolic events and their outcomes among patients with active colorectal cancer: A nationwide propensity matched analysis.
Authors: Faryal Farooq, Manoj Kumar, Muhammad Sohaib Afzal, Muhammad Sultan, Bilal Nasir, Laxman Yashwant Byreddi, Vishal Devarkonda, Shafaqat Ali, Sundeep Atluri
Journal: Journal of Clinical Oncology (2024)

e15530 Background: Venous thromboembolic events (VTE) are a major cause of morbidity &amp; mortality in patients with active cancer. We aim to investigate the outcome and incidence of acute DVT and PE in colorectal cancer compared to all other malignancies. Methods: The National Readmission Database (2016-2020) was queried to identify all-cause admissions for patients with active colorectal cancer (CRC). A Propensity Score Matching (PSM) model, matched such patients with cases having any type of other malignancies. Pearson’s x2 test was applied to the PSM-2 matched cohorts to compare outcomes. Results: Among 2.9 million all-cause hospitalizations of CRC patients, about 3.9% suffered a VTE. The majority had acute DVT (1.9%), followed by acute PE (1.3%), followed by DVT with PE (0.7%). After propensity-matching &amp; multivariate analysis, patients with CRC have a lower incidence of acute DVT (2.7% vs 2.8%, aOR: 0.92), acute PE (1.8% vs 2%, aOR: 0.84) &amp; DVT with PE (0.96% vs 1.02%, aOR: 0.90) [p &lt; 0.001] as compared to other malignancies. Among different VTEs, the mortality was highest for acute PE (aOR: 2.66), followed by DVT with PE (aOR: 2.28) &amp; DVT (aOR: 1.89) [p &lt; 0.001]. Resource utilization is also higher in CRC-related hospitalizations complicated by VTE, with patients suffering a DVT having the highest LOS (9 vs 5 days) &amp; total cost of hospitalization ($25,910 vs $17,964) [p &lt; 0.001] followed by DVT with PE and PE respectively. CRC patients had higher readmission rates for DVT as compared to PE at 30 days (18.2% vs 17%, p: 0.029) and subsequently at 90-day intervals. Conclusions: CRC-related hospitalizations had lower rates of DVT and PE compared to other active malignancies. The mortality was highest for PE in this cohort, while healthcare-related burden and readmission rates were higher for DVT.
Paradoxical association of B7H3 with clinical outcomes in patients with colorectal cancer.
Authors: Yan Huang, Xiaohua Qi, Ana Acuna-villaorduna, Radhika Gali, Radhashree Maitra, Juan Lin, Catarina Maia, Wei Zhang, Chenxin Zhang, Xingxing Zang, Qiang Liu, Sanjay Goel
Journal: Journal of Clinical Oncology (2024)

e15508 Background: Immune related biomarkers (IRB) are important predictors of outcome to immune checkpoint inhibitor (ICI) therapy; however, their role is unclear in early-stage colorectal cancer (CRC). This study aimed to evaluate the expression of novel protein IRB among CRC patients to predict clinical outcomes. Methods: A CRC tumor microarray (TMA) was constructed from a multiracial patient population, and expression of HHLA2, B7-H3, PD-L1, CK7, CK20, and CDX2 determined. Comprehensive clinical information was extracted. For curable cancers, associations between biomarker expression and relapse risk were assessed using logistic regression analysis. For metastatic(m) cancers, Kaplan Meier curves were plotted, and Cox proportional hazards regression analysis was performed to evaluate association with overall survival (OS). Results: Among 388 patients, 150 had de novo metastatic disease, 108 experienced relapses from localized cancer, and 130 patients had cured localized disease. The median age was 62.4 years, with a female predominance (53%). The majority were racial/ethnic minorities. Among curable cancers, patients with high B7-H3 expression experienced a 73% lower risk of relapse (OR 0.27, 95%Cl 0.09-0.76, p = 0.015) exceeding the relevance of nodal(N) and tumor(T) stage in predicting relapse. High HHLA2 (OR 4.79, 95%CI 1.74-14.5, p = 0.003) was associated with a higher risk of relapse. Among mCRC, low expression of both PD-L1 and B7-H3 was associated with better OS (HR 1.73; 95%CI 1.08-2.76, p = 0.023). Conclusions: In this multiracial TMA of CRC, high B7-H3 expression was associated with lower risk of relapse. Post validation, routine B7-H3 testing may enable clinicians to make more informed decisions regarding adjuvant therapy.
Trends and Inequalities in Diabetes-Related Complications Among U.S. Adults, 2000–2020
Authors: Ryan Saelee, Kai McKeever Bullard, Israel A. Hora, Meda E. Pavkov, Francisco J. Pasquel, Christopher S. Holliday, Stephen R. Benoit
Journal: Diabetes Care (2024)

We examined national trends in diabetes-related complications (heart failure [HF], myocardial infarction [MI], stroke, end-stage renal disease [ESRD], nontraumatic lower-extremity amputation [NLEA], and hyperglycemic crisis) among U.S. adults with diagnosed diabetes during 2000-2020 by age-group, race and ethnicity, and sex. We also assessed trends in inequalities among those subgroups.
Delineating histomorphological signatures of iCMS subtypes in colorectal cancer using multiplexed fluorescence-in-situ hybridization.
Authors: Ignasius Joanito, Li Bo, Grace Hui Ting Yeo, Vairavan Lakshmanan, Yurike Laurensia, Iain BeeHaut Tan, Shyam Prabhakar
Journal: Journal of Clinical Oncology (2024)

e15603 Background: Our recent single-cell transcriptomic data indicate that colorectal cancer (CRC) can be classified into two major epithelial subtypes: iCMS2 and iCMS31. iCMS3 CRC includes MSI-H and one-third of MSS tumors. The latter are enriched in KRAS, PIK3CA, and BRAF mutations. The iCMS2 subtype often exhibits chromosome instability, including copy number changes in specific chromosome regions. These genomic alterations may be associated with distinct histomorphological features, which can be assessed using hematoxylin and eosin (H&amp;E) staining. Methods: To test this hypothesis, we acquired and analyzed multiplexed Fluorescence in situ Hybridization (mFISH) and immunofluorescence (IF) staining data from 84 samples from 32 patients. For the mFISH data, we targeted 464 genes, encompassing major cell lineage markers and genes differentially expressed between iCMS2 and iCMS3 patient subtypes. Images were acquired over 31 hybridization rounds. Following the acquisition of the mFISH data, the same tissue section was stained with anti-EPCAM, anti-CD45 and anti-Vimentin antibodies to delineate cell boundaries and distinguish between the major cell lineages. Subsequently, all crypts were segmented based on their EPCAM and VIM stains, and parameters such as crypt size (number of pixels), crypt depth (distance to the nearest VIM signal), and fractal dimension were calculated for each crypt. The output of crypt segmentation was then integrated with mFISH RNA data to elucidate cell type proportions and gene expression profiles across and within individual segmented crypts. Results: Here, we found that iCMS2 crypts, in contrast to iCMS3 crypts, are significantly larger, deeper, and have higher fractal dimension. Additionally, our mFISH data demonstrated that iCMS2 tumors contain a higher proportion of undifferentiated (stem-like) cells, while iCMS3 tumors have a higher proportion of goblet (terminally differentiated) cells. The presence of larger and deeper crypts in iCMS2 may suggest a distinct cell state. Indeed, we identified specific genes whose expression was correlated with crypt depth. Conclusions: Our preliminary results suggest that these two iCMS subtypes exhibit distinct histomorphological features, which can be employed as practical and cost-effective companion diagnostics to assist in the pathological discrimination of these subtypes. References: 1 Joanito, I., Wirapati, P., Zhao, N. et al. Single-cell and bulk transcriptome sequencing identifies two epithelial tumor cell states and refines the consensus molecular classification of colorectal cancer. Nat Genet 54, 963–975 (2022).
FOLFOX-based hepatic arterial infusion chemotherapy combined with regorafenib for unresectable colorectal liver metastases.
Authors: Songlin Song, Jiacheng Liu, Yanqiao Ren, Chuansheng Zheng, Bing Liang
Journal: Journal of Clinical Oncology (2024)

e15601 Background: Hepatic arterial infusion chemotherapy (HAIC) stands out as a compelling local therapeutic strategy for patients with unresectable colorectal liver metastases (CRLM). Meanwhile, regorafenib has established itself as a systemic treatment for CRLM. The potential synergistic antitumor effect of combining HAIC and regorafenib in the treatment of unresectable CRLM remains intriguing, yet clinical evidence supporting the efficacy of this combination therapy is lacking. This study aims to evaluate the safety profile and therapeutic benefit of FOLFOX-HAIC plus regorafenib in the management of unresectable CRLM. Methods: In this retrospective analysis, we included 35 patients with unresectable CRLM who underwent FOLFOX-HAIC plus regorafenib between July 2020 and January 2023. The mFOLFOX6 regimen was employed for HAIC, comprising oxaliplatin (85 mg/m 2 for 2 h on day 1), calcium folinate (200 mg/m 2 for 2 h on day 1), and 5-fluorouracil (5-Fu) administered as a bolus of 400 mg/m 2 on day 1, followed by 2400 mg/m 2 over 46 h. Regorafenib was administered orally at a dose of 160 mg (four 40 mg tablets) once daily for the first 21 days of each 28-day cycle, with HAIC performed during the 7 days of discontinuation. The primary outcome was overall survival (OS), and progression-free survival (PFS). Secondary outcomes included objective response rate (ORR), disease control rate (DCR) and adverse events (AEs). Factors affecting the OS were also analyzed. Results: Kaplan-Meier analyses revealed a median OS of 29.0 months (95% confidence interval [CI], 17.9-40.1) and a median PFS of 13.0 months (95% CI, 9.3-16.7). Post-HAIC ORRs at 3, 6, and 12 months were 71.4%, 80.0%, and 57.2%, respectively, while DCRs were 88.6%, 91.4%, and 74.3%. In univariable and multivariable Cox regression models, ascites (HR = 5.640, 95%CI: 1.204-30.176, P = 0.033) and carcinoembryonic antigen levels &gt; 10μg/L (HR = 11.49, 95%CI: 1.232-88.758, P = 0.012) emerged as independent prognostic factors for OS. AEs associated with HAIC encompassed nausea, vomiting, abdominal pain, and fever. In the context of regorafenib, the prevailing AEs included hand-foot skin reactions and hypertension. Importantly, during the follow-up period, no life-threatening AEs were reported in patients receiving HAIC or regorafenib. Conclusions: The combination of regorafenib with FOLFOX-HAIC exhibits substantial promise in managing unresectable CRLM, providing meaningful effectiveness without exacerbating toxicity. [Table: see text]