bluuebunny/crossref_metadata_2025_split huggingface dataset:
The impact of COVID-19 on mortality, length of stay, and cost of care among patients with gastrointestinal malignancies: A propensity score-matched analysis.
Authors: Ulanja Mark Bilinyi , Beutler Bryce D. , Governor Samuel B , Asafo-Agyei Kwabena Oppong , Edusa Samuel , Antwi-Amoabeng Daniel , Ulanja Reginald N. , Amankwah Millicent , Neelam Vijay , Mabrouk Tarig , Rahman Ganiyu A. , Djankpa Francis T. , Alese Olatunji B. 
Published: June 2023

e15510 Background: The SARS-CoV-2 (COVID-19) pandemic has had a lasting impact on the care of cancer patients. Multiple studies have shown that individuals with cancer are at high risk of serious complications in the setting of COVID-19 infection, but the impact in patients with gastrointestinal (GI) malignancies remain incompletely understood. We aimed to assess the impact of COVID-19 infection on mortality, length of stay (LOS), and cost of care among patients with GI malignancies, and identify differences in outcomes based on primary tumor site. Methods: We analyzed discharge encounters collected from the National Inpatient Sample (NIS) between March 2020 and December 2020, using propensity score-matching (PSM), and COVID- 19 as treatment effect. Results: Of the 87,684 patient discharges with GI malignancies, 1,892 were positive for COVID-19 (C+ve) and eligible for matching in the PSM model. Proportion for C+ve; male (61.2%), female (38.8%), White (55.8%), Black (17.9%), Hispanic (18.6%) and other (7.6%). Median age was 69 years (1QR: 61-77). Monthly variation reflected the wave and plateau dynamics of the spread of COVID-19. Following PSM analysis, C+ve patients with GI tumors demonstrated increased mortality compared to their COVID-19-negative (C-ve) counterparts (21.3% versus 11.9%, p < 0.001). C+ve patients with colorectal cancer (CRC) had significantly higher mortality compared to those who were C-ve; 39.95% [161/403] versus 24% [54/225], p = 0.035). In addition, C+ve patients with GI tumors had a longer LOS (9.42 days versus 6.95 days, p < 0.001) and increased cost of care ($26,048.29 versus $21,625.24, p = 0.001) compared to C-ve. Higher odds of mortality from myocardial infarction among C+ve(OR = 3.54, P = 0.001) while mortality due to pulmonary embolism or liver failure was not significantly different between C+ve and C-ve groups. Conclusions: This PSM analysis suggests that prior to the introduction of vaccines, C+ve patients with GI tumors faced approximately double the odds of mortality, an increased LOS of 2.5 days, and increased cost of care of about $4,400 compared to their C-ve counterparts. The disparity of outcomes was most pronounced among CRC patients. It is possible that the direct effects of the SARS-CoV-2 virus on the GI tract may predispose to mortality and disease severity, warranting further investigation. [Table: see text]
Cost-effectiveness of ColoSTAT for primary colorectal cancer screening in the United States.
Authors: He Emily , Deak Elena , Schmitt Laetitia Helene Marie , Alesso Sonia Maria , Gilbert Glenn 
Published: June 2023

e15525 Background: Colorectal cancer (CRC) screening is at the cornerstone of strategies for reducing the mortality, healthcare and societal cost burden of CRC, the third most common cancer in the United States (US). ColoSTAT immunoassay is a simple, highly accurate, minimally invasive blood-based screening test for CRC that will be launched in the US market. Using a de novo decision analytic model, we compared the health benefits and cost-effectiveness of CRC screening with ColoSTAT with current screening offered by private insurers assuming a 5-yearly colonoscopy (COL) or biennial fecal immunochemical test (FIT) for the US population. Methods: For the three screening strategies, the expected number of CRC cases detected, and total screening program cost were estimated using a decision-analytic model based on: published CRC incidence in the US, tests performance characteristics, adherence rates to screening (61% for COL; 46% for FIT) and to diagnostic assessment via COL after a positive FIT or ColoSTAT test (80.4%). The gain in quality-adjusted life year (QALY) associated with every CRC case detected through screening, and confirmed by diagnostic assessment, was estimated by linking US-specific estimates of: CRC deaths by age-subgroups, life expectancies at the time of CRC death, quality of life projections for the general population and reduction in CRC mortality associated with screening. Healthcare cost savings associated with every CRC case detected through screening were estimated based on the distribution of CRC across disease stages by diagnosis method (screening versus symptomatically) and stage-specific CRC treatment costs. Results: Biennial screening with ColoSTAT, compared with 5-yearly COL screening offered by private insurers, is estimated to generate cost savings on screening programs of around $40 million per 100,000 people of screening age (PoSA) per one-off screening. When scaled up to the total US population within screening age covered by private insurance (66%), the estimated cost savings with ColoSTAT exceed $30 billion per one-off screening. The reduction in the number of CRC cases detected would generate a modest loss of 58 discounted QALYs per 100,000 people, that could be mitigated if ColoSTAT were to boost screening uptake. In the context of government-sponsored screening programs, replacing FIT with ColoSTAT is estimated to increase the number of CRC cases detected via screening by 9% (to 50 cases per 100,000 PoSA), assuming an unchanged screening uptake of 46%. At the commonly used value of $100,000 per QALY, this would equate to a discounted benefit of $834,820 per 100,000 PoSA per one-off screening. Conclusions: CRC screening with ColoSTAT as an alternative to COL could result in multi-billion-dollar cost savings to US private insurers while still detecting most CRC cases and generate population-health gains if used as an alternative to FIT in government-sponsored screening programs.
Immune activation-related risk score: A new tool to predict prognosis and immunotherapy applicability in colorectal cancer.
Authors: Zhu Changbin , Su Wenqing , Chen Yanhua , Gai Fei , Wang Jin 
Published: June 2023

e15534 Background: In colorectal cancer (CRC), the therapeutic potential of immune checkpoint inhibitors (ICIs) is limited to the patients with mismatch repair deficient (dMMR)/high microsatellite instable (MSI-H) tumors, which accounts for less than 5% of CRC patients. While, patients with mismatch repair proficient (pMMR)/microsatellite stable (MSS) tumors represent the vast majority (≈ 95%), particularly those with similar inflammatory tumour microenvironment characteristics to dMMR/MSI-H patients are at risk of losing the opportunity to receive appropriate treatment. Thus, there is an urgent clinical need for biomarkers that can accurately predict prognosis of CRC patients, and assist in selection of patients who may benefit from immunotherapy. Methods: A public database, GEO (GSE39582, n = 502), was used as a training cohort to assess the characteristics associated with immune activation. Individuals with immune characteristics similar to dMMR/MSI-H were identified through GSVA and unsupervised clustering analysis, and defined as MSI-Like. Limma analysis identified MSI-Like immune activation characteristic, and immune activation-related prognostic models were developed by LASSO and COX regression. In addition, the applicability of immunotherapy for immune activation-related prognostic score was estimated in an external validation cohort (n = 96) from an Asian institution. Results: 113 differentially expressed genes between MSI-Like and non-MSI-Like pMMR/MSS samples were defined as immune activation- related characteristics of MSI-Like. After stepwise regression analysis, the characteristics were reduced to 6 key genes, and combined with their regression coefficients to construct a model. Overall survival was significantly shorter in high-risk [Immune Activation-related Risk Score (IARS) ≥ 0] group than in low-risk (IARS < 0) group (p < 0.0001). The area under the ROC curve (AUC) values at 1, 5 and 10 years were 0.683, 0.708 and 0.765, respectively. Furthermore, in multiple CRC data sets, the IARS can screen out the low-risk group with significantly better prognosis (p < 0.05). Additionally, low-risk group showed more expression of immune activation-related genes compared to high-risk group. IARS did not shown significant correlations with clinically characteristic factors (e.g., gender, age, stage, etc.) or gene mutations (including TP53, KRAS and BRAF). Conclusions: For a subset of pMMR/MSS patients with immune activation characteristics similar to those of dMMR/MSI-H patients, an immune activation-related risk score model was constructed based on 6 genes associated with immune activation characteristics. This model can effectively predict the prognosis of patients and also help to assess the adaptability of patients to immunotherapy. These findings have the potential to provide new insights into the immunotherapy of patients with pMMR/MSS CRC.
Comprehensive analysis of the mutational status of early colon cancer: Real world data from the AIO ColoPredict registry study.
Authors: Gisder Doreen Maria , Wisser Sarah , Lugnier Celine , Christmann Jens , Anna-Lena Kraeft , Feder Inke Sabine , Tischoff Iris , Teschendorf Christian , Vera Heuer , Sargin Bülent , Hollerbach Stepahn , Lamberti Christof , Tannapfel Andrea , Reinacher-Schick Anke C. 
Published: June 2023

e15535 Background: The comprehensive analysis of the mutational status of colon cancer (CC) may identify targetable alterations also in early stages. This may open up potential beneficial treatment choices, e.g. immunotherapy in microsatellite instable (MSI) tumors. So far, there is few data regarding the distribution of molecular alterations in CC in a real world setting in Germany. Methods: We analyzed clinical and molecular data from our Colopredict Plus (CPP) registry trial including CC patients (pts.) stage I-III. Samples were tested for MS status by immunohistochemistry and for gene mutations (MT) using a 71 gene panel comprised for CC. Molecular data was correlated with clinicopathologic parameters. Disease free Survival (DFS) was estimated by the Kaplan-Meier method. Results: Data from 2746 pts. was included. Female: 1476/2746 (53,8 %), median age: 72 yrs (range: 22-100 yrs), right sided tumor: 1607/2746 (58,5 %), stage distribution I/II/III/NA: 414 (15,1 %)/1198 (43,6 %)/1076 (39,2 %)/58 (2,1 %). MSI/MSS: 544(19,8%)/2202/ (80,2%). A KRAS mutation was observed in 846/2746 (30,8 %). The most frequent hotspot MT were codon 12 KRAS MT with p.G12D (27%), p.G12V (19%), p.G12A (6%), and p.G12C (6%) followed by codon 13 MT with p.G13D (18%). The subtypes p.G12D, p.G12V, and p.Q61K were significantly more frequent in the right colon. BRAF MT was seen in 560/2746 (20,4%). Observed rare MT were: POLE (76/2746 (2,8 %), PTEN 188/2746 (6,8 %), and EGFR (21/2746; 0,8%). MSI CC were more frequent in the right colon and associated with BRAF MT (346/560; 61,8 %), and also MT in BRCA1 (35/53; 66 %), BRCA2 (119/171; 69,6 %), POLE (45/76 (59,2 %), PTEN 107/188 (56,9 %), and EGFR (18/21, 85,7%). In contrast, TP53 MT (1223/2746 (44,5 %)) were associated with MSS (1090/2746 (49,5 %)). 3 yrs DFS in MSI BRAF WT vs. MSS BRAF MT pts. was 0,75 (0,67 – 0,81 vs 0,52 (0,36 – 0,65) (p =0,11). DFS did not differ in specific KRAS MT variants. Conclusions: We here show a comprehensive analysis of genetic alterations in early CC in a prospective real world cohort. As expected, MSI was correlated with female sex, right sided primary tumor and BRAF MT. Interestingly, we also found a strong correlation of BRCA1 MT, BRCA2 MT, EGFR MT, POLE MT, and PTEN MT with presence of MSI while MSS was associated with TP53 MT. Broad molecular characterization of early CC may help individualize treatment strategies in the future.
Tumor immune environment in multiple primary malignancies involving colorectal cancers: Comparison with single primary colorectal cancers.
Authors: Chen Junyi 
Published: June 2023

e15536 Background: Multiple primary malignancies (MPM) are characterized by two or more primary tumors in an individual patient, excluding relapse or subordinate relationship. Because the therapeutic options usually become limited, the diagnosis of MPM cause a lot of troubles to both clinicians and patients. A comprehensive investigation in comparing the tumor immune environment in MPM involving colorectal cancers (CRC) with single primary CRC will provide clues for the etiology and the management of MPM. Methods: Three patients with MPM involving CRC and twenty four patients with single primary CRC from our hospital were enrolled in the study. FFPE samples from colorectal lesions were analyzed for the tumor infiltrating lymphocytes [PD-L1+, PD-1+, CD3+, CD4+, CD8+, CD20+, FoxP3+, CD56+, CD163+, CD68+] by multiplex immunofluorescence technique. The tumor-enriched segments and stroma areas annotated by pathologists on images. Then artificial intelligence (AI) employing algorithms of image processing, machine learning, and deep learning techniques distinguished the core and peritumor areas, and calculated the density (counts per mm2) of each marker in two regions. A nonparametric approach (Kruskal–Wallis) was used to compare the density of immune cells between MPM involving CRC and single primary CRC groups. Results: The density of CD4+, CD56dim, FoxP3+ cells in patients with single primary CRC were significantly higher than those in MPM both in the stroma and tumor-enriched segments (all, p < 0.05). In the tumor-enriched segments, the density of PD-1+ in patients with single primary CRC was also significantly more than that in MPM. Moreover, the density of PD-1+CD8+ cells in patients with single primary CRC showed a trend of higher density than those in MPM patients in the stroma area (p = 0.06). However, the density of PD-1+ and PD-1+CD8+ cells did not show significant differences related to cancer types (MPM and single primary CRC) in the stroma. Other indicators such as CD3+, CD20+, CD8+, CD68+CD163+, CD68+CD163-, CD56bright and PD-L1+, had no significant difference related to cancer types (MPM and single primary CRC) regardless of the area (tumor-enriched segments and stroma area). Conclusions: We identified that the tumor infiltrating lymphocytes such as CD4+ cells infiltrated more in single primary CRC than those in MPM involving CRC, suggesting that MPM involving CRC may unresponsive to immunotherapy monotherapy. With preclinical studies suggesting potential for synergistic effects, combining immunotherapies may be a promising approach to treat MPM, which requires a further validation with a larger sample size.
Single cell transcriptomics to identify immunological ACKR1+ DCs and their effect on clinical outcomes in left-sided CRC.
Authors: Wang Qian , Fan Tongqiang , Wang Tao , Xiao Shanshan 
Published: June 2023

e15550 Background: Myeloid cells play critical roles in the growth and metastasis of malignant tumors with both protumor and antitumor capabilities. Plenty of studies have reported they participated in modulating tumor inflammation and angiogenesis, and therapeutic strategies targeting myeloid cells are ongoing in pre-clinical and clinical trials. The functions of myeloid cells and their subtypes in left-sided and right-side CRC remain unclear. Methods: A published scRNA-seq dataset (Pelka et al., 2021) with 21 samples from left-sided CRC and 79 from right-sided CRC (colorectal cancer) was obtained. Seurat (Stuart et al., 2019) was used to perform dimensionality reduction and differential expression analysis, and the cell subtypes in the myeloid cells were identified to study the associations between clinical outcomes and different tumor tissue sites of CRC. We also obtained an immunotherapy dataset from TISMO to identify associations between cell subtypes and immunotherapy outcomes. Results: Systematic comparisons of myeloid cells (n = 39,167) from left-sided and right-sided CRC revealed that highly expressed genes from right-sided CRC showed protumor capability and those from left-sided CRC showed antitumor activity. Specifically, left-sided CRC harbored a significant (p = 0.018) higher proportion of ACKR1+ DCs compared to right-sided CRC. ACKR1+ DCs might be immunological as its marker genes were significantly positively correlated with CD8+T cells and highly enriched in APC(antigen processing presentation)-related pathways. TCGA survival analysis revealed that the higher expression of the marker genes in ACKR1+ DC was associated with better overall survival (OS, p = 0.0088). Furthermore, immunotherapy biopsy showed ACKR1+ DCs subtype significantly enriched in immunotherapy responsive group compared to non-responsive group in colon cancer (p = 0.019), melanoma (p = 0.0058) and renal adenocarcinoma (p = 3.3e-06) among the obtained TISMO dataset. Conclusions: We identified an immunological ACKR1+ DCs subtype, which was highly enriched in left-sided CRC and was correlated with better clinical outcomes and immunotherapy responses. Those findings might provide potential therapeutic target and help better understand the mechanism of treatment strategies in CRC.
Survival trends for left and right sided colon cancer using the population-based SEER database: A 45-year analysis from 1975 to 2019.
Authors: Ulanja Mark Bilinyi , Asafo-Agyei Kwabena Oppong , Buetler Bryce D , Antwi-Amoabeng Daniel , Ulanja Reginald N. , Neelam Vijay , Mabrouk Tarig , Governor Samuel B , Amankwah Millicent , Rahman Ganiyu A. , Djankpa Francis T. , Alese Olatunji B. 
Published: June 2023

e15560 Background: Survival differences between left sided (LCC) and right sided colon cancer (RCC) have been previously reported with mixed results. Many used short study periods and did not account for "other cause of mortality" (OCM). The differences in survival may exist irrespective of modern therapeutic agents, with implications for future clinical trial designs. Methods: We sought to assess the trends in the cause- specific and overall survival of colon cancer based on sidedness, using competing risk analysis. A SEER database from 1975 to 2019 was used.Time interval chosen based on clinical adoption of modern chemotherapy (1975-1989 = period A, 1990-2004 = B, 2005-2019 = C). Cox model was used for overall survival (OS), and Fine-Gray competing risk analysis for cause-specific survival (CSS). Adenocarcinoma were included, and primary rectal cancers excluded. Results: Of the 227,637 colon cancer patients, 50.1% were female and 46.2% RCC. Racial distribution of LCC vs RCC; Black-48.5% vs 51.5%, White-53.1% vs 46.9%, API/AN-63.7% vs 36.3%; p < 0.001. Age ≥ 65 were more likely to have RCC vs LCC (51.4% vs 48.6%), LCC common for age 18-49 (64.6% vs 35.4%), 50-64 (62.3% vs 37.7%), p < 0.00l. Females more likely to have RCC (50.4%vs 41.9%; p < 0.001), and males to have LCC (58.1% vs 49.6%;p < 0.001). Median CSS for LCC and RCC was 19.3 and 16.7 years respectively for 1975-1989 but median CSS for period B and C did not reach during study period. Median OS increased over time for both LCC (A = 5.5 yrs.; B = 7.6yrs and C = 10.5 yrs.) and RCC (4.3, 5.8 and 7.5yrs respectively). CSS was better for LCC than RCC for period C (aHR 0.89; 0.86-0.92; p < 0.001). LCC consistently showed superior OS for all study periods. Stage stratification showed worse CSS for localized and regional LCC in the earlier study periods, but the risk attenuated over time. However, left sided distant disease had superior CSS for all periods. Overall survival was better for LCC irrespective of stage, with gradual improvement over time(table 1). Conclusions: Over the past four decades, LCC has shown superior survival over right sided tumors. Furthermore, prognosis between LCC and RCC became more divergent in favor of LCC with the adoption of modern chemotherapy. Clinical trials for colon cancer should consider sidedness when recruiting patients for intervention. [Table: see text]
Results of a retrospective multicenter study comparing the effectiveness of regorafenib and the rechallenge of chemotherapy in patients (pts) with metastatic colorectal cancer (mCRC).
Authors: Kuzmina Evgenia , Fedyanin Mikhail , Reshetov Igor , Parts Sergey , Pokataev Ilya , Polyanskiy Maxim , Antonova Tatiana , Pikulin Dmirii , Arseneva Evgenia , Anikina Marina , Golubev Pavel , Syskova Anna , Galkin Vsevolod 
Published: June 2023

e15561 Background: Regorafenib is considered the standard third-line therapy of mCRC. However, the modest efficacy and significant toxicity of regorafenib urges the search for new therapeutic approaches. In various countries, the re-challenge of the previously effective treatment regimens is being considered. We compared the effectiveness of various variants of systemic therapy in the third and subsequent lines of the treatment. Methods: We analyzed the prospective database of pts with mCRC from two clinics of the Russian Federation. The statistical hypothesis implied the equivalence of the 6-month overall survival on the repeated chemotherapy (CT) and targeted therapy with the third line regorafenib therapy, provided the equivalence boundaries from 0.8 to 1.25. With α = 0.05, the study power is 80% with 178 patients, 89 people in each group. We conducted statistical analysis with the SPSS statistical software package (v. 20, IBM). Results: In the database, we identified 215 patients with morphologically confirmed metastatic colon cancer who received two or more lines of antitumor drug therapy from 2010 to 2021. Of them, we selected 132 patients with a history of regorafenib therapy, and 83 patients with the re-challenge of CT as the third line of the therapy. Overall survival (OS) in the re-challenge and regorafenib groups did not differ (hazard ratio [HR] 1.01 with 95%CI 0.7-1.45; p = 0.9) and the 6-month OS was 74 and 70%, respectively. Progression-free survival was significantly higher in the re-challenge group (HR 1.94 with 95%CI 1.3-2.7; p < 0.001); In the multifactorial analysis, the re-challenge of previous treatment regimens kept its independent positive effect on progression-free survival (HR 1.9 with 95%CI 1.3-2.8; p = 0.0001) also as index T < 3 (HR 0.7, 95CI 0.55-0,94); ECOG ≥1 a (HR 1.5 with 95%CI 1.16-2.05; p < 0.01) affected PFS negatively. The reduction of the regorafenib dose did not affect PFS (HR 0.9 with 95% CI from 0.9 to 1.0; p = 0.1), its starting dose (HR 0.9 with 95 CI from 0.9 to 1.0; p = 0.2), and a break in the regorafenib treatment (HR 0.9 with 95% CI from 0.5 to 1.8; p = 0.9). Conclusions: Regorafenib and the re-challenge of previously effective CT in the third-line of mCRP therapy show the similar 6-mon. OS. However, progression-free survival is significantly higher in the re-challenge group in third line therapy.