bluuebunny/crossref_metadata_2025_split huggingface dataset:
Correlation of single-cell cytokine secretion with clinical outcome in patients (pts) with metastatic colorectal cancer (mCRC) treated with capecitabine (C), bevacizumab (B), ± atezolizumab (A).
Authors: Mettu Niharika B. , Waechter Blake , Zemla Tyler J. , Liu Yingmiao , Brady John C. , Lin Lynn , Gnjatic Sacha , Weinhold Kent J. , Bekaii-Saab Tanios S. , Ou Fang-Shu , Nixon Andrew B. 
Published: June 2023

3533 Background: The BACCI trial (NCT02873195) randomized 133 mCRC pts to C+B+A (investigational) or C+B+placebo. Longer progression free survival (PFS) was observed in the investigational vs placebo arm. To investigate T-cell functional heterogeneity, we performed single-cell proteomic analyses on pts with either long or short PFS and evaluated T-cell function as a prognostic and predictive biomarker. Methods: Isolated CD8+ and CD4+ cells were analyzed at baseline and first restaging from pts with long ( > 6 mo, N = 14) or short ( < 2 mo, N = 13) PFS. Single-cell, functional proteomic analyses were conducted using the IsoLight system (Isoplexis), which assessed secretion of 32 cytokines from an average of 786 cells per sample. The cumulative readout was polyfunctional strength index (PSI), a composite score of frequency and magnitude of secreted cytokines. Cytokines are organized into effector (E), stimulatory, chemoattractive (CA), regulatory, and inflammatory (I) clusters. Differential expression analyses were done using Wilcoxon rank-sum tests. Potential predictive effects were assessed using logistic regressions with interaction between treatment and biomarkers. No multiple comparison control was done due to the exploratory nature of analyses. Results: Baseline CD8+ and CD4+ cells were stimulated ex vivo and single-cell cytokine analyses performed. Prognostic analyses indicated that CD8+ cells from pts with long PFS had ~3-fold higher PSI compared to pts with short PFS (p = 0.005). Further analysis identified that the E (p = 0.005) and CA clusters (p = 0.005) most impacted PSI, significant individual cytokines are listed in the table. Baseline CD8+ cell function was not predictive of outcome. Baseline CD4+ cell function was not prognostic or predictive of outcome. Analysis of CD8+ cells after treatment identified that changes in CA cluster was prognostic of long PFS (p = 0.024). Cytokine changes from CD4+ cells were not prognostic; however, early changes in the CD4+ CA cluster were predictive of outcome (p-int = 0.055). Similarly, early changes in the CD8+ I cluster were predictive of outcome (p-int = 0.073). Conclusions: These results reveal pts with long PFS had more functional CD8+ T-cells with a higher PSI than pts with short PFS. Predictive analyses suggested that early changes in the CD4+ CA and CD8+ I clusters were associated with benefit from immunotherapy. These preliminary results highlight the importance of single-cell functional proteomic analyses. [Table: see text]
Gut microbiome composition as predictor of the efficacy of adding atezolizumab to first-line FOLFOXIRI plus bevacizumab in metastatic colorectal cancer: A translational analysis of the AtezoTRIBE study.
Authors: Marmorino Federica , Piccinno Gianmarco , Rossini Daniele , Ghelardi Filippo , Murgioni Sabina , Salvatore Lisa , Nasca Vincenzo , Antoniotti Carlotta , Daniel Francesca , Schietroma Francesco , Conca Veronica , Silva Carolina Alves Costa , Tamburini Emiliano , Tamberi Stefano , Passardi Alessandro , Antonuzzo Lorenzo , D'Onofrio Raffaella , Zitvogel Laurence , Cremolini Chiara , Derosa Lisa 
Published: June 2023

3534 Background: Gut microbiome has emerged as a biomarker of clinical benefit to immune-checkpoint inhibitors (ICI) but no data are available in metastatic colorectal cancer (mCRC). The AtezoTRIBE study demonstrated that the addition of atezolizumab (atezo) to FOLFOXIRI plus bevacizumab (bev) prolongs progression-free survival (PFS), but this benefit is limited for patients with proficient mismatch repair (pMMR) tumors. Here, we aimed at investigating the potential predictive role of microbiome in identifying mCRC patients able to achieve benefit from ICI. Methods: AtezoTRIBE was a phase II trial in which 218 mCRC patients, unselected for MMR status, were randomized 1:2 to receive first-line FOLFOXIRI/bev (arm A) or FOLFOXIRI/bev/atezo (arm B). Stools were prospectively collected. Metagenomic (MG) data from whole genome sequencing (WGS) at level of species genome bins (SGBs) were analysed by linear models corrected for clinical and tumor-related parameters and fold-ratios. We defined as responders (R) those patients who experienced a PFS ≥ 12 months. Results: Stool samples were collected at baseline for 171 (78%) patients (55 in arm A and 116 in arm B) but only 163 were available for MG. Patients with deficient MMR (dMMR) tumors (N = 10) showed significantly lower MG diversity than pMMR ones (N = 148) harboring oral bacteria and pathobionts whose intrinsic immunogenicity has not been demonstrated. Regarding pMMR mCRC patients, baseline microbiome composition was not significantly different according to the treatment arm. The microbiome diversity was not significantly different between R and not-R in both arms, but specific immunogenic SGBs (Lachnospiraceae family members) were over-represented in R treated in arm B. Veillonellaceae and pathobionts were associated with poor prognosis and/or differential benefit from the addition of atezo. Fusobacterium nucleatum was associated with a poor prognosis, also in arm B. Conclusions: This is the largest prospective analysis showing that SGBs may be useful as a biomarker of potential benefit or detrimental effect from atezo in pMMR mCRC patients. Our results prompt the design of microbiota-centered diagnostic tests to identify pMMR mCRC patients more likely to benefit from ICI-based therapeutic strategies. Clinical trial information: NCT03721653 .
Evaluation of microsatellite instability status, a definitive predictive biomarker for immune checkpoint inhibitors (ICI), in underrepresented minorities (URM) with gastrointestinal (GI) cancers.
Authors: Balogun Fiyinfolu , Altoe Mirella , O'Connor Catherine , Chowdhury Nobel , Cercek Andrea , Lee Choong-kun , Foote Michael Bonner , Kim Daehee , Maron Steven Brad , Kim Dae Won , Ronski Karyn , Park Joon Oh , Chao Calvin Y. , Janjigian Yelena Y. , Abou-Alfa Ghassan K. , Diaz Luis A. , O'Reilly Eileen Mary , Sanchez-Vega Francisco , Chakravarty Debyani , Park Wungki 
Published: June 2023

3538 Background: Mismatch repair deficiency (dMMR) results in MSI-H state and is the first tumor type-agnostic biomarker predictive of ICI response. Among GI cancers, MSI-H is most frequent in colorectal cancer (CRC 15%), gastroesophageal (GEC, 5%) and other (small bowel, hepatopancreatobiliary; 1%). For CRC, MSI-H can be attributed to germline mutation (Lynch syndrome, 3%) or somatic inactivation (sporadic, 12%) of foundational MMR genes. Studies evaluating ICI efficacy in dMMR cancers focus primarily on non-Hispanic White (NHW) patients (pts). We present prevalence, tumor genomic features, and outcomes in pts from a large cohort at Memorial Sloan Kettering (MSK). Methods: Retrospective analysis of MSI-H GI cancers from MSK-IMPACT database. Pts were grouped by self-reported race and ethnicity into 4 study arms: NHW, Asian, non-Hispanic Black (NHB), and Hispanic. Age, tumor type, tumor mutation burden (TMB), and MMR genes were analyzed. Overall survival (OS) estimated with Kaplan-Meier. Results: Of 776 pts with MSI-H GI cancers: 623 (80.3 %) NHW, 60 (7.7 %) Hispanic, 50 Asian (6.5 %), and 43 (5.5 %) NHB. CRC (76%), GEC (14%), other cancers (10%). We present initial evaluation of CRC and GEC: Median age, TMB, and most frequently altered MMR genes (MMR gene FA) are in table. Median OS (mOS) in NHW/URM by receipt of ICI in MSI-H CRC were 38.5m/25.3m (p 0.07) in no-ICI group, 34.2m/28.7m (p 0.64) in +ICI group; MSI-H GEC 43.4m/30m (p 0.44) in no-ICI group, 28.8m/26.7m in +ICI group. Conclusions: Number of URM MSI-H CRC/GEC pts is 7 to 15-fold less than NHW, with no such difference in % MSI-H/MSS between groups; reflecting significant undertesting in URM pts. In MSI-H CRC, median age (m-Age) at sequencing was younger in URM compared to NHW; pronounced in Asian and Hispanic patients, who were 10+ years younger than NHW. No such age difference seen in GEC. No difference in mOS detected between NHW and URM, however a non-significant trend towards worse mOS in URM was observed in the no-ICI group. Next steps include validation of clinico-genomics of MSI-H GI cancers in other large cohorts, including TEMPUS (N = 768) which is ongoing. [Table: see text]
Prognostic and predictive significance of pre- and post-operative plasma tumor markers in patients with appendiceal adenocarcinoma undergoing cytoreductive surgery: Insights from a single-center study.
Authors: Yousef Abdelrahman M.G. , Yousef Mahmoud M.G. , Zeineddine Mohammad A. A. , Ito Ichiaki , Chowdhury Saikat , Gu Yue , Knafl Mark , Jin Jeff , Edelkamp Paul , Uppal Abhineet , Bhutiani Neal , Alfaro-Munoz Kristin , Neus Bota-Rabassedas Neus , Helmink Beth A , White Michael , Taggart Melissa , Raghav Kanwal Pratap Singh , Overman Michael J. , Fournier Keith F. , Shen John Paul Y.C. 
Published: June 2023

3539 Background: Appendiceal adenocarcinomas (AA) are both rare and heterogeneous diseases. Cytoreductive (CRS) surgery followed by heated intraperitoneal chemotherapy (HIPEC) remains the best treatment for AA patients with peritoneal metastasis. This study seeks to investigate the clinical utility of pre- and post-operative plasma tumor markers (TM, CEA, CA19-9, CA-125) by association with survival outcomes. Methods: Under an approved IRB protocol the Palantir Foundry software system was used to query MD Anderson internal database to identify patients with AA who underwent CRS between 2016 to 2022. Elevation of TM was defined as above the laboratory upper limit of normal (CEA > 3 ng/mL, CA 19-9 > 37 U/mL, and CA-125 > 37 U/mL). Relationship between normal and elevated serum TM and progression-free survival (PFS) and overall survival (OS) was evaluated using univariate and multivariate Cox-proportional hazards regression analysis, considering multiple clinicopathologic variables. Results: 296 patients were identified; preoperative CEA, CA19-9 and CA125 was elevated in 60%, 29% and 28% of patients, respectively. Preoperative elevation of any TM was associated with higher PCI score (22 vs. 15, p< 0.0001). Moreover, elevated preoperative TM was associated with incompleteness of cytoreduction (OR = 6.5, p< 0.0001). Compared to preoperative measurements, all TM levels dropped after surgery (Mean score 31 vs 11 for CEA, 136 vs 32 for CA19-9 and 36 vs 17 for CA125). Preoperative elevation of any TM (HR = 1.5, p= 0.0288) and post-op elevation of any TM were with poor PFS on univariate analysis, however only post-op elevated TM levels (HR = 2.3, p= 0.0001) were associated with poor PFS on multivariate analysis. Interestingly, elevated TM was not associated with OS. Post-op TM levels were analyzed to evaluate the positive and negative predictive value in prediction of relapse in 6 months from surgery, PPV was 45% and NPV was 84%. Conclusions: Preoperative elevation of TM can identify patients at higher risk for incomplete cytoreduction and relapse after surgery. Postoperative elevation of TM is a risk factor for relapse. [Table: see text]
Artificial intelligence–derived immune phenotypes for prediction of prognosis in patients with stage III colon cancer (NCCTG N0147; Alliance).
Authors: Saberzadeh Ardestani Bahar , Nelson Garth D. , Segovia Diana I , Lim Yoojoo , Yan Dongyao , Shanmugam Kandavel , Alberts Steven R , Park Gahee , Shi Qian , Ock Chan-Young , Sinicrope Frank A. 
Published: June 2023

3542 Background: Solid tumors can be characterized by distinct immune phenotypes based on the level of T cell infiltration in the tumor microenvironment (TME) which may provide prognostic information and also inform strategies to restore the anti-tumor immune response. Immune phenotypes were determined using an artificial intelligence (AI) algorithm in digitized whole-slide images (WSI) of tumors with deficient (d) mismatch repair (MMR) vs proficient (p) MMR. Methods: Stage III colon carcinomas (N = 401; 393 met QC) from participants in a phase III trial of FOLFOX-based adjuvant chemotherapy were analyzed including all available tumors with dMMR (n = 196) and a randomly selected cohort of pMMR tumors (n = 195). Using an AI algorithm (Lunit SCOPE) previously trained on solid tumors, digitized tumors were categorized into three immune phenotypes based on epithelial and stromal TIL data-driven cutpoints in dMMR and pMMR (inflamed: TIL high in epithelium (> upper 25%); excluded: TIL high in stroma (>lower 25%), low in epithelium; and desert: TIL low in epithelium and stroma). Phenotypes were then examined in relationship to disease-free survival (DFS) using Kaplan-Meier methodology. Results: Of the 3 immune phenotypes in dMMR tumors, 25% were inflamed, 50% were immune-excluded, and 25% were immune-desert. Based on univariate results, multivariable modeling was performed incorporating immune phenotype in addition to age, histological grade, N stage, T stage, performance status, treatment arm, BRAF and KRAS status and identified immune phenotypes and N stage to be significantly associated with DFS. Among dMMR tumors, immune desert phenotype was associated with the poorest DFS (Desert: HR adj 1.95, 95%CI (1.01, 3.80); Excluded: HR adj 0.89, 95%CI (0.47, 1.69); Inflamed: ref; p:0.01). When compared to immune desert tumors, immune-excluded tumors had significantly better DFS (HR adj 0.49, 95%CI (0.27, 0.88), p:0.01). At a median follow-up of 60 months, 3-year DFS of patients with dMMR was 71.2% with Immune inflamed, 78.5% with Excluded, and 54.5% with Desert phenotypes. In contrast to dMMR, univariate analyses of data-driven cutpoints in pMMR tumors was not prognostic. Using a different data-driven cutpoint (15%), the revised immune phenotypes remained non-significant for DFS within pMMR tumors. Conclusions: Distinct AI-derived immune phenotypes in the TME were identified that were significantly prognostic in patients with dMMR, but not pMMR colon cancers. A data-driven immune-desert phenotype was identified in dMMR tumors that was associated with significantly poorer survival. Further investigation of the potential predictive utility of these phenotypes for immunotherapy are planned. Support: https://acknowledgments.alliancefound.org . ClinicalTrials.gov Identifier: NCT00079274 .
A deep learning model for the prediction of microsatellite instability and pathogenic POLE mutations in colorectal cancer using histopathologic images.
Authors: Xu Ting , Yu Jinze , Tan Luxin , Wang Zhenghang , Li Jian , Dong Siyao , Zhou Haoyi , Shen Lin , Li Zhongwu , Li Jianxin , Wang Xicheng 
Published: June 2023

3543 Background: Immunotherapy has brought about a landmark change in anti-tumor treatment in the past years. High microsatellite instability (MSI-H) is now the only clinically approved biomarker predicting response to immunotherapy in CRC. Increasing evidence suggests that POLE mutations in the exonuclease domain could drive an ultra-mutational phenotype and improve the treatment outcomes of ICI in solid tumors. In this study, we set out to apply a deep learning model using H&E-stained, formalin-fixed, paraffin-embedded (FFPE) whole slide images (WSIs) of CRC primary tumors. Methods: The deep learning model is developed and validated through five-fold cross-validation using WSI of primary tumors from 506 CRC patients and externally validated using 52 WSIs from a prospective cohort. The microsatellite status, tumor mutation burden (TMB) and POLE genotype were determined by next-generation sequencing (NGS). Patients with MSS status and a low TMB (＜20Mutations/Mb) were admitted to the MSS group, and CRCs with a POLE mutation which was defined as an oncogenic mutation referring to the POLE functional mutation list at OncoKB( POLE (oncokb.org) were admitted to the POLE mutant group. Clustering-constrained-attention multiple-instance learning (CLAM) model is employed as the base model, and we conduct the model ensemble by performing a large-scale hyper-parameter search, selecting five models with the highest value in one of the performance metrics, including the AURoC, accuracy, precision, recall, and f1 score, and finally averaging the predictions of the five models. Results: The internal dataset included 237 MSS, 142 MSI-H, and 127 POLE mutant CRC. The three groups had significant differences in primary location (p ＜ 0.0001), histology (p ＜ 0.0001), tumor differentiation (p = 0.002), tumor stage (p ＜ 0.0001), Crohn's-like reaction (p ＜ 0.0001) and tumor growth pattern (p = 0.001). The cross-validation performance of the ensemble model (M E) in the internal dataset achieves an AURoC of 0.944 for three-way classification task (POLE vs. MSI-H vs. MSS) and 0.940 for two-way classification task (POLE & MSI-H vs. MSS) which were superior to the performance of each single CLAM model. To demonstrate the generalizability of the deep learning model, a domestic perspective cohort consisting of 20 MSS, 17 MSI-H, and 15 POLE mutant CRC H&E images were used to validate the external performance. And the M E retained robust performance on the external dataset, with an AURoC of 0.904 for three-way classification task and 0.836 for two-way classification task. Conclusions: A CLAM-based deep learning model could directly predict the MSI-H and POLE mutation from histological images that could be used to stratify CRC patients for immunotherapy with faster turnaround time and lower costs compared with traditional sequencing methods.
Plasma arginine as a candidate predictive biomarker for response to immune checkpoint inhibition (ICI) in metastatic colorectal cancer (mCRC): Analysis of the CCTG CO.26 trial.
Authors: Ma Lucy Xiaolu , Loree Jonathan M. , Jonker Derek J. , Kennecke Hagen Fritz , Berry Scott R. , Couture Felix , Ahmad Chaudhary E. , Goffin John R. , Kavan Petr , Harb Mohammed , Colwell Bruce , Samimi Setareh , Samson Benoit , Abbas Tahir , Aucoin Nathalie , Aubin Francine , Koski Sheryl L. , Tu Dongsheng , O'Callaghan Christopher J. , Chen Eric X 
Published: June 2023

3545 Background: Nutritional stress is one of the mechanisms used by tumour cells to evade the immune system. Arginine (ARG), an amino acid involved in several cellular functions including immunomodulation, is important in regulating T-lymphocyte cell activity and the anti-tumour response. ARG deficiency in the tumour microenvironment has been shown to impair T-cell response while ARG supplementation may promote anti-tumour immune activity. In this exploratory post-hoc analysis of the Phase II CO.26 trial (NCT02870920), we investigated the role of plasma ARG in predicting response to ICI in patients (pts) with refractory mCRC. Methods: CO.26 was a phase II trial which randomized pts with refractory mCRC to durvalumab plus tremelimumab (D+T) versus best supportive care (BSC). Plasma ARG concentrations were determined from blood samples pre-treatment using HPLC-tandem mass spectrometry. The median plasma ARG value was used as a cut-off stratifying pts into ARG-high (≥10650 ng/ml) versus ARG-low ( < 10650 ng/ml) groups. Progression-free (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method and compared between groups using the log-rank test. Cox proportional hazard models were used to analyze prognostic and predictive impacts of ARG on PFS and OS. Results: Of 180 pts enrolled in CO.26, 162 pts (N = 115 treated with D+T and 47 BSC) had pre-treatment blood samples for baseline ARG analysis. There were no significant differences in baseline characteristics between pts included in this analysis and the total study pts, or between ARG-high and ARG-low pts. In pts treated with D+T, ARG-high was associated with more favourable prognosis (ARG-high median OS 7.62 months vs. ARG-low 5.49 months, multivariable hazard ratio [HR] 0.60, 95% confidence interval [CI] 0.40-0.91, p = 0.016). In ARG-high pts, D+T significantly improved OS (median OS 7.62 months with D+T vs 3.61 months BSC; HR 0.61, 95% CI 0.37-0.99, p = 0.04). In ARG-low pts there was no OS benefit with D+T (median OS 5.49 months D+T vs 4.27 months BSC; HR 0.84, 95% CI 0.50-1.41, p = 0.51. Interaction p = 0.037). Baseline ARG values had no association with PFS or disease control rate. Conclusions: Baseline plasma ARG was prognostic in pts with mCRC treated with D+T, and high ARG was predictive of improved OS with ICI. Prospective studies should be done to validate ARG as a biomarker identifying mCRC pts likely to derive benefit from ICI. Therapeutic approaches targeting the ARG pathway should be investigated in future studies.
A prospective study of FOLFIRI plus aflibercept as second-line treatment after failure of FOLFOXIRI plus bevacizumab in patients with unresectable/metastatic colorectal cancer (CRC): EFFORT study.
Authors: Satake Hironaga , Ando Koji , Yasui Hisateru , Negoro Yuji , Kinjo Tatsuya , Yuge Koutarou , Baba Kenji , Orita Hiroyuki , Hirata Keiji , Shimokawa Mototsugu , Makiyama Akitaka , Saeki Hiroshi , Oki Eiji , Baba Hideo 
Published: June 2023

3549 Background: FOLFOXIRI plus bevacizumab (BEV) is a first-line treatment option for patients with unresectable or metastatic CRC. However, there are no clear recommendations for second-line therapy after failure of FOLFOXIRI plus BEV. The EFFORT study investigated whether FOLFIRI plus aflibercept is active following FOLFOXIRI plus BEV in unresectable/metastatic CRC. Methods: EFFORT was an open-label, multicenter, single arm phase II study. Patients with unresectable/metastatic CRC who failed FOLFOXIRI plus BEV as a first-line therapy received aflibercept plus FOLFIRI (aflibercept 4 mg/kg, irinotecan 150 mg/m2 IV over 90 min, with levofolinate 200 mg/m2 IV over 2 hours, followed by fluorouracil 400 mg/m2 bolus and fluorouracil 2400 mg/m2 continuous infusion over 46 hours) every 2 weeks on day 1 of each cycle. The primary endpoint was progression-free survival (PFS) in the full analysis set (FAS). To achieve 80% power to show a significant benefit with a one-sided alpha level of 0.10, assuming a threshold PFS of 3 months and an expected value of at least 5.4 months, 32 patients needed to be enrolled. Major secondary endpoints included overall survival (OS), overall response rate (ORR) and safety. Results: From April 2019 to May 2021, 35 patients were enrolled and FAS included 34 patients (one patient who did not met eligibility criteria was excluded). Of them, 18 were males, median age was 63 years (range: 32-78) and ECOG Performance Status was either 0 (n = 28) or 1 (n = 6). The primary tumor was left-sided in most patients (23/34) and 27 patients had liver metastases. And 23 patients had RAS mutation. The primary endpoint was met with a median PFS of 4.3 months [80% CI: 3.7-5.1]. The median OS was 15.2 months [95% CI: 8.9-22.7]. Objective tumor responses were CR (n = 1), PR (n = 4), SD (n = 21) or PD (n = 8). ORR was 14.7% (5/34) [95% CI: 5.0-31.1], and disease control rate was 76.5% (26/34) [95% CI: 58.8–89.3]. Main grade 3 or 4 adverse events were neutropenia (7/35, 20.0%), thrombopenia (3/35, 8.6%), leucopenia (2/35, 5.7%), and hypertension (3/35, 8.6%). No severe proteinuria and no treatment-related death were reported. Conclusions: Aflibercept plus FOLFIRI given after failure of FOLFOXIRI plus BEV is active and shows a manageable safety profile. This regimen maybe a useful as second-line treatment option in such patients. Clinical trial information: jRCTs071190003 .