bluuebunny/crossref_metadata_2025 huggingface dataset:
GATA6 expression in advanced pancreatic ductal adenocarcinoma (PDAC) as a prognostic and predictive biomarker in the Canadian COMPASS trial and the Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS.
Authors: Mc Laughlin Ronan Andrew , Salvatore Lisa , Barone Diletta , Deng Yangqing , Notta Faiyaz , Jang Gun Ho , Alfieri Sergio , Quero Giuseppe , Piro Geny , Carbone Carmine , Chiaravalli Marta , Bensi Maria , Bagalà Cinzia , Hutchinson Shawn , Dodd Anna , Fischer Sandra , Gallinger Steven , Knox Jennifer J. , Tortora Giampaolo , O'Kane Grainne M.
Published: June 2024

4150

Background: Modified FOLFIRINOX (mFFX) and gemcitabine + nab-paclitaxel (GnP) are current 1st line options in advanced PDAC. GATA6 expression, a transcription factor identifies the classical phenotype and is associated with superior overall survival (OS), low GATA6 predicts a basal-like phenotype, associated with a poorer prognosis. We have previously established high concordance between GATA6 expression by RNAseq and in situ hybridization (ISH). Recent studies suggest a survival difference between primary tumor anatomical locations, it is unknown if GATA6 expression influences this. This multicentre study evaluates GATA6 as a prognostic and predictive biomarker and determines its impact on primary tumor location. Methods: Patients were included from COMPASS and a retrospective IRCCS cohort. COMPASS participants had GATA6 by RNAseq and IRCCS cohort by ISH, all treated in 1st line metastatic setting with mFFX or GnP. The primary endpoint was OS by GATA6 expression and by 1st line treatment. We investigate if there are OS differences between primary tumor anatomical locations. The Kaplan Meier method was used to assess OS. The log-rank test was used to examine whether there is a significant difference between the OS in different groups. GATA6 as a predictive biomarker to response to therapy was assessed by the interaction term for GATA6 and treatment group in a Cox proportional hazards model. Results: The combined analysis included 465 pts (253 COMPASS and 212 IRCCS). Baseline characteristics were similar. The combined median age was 64 yrs (28, 84); 402 (86%) had metastatic PDAC and 63 (14%) locally advanced. 56 (12%) had prior surgery, 40 (9%) had prior adjuvant therapy. In total, 296 (64%) and 169 (36%) were GATA6 high and low respectively. OS in months (m) analyses by GATA6 expression are summarized (Table). We demonstrate no difference between OS based on primary tumor location (p=0.09), however, regardless of location, GATA6 high tumors show statistically significant better OS. We confirm, by interaction term, GATA6 as a predictive biomarker, with GATA6 high predictive of response to mFFX while low expression demonstrates less benefit with mFFX (p=0.003). Conclusions: GATA6 is a highly prognostic biomarker. We did not find an association with tumor location, which also was not prognostic in this study. Importantly GATA6 was predictive of survival in patients receiving mFFX, suggesting GATA6 low tumors should receive 1st line GnP based regimens. Clinical trial information: NCT02750657 . [Table: see text]
Serial circulating tumor DNA monitoring for predicting treatment response and prognosis in patients with pancreatic cancer.
Authors: Lee Jongchan , Ahn Jinwoo , Jung Kwangrok , Lee Jong-chan , Youn Yuna , Hwang Jin-Hyeok
Published: June 2024

4154

Background: Circulating tumor DNA (ctDNA) is considered an effective indicator for real-time monitoring of therapeutic efficacy and prognosis prediction in various malignant tumors. We conducted a study to investigate whether serial ctDNA monitoring can predict recurrence, disease progression, and prognosis in pancreatic cancer. Methods: A total of 231 with pancreatic cancer were prospectively enrolled. Among them, 167 patients (52 in the resection group, 115 in the palliative treatment group) were assessable for serial ctDNA at scheduled intervals (total ctDNA evaluations: 614). CtDNAs were analyzed using individualized droplet digital PCR to measure the mutant allele fraction of KRAS G12/13 screening multiplex Kit, with the results reported as variant allele fraction (VAF). The percent changes of ctDNA (Δ ctDNA) were correlated with radiologic response at each evaluation. Associations between ctDNA and recurrence-free survival (RFS), progression-free survival (PFS), and overall survival (OS) were evaluated. Results: CtDNAs were detected in 143 of 167 eligible patients (85.6%). The detection rate increased with the advancing stage ( P= 0.016) and varied based on the metastatic site (liver: 98.0% vs. peritoneum, 88.9%; P= 0.011). In the resection group, there was no significant difference in Δ ctDNA regarding recurrence, nor were there statistically significant difference in terms of RFS and OS based on postoperative ctDNA detection. Conversely, in the palliative treatment group, patients with progressive disease (PD) exhibited significantly higher Δ ctDNA compared to those with stable disease (SD) or partial response (PR) ( P< 0.001). Patients whose Δ ctDNA increased before radiologically PD had their Δ ctDNA levels increased an average of 2.53 months earlier. Notably, higher ctDNA were linked to shorter PFS (HR 1.84; 95% CI 1.07 to 3.18, P = 0.03) and OS (HR 2.15; 95% CI 1.20 to 3.86, P = 0.01) in metastatic patients. Patients who achieved ctDNA clearance at 8 weeks demonstrated more favorable outcomes in terms of PFS (HR 0.53; 95% CI 0.30 to 0.92, P = 0.02) and OS (HR 0.50; 95% CI 0.28 to 0.90, P = 0.02). Similar benefits were observed for those who experienced at least one ctDNA clearance (PFS, HR 0.27; 95% CI 0.16 to 0.44, P < 0.001; OS, HR 0.31; 95% CI 0.19 to 0.50, P < 0.001). Conclusions: Our findings suggest that serial ctDNA monitoring holds promise in predicting treatment response and prognosis for unresectable pancreatic cancer patients.
Post-progression therapies and outcomes for patients with advanced, BRCA-related pancreatic cancer after receipt of PARP inhibitors: A national retrospective cohort study.
Authors: Jafry Baqir , Kazmi Syed Mohammad Ali , Al Mutar Salwan , Reiss Kim Anna , Brown Timothy J
Published: June 2024

4156

Background: Maintenance therapy with poly-ADP ribose polymerase (PARP) inhibitors (PARPi) can delay progression of advanced platinum-sensitive pancreatic cancer in patients with mutations in BRCA1, BRCA2or PALB2. However, there are limited data to guide treatment decisions and outcomes following progression with PARPi. Thus, we sought to compare outcomes of post-progression platinum and non-platinum therapies for patients with pancreatic cancer after receipt of PARPi using a nationwide cohort. Methods: This study used the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database. During the study period, the de-identified longitudinal patient-level data originated from approximately 280 cancer clinics. Patients were eligible for inclusion if they received maintenance olaparib for advanced pancreatic cancer and subsequently received post-progression chemotherapy. Post-progression chemotherapy was characterized as platinum (P) or non-platinum (NP). Demographics, tumor stage, and lab values were compared using the Chi-squared test or Mann Whitney U test. Overall survival (OS) and time to treatment discontinuation (TTD) were evaluated using the Kaplan Meier method with an index date of initiation of post-progression therapy. Given the limited anticipated sample size, no formal comparisons were made between treatment groups. Cox proportional hazards models were constructed to identify associations between baseline clinical factors and outcomes. Results: Of 11,179 patients were included in the database, 26 met inclusion criteria for this analysis after progressing on olaparib and subsequently receiving post-progression chemotherapy. Most patients were white (81%) and non-Hispanic (77%). Twelve (46%) received post-progression P, while 14 (54%) received post progression NP. No significant differences were noted in baseline characteristics between groups. Among patients on P, the most common regimens were gemcitabine and cisplatin (50% n=6), FOLFIRINOX (17%, n=2), and FOLFOX (17%, n=2). Of those on NP, the most common regimens were gemcitabine and nab-paclitaxel (50%, n=7) and FOLFIRI (29%, n=4). The median OS for post progression therapies was 4.8 months for P and 4.1 months for NP group. The median TTD for these post progression therapies was 0.9 months for P and 1.5 months for NP. No baseline clinical factors were associated with time-to-event in Cox regression analyses. Conclusions: In this analysis, patients who progressed on olaparib rapidly progressed on post-progression P and NP and had limited survival. Further work will be needed to identify mechanisms of resistance to PARPi and to optimize post-progression treatments. This work adds to a growing body of literature supporting an individualized approach to post-progression therapy decisions for these patients.
Molecular landscape and site of metastasis in PDAC.
Authors: Rahman Shafia , Baca Yasmine , Singh Harshabad , Xiu Joanne , Mallick Atrayee B , Rubinstein Mark P. , Aguirre Andrew , George W. Jr.  , Pishvaian Michael J.
Published: June 2024

4159

Background: More than 50% of patients with Pancreatic ductal adenocarcinoma (PDAC) have metastatic disease at the time of diagnosis and liver is the most common site of metastatic spread. Liver metastasis (LM) is associated with poor prognosis. Herein we examine the difference in molecular landscape of PDACs with LM versus other metastatic sites (OM). Methods: Total of 7,979 PDAC tumors underwent next-generation sequencing of DNA (592-gene/whole exome) and RNA (whole transcriptome) at Caris Life Sciences (Phoenix, AZ). Tumors were then evaluated and divided into LM (N=4988) site vs OM (N=3073) sites based on tissue specimen sites. RNA expression data was used to analyze transcriptional signatures as well as tumor immune microenvironment (TME) using Quantiseq. Real-world overall survival (rwOS) information was obtained from insurance claims data and calculated from time of collection or first treatment to last contact. Hazard ratio (HR) was calculated using Cox proportional hazards model, and P values were calculated using log-rank test.Significance for molecular comparisons was calculated using either chi-square, Fisher’s exact, or Mann-Whitney U test, with p-values adjusted for multiple comparisons (q<0.05). Results: Mutations in TP53 (81% vs 67%), KRAS (88% vs 83%), ARID1A (13% vs 11%), KDM6A (4% vs 3%), and BRCA1 (1.3% vs 0.7%) were all significantly higher in LM vs OM (all <0.05). Conversely, TMB-H (3% vs 4%), MSI-H (0.7% vs 1.3%), GNAS (1% vs 3%), STK11 (1% vs 3%), ATM (3% vs 5%), PTPRD (2% vs 9%) and RNF43 (5% vs 6%) mutations were significantly lower in LM vs OM (all q<0.05). In the TME, B cells, Tregs, M1, M2 macrophages, and NK cell infiltration was lower in LM vs OM (FC: 0.62-0.91, q<0.05). However, LM had higher neutrophil infiltration vs OM (FC: 1.1, q<0.05). Both interferon-gamma score (IFG) and T cell inflamed score (TIS) were significantly higher in OM vs LM (q<0.05). OM had better OS than LM (11.4 m vs 6.8 m, HR=0.65 95% CI: 0.62-0.68, p<0.001). This association held for tumors treated with Immune Checkpoint Inhibitors (ICI) (9.6 m vs 4.6 m, HR=0.71 95% CI: 0.52-0.97, p=0.031), Gemcitabine/Nab-paclitaxel treated (15.3 m vs 8.1 m, HR=0.57 95% CI: 0.52-0.61, p<0.001) as well as mFOLFIRINOX treated tumors (20.3 m vs 12.0 m, HR=0.57 95% CI: 0.52-0.63, p<0.001). Conclusions: When comparing pancreatic LM to OM sites, our data reinforces the observation that OS is better in OM vs LM and response to ICI was better in OM vs. LM. Significant differences were observed in molecular landscape, TME and signatures that are predictive of immunotherapy response (TIS and IFG scores). [Table: see text]
Perioperative fuzuloparib plus mFOLFIRINOX for resectable pancreatic adenocarcinoma: A phase 1 study.
Authors: Zhan Qian , Wen Chenlei , Zou Siyi , Li Fanlu , Chen Dongjie , Sheng Zhen , Yu Zhixin , Gao Denghui , Shen Baiyong
Published: June 2024

4163

Background: Surgical resection followed by adjuvant mFOLFIRINOX is currently the standard of care for resectable pancreatic adenocarcinoma. Neoadjuvant therapy has the potential to induce tumor downsizing and improve R0 resection rate. In this study, we aimed to explore the feasibility of the PARP inhibitor fuzuloparib in combination with mFOLFIRINOX as the neoadjuvant and adjuvant therapy in patients (pts) with resectable pancreatic adenocarcinoma. Methods: This was a dose escalation and expansion phase 1 study in pts with histologically or cytologically confirmed, high-risk resectable or borderline resectable pancreatic adenocarcinoma. Eligible pts received perioperative treatment with fuzuloparib plus mFOLFIRINOX (up to 12 cycles of 14 days each, with 4 to 6 cycles administered preoperatively; fuzuloparib at escalating doses starting at 30 mg BID), followed by maintenance fuzuloparib at 150 mg BID. Dose-limiting toxicities (DLTs) were observed during the first 2 treatment cycles. The primary objectives were safety and tolerability. Results: As of Oct 31, 2023, 15 pts were enrolled, including 3 pts in the fuzuloparib 30 mg cohort and 12 pts in the 60 mg cohort. Twelve (80.0%) pts completed neoadjuvant therapy as planned. Eight (53.3%) pts underwent surgical resection, and all pts achieved R0 resections (100.0%; 95% CI, 63.1–100.0). Four of the 8 (50.0%) pts proceeded to adjuvant therapy (30 mg cohort: 0/2 [0%]; 60 mg cohort: 4/6 [66.7%]). There were no DLTs identified. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 12 (80.0%) pts, with the most common being decreased neutrophil count, decreased white blood cell count, hypokalemia, and anemia. No unexpected TRAEs were reported. No patients discontinued study treatment due to TRAEs. Conclusions: Perioperative fuzuloparib plus mFOLFIRINOX was generally tolerated and had acceptable safety profile in pts withresectable pancreatic adenocarcinoma. Neoadjuvant fuzuloparib plus mFOLFIRINOX prior to surgery achieved a R0 resection rate of 100%. Clinical trial information: NCT04425876 .
Does non-alcoholic fatty liver disease increase the risk for pancreatic cancer? A multi-center retrospective cohort study.
Authors: Singh Rituraj Raj , O'Reilly Eileen M.
Published: June 2024

4165

Background: Recent studies suggest that patients with non-alcoholic fatty liver disease (NAFLD) are at increased risk of hepatic and extra-hepatic gastrointestinal cancers. However, there is limited data exploring the risk of pancreatic cancer (PC) in patients with NAFLD. We aim to investigate the risk of PC in patients with biopsy proven NAFLD. Methods: We performed a multicenter retrospective cohort study utilizing an electronic health record database (TriNetX) to study the risk of PC in patients with NAFLD. The study group comprised adults ≥40 years with NAFLD who had undergone liver biopsy between January 2016 to December 2019. Comparison group was obese individuals (body mass index ≥30 kg/m2) without NAFLD. We excluded patients with other etiologies of chronic liver disease. The median follow up was 5 years. Patients who had follow up visits 1-4 years were selected. The primary outcome was a new diagnosis of PC. Results: We identified 18,513 patients with NAFLD and had undergone liver biopsy, predominantly white (75.3%) females (59.7%). Diabetes mellitus (29.4% vs. 18.8%), chronic pancreatitis (1.3% vs. 0.2%), pancreatic cyst (0.8% vs. 0.2%), tobacco use (9.4% vs. 7.7%), and a family history of GI cancers (2.7% vs. 1.5%) were observed more commonly in the NAFLD group compared with the obese control. After propensity score matching for confounding variables, the 5-year risk of developing PC was higher in NAFLD cohort (risk ratio, RR 2.18, 95% CI 1.56-3.03) compared with the control group. Overall, 5-year mortality was higher in the NAFLD cohort (8.2% vs 6.6%, RR 1.25, 95% CI 1.16-1.37). Conclusions: NAFLD probably increases the risk of pancreatic cancer in middle-aged and elderly individuals and the risk exists despite controlling for obesity and other known risk factors for PC. NAFLD should be considered in the risk stratification strategy for pancreatic cancer. Moreover, patients with NAFLD and advanced fibrosis who undergo screening for hepatoma may be considered for abdominal CT or MRI for pancreatic cancer screening if other risk factors exist. [Table: see text]
Independent blinded validation of a novel blood-based early pancreatic cancer detection test.
Authors: Strasser Patrick Christian , Bijlsma Maarten F. , Le Large Tessa Y.S. , Kazemier Geert , Thumfart Norbert , Schneider Maximilian
Published: June 2024

4166

Background: Pancreatic ductal adenocarcinoma (PDAC) frequently presents at late stages, resulting in increased mortality. Early detection is crucial for enhancing survival rates; however, available screening methods are limited. This gap underscores the critical need for advancements in early PDAC detection. To address this, Wholomics developed a proprietary early detection assay, leveraging molecular signatures found in the blood, and has further validated its efficacy through a comprehensive blinded validation study. Methods: Wholomics conducted retrospective analysis of serum samples from the Amsterdam UMC Liquid Biopsy Center and the Bank of Biological Material of the Masaryk Memorial Cancer Institute. A training cohort included 290 control subjects, 12 patients with a confirmed diagnosis of chronic pancreatitis, and 71 patients with a histopathologically confirmed diagnosis of PDAC (20 stage I, 30 stage II, 13 stage III, 8 stage IV). A blinded validation cohort comprised samples from 20 control subjects, 24 patients with non-cancerous conditions (5 with benign tumors, 10 with IPMNs, 9 with chronic pancreatitis), and 60 patients with histologically confirmed PDAC. Peripheral blood samples of cancer patients were drawn before surgery or treatment. Wholomics used its proprietary NMR-based technology to quantitatively analyze serum samples. Disease-specific molecular signatures were identified and used to develop a computational biomarker specific to PDAC. A comparative analysis via 10-fold cross-validation and a blinded validation were conducted. The accuracy, specificity and sensitivity are reported. Results: In this study, a dual-cohort design, comprising both a training and a blinded validation cohort, was utilized to assess the capability of the Wholomics technology in detecting cancer-specific molecular signatures. In the training cohort, a 94.6% accuracy was achieved in distinguishing PDAC patients from non-cancer controls. A specificity of 95.7% and sensitivity of 90.7% were reached. A similar performance was observed in the blinded validation cohort, where the blood-based test accurately differentiated PDAC patients from controls with an accuracy of 92.5%. In more detail, a specificity of 95% (noting a single false positive) and a sensitivity of 91.7% were achieved. Conclusions: The collective findings of this research indicate that utilizing disease-specific molecular markers in peripheral blood offers a highly accurate method for differentiating between PDAC patients, healthy subjects, and those with pre-cancerous diseases. Should future studies across broader cohorts corroborate these results, this testing approach has potential for consideration as a screening mechanism for PDAC, aiming to facilitate early detection and consequently enhance patient prognoses.
Survival and prognosis of anus, anal canal and anorectal carcinoma: Analysis of National Surveillance, Epidemiology, and End Results database from 2000-2020.
Authors: Guragain Ashish , Inban Pugazhendi , Vaz Clint , Poudel Urusha , Cheriyath Pramil , Nookala Vinod , Kansakar Sajog , Shikhrakar Shreeja , Maroules Michael
Published: June 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 < 0.001), followed by age 60–79 (HR = 3.665, 95% CI: 3.303- 4.432, p < 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 < 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.
Efficacy and safety of nivolumab in pretreated patients with metastatic squamous cell carcinoma of anus: A real-world experience.
Authors: Conci Nicole , Rojas Llimpe Fabiola Lorena , Di Fabio Francesca , Di Odoardo Adriana , Danielli Linda , Seminerio Renata , Tortorella Carla , Guido Alessandra , Cuicchi Dajana , Laurenzi Andrea , Dalla Via Barbara , Tardio Maria Lucia , Rihawi Karim
Published: June 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 2nd or 3rd 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 2nd line treatment in 13 pts, while 2 pts received ICI in the 3rd 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 < 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]
Paradoxical association of B7H3 with clinical outcomes in patients with colorectal cancer.
Authors: Huang Yan , Qi Xiaohua , Acuna-villaorduna Ana , Gali Radhika , Maitra Radhashree , Lin Juan , Maia Catarina , Zhang Wei , Zhang Chenxin , Zang Xingxing , Liu Qiang , Goel Sanjay
Published: June 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.
Evaluating peripheral myeloid-derived suppressor cells as factor for the diagnosis and treatment efficiency of patients with colorectal cancer.
Authors: Zhou Cong , He Lina , Gu Yi , Shi Bisheng , Cheng Xiaojiao , Zhangyuan Ruohan , Shen Yuguang , Shen Wei , Wang Zheng , Tu Shuiping
Published: June 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< 0.0001), monocyte-MDSCs (Mo-MDSCs) (0.13 vs. 0.60, p< 0.0001) and polymorphonuclear-MDSCs (PMN-MDSCs) (0.87 vs. 7.32, p< 0.0001) were increased, while early-MDSCs (eMDSCs) were decreased (0.02 vs. 0.01, p< 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< 0.001; 15.09 vs. 3.31, p< 0.001) and PMN-MDSCs (13.21 vs. 2.14, p< 0.001; 13.78 vs. 2.22, p< 0.001). Conclusions: This study disclosed that peripheral MDSCs have important diagnostic value and clinical significance for CRC.
Mutational landscape and evolutionary pattern of peritoneal metastases in colorectal cancer.
Authors: Wang Yuzhuo , Xu Xianfeng , Zheng Jinyu , Xu Lu , Zhu Yuping , Xu Rui , Shen Yan , Xu Guifang , Zhu Weiyou , Fu Zan , Sun Jing
Published: June 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.
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: Kesley Rubens , Castro Leonaldson Dos Santos , Correa José Humberto Simões
Published: June 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.
Use of epigenetic inhibitor screen to identify HDAC1/2 inhibitor as a pro-differentiation therapy in colorectal cancer.
Authors: Likasitwatanakul Pornlada , Li Zhixin , Spisak Sandor , Doan Paul , Bala Pratyusha , Liow Priscilla , Papanastasiou Malvina , Qi Jun , Sethi Nilay S.
Published: June 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 ApcKO 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.
Development of a highly efficacious, first-in-class antibody-drug conjugate against a novel MUC1-C oncoprotein for metastatic colorectal cancer.
Authors: Raina Deepak , Panchamoorthy Govind , Ahmad Rehan , Jasuja Ravi , Kharbanda Surender
Published: June 2024

e15600

Background: Poor prognosis and mortality due to metastatic colorectal cancer (mCRC) remains a stiff challenge and the management of mCRC continues to be a significant unmet medical need. An aberrantly glycosylated Mucin 1 (MUC1) is overexpressed in > 80% of CRC and development of novel approaches for targeting of MUC1 are critically needed. MUC1 is a heterodimeric oncoprotein expressed on the cell surface and consists of two (MUC1-N and MUC1-C) terminal subunits. MUC1-N subunit is shed in the blood from cancer cells and MUC1-C subunit retains at the cell surface. Multiple attempts at targeting the MUC1-N terminal shed protein have been failed earlier due to all the MUC1-N binding antibodies bind to the shed domain in blood that act as a sink. Methods: We have generated a panel of novel, first-in-class antibodies against the extra cellular domain (ECD) of MUC1-C that remains intact on the cell surface. The development of antibody-drug conjugates (ADCs) has been a major advancement in the field of oncology as ADCs are the emerging class of anti-cancer drugs consisting of tumor targeting MAbs with highly cytotoxic payloads attached through cleavable chemical linkers. We present here making of MUC1-C (3D1)-MMAE as well as generation of MUC1-C (3D1 + 7B8)-biparatopic-MMAE with preclinical characterization. Results: We demonstrate that two MAbs, 3D1 and 7B8, bind to different epitopes (3D1 binding to a3 helix; 7B8 binding to a4 helix) in the MUC1-C-ECD with high affinity and more importantly, do not cross compete with each other. Reactivity of both MAbs is specific for MUC1 expressing human cancer cells as demonstrated by both knock-in and knock-out cell line models. Both antibodies have substantial internalization by 3 hours at 37oC. Both 3D1 and 7B8 were separately conjugated to monomethyl auristatin E (MMAE) with vc-PAB linkers. The results demonstrate that treatment of diverse mCRC cell lines, SW620, SK-CO-1 and HCT116/MUC1 with 3D1-MMAE or 7B8-MMAE is associated with substantial killing with low nM IC50. To further access in vivo efficacy of 3D1-MMAE, nude mice with established HCT-116/MUC1 tumor xenografts were treated with 7.5 mg/kg once a week x 3 weeks. Significant tumor growth inhibition was observed with 3D1-MMAE without any weight loss. A bi-paratopic antibody can bind to the same antigen either on same cell or at two different cells and thereby will increase internalization substantially. Since MAbs 7B8 and 3D1 do not cross compete with each other for binding to MUC1-C-ECD, we are developing 3D1-7B8 bi-paratopic-MMAE for increasing the efficacy further. Studies are underway to test 3D1-7B8 bi-paratopic-MMAE for activity in vitro and in vivo. Conclusions: MUC1-C-ADC has demonstrated a favorable toxicity profile and potent anti-tumor activities in the mCRC. Together, these results suggest advancing the anti-MUC1-C-MMAE ADCs as a novel therapeutic for mCRC.
FOLFOX-based hepatic arterial infusion chemotherapy combined with regorafenib for unresectable colorectal liver metastases.
Authors: Song Songlin , Liu Jiacheng , Ren Yanqiao , Zheng Chuansheng , Liang Bing
Published: June 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/m2 for 2 h on day 1), calcium folinate (200 mg/m2 for 2 h on day 1), and 5-fluorouracil (5-Fu) administered as a bolus of 400 mg/m2 on day 1, followed by 2400 mg/m2 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 > 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]
Randomized study to assess colonic microbiome changes in response to energy drink consumption (ROSANNA trial).
Authors: Jang Tim , Kahramangil Doga , Lee Ji-Hyun , Kim George P. , Rogers Sherise C. , Sahin Ilyas , Ramnaraign Brian Hemendra , Terracina Krista P. , Nordenstam Johan , Read Thomas , Thomas Ryan M. , Yang Ye , Jobin Christian , George Thomas J.
Published: June 2024

TPS3630

Background: Colorectal cancer (CRC), the second leading cause of cancer deaths in the US, is increasingly diagnosed in individuals under 50. This rise in early-onset CRC (eoCRC) led the U.S. Preventative Services Task Force to recommend a reduction in the age to begin colorectal cancer screening in average-risk persons, from 50 to 45. The etiology of eoCRC is multifaceted, with one postulated theory pointing to alterations in the young adult colonic microbiome. Hydrogen sulfide (H2S) producing bacteria, like Bilophila wadsworthia, Fusobacterium nucleatum and Atopobium parvulum, are typically minor gut microbiota components but are overrepresented in CRC cases, linked to inflammation, and may promote a pro-carcinogenic environment. These bacteria preferentially use taurine, an essential amino acid, as a primary energy source. Energy drinks represent one of the largest dietary sources (6-16x normal daily intake) of taurine in contemporary diets. Our hypothesis is that high taurine levels in energy drinks could exacerbate CRC risk by promoting preferential growth and metabolic activities of already present H2S-producing bacteria, contributing to the rise of eoCRC. Methods: This randomized open-label trial is actively enrolling up to 60 young adults (18-40 years) without personal or family history of CRC, other major GI disease/distress, and baseline infrequent energy drink consumption. Group 1 (Arm A; n=30), will consist of subjects consuming at least one of two protocol-specified energy drinks daily for 4 weeks. Group 2 (Arm B; n=30), will consist of usual dietary intake. Enrollments are randomized 1:1 and stratified, by gender, age (18-25 vs. 26-40), and baseline energy drink consumption (rare/none vs. 1-2 per week). Every subject will complete: 1) a daily dietary and fitness log, 2) a weekly wellness log, 3) collection of stool/saliva/skin/urine at 3 sequential time points (baseline, after 2 weeks, after 4 weeks), and 4) blood collection at the same time points. The primary endpoint is the change in H2S-metabolizing bacterial communities between baseline and 1 month of energy drink exposure within Arm A and also compared to those in Arm B using microbiome analysis (diversity, taxonomy, sulfur-enriched gene pathways). Several secondary and exploratory assessments include changes related to subject demographic and dietary differences, concordance of microbiome changes with dietary logs and in other biospecimens beyond stool, H2S-production measurements, and analyses of subject metabolic and immune function. Trial opened in February 2024 with active enrollment ongoing. Updated data on trial status and any amendment modifications will be presented at the meeting. Clinical trial information: NCT06137248 .
Huxley's Karma and Lu Xun's Ghosts
Authors: Ying Lei
Published: June 2024

This article questions the secularist assumption in the received narrative of Chinese modernity by uncovering the religious ideas and imaginations that have since the outset mediated and shaped the Chinese discovery of evolutionary science, a massive phenomenon that has conventionally been understood in a scientistic and secularistic light. Adopting an interdisciplinary approach, this article revisits Tianyan lun—the Chinese translation of Thomas Henry Huxley's Evolution and Ethics and the single most influential book in initiating late-Qing intellectuals into social Darwinism—as a site for Buddhist global exchange and translingual practice, when the notion of “karma” offered Huxley and his Chinese translator and readers at once a ground of convergence and a point of departure. To Lu Xun and his brother Zhou Zuoren, from a hereditary perspective, karma has assumed the other name of history, while evolution unfolded in perpetual entanglements of humans and ghosts under a samsaric temporal scheme. Lu Xun's obsession with the netherworld has fostered, on the one hand, a deep pessimism about human developmental agency and the promise of the revolution and, on the other hand, an existential courage to confront the “realm of darkness.”