bluuebunny/crossref_metadata_2025_split huggingface dataset:
Penpulimab combined with anlotinib and nab-paclitaxel plus gemcitabine (PAAG) as first-line treatment for metastatic pancreatic cancer: A prospective, multicenter, single-arm, phase 2 study.
Authors: Du Juan , Tong Fan , Sha Hui-zi , Sun Yi , Zhu Yahui , Qi Liang , Li Xiaoqin , Li Wei , Yang Yan , Li Zeqing , Xu Caihua , Ni Jiayao , Gu Qing , Zhang Xing , Zhu Chan , Wang Xiaoxuan , Liu Baorui 
Published: June 2024

4135 Background: Chemotherapy currently serves as the cornerstone for treating metastatic pancreatic cancer (mPC). Nevertheless, the survival of patients with mPC remains poor. Besides, the efficacy of single-agent immune checkpoint inhibitors or antiangiogenesis in the treatment of mPC is not satisfying. Therefore, it is important to explore combination therapy options for patients with mPC. This trial was conducted to evaluate the effectiveness and safety of penpulimab combined with anlotinib and nab-paclitaxel plus gemcitabine (PAAG) for mPC. Methods: This was a prospective, multicenter, single-arm phase II trial. Eligible pts were those who aged over 18 years, histologically or cytologically confirmed PC, have not received treatment before and radiographically showed distant metastases and measurable lesions. Patients received penpulimab (200mg, IV, D1) and Anlotinib (12mg, P.O, QD, D1-14), in addition to nab-paclitaxel (125mg/m2, I.V, D1,8) and gemcitabine (1.0g/m2, I.V, D1,8), administered over a 21-day treatment cycle. The primary endpoint was objective response rate (ORR) and disease control rate (DCR). Secondary end points included Progression-free Survival (PFS), overall survival (OS) and safety. Immune microenvironmental features of baseline were analyzed as exploratory results (NCT05493995). Results: 66 pts were enrolled and received PAAG therapy, and the last follow-up time was December 31, 2023. All pts were eligible for response evaluation. The ORR was recorded at 50% (33/66) (95% CI, 37.4%-62.6%), with 33 pts achieving partial response. The DCR was 95.5% (63/66) (95% CI, 87.3%-99.1%). With median follow-up duration of 12.8 months, median PFS was 8.8 months (95% CI, 8.1–11.3) and median OS was 13.7 months (95% CI, 12.4-not reached). The most common TRAEs were anaemia, leukocytopenia, fatigue and rash. Grade 3 TRAEs were reported in 36.4% pts (24/66). In exploratory analysis, higher T cell recruiting score and lower baseline serum CA72-4 level were detected in PR pts compared with SD/PD pts. Furthermore, the B cell, NK CD56dim cell and Th9 cell scores were up-regulated in PFS-long pts. Conclusions: PAAG regimen as first-line treatment was demonstrated to be tolerable, with promising anti-tumor activity in mPC. The identified biomolecular markers revealed potential to guide precision treatment of PAAG for mPC. Clinical trial information: NCT05493995 .
NALIRIFOX versus nab-paclitaxel and gemcitabine in treatment-naïve patients with metastatic pancreatic ductal adenocarcinoma (mPDAC): Updated overall survival analysis with 29-month follow-up of NAPOLI 3.
Authors: Hussein Maen A. , Khan Gazala , Chandana Sreenivasa R , Pazo Cid Roberto A. , Kiss Igor , Gallego Javier , Macarulla Teresa , De La Fouchardiere Christelle , Goetze Thorsten , Dean Andrew Peter , O'Reilly Eileen M. , Wainberg Zev A. , Lee Woo Jin , Van Cutsem Eric , Hubner Richard , Paulson Andrew Scott , Bekaii-Saab Tanios S. , Pant Shubham , Maxwell Fiona , Melisi Davide 
Published: June 2024

4136 Background: NAPOLI 3 (NCT04083235, N = 770), a global, randomized, open-label phase 3 study, demonstrated that NALIRIFOX significantly improved overall survival (OS, primary endpoint) and progression-free survival compared with nab-paclitaxel and gemcitabine in patients with untreated mPDAC. Here, we report an updated analysis of OS. Methods: Eligible patients with histopathologically/cytologically confirmed untreated mPDAC were randomized (1:1) to receive liposomal irinotecan 50 mg/m2 + oxaliplatin 60 mg/m2 + leucovorin 400 mg/m2 + 5-fluorouracil 2400 mg/m2 (NALIRIFOX, n = 383) on days 1 and 15 of a 28-day cycle or nab-paclitaxel 125 mg/m2 and gemcitabine 1000 mg/m2 (Gem+NabP, n = 387) on days 1, 8 and 15 of a 28-day cycle. Randomization was stratified by ECOG performance status, geographic region and presence/absence of liver metastases. An updated OS analysis (data cutoff: 3 October 2023) was conducted. Kaplan–Meier methods were used to estimate median (95% confidence interval [CI]) OS and hazard ratios (HRs [95% CI]) were estimated using stratified Cox proportional hazard models. The difference between groups was tested using a stratified log-rank test. Results: The median follow-up for OS was 28.7 months in the NALIRIFOX arm and 29.7 months in the Gem+NabP arm. At data cutoff, 11 patients were still receiving study treatment, all of whom were in the NALIRIFOX arm. With a total of 673 OS events (NALIRIFOX, n = 328; Gem+NabP, n = 345), median OS was 11.1 months (95% CI 10.0–12.1) in the NALIRIFOX arm compared with 9.2 months (8.3–10.6) in the Gem+NabP arm (HR 0.84 [95% CI 0.72–0.98]; nominal p = 0.026). At 12 months and 18 months, survival rates were 45.6% (95% CI 40.5–50.5) and 26.6% (22.2–31.1), respectively, in the NALIRIFOX arm and 39.6% (34.7–44.5) and 20.0% (16.1–24.1), respectively, in the Gem+NabP arm. Conclusions: In this 29-month follow-up of NAPOLI 3, NALIRIFOX continued to demonstrate improved OS compared with Gem+NabP, with 11 patients still receiving the NALIRIFOX regimen. These data confirm NALIRIFOX as a new possible standard of care and reference regimen for the first-line treatment of patients with mPDAC. Clinical trial information: NCT04083235 .
Primary prophylaxis with pegylated-granulocyte colony-stimulating factor for patients with unresectable pancreatic cancer treated with modified-FOLFIRINOX: A randomized phase II trial.
Authors: Lee Choong-kun , Kim Il-Hwan , Kim Chang Gon , Choi Hye Jin 
Published: June 2024

4145 Background: Pancreatic cancer patients treated with FOLFIRINOX often suffer from severe neutropenia leading to dose reductions and sometimes fatal outcomes. However, there is no high-level evidence for primary prophylaxis of peg-GCSF for those patients. We report the result of a multi-institutional, open-label, randomized phase II trial of the peg-GCSF for unresectable pancreatic cancer patients treated with first-line modified-FOLFIRINOX. Methods: Treatment-naïve patients with histologically confirmed locally advanced or metastatic pancreatic cancer from two Korean cancer centers were enrolled. Patients received oxaliplatin 85mg/m2 D1 + leucovorin 400mg/m2 D1 + irinotecan 150mg/m2 D1 + 5-FU 2,400mg/m2 46h continuous infusion, every other week. After 1:1 randomization, peg-GCSF (pegteograstim 6 mg, GC Biopharma Corp.) was administered on day 4 for initial 8 cycles for primary prophylaxis group, where no G-CSF was given for control group. Crossover to administer peg-GCSF was permitted if patients in control group developed grade 3-4 neutropenia during initial 8 cycles. Co-primary endpoints were grade 3-4 neutropenia or febrile neutropenia during initial 8 cycles of mFOLFIRINOX. Secondary endpoints included relative dose intensity (RDI), patient reported quality of life, bone pain, and survival. Results: Between Feb 2022 and Jan 2024, 38 patients were randomized to peg-GCSF primary prophylaxis group and 39 patients were randomized to control group. Peg-GCSF group patients had significantly less grade 3-4 neutropenia during initial 8 cycles of mFOLFIRINOX, compared to the control (1/38, 2.6% vs 15/39, 38.5%, P=0.0001). None of peg-GCSF group patients experienced febrile neutropenia, where 5 patients (12.8%) experienced febrile neutropenia in control group. Cumulative RDIs of mFOLFIRINOX until progression or 8th cycles were similar between two groups with 93%. Although this trial was not powered for survival comparison, median PFS (9.0 vs 7.3 months) was numerically longer for peg-GCSF group compared to control. OS was not reached for both arms, but hazard ratio was 0.48 for peg-GCSF group. Conclusions: Primary prophylaxis with peg-GCSF significantly reduced grade 3-4 neutropenia and febrile neutropenia in patients with locally advanced or metastatic pancreatic cancer treated with mFOLFIRINOX events. Considering the study design of permitting the crossover, cumulative RDI was similar. Further follow-up of survival and quality of life results will be presented. Clinical trial information: KCT0006536 .
The function of KRAS4B isoform in pancreatic cancer.
Authors: Wang Kexin , Sangüesa Laura Beltran , Kalla Daniela , Pauli Theresa , Schnieke Angelika , Flisikowska Tatiana , Flisikowski Krzysztof 
Published: June 2024

4147 Background: Pancreatic ductal adenocarcinoma (PDAC) remains a significant challenge in the field of oncology, demanding the creation of models that faithfully replicate the human condition to aid in early diagnosis and the discovery of effective treatments. To address this need, we have developed the genetically engineered pig PDAC model. The model closely recapitulates the pathophysiological aspects of the human disease, including disease progression, histopathological subtypes of tumors, and the occurrence of metastasis. Alternative splicing variants have been proven to be novel targets in PDAC. KRAS undergoes mutations in PDAC more often than any other oncogene. The distinction between the two KRAS isoforms arises from the alternative splicing of exon 4 within the KRAS locus, resulting in the expression of major KRAS4A and minor KRAS4B splice isoforms, with KRAS4B is understudied, and functions in cancer are unknown. Based on this strong rationale, we initiated a study to functionally validate the role of the KRAS4B isoform in PDAC. Methods: qPCR was carried out to determine the expression level of KRAS4A and KRAS 4B in PDAC tumors and cell lines as well as in different tissues. To investigate the function of KRAS4B, we generated two pancreatic cancer cell lines harboring the genetic signature of PdxCre/KrasG12D/p53R167H mutation (KPC) or PdxCre/KrasG12D mutation (KC). Using CRISPR/Cas9 technology to knockout KRAS4B isoform. Additionally, we designed a vector for investigating the overexpression of KRAS4B. Results: At the molecular level, we revealed a differential expression of KRAS isoforms 4A and 4B in PDAC tumors and cell lines. Notably, the KRAS4B isoform was exclusively expressed in the advanced stages of PDAC. At the cellular level, we successfully disrupted the KRAS4B isoform in both cell lines. The overexpression vector of KRAS4B has been successfully constructed for further analysis. Subsequent functional assays will encompass analyses of mRNA and protein expression levels, along with assessments of key cellular behaviors, including proliferation, invasion, migration, and morphological alterations. Moreover, we will discern changes in tumor subtypes by examining the distinct expression patterns of epithelial and mesenchymal markers. Conclusions: Therefore, we engineered KRAS4B knockout and overexpression vectors to investigate its role in PDAC, utilizing our cell lines derived from our genetically engineered pig model. This approach offers a robust platform that enhances the bridge between translational and preclinical research in studying PDAC.
Investigating racial, gender, and socioeconomic disparities in early-onset versus late-onset colorectal cancer: An analysis using the NIH All of Us database.
Authors: Eun Yong , Olusoji Rahman Adesoji , Osei Noah , Omore Ibrahim , Ahluwalia Meena 
Published: June 2024

e15520 Background: Colorectal cancer (CRC) is a significant public health concern, with disparities based on race, gender, and socioeconomic status increasingly recognized. The incidence of early-onset CRC (EOCRC) is rising, highlighting the need for detailed examination of disparities in EOCRC compared to late-onset CRC (LOCRC). This study utilizes the NIH All of Us database to explore these disparities. Methods: We conducted a cross-sectional analysis of 266,520 participants from the NIH All of Us Registered Tier Dataset v7. CRC cases were identified based on at least two recorded diagnoses in electronic health records. Participants were categorized into EOCRC if diagnosed before age 50 and LOCRC if diagnosed at age 50 or above. We compared demographic and socioeconomic variables, including gender, race/ethnicity, income, education, and smoking status, between the groups, using questionnaire responses. Statistical analyses were performed using R. Results: The average age at diagnosis was 42.1 years for EOCRC patients and 63.7 years for LOCRC patients. The EOCRC group had a higher proportion of females (57.8%) compared to the LOCRC group (49.2%, p = 0.006). Whites constituted the majority in both categories, but Hispanics were significantly more represented in the EOCRC group (21.1%) compared to the LOCRC group (11.1%, p < 0.001). Individuals with a higher income (more than $100,000 per year) were more prevalent in the EOCRC group (29.9%) than in the LOCRC group (17.7%, p < 0.001). There was no significant difference in education levels between the two groups (p = 0.52). A history of smoking 100 or more cigarettes was less common in EOCRC patients (32.8%) than LOCRC patients (48.1%, p < 0.001). Conclusions: This analysis highlights significant disparities in racial and gender representation as well as income level. Despite observed differences between the two groups, Hispanics, females, and higher income alone may not explain the only influencing factors as other cofounders, like insurance level, may have impacted the result. Cigarette exposure was more prevalent in the LOCRC group, which may represent a stronger environmental influence on CRC within this group. These findings highlight the need for further research to understand the underlying causes of these disparities and to develop targeted interventions. By addressing these disparities, we can move towards more equitable outcomes across all populations. [Table: see text]
Racial differences in genomic profiles and clinical outcomes of patients with colorectal carcinoma: A single institution retrospective study.
Authors: Titus Abraham , Lund Alexander , Sharma Gaurav , Escobar Daisy E , Abdalla Ahmed 
Published: June 2024

e15582 Background: In the era of precision oncology, there is an immediate need to study the heterogeneity of molecular biology and clinical outcomes in racially diverse colorectal cancer (CRC) patients. Black patients are known to have poorer outcomes compared to their white counterparts. Understanding differences in patients’ molecular and genomic profiles may help explain these racial disparities. Methods: Demographic and clinical outcome data was abstracted from medical records of colorectal cancer patients who were diagnosed between 2008 and 2021 at The University of South Alabama. Tumor only next generation sequencing (NGS) of DNA (592 or WES) and RNA (WTS) was performed at Caris Life Sciences (Phoenix, AZ). Overall survival (OS) was defined as time from diagnosis to death or last contact. Descriptive analyses were performed using t-test and chi-square test, survival analyses were performed using Kaplan-Meier method and Log rank test (GraphPad Prism version 10.1.1). Results: 66 patients with CRC were included, 73% were white and 27% were black. The median age for white patients was 60.5 years and for black patients was 55.5 years (p = 0.049). In the white population, 52.1% of the patients were male and 47.9% were female. In the black population, 33.3% were male and 66.7% were female. The most common sites of malignancy for white patients were rectum (32.6%) and sigmoid (26.1%), whereas for black patients the most common sites were sigmoid (27.8%) and cecum (22.2%). Overall, the most common mutations were TP53 (68.2%), APC (65.2%), KRAS (47%), SMAD4 (16.7%), and FBXW7 (13.6%). The prevalence rates of TP53 (77.8 vs 64.6%), APC (72.2 vs 62.5%), KRAS (66.7 vs 39.6%), and SMAD4 (27.8 vs 14.6%) trended higher in black patients, with KRAS being statistically significant (p = 0.049). FBXW7 trended higher in white patients (14.6 vs 11.1%). Eleven (23%) white patients had a variant of uncertain significance in the ATM gene, which was not observed in black patients. More white patients had stage IV disease compared to black patients (69% vs 50%). No statistically significant difference in OS was found between races (HR 0.68, 95% CI of 0.35 to 1.3, p = 0.2). However, white patients had a median OS of 1334 days compared to 927 days for black patients. Conclusions: White and black CRC patients have unique molecular tumor profiles that may better explain the differences in survival. Our results warrant larger studies with racially and ethnically diverse patient populations to explore these racial disparities and close the gap in colorectal cancer care.
Simultaneous operations in patients with colorectal cancer with liver metastases.
Authors: Islamov Hurshid , Tillyashaykhov Mirzagaleb , Saydullaev Sunnatilla , Ziyaev Yakhyo , Ten Yakov , Sobitov Abdurakhmon , Khudoyorov Sanzhar , Botir Karakhodjaev , Yusupov Adxamjon 
Published: June 2024

e15586 Background: Metastatic colorectal cancer (CRC) treatment is a complex process involving surgical oncologists, chemotherapy specialists, and radiation oncologists. Objective: To assess the long-term outcomes of treating patients with metastatic CRC who has gone through simultaneous liver operations. Methods: Data and medical records of 61 patients with primary metastatic CRC treated at the Republican Specialized Scientific-Practical Center of Oncology and Radiology of the Republic of Uzbekistan between 2016 and 2020 were reviewed. Disease diagnosis and treatment were conducted following the current recommendations of the Ministry of Health of the Republic of Uzbekistan. The median follow-up period was 35 months. Results: The mean age of the patients included in the study was 59.1 years (ranging from 36 to 81 years). Of them, 32 male and 29 female patients. Metastatic cancer of the rectum was diagnosed in 18 patients (29.5%), rectosigmoid junction in 9 (14.8%), and colon in 34 (55.7%). Among the patients, 3 had low-grade tumor differentiation, 24 had medium-grade, and 34 had high-grade. According to the "T" criterion, 65.6% of the tumors were categorized as T3, 29.5% as T4, and 4.9% as T2. Different types of surgeries were performed for primary tumor localization, including abdominoperineal resection of the rectum (2 patients), right hemicolectomy (10 patients), rectal resection (5 patients), rectosigmoid junction resection (4 patients), colon resection (6 patients), left hemicolectomy (5 patients), and transabdominal rectal resection (4 patients). Postoperative complications were observed in 16 patients (bile leakage from drainage, wound suppuration, pneumonia, bladder atony). Anastomotic complications were detected in 2 patients. There were no deaths in the early postoperative period. The median overall survival was 36 months. The one-year overall survival rate in the overall group was 91.7% ± 3.7%, two-year - 76.2% ± 5.6%, three-year - 51.9% ± 7.5%. For colon cancer, the three-year overall survival was 62.7% ± 9.3%, rectosigmoid junction - 43.2% ± 20.8%, rectal cancer - 36.8% ± 13.7 (p = 0.974). Conclusions: Simultaneous operations for CRC and liver metastases combined with combination therapy contribute to stabilizing the tumor process and increasing overall survival rates.
A single-sample gene-expression classifier for the intrinsic consensus molecular subtypes in colorectal cancer.
Authors: Tsantoulis Petros , Hong Yourae , Wirapati Pratyaksha , Pu Ting , Peddle Allyson , McKee Thomas , Tejpar Sabine 
Published: June 2024

e15587 Background: An analysis of colorectal cancer epithelial cells showed two intrinsic subtypes called iCMS2 and iCMS3, in addition to the bulk consensus subtypes (CMS1-4). The intrinsic subtypes are prognostically important. We present a robust method for calculating the iCMS subtypes in individual samples, as opposed to batches, applicable in a clinical setting. Methods: We selected the subset of iCMS genes (N = 201) with the strongest epithelial expression in colorectal cancer, aiming to reduce the signal from other cell types. We then calculated gene expression centroids by taking the per-gene mean expression of 8 random samples from three non-batch corrected datasets (1779 samples total) that were previously used to derive the iCMS subtypes. Thirty-two centroids were calculated per dataset and per iCMS, for a total of 192 centroids. The single sample classifier (SSC) calculates the most likely iCMS class based on the class of the nearest centroid by non-parametric correlation distance. A confident call is made when the correlation is at least 0.1 and distance from the nearest centroid of the opposite iCMS class is greater than 0.05. Results: The SSC achieved 98.3% agreement with the reference calls in training data. The SSC was applied to unseen data for validation, by classifying non-batch corrected samples one at a time. The same data were clustered with the reference published iCMS public dataset and the reference iCMS was estimated at the batch level by proximity to reference samples in the hierarchical tree structure. Concordance between reference and SSC calls was 91.4% in non-batch corrected data and only modestly improved to 93.9% when batch correction was applied, showing the robustness of this approach. Concordance remained acceptable even when non-confident SSC calls were included (86.9%). The proportion of calls that were judged confident with the SSC was 77.9%, slightly lower than the proportion of confident reference calls (87.6%). In addition, the SSC was applied to data from the VELOUR trial, for which reference iCMS calls were also available. The SSC iCMS was prognostic (HR 0.601 for OS in iCMS2 vs iCMS3, P < 0.00001) and performed at least as well as the reference iCMS (HR 0.669, P = 0.0004). Conclusions: The SSC reproduces the iCMS classification and appears robust to batch effect. The SSC calls are prognostic in clinical trial data. The SSC R package is available for download (https://github.com/CRCrepository/iCMS.SSC). [Table: see text]