bluuebunny/crossref_metadata_2025_split huggingface dataset:
De-escalation and dose density in real-world patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) who received FOLFIRINOX in the first line.
Authors: Dennen Syvart , Shao Anran , Dennen Syvart , Cockrum Paul , Paluri Ravi Kumar 
Published: January 2024

628 Background: FOLFIRINOX (FFX) is a recommended first-line (1L) treatment for patients (pts) with mPDAC and good performance status but is known for high toxicity. To make the regimen more tolerable for pts, clinicians may omit components and/or reduce doses (referred to as “de-escalation”). To better understand the frequency and degree of de-escalation in outpatient clinical practice, we examined real-world (RW) treatment patterns among mPDAC pts receiving FFX in 1L. Methods: This retrospective observational study utilized the Ontada Clinical Data View: Pancreatic Cancer database. Adult pts diagnosed with mPDAC between November 2018 and November 2022 who initiated treatment with FFX in 1L within 90 days of their diagnosis for metastatic disease were included in the study. Receipt of FFX was defined as receiving all four regimen components within 28 days of 1L initiation. Modified FFX (mFFX) was defined as administration of <150mg/m2 of irinotecan or <2,720mg/m2 5-FU total (bolus + infusion) during cycle 1. 6-week dose density was defined as the actual dose received of each component in the 6 weeks following treatment initiation as a percent of the expected dose over 3 two-week cycles [expected FFX dose defined as 2800 mg/m2 of 5-FU (bolus + infusion), 400 mg/m2 of leucovorin, 180 mg/m2 of irinotecan, and 85 mg/m2 of oxaliplatin per cycle]. Results: 1,215 mPDAC pts met the study inclusion criteria, with >99% receiving mFFX. The median age at 1L initiation was 65yr (IQR: 58–71), 57% were male, 68% were white, 15% had an ECOG score of 0, 39% had an ECOG score of 1, and 6% had an ECOG of 2. The median number of FFX cycles was 5 (IQR: 2–9). In the first administration, 97% of pts received FFX/mFFX, 2% received FOLFIRI (omitting oxaliplatin), and 1% received other combinations. The number of pts in treatment declined over subsequent administrations, as did the number receiving FFX: by the 10th administration, 390 pts were treated, with 74% receiving mFFX, 13% FOLFIRI, 5% FOLFOX (omitting irinotecan), and 7% other combinations. At the 15th administration, 149 pts continued treatment, with 36% receiving mFFX, 44% FOLFIRI, 5% FOLFOX, 8% 5FU + leucovorin, and 7% other (either 5FU alone or with oxaliplatin and/or irinotecan). Median 6-week dose density was 69% for 5FU (IQR: 40–93%), 100% for leucovorin (IQR: 66–133%), 83% for irinotecan (IQR: 56–130%), and 99% for oxaliplatin (IQR: 68–127%). Conclusions: De-escalation was common among pts continuing FFX/mFFX treatment, with oxaliplatin the most frequently omitted component in later administrations. Over the 6 weeks following FFX treatment initiation, the actual vs. standard dose was lowest for 5FU, followed by irinotecan, while median leucovorin and oxaliplatin doses were close to standard dose over 3 two-week cycles. The omission of components of the regimen may indicate that mFFX lacks tolerability for many pts.
Non-responders to neoadjuvant chemotherapy in pancreatic adenocarcinoma: Characteristics and outcomes.
Authors: Hagerty Brendan , Fekrmandi Fatemeh , Kukar Moshim , Cherkassky Leonid , Calvo Benjamin 
Published: January 2024

662 Background: For patients with localized pancreatic adenocarcinoma, resection and systemic therapy remain the mainstays of curative-intent treatment. Neoadjuvant chemotherapy has been frequently employed with the goals of addressing systemic disease early and improving patient selection for surgery. Those who do not respond to neoadjuvant therapy present a challenge with a lack of randomized data to aid in decision making. Here we sought to define the characteristics and outcomes of those patients to guide clinical practice. Methods: This was a single-institution retrospective cohort study using a prospectively maintained database of those diagnosed with pancreatic adenocarcinoma. Patients included in the study were those who received neoadjuvant chemotherapy. Non-responders were defined as those with both no radiographic and no biochemical response at the first re-assessment after initiation of therapy. Results: A total of 176 patients were identified who were treated with neoadjuvant chemotherapy with curative intent. Of those, 42 (23.8%) patients had no evidence of either radiographic or biochemical response. Of those patients, 14 were upfront resectable (33.3%) and 20 were borderline resectable (47.6%). An additional 8 (19%) were locally advanced. Most patients received FOLFIRINOX as a first line chemotherapy agent (n = 25, 59.5%). A total of 12 (28.6%) patients underwent neoadjuvant radiation therapy. A total of 19 (45.2%) proceeded to surgery and two of those were found to be unresectable at exploration, resulting in 17 (40.5%) who ultimately received curative-intent resection. Exactly half (n = 21) of the patients had their chemotherapy switched (CS). Of those who had CS, 11 (52.4%) had evidence of local tumor progression on their initial restaging scan compared to just 3 (14.3%) of those who did not (p = 0.02). Additionally, patients who had CS had higher incidence of vascular involvement on their initial scan (90.5% vs 52.3%, p = 0.051). A total of 6 (28.6%) who underwent CS had subsequent biochemical response compared 4 (19.0%) of those who did not. Ultimately, 6 (28.6%) of those who had CS ultimately proceeded to surgery compared to 13 (61.9%) of those who did not (p = 0.062). Interestingly, there was no significant difference in median overall survival between those who had CS (18.6 months) and those who did not (19.9 months, p = 0.525). Conclusions: Non-responders to frontline neoadjuvant systemic therapy present a clinical challenge and have poor rates of curative-intent resection. Chemotherapy switch was employed mostly in cases with worse prognostic factors and thus infrequently lead to resection. Despite this, patients who underwent CS had similar overall survival to those who did not. These data suggest there may be a role for chemotherapy switch in those who do not respond to front line chemotherapy.
Paclitaxel protein bound (A) plus gemcitabine (G) plus cisplatin (C) and hydroxychloroquine (HCQ) neoadjuvant therapy for localized pancreatic ductal adenocarcinoma (PDAC).
Authors: Borazanci Erkut Hasan , Jameson Gayle S. , Snyder Courtney Edwards , Thosani Amar , Sckolnik Steven , Korn Ronald Lee , Rahmanuddin Syed , Mocan Dan , Pearse Shelby , Gordon Michael S. , Von Hoff Daniel D. , Modasi Aryan , Amini Albert 
Published: January 2024

667 Background: Neoadjuvant therapy has become the consensus treatment for individuals with locally advanced (LA) and borderline resectable (BR) PDAC. Neoadjuvant therapy for resectable (R) PDAC has been in greater use due to concerns over micro metastases at diagnosis. Typical therapies involve the use of multiagent systemic chemotherapy with or without radiation therapy. In retrospective studies, Cancer Antigen 19-9 (CA 19-9) normalization in borderline resectable (BR) and locally advanced (LA) PDAC has been associated with greater OS. The addition of cisplatin (C) to gemcitabine (G) and paclitaxel protein bound (A), has shown promising clinical data in a previously reported study in advanced PDAC [JAMA Oncol. 2020;6(1):125-132]. HCQ has been shown to target autophagy in PDAC and has demonstrated higher response in combination with GA. We conducted a prospective, phase 2 clinical trial of patients with R, BR, and LA PDAC utilizing a regimen combining A + G + C + HCQ with the primary endpoint of CA 19-9 normalization (NCT04669197). Methods: Eligibility criteria include patients with histologically confirmed R, BR, or LA PDAC, elevated CA 19-9, and a KPS ≥ 70% with normal end organ function. Doses are A 125 mg/m2, G 1000 mg/m2, C 25 mg/ m2 on days 1, 8 of a 21-day cycle (IV) along with HCQ 600 mg po bid. Primary objective is to evaluate CA 19-9 normalization with the neoadjuvant chemotherapy. Secondary objectives are to assess R0 rate, pathologic complete response (pCR), safety and tolerability, radiologic response rate (by RECIST 1.1), and 2 year overall survival (OS) from date of study entry. Exploratory objectives include evaluating imaging biomarkers and vascular involvement by tumor in relation to therapy. Results: To date all planned 12 patients have been enrolled, 11 evaluable. 8 male, 4 female; age range 50 to 76 yo. Patient classifications is 3 R; 4 BR; 5 LAPC. Most common drug related grade (gr) 3-4 adverse events (AEs) are: thrombocytopenia gr 3 27%, gr 4 27%, anemia gr 3 36%, and neuropath gr 3 36%. CA 19-9 normalization occurred in 36% (4/11) who have completed at least 1 cycle of treatment. To date, 3 individuals went to surgery, with 3 achieving R0. Overall response rate in measurable patients is 45% (1CR, 4 PR). Median OS and 2-year survival data are not yet matured. Conclusions: In patients with non-metastatic PDAC, the use of A+G+C+HCQ resulted in a CA 19-9 normalization rate in 36% of individuals. Most patients did not go to surgery. The OS data is maturing. Supported by grants from the HonorHealth Foundation and Marley Foundation. Clinical trial information: NCT04669197 .
Trends in colorectal cancer screening from NHIS survey: Analysis of modalities impact on overall screening.
Authors: Ebner Derek W. , Finney Rutten Lila J , Miller-Wilson Lesley-Ann , Markwat Niels , Vahdat Vahab , Ozbay A. Burak , Limburg Paul J. 
Published: January 2024

67 Background: Colorectal cancer (CRC) is the second leading cause of cancer-related mortality among men and women combined in the United States (US). Although the national screening rate has increased over the years, it remains below the target of 80% recommended by the National Colorectal Cancer Roundtable for improved CRC outcomes. In most recent years, and particularly during COVID-19, screening-eligible individuals preferred at-home, non-invasive screening options over invasive tests such as colonoscopy due to convenience and accessibility. The objective of this study was to understand the CRC screening trends over the last two decades, and the impact of various screening modalities on the overall CRC screening rate. Methods: Using National Health Interview Survey (NHIS) data from 2005 onwards, we examined CRC screening (colonoscopy, mt-sDNA, FIT/FOBT, and sigmoidoscopy) rates among adults aged 50-75 years. A pseudo-time-series cross-sectional (pseudo TSCS) analysis was conducted including random effects Generalized Least Square (GLS) regression model to estimate the relative impact of each modality on the overall increase in CRC rates from 2018 to 2021. Results: Among 50-75 years old individuals, the estimated CRC screening use increased by 32% from 2005 to 2021 (47.7% to 69.9%). Between 2018 to 2021, the rates increased from 64% to 70%, driven largely by increased use of mt-sDNA, a 62.1% increase from 2018 to 2021 (2.5% to 6.6%). During this time period, colonoscopy utilization increased by 4.4% (61.2% to 64.0%), while FOBT/FIT utilization increased by 3.6% (5.3% to 5.5%). A pseudo-TSCS analysis showed that mt-sDNA contributed substantially to the overall CRC screening rate increase during years 2018-2021 (77.3%; p < 0.0001). Conclusions: While CRC screening rates are increasing, they remain below the national goal of 80%. Mt-sDNA as a home-based, non-invasive screening, recommended at a 3-year interval, has been leveraged to improve overall CRC screening rates, particularly to address the screening backlog created during the COVID-19 pandemic. A collaborative approach between healthcare providers and screening-eligible individuals is needed to empower patients with choice for their CRC screening modality to achieve the national goal.
Prevalence of cancer and alcohol use in patients with exocrine pancreatic insufficiency compared to patients with cystic fibrosis.
Authors: Peeples James , Gore James , Romo Karina G. , Noor Abdullah A. , Uwaifo Gabriel I. 
Published: January 2024

680 Background: Cystic fibrosis (CF), the most prevalent genetic disorder among persons of European decent, is an autosomal recessive disorder due to CFTR gene mutations which lead to abnormally viscid exocrine secretions of the pancreas and other exocrine glands of the body. Exocrine pancreatic insufficiency (EPI) is a condition seen in ~85% of CF patients, in which the pancreas is unable to secrete adequate amounts of digestive enzymes. Although most patients with CF develop EPI, not all cases of EPI are caused by CF. Other risk factors for EPI include acute or chronic pancreatitis which may be triggered by alcohol, among other etiologies. Some studies suggest alcohol use as a possible independent risk factor for development of various cancers. Given these associations, we sought to characterize the prevalence of both alcohol use and cancer in patients with EPI vs patients with CF. Methods: A retrospective observational study was performed using electronic health records in Ochsner System, Louisiana, over a 3 year period: January 2017 to January 2020. Two cohorts were reviewed: patients with EPI excluding CF (n=596) and patients with CF (n=81). Results: While there was no significant difference in the prevalence of cancer at start vs end of the 3 year observation period in the CF cohort (4.1% at start, 7.2% at end), the prevalence of cancer was significantly greater among patients in the EPI cohort, both at start and end of the 3 year period: 15.95% at start, 43.9% at end (p <0.05). Also, while there was no significant change in alcohol use over the 3 year period for the CF cohort, the prevalence of alcohol use was significantly lower in CF cohort (0.45% at start, 2.2% at end) compared to EPI cohort which showed significant increase in alcohol use over the observation period: 7.7% at start vs 16% at end (p <0.05). Conclusions: There was a significantly higher prevalence of cancer in the EPI cohort compared to the CF cohort; while this may be due to higher prevalence of pancreatic cancer associated with EPI compared to CF, it does not explain the entirety of this observation. Not only was there a significantly higher prevalence of alcohol use in EPI cohort compared to CF cohort, but over the 3 year observation there was a 2-fold increase in prevalence of alcohol use within patients who already had a diagnosis of EPI. Within the EPI cohort, the observed increase in cancer prevalence and the increase in alcohol warrant further investigation into which factors unique to EPI patients without CF may modulate these social and health risk indices.
Association between TP53 gain of function and loss of function mutational subgroups and survival in pancreatic adenocarcinoma.
Authors: Zohar Nitzan , Blais Edik Matthew , Mueller Adam , Thach Dzung , de Arbeloa Patricia Miren , Matrisian Lynn McCormick , Petricoin Emanuel , Pishvaian Michael J. , Hendifar Andrew Eugene , Basu Mallick Atrayee , Lavu Harish , Yeo Charles J. , Bashir Babar , Nevler Avinoam 
Published: January 2024

694 Background: TP53 is a commonly mutated tumor suppressor in pancreatic adenocarcinoma (PDAC) but the clinical implications for different classes of TP53 variants remain unclear. In contrast to loss of function (LOF) mutations, TP53 gain of function (GOF) mutations alter DNA conformational binding (e.g. R175H, G245S, R249S, R282H) or modify DNA contact hotspots (e.g. R248Q, R248W, R273H) and are associated with aggressive phenotypes. Here, we analyze progression-free survival (PFS) on standard therapies and overall survival (OS) of PDAC patients (pts) within TP53 mutational subgroups: GOF, LOF, and wild type (WT). Methods: We analyzed longitudinal outcomes across 775 pts with next generation DNA sequencing (NGS) results from Perthera’s Real-World Evidence database who received at least 1 line of therapy in the advanced setting for PDAC. PFS was evaluated from initiation of 1st line for advanced disease until discontinuation. Hazard ratios and p-values were computed via Cox regression when comparing OS relative to date of advanced diagnosis and PFS on subsets who received 1st line FOLFIRINOX (FFX) or 1st line gemcitabine/nab-paclitaxel (GA). Differences in frequencies of genomic alterations between TP53 mutational subgroups were analyzed by Fisher’s exact test. Results: In the TP53 LOF subgroup, median PFS on 1st line GA was significantly worse than 1st line FFX (Table) but this difference was not observed in TP53 GOF or WT subgroups. Irrespective of 1st line therapy choice, median OS in the WT subgroup (2.1y [1.8-2.4]) was significantly longer (p<0.05) than pts with TP53 GOF (1.5y [1.3-2.1]) or TP53 LOF (1.4y [1.3-1.5]). KRAS mutations were enriched (unadjusted p<0.05) for co-occurrence with TP53 in GOF (93.7%) and LOF (93.3%) subgroups relative to WT (74.5%). Mutations in BRCA1/2 were less common in the TP53 GOF subgroup (2.5%) relative to LOF (5.1%) and WT (11.6%). ATM mutations as well as an expanded set of genomic alterations within the DDR pathway were also enriched with similar trends (GOF<LOF<WT). Other potentially confounding factors will be discussed in the context of multivariate OS/PFS analyses. Conclusions: TP53 mutations correlated with worse prognosis in advanced PDAC. Potential predictive associations favoring FFX over GA in the TP53 LOF subgroup (but not in GOF or WT subgroups) warrant further exploration. [Table: see text]
Income and its impact on adenomatous neoplasms outcomes: An analysis of the National Cancer Database.
Authors: Nielsen Eric G. , Bine Christopher Reese , Lee Aron , Czaplicki Alec , Silberstein Peter T. 
Published: January 2024

723 Background: Adenomatous neoplasmsof the small intestine are rare benign tumors but are occurring with increasing incidence. They exhibit a slight male predominance, with a median age of diagnosis in the 6th decade of life. The duodenum is the most frequent location of onset. Proposed environmental risk factors include high animal fat and protein diets, intestinal flora composition, and hereditary factors. Additionally, intestinal diseases, such as Crohn’s disease or Lynch syndrome, predispose individuals to develop small intestine adenomatous neoplasms. Despite this knowledge, no National Cancer Database (NCDB) research exists analyzing the association between survivability and income. Therefore, the objective of this study is to investigate overall survival rates among individuals with adenomatous neoplasms based on income levels. Methods: The NCDB was used to identify patients diagnosed with small intestine adenomatous neoplasms from 2004 to 2019 using the histology code 8140 as assigned by the Commission on Cancer Accreditation program. Kaplan-Meier, ANOVA Chi-Square tests were performed, and data were analyzed using SPSS version 27. Statistical significance was set at α = 0.05. Results: Of 19,582 patients included in the sample, 6,326 (30.8%) were from the highest income bracket, defined as annual income greater than $46,000, while 3,629 (24.4%) were from low-income brackets, defined as earnings less than $30,000. High-income patients experienced longer mean overall survival (58.5 months) compared to middle (49.7 months) and low (46.7 months) income patients (p<0.001). After controlling for age at diagnosis, sex, race, facility type, surgery status, adjunctive therapies, and insurance type, both the low- and middle-income brackets were associated with an independent increase in hazard (HR = 1.284 and 1.177 respectively; p<0.001). High income was associated with fewer comorbidities (72.2%) compared to low (65.9%) and middle-income (68.4%) patients (p<0.001). High-income patients were more likely to be treated at academic facilities (41.9%) compared to low (39.2%) or middle-income (35.4%) individuals (p<0.001), which have longer survivability (58.9 months vs. 47.8 months in non-academic facilities; p<0.001). Additionally, high income was also associated with increased rates of private insurance ownership (38.0%) while low-income individuals were more likely to have Medicaid (9.5%) or be uninsured (5.1%; p<0.001). No significant differences were found in tumor grade or differentiation, staging, metastasis, or surgical margins. Conclusions: This study indicates an association between high-income patients and increased survivability, while also observing an association with low-income and decreased survivability. Further research is required to assess specific environmental risk factors of adenomatous neoplasms and their relation to income level.
Effect of PD-1/ PD-L1 and statin combination therapy on gastrointestinal toxicity related to immune checkpoint inhibitors and on survival.
Authors: Wang Yinghong , Shah Jay Sanjay , Urias Rivera Andres Caleb , Mathew Antony , Thomas Anusha , Altan Mehmet , Zhao Dan 
Published: January 2024

742 Background: Immune Checkpoint Inhibitor (ICI) therapy has greatly expanded its approval to treat a variety of malignancies with high efficacy. Inhibitors of programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) are two of the most common classes of ICI therapy. There has been significant research into medications that may have a synergistic effect with ICI therapy, notably statins due to their pro-apoptotic effect. The addition of statins to immunotherapy may also increase the risk of developing certain immune related adverse events (irAEs). We sought to investigate the effect of statin use on the development of gastrointestinal (GI) irAEs and on survival of patients on PD-1/L1 therapy. Methods: We conducted a review of select cancer patients at a tertiary cancer center who received PD-1/L1 inhibitors and statins between 2016 and 2022. The clinical characteristics and overall survival were compared to a control group who received PD-1/L1 inhibitors without statins. Results: A total of 823 patients were included in the statin group and compared to 11101 patients in the control group. In the statin group 707 received a PD-1 inhibitor, 86 received a PD-L1 inhibitor, and 30 received both checkpoint inhibitors. The included cancer types were lung cancer (44%), kidney cancer (26%), head/neck cancer (19%), and GI cancer (7.0%). The overall incidence of GI irAEs in patients receiving statins was 10.8%, which was comparable to patients without statin treatment (11.1%, p=0.83). In addition, statin treatment appeared to be associated with a more favorable survival in patients overall (p= 0.004) and also those with GI irAEs (p=0.047). Conclusions: Synergism between statins and PD-1/L1 inhibitors continues to be a developing field of interest. Our data showed the combination therapy’s survival benefit without exacerbating GI toxicity, which warrants further investigation of this treatment strategy.