bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular characterization and clinical outcomes of pancreatic neuroendocrine tumors (pNENs) harboring PAK4-NAMPT alterations.
Authors: Azar Ibrahim , Gandhi Nishant , Nagasaka Misako , Gong Jun , Nazha Bassel , Choucair Khalil , Khushman Moh'd M. , Soares Heloisa P. , El-Deiry Wafik S. , Philip Philip Agop , Lou Emil , Farrell Alex Patrick , Swensen Jeffrey , Oberley Matthew James , Abraham Jim , Nabhan Chadi , Goel Sanjay , Korn Wolfgang Michael , Shields Anthony Frank , Azmi Asfar S.
Published: January 2023

649

Background: The mTOR inhibitor, Everolimus (EVE), is FDA-approved for the treatment of advanced PNENs on the basis of delay of progression. The RADIANT-3 trial showed an increase in PFS from 4.6 to 11 months compared to placebo with an ORR of only 5%. Prior studies suggest that targeting the aberrant expression of mTOR regulators p21 activated kinase 4 (PAK4) and nicotinamide adenine dinucleotide biosynthesis enzyme nicotinamide phosphoribosyltransferase (NAMPT) in PNENs sensitizes these tumors to EVE. To further qualify these observations, we queried a large real-world dataset of PNENs, characterizing the molecular and immune landscapes, as well as the clinical outcomes associated with aberrant PAK4 and NAMPT expression. Methods: 294 cases of PNENs were analyzed using Next Generation Sequencing (NextSeq) and Whole Exome and Whole Transcriptome Sequencing (NovaSeq) at Caris Life Sciences (Phoenix, AZ). For our analyses, we stratified our study cohort into four groups based on the median expression of PAK4 and NAMPT: PAK4-low/NAMPT-low, PAK4-low/NAMPT-high, PAK4-high/NAMPT-low and PAK4-high/NAMPT-high. Significance was determined using chi-square, Fisher-Exact or Mann-Whitney U, and p-values were adjusted for multiple comparisons (q < 0.05). Results: High prevalence of mutations in PTEN (10.71% vs 1.18%; p < 0.05, q > 0.05), a tumor suppressor of the mTOR pathway and high expression of genes activated in response to mTOR activation such as SLC2A1 (3.07-fold), PFKP (3.32-fold), SCD (2.70-fold), MVK (2.92-fold) and G6PD (2.58-fold) were observed in PAK4-high/NAMPT-high compared to the PAK4-low/NAMPT-low tumors (all q < 0.05). A congruent enrichment of PI3K/AKT/mTOR and glycolysis pathways by single-sample gene set enrichment analysis was observed in these tumors (all q < 0.05). When querying the immune landscape, we observed enrichment in inflammatory response, IL6/JAK/STAT3, IL2/STAT5 signaling pathways and immune checkpoint genes such as PDCD1 (5.14-fold), CD274 (2.84-fold), PDCD1LG2 (2.44-fold), CD80 (3.00-fold), CD86 (2.82-fold), IDO1 (1.92-fold), LAG3 (3.09-fold), HAVCR2 (2.66-fold) and CTLA4 (4.49-fold) in the PAK4-high/NAMPT-high tumors (all q < 0.05). Immune cell infiltration estimates revealed an increase in Neutrophils, NK cells and Tregs in the PAK4-high/NAMPT-high tumors (p < 0.05, q > 0.05). Conclusions: Our study demonstrates that PAK4-high/NAMPT-high PNENs are associated with distinct molecular and immune profiles. While the dual blockade of PAK4 and NAMPT has been reported to enhance the efficacy of EVE in PNENs, whether such a blockade would enhance the efficacy of immunotherapeutics warrants further investigation.
Disparities in late-stage pancreatic cancer: Retrospective analysis of genomic testing and outcomes between Hispanics and non-Hispanics.
Authors: Estrada-Mendizabal Ricardo J. , Halder Ritika , Rao Amith , Cheng Ce , Dominguez Isabellyana , Veeravelli Sumana , Recio-Boiles Alejandro
Published: January 2023

663

Background: Late-Stage Pancreatic Cancer (LS-PC) represents the 7th leading cause of cancer-related deaths worldwide. Hispanic (H) ethnicity is underrepresented in genomic studies and disparities have been demonstrated in overall treatment and outcomes. Germline, somatic tissue, and somatic liquid testing are effective tools that aid in identifying targeted genetic alterations. We comprehensively evaluated the differences in genomic testing among H and Non-Hispanic (NH) patients with LS-PC. Methods: This is a retrospective analysis of LS-PC with ductal adenocarcinoma from the University of Arizona Cancer Center from 2013 to 2021. Data collected included: patient demographics, clinical characteristics, treatment regimens, germline, somatic tissue, and somatic liquid genetic testing, and outcomes. LS was defined as unresectable and/or metastatic de novo or recurrence. Univariate comparisons used parametric and nonparametric tests as appropriate to evaluate for differences between H and NH groups. Fisher's exact tests were performed to evaluate the difference in frequency. Kaplan Meier and Cox regression analysis assessed progression-free and overall survival. Results: The analysis included 198 patients who had LS-PC with 20.7% H. 64.1%, 48.9%, and 48.9% of the patients had germline, somatic tissue, and somatic liquid testing, respectively. No significant differences were noted in baseline characteristics, treatments, and outcomes [PFS (HR 1.1, 95% CI 0.7-1.6, p=0.70) / OS (HR 1.2, 95% CI 0.7-1.9, p= 0.54)]. There was no statistically significant difference in common mutations or variants among groups. Conclusions: To our knowledge, this is the first and largest study to report LS-PC genomic and therapeutic implications in H patients. H were significantly less likely to receive germline screening and more likely to have potentially actionable pathogenic variants via somatic tissue and liquid biopsy testing. This highlights the importance of genetic testing to reveal mutations that can be targeted by clinical trials for LS-PC on minorities. Although our review revealed increased germline, somatic tissue, and somatic liquid biopsy genetic testing over time, there remains a critical need towards advancing genomic sequencing efforts to improve outcomes for LS-PC in the underrepresented H population.[Table: see text]
Evolution of pancreatic ductal adenocarcinoma diagnosis during the last decade.
Authors: Jiménez Rodríguez Roberto , Gonzalez Caraballo Irene , Martín Lozano Rocío , Alva Bianchi Manuel , de Lucas Mónica Benavente , Gómez María Palma , Muñoz Marc Ariant Cañete , Lobato Delgado Bárbara , Tirado Anula Victoria , Morón García Blanca , Ruiz Zamorano Magdalena , Marquez-Rodas Ivan , Echavarria Diaz Guardamino Isabel , Torres Pérez-Solero Gabriela , Calvo Ferrándiz Aitana , Ortega Laura , Soria Jose Manuel , Garcia-Alfonso Pilar , Martin Miguel , Muñoz Martín Andrés J.
Published: January 2023

670

Background: Pancreatic Ductal Adenocarcinoma (PDAC) has historically been an important diagnostic and therapeutic challenge. The multidisciplinary approach and new diagnostic techniques’ implementation have modified this process. Methods: We conducted a retrospective analysis based on clinical data of patients with PDAC between the years 2010 to 2021, analyzing the diagnosis and initial treatment evolution. Results: 673 patients between 2010-2021 with a suspected diagnosis of pancreatic adenocarcinoma were reviewed. Most of them were metastatic (n=362; 53.8%), followed by locally advanced unresectable (n=166; 24.7%) and resectable or borderline resectable (n=145; 21.5%). Regarding the pathological diagnosis, it was not possible in 62 patients (9.2%), varying over time from 21.2% in 2010-2012 to 1% in 2019-2021 (p<0,0001). Moreover, the number of biopsies has decreased with a mean number of biopsies to obtain a pathological diagnosis of 1.55 (2010-2012) vs 1.31 (2019-2021). During this last period, most of the diagnoses were made by cytological analysis (61.4%; n=121). Specifically in the 2019-2021 patients subgroup, we found that 18 NGS (9,1%) were performed in this period (solid tumor), with 4 patients having actionable mutations (22.2%; 3 KRAS G12C). Germline (g) mutational panels were carried out in 89 patients, finding only 9 positive cases (10.1%), being 3 of them gBRCA1/2 mutated (3,4%). In our study, a decrease in palliative management was evidenced over time. In 2010-2012, 28,8% of patients received exclusively palliative care against 9,6% in 2019-21 (p< 0.0001). An increase in PDAC diagnosis was observed since 2010, 44 patients/year in 2010-12 vs. 66 patients/year in 2019-21 (including COVID-19 pandemic period). All previous results are summarized. Conclusions: The diagnosis of PDAC has changed throughout the last decade, increasing the percentage of patients with a pathological diagnosis without increasing the number of invasive procedures. The number of patients suitable for anti-cancer therapy has also increased among time. In our cohort, the implementation of molecular testing would change the therapeutic approach in more than 20% of patients.[Table: see text]
Early detection of pancreatic cancer using 5-hydroxymethylation profiles in plasma-derived cell-free DNA.
Authors: Bergamaschi Anna , Haan David , Collins Micah , Guler Gulfem , Peters Melissa , Gigliotti Lauren , Chowdhury Shimul , Volkmuth Wayne , Levy Samuel
Published: January 2023

672

Background: Pancreatic cancer is one of the deadliest cancers, with approximately 15-20% of patients who present at diagnosis with a resectable disease. The major barrier to better outcomes is the lack of early-detection molecular tools to enable timely intervention. We have developed a test that enables the detection of pancreatic cancer from a simple blood draw. The test incorporates a novel, genome-wide sequencing-based epigenomics detection method that enriches for DNA loci that undergo active de-methylation. The measurement of 5-hydroxymethylcytosine (5hmC) provides a unique and stable biomarker for the early detection of cancer including pancreatic cancer. Methods: Whole-blood was obtained from a training cohort of 660 individuals (consisting of 132 pancreatic cancers (PaCa) and 528 non-cancers) and a validation cohort of 2,150 individuals (consisting of 102 PaCa and 2,048 non-cancers). Cell-free DNA (cfDNA) was isolated from plasma from which 5hmC and whole-genome libraries were generated and sequenced. Logistic regression algorithms were employed using 5hmC feature sets combined with physical characteristics of DNA fragments to optimally partition cancer from non-cancer samples. Results: Cross validation of the training model yielded an overall sensitivity of 65.9%,(95% CI, 57.2%–73.9%), early-stage (stage I-II) sensitivity of 57.1% (95% CI, 44%–69.5%) and a specificity of 98%. The model was further validated in a separate, non-overlapping set of blinded and independently processed samples and yielded an early-stage sensitivity of 68.3% (95% CI, 51.9%–81.9%) and a specificity of 96.9% (95% CI, 96.0%–97.6%). Conclusions: Our results demonstrate that plasma-derived cfDNA 5hmC profiles enable the accurate detection of early-stage PaCa, providing a valuable non-invasive tool especially for those individuals at high risk for the disease, including individuals with genetic predisposition and newly diagnosed type 2 diabetes. A larger clinical study (NODMED - NCT05188586) is ongoing and will provide clinical validation for the detection in individuals at high risk for this deadly disease.
The prognostic value of C-reactive protein/albumin ratio and platelet-lymphocyte ratio in patients with pancreatic cancer.
Authors: Shen Yang-Chen , Chu Chi-Hsiang , Chen Po-See , Lin Cheng-Feng , Liu Ping-Yen , Lin Peng-Chan , Yen Chia-Jui , Shan Yan-Shen
Published: January 2023

678

Background: Pancreatic cancer is a highly malignant tumor with poor prognosis. Therefore, identification of prognostic markers is very crucial for improved risk stratification in pancreatic cancer patients. Although various systemic inflammatory markers have been investigated for their prognostic roles in pancreatic cancer, inconsistent results have been found across studies. Accordingly, the present study aimed to identify the prognostic value of inflammatory markers for patients with pancreatic cancer. Methods: The study enrolled 185 patients with pancreatic cancer. The inflammatory markers, namely, the modified Glasgow Prognostic Score (mGPS), the prognostic nutritional index (PNI), the neutrophil/lymphocyte ratio (NLR), the platelet/lymphocyte ratio (PLR), the C-reactive protein (CRP)/albumin ratio (CAR), the platelet/albumin ratio (PAR), and the CRP/lymphocyte ratio (CLR), were evaluated. Receiver operating characteristics curve analysis was performed to determine the cut-off values. The Cox proportional hazards model was used to analyze the factors affecting the prognosis. Results: The mean age of the patients was 64.1 years (with a standard deviation of 11.1), and their average overall survival (OS) was 10.5 months (95% confidence interval [CI] = 9.7–11.4). In the univariate analysis, metastatic disease, carbohydrate antigen (CA)19-9, mGPS, PNI, NLR, PLR, CAR, and CLR were significantly associated with OS ( P< 0.05). In the multivariate analysis, metastatic diseases (hazard ratio [HR] = 2.52, 95% CI = 1.03–6.15, P = 0.04), CA19-9 (HR = 3.96, 95% CI = 2.01–7.79, P< 0.001), PLR (HR = 2.37, 95% CI = 1.11–5.04, P = 0.03), and CAR (HR = 4.45, 95% CI = 2.19–9.03, P < 0.001) were identified as independent prognostic factors for OS. Conclusions: Pretreatment PLR, CAR, CA 19-9 , and metastatic diseases were found to be independent indicators of poor prognosis in patients with pancreatic cancer. We believe that our findings will shed light on the identification of prognostic factors, which might enable a better risk stratification in pancreatic cancer patients.
Real-world impact of initial treatment modality on survival outcomes in patients with stage I-III pancreatic ductal adenocarcinoma.
Authors: Prakash Ajay , Schwanke Joschua , Le-Kumar Thuy-Hong , Patterson Brooke , Marmor Schelomo , Tignanelli Christopher , Jensen Eric Hans , Lou Emil
Published: January 2023

684

Background: Management of non-metastatic pancreas cancer has been extensively studied in clinical trials over the past two decades, with a growing body of non-randomized data supporting the use of neoadjuvant chemotherapy in combination with surgery. Guidelines now recommend use of this treatment paradigm, but real-world follow-up is critical in understanding how these recommendations are translated into the clinic. Using real-world data, we aimed to evaluate the treatment modalities and subsequent survival outcomes for patients diagnosed with pancreatic adenocarcinoma within the MHealth/Fairview medical system. Methods: We identified 844 patients diagnosed with stage I-III pancreatic adenocarcinoma within the MHealth/Fairview system (Minneapolis, MN) from 2001-2021 with EHR data enriched by cancer registry abstracted data. Diagnoses were confirmed with ICD-10 coding and clinical staging. Patients were stratified by initial treatment with either surgery (N = 345) or neoadjuvant-intent chemotherapy (n = 499). Correlation between initial treatment modality, demographic identifiers, and time to treatment was calculated using both Pearson and Spearman method. Effect of initial treatment modality on overall survival was calculated using a Cox proportional Hazard (CPH) model controlling for age, sex, clinical stage, and time to treatment initiation (TTI). A sub-analysis with race was performed on samples where these data were available. Results: Relative to neoadjuvant chemotherapy, up-front surgery was associated with a significantly improved overall survival (Hazard Ratio (HR) 0.55 95% Confidence Interval (CI): 0.37 – 0.76; p < 0.001), when controlling for age, sex, clinical stage, and TTI. Surgical patients also had shorter mean TTI values (21 days; p < 0.001) relative to chemotherapy (28 days), and a slightly younger patient population (mean age 63, vs 66 for chemotherapy, p = < 0.001; rho = -0.14). We observed no significant correlation between age (p = 0.027) or TTI (p = 0.12) and survival within this population. We noted no significant correlation between race, sex, or clinical stage and initial treatment modality or overall survival. Conclusions: We observed that MHealth/Fairview system patients who received upfront surgery for stage I-III pancreas cancers demonstrated improved overall survival relative to other treatment modalities, even after controlling for the differences in age and TTI found between these patients and those who undergo initial chemotherapy. This is likely due to a multitude of factors not readily captured within this data set, including surgical patient selection and tumor biology. Further work is needed to understand why these findings diverge from study norms, and to optimize care for all patients with pancreatic adenocarcinoma.
Prospective characterization of oral and gut microbiome in a high-risk pancreatic cancer cohort.
Authors: Baydogan Seyda , Mohindroo Chirayu , Montiel Maria Fernanda , Petrosino Joseph , Maitra Anirban , Kim Michael Paul , Bhutani Manoop S. , White James R , McAllister Florencia
Published: January 2023

691

Background: Pancreatic cancer (PC) is the third leading cause of cancer death in the United States. The high mortality associated with PC is attributed to multiple reasons: lack of effective therapies, aggressive biology and late diagnosis. Due to the absence of reliable early disease biomarkers, PC screening is largely dependent on imaging. Recent studies have highlighted the importance of the gut and tumor microbiome in PC. We present here the first report of oral and gut microbiome prospective analysis of PC high-risk individuals (PC-HRI) undergoing screening. Methods: We collected periodontal and stool samples at the University of Texas MD Anderson Cancer Center from 2017-2022. A total of 448 samples, consisting of 250 oral and 198 gut samples were obtained. Samples were collected from PC (n=73), PC-HRI (n=34), and healthy (n=143) individuals. 16s rRNA sequencing was used to characterize the oral and gut microbiome and statistical analysis and correlation with imaging and clinical characteristics were performed. Results: We identified three phyla, namely Proteobacteria, Actinobacteria, and Fusobacteria as significantly more abundant in the gut microbiome of PC patients. Conversely, Proteobacteria was decreased in the oral microbiome of PC patients. At the class level, Gammaproteobacteria (GP) oral/gut ratio was significantly decreased in PC patients compared with healthy individuals (p=0.02). Analysis of PC-HRI revealed also low GP oral/gut ratio in high-risk individuals who were diagnosed with worrisome pancreatic focal lesions. Interestingly, Gammaproteobacteria (GP) is one of the main classes of bacteria detected in pancreatic cancer tissue. GP shifts in oral and gut environments could be implicated in pancreatic early tumorigenesis and serve as biomarker of the disease. Additionally, gut bacteria with metabolic pathways related to lipid metabolism were more enriched in PC patients and PC-HRI with focal lesions compared to healthy controls. Conclusions: Gammaproteobacteria oral/gut ratio represents a potential novel biomarker which could predict presence of early high risk-pancreatic focal lesions in PC-HRI. Taken together, this report provides observational evidence about changes in oral and gut microbiome in patients with pancreatic cancer but even more importantly, the fact that those changes could be detected in PC-HRI with early high-risk lesions. Broader validation in other high-risk cohorts would be required. Detection of GP oral/gut ratio would represent an inexpensive, non-invasive method that could be useful for PC screening. Functional studies should be performed to determine how GP shifts can contribute with pancreatic tumorigenesis. Research supported by CPRIT (Grant Number: RP200173) and philanthropic funding through the MD Anderson Moonshot Program.
Analysis of the treatment outcome of ampulla of Vater carcinoma and the usefulness of postoperative adjuvant chemotherapy.
Authors: Ogawa Shinichiro , Adachi Tomohiko , Matsushima Hajime , Imamura Hajime , Kurotaki Koki , Fukumoto Masayuki , Yoshino Kyohei , Enjoji Takahiro , Tetsuo Hanako , Matsumoto Ryo , Hara Takanobu , Soyama Akihiko , Ito Shinichiro , Hidaka Masaaki , Kanetaka Kengo , Eguchi Susumu
Published: January 2023

692

Background: Patients with ampulla of Vater carcinoma with lymph node metastasis reportedly have a poor prognosis and require postoperative adjuvant therapy. However, due to the small number of published cases, the efficacy of postoperative adjuvant therapy has not yet been established with a high level of evidence. Objective: The aim of this study was to describe the outcome of patients surgically treated for ampulla of Vater carcinoma in our department, evaluate the effectiveness of adjuvant chemotherapy (AC), and clarify which patient groups may benefit from AC. Methods: The study cohort comprised 46 patients who underwent surgery for ampulla of Vater carcinoma in our department from October 2005 to March 2022. We evaluated the clinicopathological background characteristics (tumor size, gross morphology, pancreatic/duodenal invasion, peripancreatic head lymph node metastasis), overall survival (OS), and relapse-free survival (RFS), and compared the OS and RFS in patients with versus without AC. We then analyzed the factors related to the long-term outcome of patients treated for ampulla of Vater carcinoma. Results: During a median observation period of 33.7 months, the 5-year OS and RFS were 63.1% and 61.7%, respectively. Recurrence was observed in 14 patients (30%), with recurrence occurring less than 1 year postoperatively in seven patients (15%). Fifteen patients received AC (chemotherapy regimen: S-1 in 11 patients, GEM in four). The 5-year OS rates with and without AC were 70.3% and 48.2%, respectively (p=0.093). The 5-year RFS rates with and without AC were 72.5% and 42.8%, respectively (p=0.058). Univariate analysis of the total patient cohort showed that the factors related to 5-year RFS were pancreatic invasion (p=0.01), duodenal invasion (p=0.03), and N+ (p=0.004). In multivariate analysis, the only factor related to 5-year RFS was N+ (HR 3.53; 95% CI, 0.99–12.6; p=0.03). The 5-year OS rates in patients with and without N+ were 77.1% and 42.7%, respectively (p=0.04). The 5-year RFS rates in patients with and without N+ were 80.4% and 32.1%, respectively (p=0.004). Conclusions: AC showed a tendency to be effective in preventing postoperative recurrence of ampulla of Vater carcinoma. AC may be particularly beneficial in N+ cases.
Effect of neoadjuvant therapy pathway (NATP) for pancreatic cancer on overall patient outcomes.
Authors: Cooper Dylan , Sidiqi Baho , Parakrama Ruwan , Demyan Lyudmyla , Pasha Shamsher , Pinto Danielle , Zavadsky Tiffany , Zou Xianghui , Patruni Sunita , Kapusta Adrianna , Standring Oliver , Nosrati Jason , Tchelebi Leila T , Weiss Matthew John , Herman Joseph M. , King Daniel
Published: January 2023

695

Background: Significant variation exists in the management of potentially resectable pancreatic ductal adenocarcinoma (PDAC) across healthcare systems. We describe the results of a newly implemented neoadjuvant therapy pathway (NATP) in New York’s largest, most diverse health care system. Methods: The NATP was established in June 2019, consisting of a single-day pancreas multi-disciplinary clinic (PMDC) visit, followed by neoadjuvant therapy (NAT), imaging at specific intervals, and PMDC re-reviews at two and four months, prior to consideration of radiation and surgical resection. We conducted an IRB-approved retrospective analysis of patients enrolled in this pathway. Primary endpoints included completion of NATP and overall survival (OS). Results: The cohort consisted of 67 patients reviewed at PMDC and planned for NAT: 45% men, mean age 69.9 years, and 43% non-White between June 2019 and February 2022. Surgical stage at diagnosis was locally advanced (LAPC) 48%, borderline resectable (BRPC) 37% and resectable (RPC) 15%. Of 67 patients, 55 began the NATP (9 transferred care, and 3 declined NAT) and 28 (51%) completed NATP and underwent surgical exploration. Ten completed NATP and did not become surgical candidates, and 2 are still undergoing NAT. NATP was not completed in 15 patients due to 11 metastases (73.3%), 3 deaths (20%) and 1 local progression (6.7%) during NAT. NAT consisted of gemcitabine/nab-paclitaxel (GnP, 28%; 201 total cycles), FOLFIRINOX (45%; 251 total cycles), or a combination of both regimens (26%) with 31 (56%) patients receiving radiotherapy (97% SBRT). Of 28 patients who were explored, 86% underwent successful resection (62.5% R0, 16.7% R1 < 1mm and 20.8% R1). With median follow-up of 12.6 months, there were 17 deaths (31%) and median OS was reached at 20.9 mo (95% CI 10.5, 31.2); GnP vs. FOLFIRINOX median OS were 12.7 mo (95% CI 7.8, 17.6) vs. 26.1 mo (95% CI 9.3, 42.9) (p = 0.026). Median OS was not reached for the resected patients vs.16.3 months for non-resected (p = 0.006). Pathway adherence was seen in 28 (53%), with adherence improving median OS 20.9 mo vs. 16.3 mo (p = 0.039). NATP completion improved median OS 26.1 mo vs. 15.9 mo (p < 0.001). The percentage of patients that remained within the Northwell Health system for their post-NAT was higher among patients in the pathway, compared to prior (87% versus 44%). Conclusions: Implementation of NATP for pancreatic cancer within a single healthcare system increased the percentage of PDAC patients who underwent surgical resection and improved patient retention rate. Our data lay the foundation for further analysis of long-term outcomes of NAT in these patients.
The association of the CARE Frailty Index with survival among older adults with pancreatic cancer.
Authors: Kumar Vinod , Williams Grant Richard , Giri Smith , Outlaw Darryl Alan , Akce Mehmet , Dotan Efrat , El-Rayes Bassel F. , Harmon Christian , Tucker Abigail , Reddy Sushanth , Rose J. Bart , Dudeja Vikas , Hashmi Salila
Published: January 2023

699

Background: Outcomes of older adults with pancreatic cancer are highly variable with increased susceptibility to chemotherapy toxicities and inferior survival compared to younger patients. Determining which older adults are at higher risk for adverse outcomes remains a clinical challenge. We evaluated the association of a novel patient-reported geriatric assessment (GA)-based frailty index with survival among older adults with pancreatic cancer. Methods: Older adults (≥60y) referred for initial consultation at the UAB GI oncology clinic were prospectively enrolled in the Cancer and Aging Resilience Evaluation (CARE) registry. All patients underwent a patient-reported GA capturing multiple aging-related domains of health. The 44-item CARE frailty index (CARE-FI) based on the principles of deficit accumulation was utilized to determine frailty. The primary outcome was overall survival (OS) from the time of GA. Kaplan Meier method was used to estimate OS and comparisons between groups were by log-rank. A multivariate Cox regression model adjusted for age, sex, race, and cancer stage. Results: A total 254 older adults with pancreatic cancer were included; median age 70y, 52.4% male, 77% non-Hispanic white and 43.4% with stage IV disease. Overall, 40.1% (n=102) were frail, 26.0% (n=66) pre-frail and 33.9% (n=86) robust. No significant clinico-demographic differences across the 3 frailty groups were found. Differences in OS over two-year period was observed across the three frailty groups by the KM method ( p=0.008). In multivariate cox regression, frail status was associated with an increased risk of mortality (HR 1.9 [95% CI 1.19 – 2.98]; p=0.01) compared to robust status after adjustment for aforementioned confounders. Conclusions: The CARE-FI is a novel frailty index built on the principles of deficit accumulation using a patient-reported GA and is independently associated with survival among older adults with pancreatic cancer.[Table: see text]
Calculator for detection of colorectal adenomas by using artificial intelligence models in patients with chronic hepatitis C.
Authors: Gogtay Maya , Singh Yuvaraj , Yekula Anuroop , Abraham George M.
Published: January 2023

70

Background: Hepatitis C virus (HCV) is known for its oncogenic potential, especially in hepatocellular carcinoma and non-Hodgkin lymphoma. On review, several studies have indicated that patients with chronic hepatitis C (CHC) have an increased risk of developing colorectal cancer (CRC). We developed an artificial intelligence (AI) based tool using machine learning (ML) algorithms to help stratify these patients into a higher risk of CRC/adenomas. Methods: The study was approved by the institutional review board. We developed an AI automated calculator uploaded to a graphical user interface (GUI), and we applied ML to train models to predict the probability and the number of adenomas detected on colonoscopy. Data collected were age, smoking history, significant alcohol consumption, aspirin intake, ethnicity, HCV status, gender, body mass index (BMI), and colonoscopy findings. The models can operate either in the presence or absence of the above parameters. Data sets were split into 70:30 ratios for training and internal validation. Scikit-learn StandardScaler was used to scale values of continuous variables. We used the colonoscopy findings as the gold standard and applied a deep learning architecture to train six ML models for prediction. The ML models used were Support Vector Classifier, Random Forest, Bernoulli Naïve Bayes (BNB), Gradient Boosting Classifier (GBC), Logistic Regression, and Deep Neural Networks. Additional regression models were trained and tested to predict the number of polyps. A Flask (customizable python framework) application programming interface (API) was used to deploy the trained ML model with the highest accuracy as a web application. Finally, Heroku was used for the deployment of the web-based API to https://adenomadetection.herokuapp.com. Results: Data was collected for 415 patients, of which only 206 had colonoscopy results. On internal validation with the remaining patients, BNB predicted the probability of adenoma detection with the highest accuracy of 56%, precision of 55%, recall of 55%, and F1 measure of 54%. Support Vector Regressor (SVR) predicted the number of adenomas with the least mean absolute error (MAE) of 0.905. Conclusions: Our AI-based tool shows an association between CHC and colorectal adenomas. This tool can help providers stratify patients with CHC for early referral for screening colonoscopy. Along with giving a numerical percentage, the calculator can also comment on the number of adenomatous polyps a gastroenterologist can expect while doing a colonoscopy, thus prompting a higher adenoma detection rate.
Efficacy of the third-line chemotherapy in patients with advanced pancreatic cancer.
Authors: Kim Bomi , Ahn Jinwoo , Jung Jae Hyup , Jung Kwangrok , Lee Jong-Chan , Hwang Jin-Hyeok , Kim Jaihwan
Published: January 2023

711

Background: First-line FOLFIRINOX or gemcitabine plus nab-paclitaxel (GNP) have improved the survival outcomes of patients with advanced pancreatic cancer (APC) and nano-liposomal irinotecan (nal-IRI) plus 5-FU/leucovorin is proven as the second-line agents. The current study aims to assess the efficacy of the third-line palliative chemotherapy in APC. Methods: Medical records were retrospectively reviewed in a single tertiary hospital between 2012 and 2020. The enrolled patients have APC who received the first and second-line chemotherapy. To fine the efficacy of the third-line chemotherapy, Kaplan Meier curve with cox-regression analysis was performed. Results: Of total 1,152 patients with pancreatic cancer, 362 patients were enrolled. Of these, 125 received the third-line chemotherapy and 238 received only supportive care after progression of the second-line chemotherapy. Median age at diagnosis was 60.3 years (range 36.0 – 86.0) and males were 52.0%. The first-line chemotherapy regimen was FOLFIRINOX (85, 68.0%), GNP (33, 26.4%), and others (7, 5.6%). The second-line chemotherapy regimen was GNP (55, 44.0%), FOLFIRINOX (34, 27.2%). As the third-line regimen, TS-1 and nal-IRI plus 5-FU/leucovorin were 73 (58.4%) and 20 (16.0%). The median overall survival (OS) from diagnosis was 18.0 months in all patients (95% CI, 14.6 – 21.4). The median OS after progression of the second-line therapy were 15.1 (95% CI, 12.8 – 17.5) and 8.5 weeks (95% CI, 7.7 – 9.4, p=0.007) between the patients with the third-line chemotherapy and supportive care only. Of the patients with the third-line chemotherapy, female showed the significant longer OS than male (12.4 (95% CI 10.2-14.6) vs. 6.6 weeks (95% CI 13.4-19.7), p=0.042). Conclusions: The current study suggested that proceeding with the third-line chemotherapy could be recommended in some patients. Females showed significantly more benefit than males. Further research on the selection for patient who will get the benefit from the third-line therapy is necessary.
Internet-based assessment tools for predicting colorectal cancer risk: How do they communicate individualized risk to the young adult?
Authors: Janak Allison , Peacock Oliver , White Michael , Guraieb-Trueba Montserrat , Nguyen Sa Thi , Alshenaifi Jumanah , Kopetz Scott , Johnson Benny , Smith Grace L. , Chang George J. , You Y. Nancy
Published: January 2023

72

Background: Online prediction tools for cancer risk can inform individuals about their risk and potentially encourage adoption of risk-modifying health behavior. The Colorectal Cancer Risk Assessment Tool (CCRAT) is an interactive tool developed by the National Cancer Institute for estimating colorectal cancer (CRC) risk for individuals between the ages of 45 and 85 without high risk predisposing conditions. Given the rising incidence of CRC among young adults under age 50, we aimed to investigate the performance of CCRAT in estimating their CRC risk. Methods: An institutional protocol prospectively enrolled 563 patients newly diagnosed with non-hereditary CRC and administered a health behavior questionnaire at baseline. Self-reported demographics, diet and physical activity, medication use, and family history were extracted and entered into the CCRAT ( https://ccrisktool.cancer.gov/calculator.html ) to calculate their predicted 5-year and lifetime CRC risks. Health behaviors and the predicted CRC risks in reference to the population average were compared among three groups: youngest- (aged 18-44, N = 276, 49%), young- (aged 45-50, N = 178, 32%), and older-onset (aged > 50, N = 109; 19%). Results: The patient groups did not significantly differ in gender or in family history of CRC, but the youngest group had significantly more non-White patients (27, 22, vs. 19%; p = 0.008) and distal tumors (80, 76 and 65%; p = 0.05). The youngest and young groups had a higher prevalence of morbid obesity (18 and 15% vs. 12%; p = 0.002) and active smokers (6 and 8% vs. 3%; p = 0.005). There were no significant differences in vegetable intake, moderate exercise, NSAID use, or female hormone use. The 5-year CRC risk was correctly predicted as “higher than average population” for a significantly smaller proportion of the youngest (42%) and young (45%) patients, when compared to their older counterpart (71%; p < 0.001). Similarly, the tool communicated “higher than average” lifetime risk for CRC in only 56 and 60% of the youngest and young patients, but 72% of the older ones (p = 0.021). Conclusions: The existing risk prediction tool inadequately communicated CRC risk for adults younger than 50 years of age. Risk factors underlying young-onset CRC likely differ from and extend beyond those as currently assessed. New tools capturing age-specific risk factors are needed to accurately communicate individualized risk and potentially motivate risk-modifying lifestyles.
Effects of losartan and vitamin D on outcomes in metastatic pancreatic adenocarcinoma.
Authors: Adika Adam , Ioffe Dina , Connors Meghan , Duboy Emily C. , Sorice Kristen A. , Hasler Jill , Lynch Shannon M. , Cukierman Edna , Reddy Sanjay S. , Astsaturov Igor A. , Dotan Efrat
Published: January 2023

723

Background: Active modification of surrounding stroma is a critical mechanism of tumor cell growth in pancreatic ductal adenocarcinoma (PDAC). There is some early translational evidence that losartan (L) and vitamin D (D) may affect the tumor microenvironment and supportive stroma in PDAC to help restore a physically and biologically tumor-suppressive stroma. These effects of potentially stroma-modifying drugs have not been established in the clinical management of metastatic PDAC (mPDAC), where there have been limited advances in treatment and prognosis remains poor. Methods: This is a single center, retrospective analysis of patients with mPDAC treated at Fox Chase Cancer Center from 2010 to 2019. All data including L and D use were extracted from the medical record. Patient characteristics were compared across subgroups using Chi-square tests, Fisher’s exact tests, and Wilcoxon rank sum tests. The primary outcome was overall survival (OS) from the time of metastatic diagnosis. Kaplan-Meier curves and log-rank tests were used to compare unadjusted OS across subgroups. Cox proportional hazards models were used to characterize OS adjusted for age at metastatic diagnosis, sex, initial stage at diagnosis, performance status, Charlson Comorbidity Index (CCI), hypertension, and renal disease. Results: 518 patients were included; a majority were male (54.1%), White (82.4%), and diagnosed with de novo mPDAC (54.6%). About half of patients had hypertension (53.5%) and few had renal dysfunction (5.6%). 153 (29.5%) patients were taking D and 41 (8%) patients were taking L. Women were more likely to take D than men (p < 0.001) and White patients were more likely to take L than other races/ethnicities (p = 0.006). Median OS since metastatic diagnosis for patients taking L was 11.4 months compared to 9.6 months for patients not taking L (p = 0.07). Median OS for patients taking D was 11.3 months compared to 8.7 months for those not taking D (p = 0.10). A Cox proportional hazards model adjusting for confounders, however, showed that both L (HR 0.66, p = 0.02) and D (HR 0.81, p = 0.04) were significantly associated with improved OS from time of metastatic diagnosis. Conclusions: This large retrospective study demonstrates potential clinical and survival benefit of L and D in conjunction with mPDAC treatment. L and D are safe, well tolerated, and widely used in general medical practice. These results support further investigation of the stroma-modifying potential of L and D, as well as conducting prospective trials with these agents to further validate these findings.
Irreversible electroporation as treatment option within a multidisciplinary approach for locally advanced pancreatic cancer.
Authors: Ricker Ansley Beth , Iannitti David A
Published: January 2023

727

Background: The treatment plan for patients diagnosed with locally advanced pancreatic cancer (LAPC) is developed by a multidisciplinary team by which systemic chemotherapy is employed followed by surgical resection. Strategies that provide local control in LAPC patients who demonstrate stability/regression without metastasis have gained increasing attention. Irreversible electroporation (IRE) is a non-thermal ablative approach that employs short, high-voltage electrical pulses to create permanent nano-defects in the tumor cell membrane resulting in lethal disruption of tumor cell homeostasis while preserving the integrity of the underlying vascular architecture. This study sought to review IRE outcomes at a high-volume, single institution hepato-pancreato-biliary surgical center. Methods: After obtaining institutional review board approval, data for patients treated with IRE was retrieved from the electronic medical record from 2013-2022. IRE in situ is defined as non-thermal ablation to a tumor without resection. Margin enhancement IRE is defined as non-thermal ablation to residual tumor that could not be resected in its entirety within the adventitial plane. IRE assisted resection is defined as non-thermal ablation to a tumor encasing surrounding structures to allow for complete resection. Results: A total of 101 IREs have been performed at our institution from 2013-2022. Demographics for our cohort include 48 (47.5%) female patients, an average age of 63 years (range 43 – 84), and an average BMI of 26.4 kg/m2 (range 17 – 47). Of these IRE operations, 27 (26.7%) were in-situ, 35 (34.7%) were margin enhancement, and 50 (49.5%) were assisted resections. 2.0% and 11.9% died within 30 and 90 days of the operation, respectively. Median disease-free survival for our patient cohort was 15 months (range 0 to 74). 1-year, 3-year, 5-year, and overall survival for the three cohorts are shown. Conclusions: Using IRE in patients presenting with LAPC provides additional treatment options to the standard treatment pathway. Further classifying IRE use to in situ, margin enhancement, and assisted resection and incorporating these procedures into a multidisciplinary treatment approach has the potential to improve survival rates for appropriately selected LAPC patients. [Table: see text]
Pressure-Enabled Drug Delivery (PEDD) of a class C TLR9 agonist in combination with checkpoint inhibitor therapy in a murine pancreatic cancer model.
Authors: Capacio Benedict , Shankara Narayanan Jayanth , Vicente Diego , Liu Yujia , LaPorte Jason , Cox Bryan , Jaroch David , Katz Steven , White Rebekah Ruth
Published: January 2023

729

Background: Systemic immunotherapy has had limited clinical benefit in pancreatic ductal adenocarcinoma (PDAC). This is thought to be due to its desmoplastic immunosuppressive tumor microenvironment in addition to high intratumoral pressures that limit drug delivery. Recent pre-clinical cancer models and early-phase clinical trials have demonstrated the efficacy of toll-like receptor 9 agonists (TLR9a), including the synthetic CpG oligonucleotide SD101, to stimulate innate and adaptive immune cells and eliminate suppressive myeloid cells. We hypothesized that Pressure Enabled Drug Delivery (PEDD) via Pancreatic Retrograde Venous Infusion (PRVI) of a TLR9a would improve responsiveness to systemic anti-programmed death receptor-1 (PD-1) checkpoint inhibitor therapy in a murine orthotopic PDAC model. Methods: Murine PDAC (KPC4580P) tumors were implanted into the pancreatic tails of C57BL/6J mice and treated 8 days after implantation. Mice were assigned to PRVI saline (pSAL, n=9), systemic anti-PD1 100 mcg/mouse on Day 0, 2 and 4 (sAPD1, n = 6), 30mcg PRVI TLR9a (pTLR9a, n=9), 30mcg systemic TLR9a (sTLR9a, n=7) on Day 0, and combination 30mcg PRVI TLR9a on Day 0 and systemic anti-PD1 100 mcg/mouse on Day 0, 2 and 4 (COMBO, n =9). Fluorescently-labeled TLR9a (radiant efficiency [RE]) was measured on day 1. Blood and tumors were collected at necropsy 12 days after infusion. Results: All mice survived to necropsy. Site of tumor fluorescence measurements revealed higher intensity fluorescence in pTLR9a compared to sTLR9a (7.5x10^5 vs. 2.4x10^5 RE, p= 0.048). Significantly lower MDSCs in the COMBO vs. pSAL are shown. Tumor weights were significantly lower in the COMBO group compared to pSAL (400 vs. 964 mg, p=0.003), and were also lower, although not significantly, than in the pTLR9a (400 vs. 518mg, p=0.50), and sAPD1 (400 vs. 645 mg, p = 0.70) groups. Conclusions: PEDD of TLR9a by PRVI with systemic anti-PD-1 demonstrated improved PDAC tumor control. These results support study of this combination therapy in PDAC patients and expansion of ongoing PEDD clinical trials. [Table: see text]
Prognostic indicators of KRAS G12X mutations in pancreatic cancer.
Authors: Ardalan Bach , Ciner Aaron , Baca Yasmine , Darabi Sourat , Kasi Anup , Lou Emil , Azqueta Jose Ignacio , Xiu Joanne , Nabhan Chadi , Shields Anthony Frank , Pishvaian Michael J. , Korn Wolfgang Michael , Goel Sanjay
Published: January 2023

735

Background: We have studied the role of KRAS mutations in relation to the prognosis in patients with advanced pancreatic ductal adenocarcinoma (PDAC). KRAS is a well-described oncogenic driver in PDAC, with mutations identified in over 90% of cases, typically involving codon 12. The three predominant missense variants include G12D, G12V and G12R. PDAC has the highest rate of G12R mutations compared to other malignancies, comprising 15-20% of KRAS-mutated tumors. This study presents a new finding in the progression of advanced PDAC utilizing a large clinical and genomic database to further characterize the clinical features of pathogenic KRAS variants in PDAC with a focus on G12R. Methods: PDAC samples were tested using whole transcriptome sequencing (WTS; Illumina NovaSeq) and NextGen DNA sequencing (NextSeq, 592 Genes and NovaSEQ, WES) at Caris Life Sciences (Phoenix, AZ). Transcriptomic signatures including MPAS (MAPK activation score), T-cell inflamed score and tumor micro environment (TME) characterization were calculated on WTS data. Significance was determined by X2 and Fisher-Exact and p adjusted for multiple comparisons (q) was < 0.05 (Benjamini-Hochberg). Real-world overall survival (rwOS) was obtained from insurance claims data and calculated from tissue collection to last contact; time-on-treatment (TOT) was calculated from start to finish of specific treatments; comparison was done by Kaplan-Meier test. Results: A total of 5,555 patients with PDAC harboring either KRAS G12D (n = 2,671), G12V (n = 1,871) G12R (n = 904) or G12C (n = 109) variants were identified. The patients with KRAS G12R mutant tumors had significantly longer median real-world overall survival (mRWOS) compared to G12D (452 vs 358 days, HR 0.82, CI 0.74 – 0.9, p < 0.0001). This difference persisted regardless of treatment with FOLFIRINOX or gemcitabine plus nab-paclitaxel. There was no difference in outcomesbetween patients with KRAS G12R, G12V or G12C. PD-L1 expression was significantly lower in G12R than in G12C or G12D (13% vs 27% vs 19%,) while the prevalence of TMB-H and dMMR was comparable across isoforms. Conclusions: Patients with KRAS G12R variants has improved rwOS compared to G12D irrespective of the chemotherapy regimen administered. Immune profiling suggested that the immune contexture in G12R-driven tumors are distinct from G12D as reflected by reduced PDL1 staining, decreased levels of multiple checkpoint receptors. We aim to further explore the molecular basis for these differences with a focus on PI3K and MAPK pathways. Based on this data, survivorship studies in patients with advanced PDAC should consider reporting KRAS mutational status.