bluuebunny/crossref_metadata_2025_split huggingface dataset:
Homologous recombination deficiency (HRD) alterations as a predictor of responsiveness to combination pancreatic cancer in advanced pancreatic ductal adenocarcinoma (PDAC).
Authors: Randall Jamie , Cannon Timothy Lewis , Wadlow Raymond Couric , Wang Hongkun , Winer Arthur 
Published: June 2022

e16259 Background: Advanced PDAC is associated with a poor prognosis and median survivals of less than one year. FOLFIRINOX and Gemcitabine/Nab-Paclitaxel are both considered standard of care in the first line setting, though there is considerable variability among oncologists regarding sequencing of these regimens. Pre-clinical and clinical data support the use of platinum therapy in HRD+ PDAC, but little is known about how this translates into best practices regarding sequencing of treatment or clinical benefit relevant to Gemcitabine based therapies in this population. Methods: Using the cancer registry and Inova molecular tumor board database, we retrospectively reviewed all patients from January 2015 until November 2021 with unresectable PDAC who had NGS performed and stratified by the presence or absence of HRD mutation. HRD mutations included by BRCA1, BRCA2, PALB2, ATM, ATR, CHEK2, ARID1A, FANCA, FANCL. We analyzed for RR to Folfirinox/Folfox and Gemcitabine based therapies, adjusted time to progression on Folfirinox/Folfox (time from first dose of oxaliplatin based combination to first dose of gemcitabine to account for those who stopped oxaliplatin early for neuropathy or received maintenance therapy), and time on gemcitabine based therapy. Results: 142 consecutive patients with advanced PDAC were examined, including 20 with HRD variants. When excluding those who eventually received surgery and those who never received platinum therapy, we were left with 87 (74 in Control and 13 in HRD) for analysis. RR to Folfirinox/Folfox was 60% in HRD+ and 31.25% in control (p = 0.71) (Table). Mean adjusted time to progression on Folfirinox/Folfox was 320.0 days in HRD+ group and 252.9 in the control group (p = 0.57) (Table 2). The time on treatment for gemcitabine based combination therapy was 260.7 in HRD+ and 165.1 in control group. Conclusions: HRD+ patients had longer durations of treatment on both 5-FU based therapy and Gemcitabine based combinations. These data challenges the importance of first line platinum therapy in HRD+ patients, and further exploration should be considered.[Table: see text]
A novel RAS inhibitor for pancreatic ductal adenocarcinoma.
Authors: Arshad Tariq 
Published: June 2022

e16263 Background: Pancreatic cancer has a dismal survival rate and no good therapeutic options. Of all types of cancer, it is Pancreatic cancer that is most closely associated with activating mutations in the RAS oncoprotein. Approximately 90% of pancreatic adenocarcinomas carry point mutations activating RAS. Ras directed targeted therapy is the obvious approach to enhancing treatment options for the disease. There is now an FDA approved targeted RAS therapeutic specific to the RAS12C mutant form. However, this particular mutation is uncommon in Pancreatic cancer. Therefore, drugs which act more broadly on RAS are required. There are currently no approved pan-RAS inhibitors. We have developed a small molecule pan-RAS inhibitor which binds directly to all forms of RAS. It acts to block the ability of RAS and to bind and signal through its effectors. It is active in vitro and in vivo against multiple models of pancreatic cancer. Methods: In silico screening of a virtual compound library was performed to identify an initial candidate inhibitor. Iterative rounds of Medicinal Chemistry informed by structural modeling and bioassay in 3D vs 2D growth assays were performed to identify an enhanced activity derivative. Target binding was confirmed by Microscale Thermophoresis and NMR. RAS/RAF complex status was measured by co-immunoprecipitation of the endogenous proteins. Ras signaling was assayed by Western analysis of Phospho-ERK and RAL-GTP pull down assays. In vitro activity was measured using 3D soft agar assays. In vivo activity was measured by ip or po administration against pancreatic tumor cell line xenografts and pdx systems. Results: The current lead, designated RAS-F binds all three main isoforms of RAS at low uM kd and modulates the RAS effector domain in NMR studies. It suppresses RAS signaling pathways in transient assays and suppresses pancreatic tumor cell growth in soft agar with IC50s below 500nM. It suppresses xenograft development of human and mouse RAS driven pancreatic tumor cell lines and reduces the growth of a pancreatic cancer pdx. Conclusions: We have developed a pre-clinical pan-RAS inhibitor that is active in vitro and in vivo against pancreatic cancer models. Funding: NIH 5U01HL127518-03, Kentucky Lung Cancer Research Program (GJC), Qualigen Therapeutics LLC.
Deep learning on time series laboratory test results from electronic health records for early detection of pancreatic cancer.
Authors: Park Jiheum , Artin Michael , Lee Kate E , Pumpalova Yoanna S , Ingram Myles , May Benjamin , Park Michael , Hur Chin , Tatonetti Nicholas 
Published: June 2022

e16268 Background: Pancreatic cancer (PC) has a uniquely poor survival rate due to the absence of proven and effective methods for early detection. We thus aimed to leverage recent advances in deep learning towards the task of inferring early risk of PC from longitudinal laboratory test data contained within Electronic Health Records (EHR) data. Methods: In this study, we develop a novel deep learning framework for incorporating longitudinal clinical data from EHR to infer risk for PC. This framework includes a novel training protocol, which enforces an emphasis on early detection by applying an independent Poisson-random mask on proximal-time measurements for each variable. Data fusion for irregular multivariate time-series features is enabled by a “grouped” neural network (GrpNN) architecture, which uses representation learning to generate a dimensionally reduced vector for each measurement set before generating a final prediction. These models were evaluated using EHR data from Tripartite Request Assessment Committee (TRAC). Results: Our framework demonstrated better performance on early detection (AUROC 0.671, CI 95% 0.667–0.675, p < 0.001) at 12 months prior to diagnosis compared to a logistic regression and a feedforward neural network baseline (black-box model). We demonstrate that our masking strategy results greater improvements at distal times prior to diagnosis, and that our GrpNN model improves generalizability by reducing overfitting relative to the feedforward baseline (Table). The results were consistent across reported race. Conclusions: Our study presents new approaches for integrating multimodal longitudinal clinical data with bias reduction strategies which results in improved early detection of PC. This study demonstrates for the first time the utility of multivariate time series laboratory test results for early detection of PC. Our proposed algorithm is potentially generalizable to improve risk predictions for other types of cancer and other diseases where early detection can improve survival. We split data into train set (80%) and hold-out set (20%) and presented mean AUROC and AUPRC with 95% confidence intervals.[Table: see text]
Metabolomics in advanced pancreatic cancer (PC) patients (pts) achieving weight stability on enteral feeding for cachexia.
Authors: Akinsola Rasaq , Muranaka Hayato , Hendifar Andrew Eugene , Osipov Arsen , Moshayedi Natalie , Thomassian Shant , Stotland Aleksandr , Parker Sarah , Van Eyk Jennifer , Devkota Suzanne , Bhowmick Neil , Gong Jun 
Published: June 2022

e16291 Background: We previously showed that enteral feeding was associated with weight stability and compositional changes in the gut microbiome with increased abundance of the gram-negative genera Veillonella over time. Here, we evaluated the potential of plasma metabolites as predictors of weight stability and high Veillonella abundance in enteral fed pts. Methods: The PANCAX-1 (NCT02400398) prospective trial enrolled 31 cachectic advanced PC pts to receive jejunal tube peptide-based diet for 12 weeks (wks) who were planned for standard chemotherapy. In preplanned exploratory analyses, serial blood samples were collected over 12 wks of enteral feeding. Up to 219 plasma metabolites were analyzed by mass spectrometry and high-performance liquid chromatography. Analytes were compared by relative area under the curve (AUC) and differences evaluated by two-sample t-tests. Pts were stratified by weight stable (WS, defined as weight change < 0.1 kg/baseline BMI-unit over 12 wks of enteral feeding) vs. weight unstable (WU) and high (HV) vs. low Veillonella (LV) abundance (defined by dichotomizing at the mean relative abundance in WS pts). Results: Of 31 cachectic pts enrolled into PANCAX-1, a total of 55 blood samples were collected from 28 pts for plasma metabolomics. Out of 16 evaluable pts, 62.5% receiving enteral feeding met the primary endpoint of weight stability at 12 wks. Plasma metabolomics in 10 pts showed that WU pts (n = 4) had significantly decreased levels of essential amino acids (AAs, L-histidine, L-phenylalanine) and non-essential AAs (L-citrulline, L-tyrosine, all p < 0.05) than WS pts (n = 6) at the end of 12 wks of enteral feeding. In 7 WS pts with complete serial sets of blood samples available, enteral feeding over 12 wks was associated with increases in markers of muscle mass (creatinine) but decreases in nucleotide precursors (all p < 0.05) compared to baseline. Comparison of baseline metabolites between 6 WS pts with HV and 4 WU pts with LV showed that HV was associated with increases in the nucleotide dCDP and essential AA L-isoleucine but decreased TCA cycle metabolite alpha-ketoglutarate (all p < 0.05). Decreases in lactic acid was observed at 12 wks of enteral feeding in HV pts when compared to baseline (p < 0.05). Conclusions: Our findings are hypothesis-generating in that metabolites unique to weight stability and Veillonella abundance may inform future studies of anti-cachexia therapies involving enteral feeding or microbial modulation.
The mutational pattern of DNA damage repair pathway in pancreatic cancer patients.
Authors: Song Yanfang , Wang Huina , Liu Huanhuan , Zhang Yanrui , Li Mingwei , Lou Feng , Cao Shanbo 
Published: June 2022

e16293 Background: Besides BRCA1/2, there are various genes involved in DNA damage repair that could predict patients’ response to treatments such as platin-based therapy, PARP inhibitors, and immunotherapy. While the mutational pattern of DNA damage repair (DDR) gene alterations in pancreatic patients remains unknown. Methods: Tumors and blood samples from 490 pancreatic patients were analyzed with next-generation sequencing (NGS) that covered 808 genes. Patients were classified based on the presence or absence of deleterious mutations across a panel of 98 DDR genes. Results: 70.4% (345/490) pancreatic cancer patients harbored DDR gene pathogenic mutations (mut). Among DDR-mut patients, 84.6% (292/345) had only somatic DDR gene alterations, 6.4% (22/345) had only germline DDR gene alterations, and 9.0% (31/345) had both. The most frequently mutated somatic DDR genes were TP53 (73.9%), CDKN2A (17.1%), ARID1A (10.1%), ATM (4.1%), and BRCA2 (4.1%). The most commonly mutated germline DDR genes were BRCA2 (4.1%), RAD51B (2.0%), ATM (2.0%), FANCE (0.9%), PALB2 (0.9%). Among the functional pathways of DDR genes, the most commonly mutated pathways were others (77.2%), FA (10.1%), CCC (7.7%), HR (1.5%), NHEJ (1.4%), MMR (1.4%), and BER (0.8%). No patients were found to harbor mutations in NER, TLS, and DR pathways. In addition, the mean TMB was significantly higher in the DDR-mut group compared with the wild-type DDR (wt) group (6.2 vs. 5.0 muts/Mb; p < 0.05). No significant difference in microsatellite instability was observed between DDR-mut and DDR-wt patients (p = 0.67). In terms of HRD status, 87.5% (28/32) HRD-positive patients and 73.1% (19/26) HRD-negative patients had DDR gene mutations. No significant difference in DDR variants was found between HRD-positive and HRD-negative patients, suggesting that HRD detection is necessary for DDR-mut patients. Within individual DDR genes, CDKN2A mutation was significantly associated with HRD-positivity (p < 0.05) whereas BRCA1, BRCA2, ATM, and PALB2 were not. Conclusions: An expanding set of DDR genes profiling provides more therapeutic opportunities for pancreatic patients who might benefit from PARP inhibitor owing to pathogenic mutations in DDR genes. This retrospective study may serve as a benchmark for the future design of an expanded association study between DDR mutations and the therapeutic outcome of pancreatic cancer.
KRAS mutation detection and cfDNA in liquid biopsy as prognostic factors in pancreatic adenocarcinoma.
Authors: Fabregat-Franco Carles , Matito Judit , Martin Agatha , Verdaguer Helena , Castet Florian , Aymar Josep Maria Miquel , Castillo Gloria , Sierra Alexandre , Vivancos Ana , Macarulla Teresa 
Published: June 2022

e16302 Background: Approximately 80% of pancreatic ductal adenocarcinoma (PDAC) patients present with advanced disease at diagnosis, with a 5-year survival rate of less than 5%. According to molecular profiling, mutations in KRAS have been described in 90% of PDAC patients, and correlated with poor prognosis. Nevertheless, the invasiveness of tumor biopsy and the difficulties in obtaining quality samples in some patients remains a concern. Circulating free DNA (cfDNA) is considered a surrogate marker of tumor burden and may also act as a prognostic factor that can be used independently from tumor biopsy. In this study, we aim to explore molecular prognostic biomarkers using plasma samples. Methods: Patients with metastatic PDAC harboring KRAS mutation in tissue samples and treated with first-line chemotherapy were identified at Vall d’Hebron University Hospital. Clinical features and plasma samples were collected before starting any treatment. DNA mutations were analyzed in plasma and compared with tissue samples. In plasma, detection of KRAS mutation and total cfDNA concentration were evaluated for clinical significance. A cfDNA minimum 100 genome equivalent threshold was proposed based on results and utility. A Chi-square test was planned to prove the independence between cfDNA levels and KRAS detection in plasma. Survival analysis was performed using the Kaplan-Meier method. Results: We included 33 PDAC patients with a median age of 66.1 years old, 57% were women. All of them were treated with gemcitabine and Nab-paclitaxel. At the final analysis cut-off, 31 patients had died . KRAS mutation was detected in 25 patients’ blood samples (75.8%) and cfDNA-High levels were considered for 20 patients (60.6%). 19 of 20 (95%) patients with cfDNA-High correlated with KRAS blood detection, showing significant dependence (p-value 0.001). Median overall survival (OS) was 10.5 months in the KRAS detected group compared with 22.6 months in the KRAS non-detected group (HR for death 4.70; confidence interval (CI) 1.70-12.98, p-value 0.002). Better separation was seen using cfDNA where median OS was 9.8 months in the cfDNA-High group compared with 21.0 months in the cfDNA-Low group (HR for death 5.38; CI 2.17-13.31, p-value < 0.001). Conclusions: Liquid biopsy can provide quality prognostic information in metastatic PDAC patients. On account of this, the cfDNA level is proposed as a prognostic factor. However, prospective cohorts to validate this information are needed.[Table: see text]
A multivariate logistic model to predict odds of small bowel cancer by various risk factors.
Authors: Franco Diana , Farooq Umer , Rehman Mohammad Ebad Ur , Ma Irene 
Published: June 2022

e16307 Background: Small bowel cancer (SBC) is a rare malignancy, and current epidemiologic literature consists of small single-center studies describing various etiologic associations. Therefore, we evaluated the strength of association of various SBC risk factors using a nationally representative patient sample. Methods: We investigated the National Inpatient Sample 2019 employing International Classification of Diseases-10 (ICD-10) codes to include adult patients with SBC. Odds of SBC were tested for various risk factors individually using univariate logistic regression. In addition, a multivariate regression model was developed to test the odds of developing SBC while controlling for all other risk factors. Analyses were performed using STATA (v 14.2), considering 2 sided P< 0.05 as statistically significant. Results: Out of 30,200,000 adult hospitalized patients in 2019, 9,629 had a diagnosis of SBC. Each one-year increase in age predicted a 4% increased odds of SBC. Males had 28% higher odds compared to females. Compared to whites, Blacks and Asians had higher odds of SBC while Hispanics did not. Smoking, alcohol, HIV, and low socioeconomic status were associated with higher odds of SBC while controlling for all other risk factors ( P < 0.05). Disorders of lipid metabolism, hormone replacement therapy, prior cholecystectomy, celiac disease were associated with lower odds. Crohn’s disease, familial adenomatous polyposis (FAP), and Lynch syndrome were not significantly associated with higher odds of SBC ( P > 0.05). Conclusions: FAP and Lynch syndrome appear to increase the risk of polyp formation in the small intestine but not SBC. The lower odds mentioned for certain variables are merely an association and do not imply a protective effect. The reliance on ICD-10 codes and the inability to distinguish between various cancer subtypes limits our conclusion and needs to be addressed in future studies.[Table: see text]
Identification of molecular feature in tumor immune microenvironment of bladder cancer patients.
Authors: Cao Ming , Xue Wei , Zhang Jiali 
Published: June 2022

e16500 Background: Bladder cancer (BC) is the most common malignant tumor of the urinary system, with various heterogeneity. Immunotherapy has become one of the hot areas of cancer research. Tumor immune microenvironment is closely related to prognosis and immunotherapy effect. Therefore, Immune cell infiltration analysis is necessary for the prognosis and treatment of BC. Methods: In this study, we analyzed IMvigor210 dataset, which included complete expression data and detailed clinical information from a cohort associated with Bladder Urothelial Carcinoma (BLCA) immunotherapy. The dataset was divided into two groups based on tumor remission after immunotherapy, including 68 remission samples and 230 stable samples. The CIBERSORT program package was used for immune invasion analysis to compute the relative proportion of immune cells in the tumor tissue from tissue gene expression profiles. Results: Significant results of differentially immune cells proportion were obtained in 126 BC patients by CIBERSORT analysis ( p< 0.05). Compared with the stable group, the number of resting memory CD4+ T cells decreased and the number of CD8+T cells increased in the remission group. The relative proportion of immune cells in tumor microenvironment has certain influence on the occurrence and development of tumor. Conclusions: Memory CD4+ T cells in the resting state did not promote the activation and proliferation of CD8+ T cells, whereas resting memory CD4+ T cells were associated with poor outcome. The increased level of CD8+ T cells in tumor microenvironment was associated with the anti-tumor effect and improved prognosis of various cancers. The results indicate that resting memory CD4+ T cells and CD8+ T cells may be the target of immunotherapy.
Real-world outcomes in advanced renal cancer patients treated with stereotactic radiosurgery for intracranial metastases.
Authors: Fatimilehin Abiola , Mahabubabinta Hossain , Stephen Kennedy , Pillai Manon Rhys , Charnley Natalie 
Published: June 2022

e16516 Background: The proportion of metastatic renal cancer (mRC) patients with intracranial involvement is 8%, and 2% develop brain secondaries exclusively [1]. Although renal cancer is generally regarded as relatively radioresistant, studies have shown patients treated with stereotactic radiosurgery (SRS) demonstrate a local progression free survival (PFS) rate of 79-84% at 1 year and median overall survival (OS) of 9.6 – 13.9 months [2,3]. We evaluate the outcomes of patients with mRC who have received SRS to intracranial metastases at two tertiary centres in the North West of England. Methods: Patients who received SRS from January 2017 to July 2019 at Royal Preston Hospital, and from May 2016 to March 2021 at the Christie were retrospectively identified from the database of the respective hospitals. Clinical records were used to obtain demographics, therapies received and follow up data. Results: A total of 41 patients were identified. 31 patients (76%) were male and the average age at treatment was 59.6 years. 5 patients received treatment on >1 occasion, but only the first episode was considered for analysis. 80.4% had a performance status of 0-1 and most patients had clear cell histology. 19 patients (46.3%) had lesions treated bilaterally. The median follow up time was 11 months. Prescribed doses ranged between 18Gy to 30Gy in 1-5 fractions. 11 patients (26.8%) progressed during the follow up period, with a median time to progression of 5 months. The longest time to progression was 17 months, in a patient who received Nivolumab following SRS. 28 patients (68.3%) died during the follow up period with a median time to death of 9.1 months. Median OS was 11 months, with 19 out of the 28 patients (67.9%) dying within the first year. The 1 year survival rate was 52.6% and 2 year survival rate was 16.2%. A range of systemic agents were used pre and post SRS including immunotherapy. 6 patients (23%) commenced immunotherapy following SRS (nivolumab +/- ipilimumab), with OS ranging from 6 – 49 months (average 25.5 months). Conclusions: We found that outcomes in this cohort of patients treated with SRS were comparable to previous findings. A subgroup who commenced Nivolumab following SRS demonstrated an average survival of over 2 years.[Table: see text]