bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association between metastatic pancreatic cancer and environmental quality index.
Authors: Ozer Muhammet , Goksu Suleyman Yasin , Khatib Jude , Al Mutar Salwan , Aguilera Todd Anthony , Zeh Herbert , Beg Shaalan Shaalan , Kazmi Syed Mohammad Ali 
Published: June 2022

e16232 Background: Pancreatic cancer ranks as the 3rd leading cause of cancer mortality. Overall more than 50% of patients have metastatic disease at diagnosis. In this study, we evaluated the association between the national level Environmental Quality Index (EQI) and metastatic pancreatic cancer in the US. Methods: Adult patients with pancreatic cancer in the SEER database from 2010-2016 were included in this study. The unknown stage was excluded. Patients were categorized into two groups: metastatic vs. non-metastatic disease. EQI provides county-level environmental quality data from 2005-2010 and presents five domains (built, sociodemographic, air, water, land). EQI was categorized into quintiles, with the 5th quantile representing a poorer environmental quality. We used the multivariable logistic regression analysis to assess the association between EQI quintiles and metastatic pancreatic cancer adjusting by age, gender, and race (White, Black, and Others). In addition, the SEER*Stat was used to evaluate the age-adjusted incidence rate, and the correlation coefficient between EQI domains and incidence rate was calculated. Results: A total of 75,461 pancreatic cancer patients were included; 55% had metastatic disease. In the adjusted multivariable analysis, metastatic pancreatic cancer was associated with poor built EQI (OR 1.06 [1.01-1.11]). Among metastatic pancreatic cancer patients, poor overall EQI was strongly associated with age > 50 years (OR 1.06 [1.01-1.11]) and Black race (OR 1.29 [1.10-1.51]). Lower built EQI domain was associated with > 50 (OR 1.07 [1.02-1.12]) and White race (OR 1.07 [1.02-1.12]). The incidence rate of metastatic pancreatic cancer was positively correlated with total EQI (rho = 0.02, p < 0.001), sociodemographic EQI (rho = 0.23, p < 0.001), land EQI (rho = 0.14, p < 0.001), and air EQI (rho = 0.34, p < 0.001). Conclusions: Using population-based environmental data, we found built EQI to be associated with metastatic pancreatic cancer. Among metastatic pancreatic cancer patients, total environmental quality was associated with older age at diagnosis and the Black race, while built EQI domain was associated with older age at diagnosis and the White race. Environmental quality was positively correlated with the incidence rate of metastatic pancreatic cancer.
Pancreatic cancer germline mutation report: An in-depth analysis of demographics, mutation profile, and patient survival.
Authors: Zou Xianghui , Sidiqi Baho , Patruni Sunita , Hollweg Christopher , Kauff Noah D. , King Daniel 
Published: June 2022

e16233 Background: Germline genetic testing is now recommended for patients with pancreatic ductal adenocarcinoma (PDAC). We explored whether attributes of testing, such as uptake fraction and rate, were associated with various clinical features. Here we examined germline mutations found in our database, identified barriers to germline testing, and explored a relationship between mutations and survival in our cohort of patients from New York’s largest healthcare system. Methods: Patients with PDAC were identified using billing records across our institution with an IRB-approved protocol. Germline mutation data were assessed through chart review. Median income was annotated using zip codes and www.census.gov. Date of diagnosis (DOD) was recorded as the date of biopsy or, if no biopsy was performed, the date of earliest lesion-found CT scan. Lag of testing was calculated as the difference between DOD and the date of germline sample collection. Overall survival (OS) was calculated by mutational status. Results: Between Mar 2016 and Feb 2022, 305 patients with PDAC were identified, with 103 (36.3%) having reports found (F), and 202 (63.7%) not having reports found (NF). Availability of germline testing did not vary by median income (F: 95954 dollars vs NF: 94368 dollars, t = 0.414, p = 0.68). The geographic distribution of patients among F and NF is listed below in Table. Pearson analysis between median income and lag of testing showed a negative correlation (y = -0.0027x+315.6, R = -0.241, p = 0.014). Level of income (cutoff: 100k) also affected the mean days in lag of testing (below: 111.8d, above: -44.0d, t = 2.190, p = 0.031). There was no difference in the median survival between F and NF (median: F: 573d, NF: 717d, HR 0.459-1.155, p = 0.17). For mutational analysis, 103 patients with PDAC were identified: 59 without germline mutations (GMs) (12 deaths), and 44 with GMs (16 deaths). We identified 7 patients with pathogenic GMs (APC, ATM, BRCA2, CHEK2, CDKN2A, and PALB2) and 41 patients with variants of unknown significance (VUS), including ATM (6), BRCA2 (4), MSH6 (3) and CHEK2 (2). OS was not statistically different between GM and no GM (Median OS: no GM 1520d; GM 573d, HR 0.394-1.871, p = 0.702). Conclusions: Analysis of germline and clinical data from our 305-patient cohort identified a striking and concerning negative correlation between patient median income and lag between DOD and germline testing. These results compel further investigation into the operational processes that prompt germline testing at our institution. [Table: see text]
Repurposing HDAC and mTOR inhibitors for pancreatic cancer.
Authors: Biermann Mitch , Quintero Cynthia , Ferguson Paige , Rajbhandari Nirakar , Park Donglim Esther , Patel Hitendra , Reya Tannishtha 
Published: June 2022

e16234 Background: Pancreatic ductal adenocarcinoma (PDAC) will be the second leading cause of cancer death by 2030 through early onset dedifferentiation and metastasis that results in limited treatments. FDA-approved targeted therapies–including proteasome, mitogen-activated protein kinase (MEK), histone deacetylase (HDAC), and mammalian target of rapamycin (mTOR) inhibitors–have shown preclinical benefit but failed in clinic. However, combination targeted therapy has been largely unexplored in clinical trials. We hypothesized based on prior drug screening efforts in the lab on aggressive subtypes of pancreatic cancer that combinations of these targeted therapies could be synergistically active in preclinical PDAC models. Methods: We optimized combinations of proteasome, MEK, mTOR, and HDAC inhibitors by performing cell viability experiments in human PDAC lines in 2D and 3D cell culture conditions in vitro. Optimized drug combinations from these experiments were then trialed in two different in vivo animal models–human FG xenografts in immunocompromised mice (NSG) and spontaneous primary PDAC tumors from transgenic pancreatic-specific Kras-overexpressing, P53-deficient mice (KPC). RNA-sequencing and Seahorse metabolic assays were utilized to analyze molecular mechanisms of drug synergy. Dedifferentiation was assessed by histology of KPC tumors. Results: The HDAC inhibitor Panobinostat and mTOR inhibitor Everolimus synergistically killed human pancreatic cancer cell lines grown in 2D and 3D cell culture in vitro. Synergy was highest at low concentrations of Panobinostat. In vivo, low-dose Panobinostat and Everolimus synergistically blocked growth of human FG xenografts in NSG mice. In vivo synergy of low-dose Panobinostat and Everolimus was highest in the KPC mouse model, where only combination therapy could significantly reduce tumor growth, stall dedifferentiation, and improve survival. Mechanistically, RNA-sequencing of Panobinostat/Everolimus-treated FG cells revealed that Panobinostat increased tumor suppressor genes opposing dedifferentiation such as p21, EGR1, and CCN2. Everolimus complemented Panobinostat by decreasing expression of enzymes metabolizing acetyl groups such as fatty acid synthase, stearoyl-CoA desaturase, and sterol response element binding factors. Functionally, Everolimus’ activity to reduce oxidative consumption increased histone acetylation specifically in the presence of Panobinostat. Conclusions: A combination of FDA-approved, targeted oral therapies (low-dose Panobinostat/Everolimus) is synergistically active in preclinical models of pancreatic cancer in vitro and in vivo. mTOR inhibitors create drug synergy by specifically increasing histone acetylation in HDAC inhibitor-treated cells by reversing HDAC inhibitor de-repression of acetyl/oxidative metabolism, illustrating a novel connection between cancer epigenetics and metabolism.
Outcomes of pulmonary embolism in patients with pancreatic cancer: A nationwide inpatient sample study.
Authors: Obeidat Khaldun , Turk Ekrem , Deenadayalan Vaishali , Weir Catherine , Vakil Jay , Rodriguez Alarcon Pierre Alexander , Batra Kunnal 
Published: June 2022

e16235 Background: Pancreatic cancer is considered one of the most aggressive cancers with five-year relative survival of 10.8% as per the national institute of health (NIH); Thromboembolism is a well-known complication of pancreatic cancer which contributes to increased morbidity, mortality and burden on the health care system. We attempted to evaluate the outcomes of pulmonary embolism in patients with pancreatic cancer. Methods: Healthcare Cost and Utilization Project National Inpatient Sample (HCUP-NIS) was queried to identify Pulmonary embolism admissions between 2016-2018 In Adult patients with diagnosis of pancreatic cancer using International Classification of Disease 10th Revision (ICD-10) codes. We evaluated mortality, Need for ventilation, Tissue plasminogen activator (TPA) administration, Embolectomy, Inferior vena cava (IVC) filter insertion and Acute kidney injury. Secondary outcomes included mean length of stay (LOS) and the mean cost of hospitalization. Results: A total 5335 admissions with PE and Pancreatic cancer were identified; in the baseline characteristics mean age was 67.4 at time of diagnosis with 51% being females and the white race constituted 73% of the total admissions. 385 patients (7%) died during hospitalization,165 patients (3%) required ventilation, 140 patients (2.6%) had TPA administration,560 patient (10.4%) had IVC inserted, 640 patients (12%) developed Acute kidney injury, and none had embolectomy. Mean length of stay was around 5 days and the mean cost of hospitalization was $12405. Conclusions: Pulmonary embolism increases mortality among patients with Pancreatic cancer; in addition to its effect on morbidity and burden on health care system; Efforts should be made to identify those with pancreatic cancer and considered high risk for Venous thromboembolism who may benefit from primary prophylaxis.
Value-based care outcomes in pancreatic cancer patients with and without access to registered dietitians: A retrospective cohort study of patients enrolled in the Oncology Care Model.
Authors: Smith Karen , Hodac Nicole , Jensen Terry Lynn , Torres Vanessa , Ortega Lance , Broussard Stephanie Broadnax , Books Holly , Hudson Kathryn Elizabeth , Hoverman John Russell , Wilfong Lalan S. 
Published: June 2022

e16249 Background: Patients with pancreatic cancer face many nutrition-related concerns, although few guidelines exist to direct clinical nutrition services in this population. Examining quality outcomes for patients in clinics with and without access to a Registered Dietitians (RD’s) can help examine the contributions of RD’s in this area. Methods: A retrospective cohort design was used to compare Total Cost of Care (TCOC), hospital admissions and Length of Stay (LOS), and Emergency Department (ED) and Observation visits for patients with pancreatic cancer who were enrolled in the Oncology Care Model (OCM) during Performance Periods (PP) 1-6 (July 1, 2016–June 30, 2019). Patient deaths during the initial episode of care were also examined. Patients from a geographically concentrated metropolitan hub were divided into cohorts based on clinic access to an RD. Each patient’s initial six-month OCM episode of care was used for analysis. Results: Of the 389 OCM patients identified with pancreatic cancer from PP1-6, 203 were treated at 10 clinics with an RD and 186 in 17 clinics without an RD. In the RD cohort, 43.3% of patients were admitted to the hospital with an average LOS of 8.9 days. By contrast, 52.2% of patients in the non-RD cohort were admitted to the hospital with an average LOS of 10.0 days. TCOC for the 6-month episode was lower in the RD cohort at $37,185 versus the non-RD cohort at $40,907. During the initial 6-month episode of care, 37% of patients in the non-RD cohort died during the initial 6-month episode vs only 28% in the RD cohort. A higher percentage of patients in the RD cohort (35%) had ED or Observation visits, compared with the non- RD cohort (32%). Conclusions: Amongst OCM patients with pancreatic cancers, treatment at a clinic with an RD was associated with lower TCOC, reduced LOS for patients that were admitted to the hospital, and lower percentage of deaths in the first 6-month episode of care. The percentage of patients with ED and Observational visits was slightly higher in the cohort that had access to an RD. This analysis shows the potential benefit of RD services in an outpatient setting and justifies further study. Future multilevel modeling will evaluate the statistical significance of these results.[Table: see text]
TP53 gain-of-function mutations and impact on CDKN2A mutation on prognosis of pancreatic ductal adenocarcinoma.
Authors: Pan Minggui , Jiang Chen , Zhang Zheyang , Achacoso Ninah , Tse Pamela , Solorzano Aleyda , Chung Elaine , Sundaresan Tilak Kumar , Suga Jennifer Marie , Huang Jianliang , Thomas Sachdev P. , Habel Laurel A. 
Published: June 2022

e16294 Background: Developmentally pancreas head derives from ventral bud while pancreas neck, body and tail derive from dorsal bud. Pancreatic ductal adenocarcinoma (PDAC) frequently harbors multiple mutations including KRAS, TP53, CDKN2A, and others. It is unknown how TP53 gain-of-function (GOF) and non-gain-of-function (non-GOF) mutations affect the prognosis. Methods: We retrospectively examined a cohort of 741 Kaiser Permanente (KP) patients with locally advanced/metastatic PDAC who had NGS performed to determine the association of KRAS (mutKRAS), TP53 (mutp53) and CDKN2A (mutCDKN2A) mutations (individually and in combination) with overall survival (OS). We used Cox modeling to estimate hazard ratios (HR) adjusted for age, sex, ethnicity, performance status, Charlston Comorbidity Index, chemotherapy received, anatomic location and co-mutations. We also analyzed the TCGA PDAC dataset to examine the association of OS with these same mutations. Results: In the KP cohort, patient ages ranged from 36 to 94 years and approximately 50% were female. In 384 patients PDAC was on the head, and 357 patients had PDAC on a non-head location (neck, body, and tail). Those with head PDAC had modestly better OS compared to non-head PDAC (HR = 0.87), and this appeared to be driven by the subsets of patients with wtp53 (HR = 0.68), with wtKRAS (HR = .74) and with wtCDKN2A (HR = .78). Approximately 67.5% of patients had mutp53, 89.2% had mutKRAS and 44.8% had mutCDKN2A. Among all KP patients, OS was similar for patients with mutp53 vs. wtp53 (HR = 1.05); worse for patients with mutKRAS vs. wtKRAS (HR = 1.26), and worse for patients with mutCDKN2 vs. wtCDKN2A (HR = 1.51). Interestingly, among patients with a GOF mutp53, those with mutCDKN2A had substantially worse OS vs patients with wtCDKN2A (HR = 2.56, 95% CI 1.46-4.50). In contrast, among patients with a non-GOF mutp53, patients with mutCDKN2A had only moderately worse OS compared to patients with wtCDKN2A (HR = 1.37, 95% CI 1.06-1.79). Analysis of the TCGA PDAC dataset showed that the number of mutations (0, 1, 2, or 3, of p53, KRAS and CDKN2A) was associated with incrementally worse OS ( p < .001). Conclusions: Better OS of head vs. non-head PDAC was primarily driven by patients with wtp53, wtKRAS, and wtCDKN2A. The adverse effect of mutCDKN2A on OS appears to be most pronounced in patients with GOF mutp53. Our TCGA analysis suggests interactions among TP53, KRAS and CDKN2A mutations in affecting PDAC survival.
HALP score as a biomarker for nutritional status to predict overall survival in patients post radical cystectomy.
Authors: Farag Christian Mark , Haji-Momenian Shawn , Whalen Michael Joseph 
Published: June 2022

e16504 Background: Radical Cystectomy (RC) is the gold-standard treatment for recurrent high grade T1 or muscle-invasive bladder cancer. Nutritional status is a well-defined independent predictor of overall survival post-RC. Various prognostic biomarkers have been proposed as surrogates for nutritional status to help predict postoperative outcomes. These biomarkers include albumin, anemia, thrombocytopenia and sarcopenia. Recently, the Hemoglobin, Albumin, Lymphocyte, Platelet (HALP) score has been postulated as an all-encompassing biomarker and has been shown to predict overall survival (OS) post-RC in a single previous study. Due to the paucity of studies looking at HALP and RC outcomes, and optimal cutoffs for HALP have not been defined. Our study sought to analyze and optimize HALP thresholds for OS, as well as examine the Psoas Muscle Index (PMI) as a possible additional predictor that can be used with HALP. Methods: Seventy-three RC patients were evaluated from 2010 to 2021. Of 73 RC patients, 50 had sufficient pre-operative laboratory data to calculate HALP. Sixty-two patients had CT scans to analyze PMI, which was calculated using patient height and the psoas major muscle cross-sectional area measured at the L3 vertebral level. Patient date of surgery, tumor grade and stage, American Society of Anesthesiologists (ASA) Classification, survival status, and date of last contact were extracted from our institutional cancer registry. X-tile software was used to find optimal biomarker cutoffs for HALP. The Cox Proportional Hazards model was used to identify predictors of OS. Results: Median age was 67 (58-74) years, 58 (79.5%) were male, and 36 (49.3%) received neoadjuvant/adjuvant chemotherapy. Forty-seven (64.4%) had pathological stage ≥pT2, 25 (35.7%) had lymph-node involvement, and 4 (5.5%) had palliative surgery. Median HALP score was 28 (21 – 42). Median PMI was 569 (456 –700). Fifty-six (76.7%) had an ASA ≥ 3. Median follow up was 29.3 months (12.0– 51.9). Forty-eight (65.8%) were alive at last follow-up. HALP (continuous variable) was a significant predictor of OS on multivariable Cox regression analysis (HR 0.95, 95% CI 0.90 - 0.99) (P = 0.021), adjusting for age, sex, and node involvement; PMI and ASA were not significant. X-tile analysis showed an optimal HALP cutoff of 25.0. Patients with HALP < 25 had inferior OS (median, 32.5 months) compared with those with HALP ≥ 25 (median, not reached) (P = 0.025). Conclusions: We conclude that patients with low HALP Score were shown to have a significantly inferior OS, with an optimum HALP cutoff of 25.0. We further suggest that the HALP score can be a reliable prognostic biomarker to assist in nutritional management before surgery. PMI was not a significant predictor of OS and did not add value to HALP score. Future studies may investigate better measures of sarcopenia, which could potentially be combined with HALP score to better predict OS in RC patients.
Single cell transcriptomic characterization of natural killer (NK) cell populations in clear cell renal cell carcinoma and association with clinical outcomes.
Authors: Xu Wenxin , Bharadwaj Maheetha , Birch Grace , Schindler Nicholas , Labaki Chris , Saliby Renee Maria , Bakouny Ziad , Freeman Dory , O'Toole Jillian , Lee Gwo-Shu Mary , McGregor Bradley Alexander , Hirsch Michelle S. , Shukla Sachet A. , McDermott David F. , Signoretti Sabina , Romee Rizwan , Choueiri Toni K. , Braun David A. 
Published: June 2022

e16521 Background: Natural killer (NK) cells are thought to play a key role in the immune response against cancer, including clear cell renal cell carcinoma (ccRCC). However, the transcriptomic landscape of NK cells in ccRCC and the mechanisms of NK cell evasion by ccRCC are poorly understood. Methods: We analyzed scRNA-sequencing (10x Genomics) data from tumor specimens and adjacent non-tumor tissue from ccRCC at various clinical stages. Clustering analysis and NK cell lineage markers were used to identify distinct NK cell populations. Differential gene expression analysis was used to characterize each cluster compared to the total population of NK cells. Results were correlated with clinical stage. Gene signatures, derived from NK cell subclusters of interest, were then used to interrogate bulk transcriptomic datasets and associate expression with clinical outcomes. Results: Single-cell RNA-sequencing data was analyzed from 13 patients, corresponding to > 23,000 individual NK cells. Clustering analysis revealed 11 distinct NK cell subsets, including two “resident” NK cell clusters that were enriched among patients with metastatic disease. These clusters expressed CD9, ITGA1/CD49a, and ITGAE/CD103. Further examination of these clusters showed a common panel of differentially expressed genes, including decreased expression of cytotoxicity markers and upregulation of inhibitor checkpoints such as KLRC1/NKG2a. A gene expression signature representing this resident NK cell phenotype was associated with worse overall survival in two large, independent patient cohorts (TCGA and CheckMate-025). Conclusions: Among patients with ccRCC, a retrospective single cell transcriptomic analysis revealed heterogeneous NK cell populations. A seemingly dysfunctional, “resident” NK cell phenotype is enriched among patients with metastatic disease and is associated with worse survival in patients with advanced ccRCC, including those treated with immune checkpoint inhibitors. Restoration of NK cell function could be a future therapeutic opportunity among patients with ccRCC.