bluuebunny/crossref_metadata_2025_split huggingface dataset:
Proteomic quantification of HER-2 abundance and activation in pancreatic ductal adenocarcinoma tumor specimens using reverse phase protein array.
Authors: Randall Jamie , Cannon Timothy Lewis , Hunt Allison L , Nutcharoen Aratara , Johnston Laura , Wang Hongkun , Wadlow Raymond Couric , Winer Arthur , Huynh Jasmine , Bateman Nicholas W. , Davis Justin B , Corgiat Brian , Petricoin Emanuel , Conrads Thomas P. 
Published: June 2023

e16299 Background: Pancreatic adenocarcinoma (PDAC) is associated with poor survival and low response rates to available therapies, warranting a critical need for new treatment paradigms. Enrichment of tumor epithelium via laser microdissection (LMD) prior to reverse phase protein array (RPPA) analysis allows for the quantitative measurement and functional assessment of the activation state of protein drug targets. As part of an IRB-approved Molecular Tumor Board study at Inova Schar Cancer Institute, we harvested enriched tumor epithelium using LMD to support CLIA-based RPPA analysis of patients with pancreatic, breast, and other solid tumor malignancies to examine quantitative expression and activation (phosphorylation) of HER-2/3 and other known cancer-related pathways. Methods: Formalin fixed paraffin embedded (FFPE) primary and/or metastatic tumor biopsy specimens were obtained from 14 patients with PDAC, 14 patients with breast cancer, and 40 patients with other solid tumor malignancies. Tumor epithelium (5-10 µm2) was enriched via LMD prior to RPPA analysis for quantification of HER-2Total and phosphorylated (p)HER-2Y1248 and (p)HER-3Y1289 abundances as part of a 32-marker, CLIA-based RPPA panel examining the total and phosphoprotein abundances of targets with known relevance in solid tumors. Next generation sequencing (NGS; DNA-seq and RNA-seq) was performed on remaining tissue from each specimen. Fisher’s Exact test was used to compare activated HER2Total, pHER2Y1248 and pHER3Y1289. Results: RPPA analysis of LMD enriched tumor samples revealed significant HER-2Total expression in patients with PDAC vs other solid tumors (p=0.0112), with HER-2Total levels comparable to those measured in patients with breast cancer (p=0.0962). The mean HER-2Total abundances in PDAC, breast, and all other solid tumor malignancies were 1.6, 1.3, and 0.9, respectively. Activated pHER-2Y1248 and pHER-3Y1289 abundances did not differ between patients with PDAC vs all other solid tumors or between patients with PDAC vs breast cancer (p>0.05). RNA-seq analysis revealed ERBB2 overexpression in four of the 14 PDAC patients, while ERBB2 amplification by DNA-seq was not observed in any of the PDAC cases. Conclusions: HER-2 expression is not routinely evaluated in clinical practice in PDAC, but our results show higher median expression in PDAC than our solid tumor cohort, with nearly 50% of PDAC cases having total HER2 expression of 2+ or above. Our results may have clinical implications, especially as new classes of HER2 antibody drug conjugates are considered for patients with HER2 non amplified tumors across organ sites, and justify further investigation in a larger cohort. Clinical trial information: U20-11-4308 . [Table: see text]
Effect of locoregional injection of RNA oligonucleotide targeting carbohydrate sulfotransferase 15 on both tumoral and lymph node MDSCs and T cell infiltration in pancreatic tumor in mice.
Authors: Ye Juanjuan , Suizu Futoshi , Yamakawa Keiko , Kato Motohiko , Tsuchiya Takayoshi , Yoneyama Hiroyuki , Yahagi Naohisa 
Published: June 2023

e16310 Background: Carbohydrate sulfotransferase 15 (CHST15) is a proteoglycan biosynthetic enzyme and is responsible for tumor matrix remodeling. Intratumoral injection of CHST15 siRNA was shown to increase tumor-infiltrating T cells in patients with pancreatic cancer in the phase I/IIa study. However, the mechanism underlying the enhanced T cell accumulation is not fully explored. Here we investigated the effect of locally injected CHST15 siRNA on modulating tumor immune microenvironment in mice. Methods: For in vivo pharmacokinetics after a single local injection of CHST15 siRNA to normal C57BL/6J mice, RNA oligonucleotides were isolated from tissues and detected by HPLC. Mouse pancreatic cancer KPC cells were implanted subcutaneously into the left hind footpad of syngeneic C57BL/6J mice and the tumor growth was monitored. From week 1, intratumoral injections with 1 mg/mL of CHST15 siRNA or vehicle were performed twice a week for 2 weeks and mice were sacrificed at week 3. In separate experiments, human BxPC-3 cells were implanted subcutaneously in T cell-deficient nude mice, and the effect of intratumoral injections of CHST15 siRNA or vehicle for 2 weeks was also investigated. Immunohistochemical staining was performed for the tumor and tumor-draining lymph node (TDLN). Results: CHST15 siRNA was detectable in not only the local sites but also the draining LNs of normal mice 1 and 4 hours after locoregional injection. In the KPC-implanted syngeneic mouse model, CHST15 siRNA showed significant tumor growth inhibition compared to the vehicle. In tumor, CHST15 was expressed by tumor cells, and to a lesser extent, Ly6C/G+ MDSCs. CHST15 siRNA altered tissue remodeling by repressing dense fibrotic architecture and NETosis. CHST15 siRNA significantly diminished Ly6C/G+ MDSCs while increasing CD4+ and CD8+ T cells. In TDLN, CHST15 was expressed by Ly6C/G+ MDSCs. Locally injected CHST15 siRNA markedly diminished Ly6C/G+ MDSCs, while increasing Ki-67+ proliferating CD4+ and CD8+ T cells. In the BxPC-3-implanted nude mouse model, locally injected CHST15 siRNA repressed excessive fibrosis and NETosis in tumor, diminishing both tumoral and TDLN MDSCs, but tumor growth inhibition was marginal. These results suggest that locally injected CHST15 siRNA could enter into TDLN, directly diminishing CHST15+ MDSCs, and expanded T cells. Tumor growth inhibition was largely T-cell medicated. Conclusions: The present study demonstrated that CHST15 siRNA locally and remotely diminished MDSCs, leading to the enhancement of anti-tumor T cell activity. A novel role of locally-delivered RNA oligonucleotide is suggested.
Circulating tumor DNA (ctDNA) and disease recurrence in early stage pancreatic cancer.
Authors: Gong Zimu , Esmail Abdullah , Abdelrahim Maen 
Published: June 2023

e16313 Background: Surgical resection with neoadjuvant and/or adjuvant chemotherapy remains to be the cornerstone in treatment for early-stage pancreatic adenocarcinoma. Disease recurrence after curative intent treatment remains to be very common, and early detection of disease recurrence remains challenging. Recent studies explored the role of ctDNA in guiding adjuvant treatment in colon cancer, but its role in pancreatic cancer remains unknown. Methods: Through comprehensive chart review, we identified patients who: 1. Diagnosed with early-stage pancreatic adenocarcinoma; 2. Underwent curative intent surgery at our institution from 2019 to 2021; 3. Have postoperative tissue informed ctDNA results with commercially available assay (Signatera, by Natera Inc). Results: A total of 14 patients, including 7 males and 7 females, were included in the study. Depending on location of tumor, types of surgery included Whipple procedure (N = 13) and distal pancreatectomy (N = 1). The median age at time of surgery was 62 years (Range: 41-83 years). Two patients received neoadjuvant chemotherapy, and 13 patients received adjuvant chemotherapy. Two patients also received adjuvant radiation. A total of 41 ctDNA readings were obtained. The median time from surgery to first ctDNA assay was 2.4 months. First post-op ctDNA was positive in 6 patients, all of whom received adjuvant chemotherapy but still experienced clinical recurrence after a median of 3.7 months. The median overall survival of those ctDNA+ patients was 11.4 months. In the remaining 8 patients, the median progression free survival was 14 months, with clinical recurrence being observed in 4 patients. Median overall survival was not reached at median follow up of 30.5 months (one patient died at 6 months without disease recurrence, and another died at 14 months with progressive disease). In the 4 patients who had clinical recurrence despite initially negative ctDNA, ctDNA turned positive 1 month before clinical recurrence in 1 patient. However, in the other 3 patients, recurrence occurred 3.1, 1.9 and 3.5 months after the most recent negative ctDNA result. Conclusions: Our study demonstrated that positive ctDNA reliably predicts clinical recurrence in early-stage pancreatic cancer after surgery, with a positive predictive value of 100%. Negative result appears to be less reliable. This may be explained by different shedding pattern and test sensitivity. Larger scale study is underway to further evaluate its role in determining prognosis and guiding adjuvant treatment.
miRNAs targeting RAS and their clinical relevance in resected pancreatic adenocarcinoma (PC): Results from a prospective study.
Authors: Lavacchi Daniele , Caliman Enrico , Pillozzi Serena , Polvani Simone , Scolari Federico , Boddi Anna , Pasqui Adriano , Fancelli Sara , Giommoni Elisa , Pellegrini Elisa , Vannini Agnese , Brugia Marco , Pugliese Lavinia , Messerini Luca , Taddei Antonio , Moraldi Luca , Galli Andrea , Antonuzzo Lorenzo 
Published: June 2023

e16314 Background: Pancreatic adenocarcinoma (PC) is one of the big killers with a 5-year disease-free survival (DFS) rate of 19-26% after resection despite adjuvant treatments. KRAS mutations have been reported in approximately 90% of PC cases and, beyond KRAS activation by gene mutations, several miRNAs directly targeting KRAS have been reported to be simultaneously downregulated, strengthening the already activated RAS signaling. In addition, the interplay between miRNAs and RAS includes downstream miRNA effectors whose role needs to be elucidated. The aim of this study was to evaluate the expression of candidate miRNAs strictly related to KRAS expression in order to elucidate the prognostic value. Methods: In this single-center observational prospective study we included patients with pathologically confirmed PC, who underwent radical surgery and were referred to the Clinical Oncology Unit, Careggi University Hospital, Florence (Italy), between 2015 and 2022. Total RNA was extracted from FFPE sections, retro-transcribed and the resulting cDNA was then used for qPCR analysis. Results: Among 44 patients included in the study, 34.1% were male and 65.9% female (median age 75 years). The majority of cases had the primary tumor located at the head of the pancreas (65.9%) and the pathological stage was pT1-2 in 45.5%, pT3 in 54.5%, pN0 in 22.7%, pN+ in 77.3%. Overall, 63.6% of patients received adjuvant chemotherapy and 69.0% experienced disease recurrence. Twenty-three specimens were adequate for miRNA analysis. A different expression of the three target miRNAs between PC and healthy tissue was observed: miR-155 was overexpressed and miR-206 downregulated in PC, while miR-143 had a similar expression in both tissues. miR-143 overexpression was associated with nodal involvement (pN+) at the pathological examination (p = 0.029). Among clinicopathological features, pN+ was associated with shorter DFS (p = 0.009) and overall survival (OS) (p = 0.021) compared to pN0. A trend toward inferior DFS was observed for higher expression of miR-206 (p = 0.095) and miR-143 (p = 0.092). Among patients receiving a first-line treatment for advanced disease, miR-155 was overexpressed in responders vs non-responders (p = 0.048). Conclusions: miRNA expression is involved in tumorigenesis and metastatic spread in PC. A comprehensive analysis of the miRNA-RAS interplay deserves to be further investigated as a predictor of clinical outcome, especially for miR-143 overexpression which was associated with lymphatic spread and, consequently, poor prognosis.
A single-institution analysis of a rare variant of pancreatic neoplasm-osteoclastic giant cell tumor.
Authors: Kesireddy Meghana , Asif Samia , High Robin , Yu Fang , Krishnan Mridula 
Published: June 2023

e16315 Background: Pancreatic osteoclastic giant cell tumor (OGCT) is a rare variant (<1% cases) of pancreatic neoplasm. Due to its rarity, prospective studies on management are limited. The prognosis and molecular characteristics may differ from pancreatic adenocarcinoma. Methods: We analyzed demographics, clinical features, treatment modalities, and outcomes of overall survival (OS) and progression-free survival (PFS) in patients with pancreatic OGCT at our institution from 2005-2022. Results: We identified 8 OGCT patients with a median age of 67, of whom 7 had locoregional disease (resectable- 5, borderline resectable- 1, locally advanced-1), and 1 had denovo metastatic disease at diagnosis. The borderline resectable and locally advanced patients eventually developed metastatic disease. The majority of patients were male (n=5), Caucasian (n=7), former smokers (n=5), had no significant alcohol use (n=8) and had no pre-existing pancreatitis (n=8). 4 of the 5 resectable patients had surgery, and 2 received adjuvant chemotherapy. The median OS was 54 months for locoregional disease (n=5) vs.16 months for metastatic disease (denovo metastatic and progression to metastatic disease, n=3). The median OS was 54 months for surgical resection (n=4) vs. 25 months for those without surgical resection (n=4) based on quartile computations from the Kaplan-Meier survival curve. Conclusions: Our patients had a longer OS than the previously reported OS of less than 12 months for all stages of pancreatic OGCT. There was no progression in resectable patients, indicating an indolent disease with an overall good prognosis. Patients with locoregional disease or those who underwent surgical resection had longer OS, but due to the small sample size and censored patient survival times (i.e., patients still alive), the statistical significance of this trend could not be calculated. Studies are required to understand tumor biology and determine the optimal multidisciplinary treatment. [Table: see text]
In-hospital outcomes of patients with pancreatic cancer and venous thromboembolism.
Authors: Sanghvi Ankushi , Nanavaty Dhairya , Bansal Kannu , Yekula Anuroop , Narayan Gayatri , Janamejey Fnu , Shah Shailja 
Published: June 2023

e16317 Background: Pancreatic cancer accounts for about 3.2% of all new cancers in the US. It has dismal 5-year relative survival of 11.5% and accounts for 8.2% of all cancer deaths. Studies have shown a strong association of pancreatic cancer with venous thromboembolism (VTE). However, data surrounding outcomes associated with VTE in this population is limited. We aim to estimate the effect of VTE on mortality and healthcare utilization in this population. Methods: We queried the National Inpatient Sample (NIS) 2017-2019 for all adult patients with a diagnosis of pancreatic cancer. The cohort was further classified by the presence of VTE (either acute deep vein thrombosis (DVT) or acute pulmonary embolism (PE)). The primary outcome of interest was in-hospital mortality, and secondary outcomes included hospitalization cost and length of stay, reflecting resource utilization. Multivariable regression analysis was performed to examine the association. Results: Over a period of 3 years, 392,744 admissions were identified with a diagnosis of pancreatic cancer. The mean age was 67 years, and 48% were females. The prevalence of acute DVT and acute PE was 5.0% and 5.8% respectively. In-hospital mortality was roughly 12% in the study cohort who had either DVT or PE. The odds of all-cause mortality were higher in pancreatic cancer admissions complicated by DVT (OR 1.59, 95% CI: 1.34-1.70, p<0.001) or PE (OR 1.39, 95 %CI: 1.23-1.58, p<0.001). The presence of VTE was also associated with higher hospital costs ($17,351 (14,256-20,446, p<0.001) for DVT, and $5,710 (2,679-8,740, p<0.001) for PE and longer hospital stay (7.2 vs 5.7, p<0.001) for DVT and (6.6 vs 5.7, p<0.001) for PE. Conclusions: Our study suggests that the presence of VTE portends poor outcomes in patients with pancreatic cancer. They also increase healthcare expenditure and lead to a longer hospital stay. Current guidelines (2020) recommend against offering thromboprophylaxis to patients with any cancer. Given the worse outcomes, this study reflects the need to formulate risk assessment models for the role of primary thromboprophylaxis in pancreatic cancer.
Predicting the risk of pancreatic cancer in patients with new-onset diabetes based on CT image.
Authors: Zhou Yu , Yang Jiabin , Zeng Liangtang , Wu Lei , Wu Zhuo , Liu Si-Yang , Zheng Shangyou , Chen Changhao , Chen Rufu 
Published: June 2023

e16320 Background: While long-standing diabetes mellitus (LsDM) is an etiologic factor for PC, new-onset diabetes (NoDM) has been considered as a manifestation and harbinger of this cancer as well. Current evidence support that the PC-associated NoDM was mainly caused by disease of the exocrine pancreas, which was different from the typical type 2 DM. Therefore, we hypothesize that, in the NoDM patients, CT image features of “normal” pancreas from PC-associated NoDM patients might be different from that of the new-onset type 2 DM. We sought to develop and validate a risk prediction model to facilitate the distinction between NoDM vs potential early PC-associated NoDM on pancreatic CT imaging. Methods: We retrospectively collected CT imaging from three types of patients at Guangdong Provincial People's Hospital between January 2015 and December 2022: PC patients with pathological diagnosis of pancreatic ductal adenocarcinoma (n=249: 139 patients without DM, 63 patients with NoDM, 47 patients with LsDM), NoDM patients diagnosed with PC within 3 years (n=12), NoDM patients without development of cancer within the next 5 years (n=151). We used four different machine learning algorithms, including support vector machine (SVM), random forest (RF), eXtreme Gradient Boosting (XGB), and generalized linear model (GLM), and gradient boost methods, to build prediction models based on PC pateints and cancer-free NoDM patients. The algorithm with best ROC was used to build a final model, which was validated in the “normal” CT images of NoDM patients prior to their diagnosis of PC within 3 years. Results: In PC cases, the radiomics features exclusive to NoDM-PC cases were selected using a non-parametric test, and 134 radiomics features were retained (86 from arterial and 48 from venous phases, respectively). The RF algorithm showed best prediction skill (AUC of ROC: 0.952). Based on the variable importance measures in the RF algorithm, a risk-scoring model was generated for NoDM patients as a tool to differentiate between PC patients and cancer-free DM patients. As a result of validation, the scores calculated based on the “normal” CT images of NoDM patients prior to their diagnosis of PC within 3 years, were significantly higher than the scores from CT images of NoDM patients who were cancer-free within the next 5 years (P < 0.01). Conclusions: In NoDM patients, even the PC lesion was nonvisible on CT, the radiomics features of “normal” pancreas of PC patients were different from that of the real DM patients. Our model has the potential for identifying individuals with PC in the whole NoDM population.
Impact of cirrhosis on mortality in gastrointestinal malignancies: A retrospective study from nationwide database.
Authors: Pan Chun-Wei , Cuartas Mesa Maria Cristina 
Published: June 2023

e16324 Background: Cirrhosis is a leading cause of death in the United States, and it represents a significant cause of deterioration in the quality of life of patients worldwide. Patients with cirrhosis can be affected by malignant and non-malignant co-morbid conditions, which can impact their prognosis. Among these, gastrointestinal (GI) malignancies like colorectal, pancreatic, and hepatic represent some of the most prevalent tumors affecting the GI tract. As both cirrhosis and cancer rates rise, our study aims to explore the impact of cirrhosis on hospitalization outcomes in gastrointestinal (GI) Cancer. Methods: We used the National Inpatient sample from 2016-2020 and identified admission with a diagnosis of GI cancer using International Classification of Disease-10 codes. The cohort was further stratified into patients with a secondary diagnosis of Cirrhosis compared to those without cirrhosis. All analysis was performed using STATA V17, considering P < 0.05 statistically significant. Multivariate regression analysis was used, and confounding variables adjusted were age, gender, race, insurance, and baseline hospital characteristics. Results: A total of 1,391,165 admissions with GI malignancies were identified from 2016 to 2020. Among these, 272,729 (19.6%) had a secondary diagnosis of cirrhosis, while 1,118,435 (80.4%) did not. The cirrhotic cohort was more likely to be male (71.4%) compared to the non-cirrhotic cohort (55.5%). Cirrhosis was most commonly associated with hepatocellular carcinoma (81.7%), pancreatic cancer (8.1%), and colorectal cancer (5.7%). Patients with cirrhosis have higher mortality rates in various GI cancers. This includes esophageal cancer (17.0%) compared to those without cirrhosis (10.7%), with an adjusted odds ratio of 1.55 (95% confidence interval: 1.02-2.34, P < 0.05). Similarly, higher mortality rates were observed in gastric cancer (15.8%), colorectal cancer (12.6%), hepatocellular carcinoma (11.1%), biliary tract cancer (13.9%), and pancreatic cancer (11.5%) compared to those without cirrhosis, with adjusted odds ratios of 1.63, 2.06, 1.41, 1.78, and 1.41 respectively. Conclusions: In this study of 1.4 million gastrointestinal malignancy-related admissions from 2016 to 2020, 19.6% had a secondary diagnosis of cirrhosis. This cohort of patients had a higher mortality rate in various gastrointestinal cancers than those without cirrhosis. Cirrhosis was more commonly associated with hepatocellular carcinoma, followed by gastric cancer. These findings suggest that cirrhosis is a significant risk factor linked with higher mortality in gastrointestinal malignancy-related admissions. Further research is necessary to characterize this association better in order to improve outcomes for patients with cirrhosis and GI malignancies.