bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of silencing tumoral carbohydrate sulfotransferase 15 on T cells in a murine model of pancreatic cancer.
Authors: Ye Juanjuan , Suizu Futoshi , Yamakawa Keiko , Kato Motohiko , Tsuchiya Takayoshi , Yoneyama Hiroyuki , Yahagi Naohisa , Matsuda Yoko 
Published: June 2022

e16241 Background: Limited T cell infiltration within immunosuppressive microenvironment is still a hurdle for immune checkpoint inhibition therapies in pancreatic cancer. Carbohydrate sulfotransferase 15 (CHST15) is a proteoglycan biosynthetic enzyme and responsible for tumor matrix remodeling. To investigate the role of CHST15 on tumor immune microenvironment, we evaluated the changes in tumor immune cell profiling in a syngeneic mouse model by implanting pancreatic cancer cells with silencing of CHST15 gene. Methods: We constructed CHST15 shRNA-transfected mouse pancreatic cancer cell line KPC, confirmed repression of CHST15 protein then used as tumor-specific CHST15 knocked-down KPC (CHST15 KD). Wild-type KPC (WT) or CHST15 KD cells were implanted subcutaneously to left hind footpad of syngeneic C57BL/6J mice and the tumor growth was monitored. Kinetics of immune cell components were analyzed by immunohistochemical staining for both tumor microenvironment and tumor draining lymph node (TDLN) at weeks 1, 2, 3 and 4 after inoculation (n = 5-6 at each time point). Results: In the WT group, tumor growth was accelerated from week 2 to week 4, while the growth was almost completely inhibited in the CHST15 KD group. Quantitative analyses for immune-stained tissues at week 4 showed the significant repression of CHST15 in the CHST15 KD group. This was associated with the significant increase of CD3+, CD4+ and CD8+ T cells in tumor microenvironment, while T cells were barely detected in the WT group. A significant number of EdU+ proliferating T cells and Granzyme+ CD8+ T cells were found in the CHST15 KD group compared to the WT group. In the TDLN, EdU+ CD4+ and CD8+ T cells were diminished at week 2 from week 1 in the WT group, suggesting active T cell suppression occurred at week 2, which was prior to rapid tumor expansion. In strikingly contrast, massive proliferation of CD4+ and CD8+ T cells was observed in the CHST15 KD group from week 2. RNA expression analysis revealed that anti-tumor T cell activity-related genes including recognition of cancer cells by T cells, cancer antigen presentation, killing of cancer cells, were significantly up-regulated in both tumor and TDLN in the CHST15 KD group. These results suggest that tumoral CHST15 remotely provides T cell suppressive signal to TDLN and blockade of CHST15 reactivates T cell immunity, leading to accelerated tumor-infiltrating T cells. Conclusions: The present study demonstrated that blockade of tumoral CHST15 augments the number of activated tumor-infiltrating T cells and inhibits tumor growth in mouse pancreatic cancer. The effect of tumoral T cell accumulation is followed by boosted T cell priming in immune suppressive TDLN. These findings suggest the possibility of a new immunotherapy by enhancing T cell infiltration in refractory pancreatic cancer.
Effect of obesity on time to progression in patients with resectable and potentially resectable pancreatic cancer.
Authors: Asawa Palash , Vusqa Urwat Til , Karna Rahul , Attah Abraham Attah , Sweeney Ryan , Shah Shivani , Jayakrishnan Thejus , Srinivasamaharaj Srividya , Samhouri Yazan , Monga Dulabh K. 
Published: June 2022

e16246 Background: Obesity has been identified as a risk factor for pancreatic cancer. The prevalence of obesity has been on a rise in the last two decades. Obesity is defined by the world health organization (WHO) as body mass index (BMI) > 30.0 kg/m2. Studies have shown obese patients to have worse survival than non-obese patients with pancreatic cancer. However, there is limited data on effect of obesity on disease progression. We sought to identify the relationship between obesity and time to progression in patients with resectable and potentially resectable pancreatic ductal adenocarcinoma (PDAC). Methods: We performed a retrospective review of charts of all patients diagnosed with PDAC from 2017-2019 at Allegheny Health Network. Demographics (including age, sex, and race), treatment details, and time to progression date of diagnosis (rounded off in months) were obtained. Two-sided Mann-Whitney U test and Fischer’s exact test were used to evaluate differences between groups with continuous and categorical variables respectively. Furthermore, paired t test was used to compare mean time to progression between the patients in the obese and non-obese groups. A p-value of < 0.05 was considered as level of significance. Results: Out of the 121 patients who received treatment at our institution, 40 patients who had resectable or potentially resectable disease and had progression of disease were included in the analysis. The median age of patients was 68. The majority were females (60%), Caucasians (90%), had Stage I (65%) and potentially resectable disease (55%). Around 70% of patients were treated surgically, 80% received chemotherapy and 26% received radiation therapy. Twelve out of 42 patients were obese (27.5%). No difference in patient characteristics including demographics, staging, and treatment characteristics (proportion of patients who received surgery, chemotherapy, and radiotherapy) was identified between obese and non-obese group patients. The mean time to progression was 11.9 months in obese group as compared to 13.7 months in non-obese group (p = 0.63). Conclusions: Our study showed no significant difference in time to progression of disease between obese and non-obese patients with resectable/potentially resectable pancreatic cancer. Our study is limited by its small sample size, retrospective nature, and unidentifiable confounding factors that could potentially affect outcomes. Larger scale studies are needed to investigate the effect of obesity as a prognostic factor for disease progression in patients with pancreatic cancer.
MEK-inhibitor (inh) and hydroxychloroquine (HCQ) in KRAS-mutated advanced pancreatic ductal adenocarcinoma (PDAC).
Authors: Mehdi Maahum , Thalji Samih Z , Shreenivas Aditya V. , Chakrabarti Sakti , Thomas James P. , Christians Kathleen K. , Evans Douglas B. , Hall William A. , Erickson Beth , Thapa Bicky , Ahmed Gulrayz , Yazdanpanah Omid , Kurzrock Razelle , Aldakkak Mohammed , Holden Mary Beth , George Ben , Tsai Susan , Oxencis Carolyn , McFall Thomas , Kamgar Mandana 
Published: June 2022

e16260 Background: Therapeutic inhibition of constitutive signaling mediated by mutated KRAS in PDAC remains a challenge except for modest success reported with KRAS G12C inhibition. A combinatorial strategy utilizing simultaneous MEK and autophagy inhibition holds therapeutic promise based on mechanism of action and preclinical data. We described characteristics and outcomes of patients (pts) treated with MEK-inh and HCQ at our institution. Methods: Ten KRAS-mutated advanced PDAC pts were treated with trametinib-HCQ (n = 9) or cobimetinib-HCQ (n = 1) off label due to lack of standard treatment options or toxicity concerns with cytotoxic systemic therapy. Trametinib dose was 2 mg once daily orally, Cobimetinib dose was 20 mg BID orally for 3/4 weeks cycles. HCQ was started at 200 mg BID and up-titrated weekly to 600 mg BID. Description of baseline and treatment (tx) characteristics, safety and efficacy is provided. Results: Median age at diagnosis was 61.3 years, and 7 pts were female. The number of prior lines of tx were 0/1/2/3/4 in 3/2/1/2/2 pts, respectively. KRAS mutations were: G12R/G12D/G12V/Q61H in 6/2/1/1 pts. Median overall survival was 6.6 months (m) in all pts, and 6.6/1.7 m in KRAS G12R/other KRAS (p = 0.31). Median progression-free survival was 5.7/6.2/1.5 m in all/ KRAS G12R/other KRAS (p = 0.16). Among 8 pts with evaluable response, 1 (12%) had partial response ( KRAS G12R) and 4 (50%) stable disease (3/4 KRAS G12R) as best response with disease control rate of 63%/80%/33% in total/ KRAS G12R/other KRAS (p = 0.29). Toxicity data are summarized in table 1. Conclusions: MEK-inh-HCQ demonstrated modest efficacy and manageable toxicities among KRAS G12R PDAC pts. Unlike G12D and G12V mutations in the KRAS gene, G12R is defective of conductive interactions for both PI3Ka and NF1. This ultimately results in a weakened signal being shunted through MAPK cascade and provides a unique opportunity where MEK inh can ablate signaling without the alternate pathways and WT-RAS isoforms compensating. Furthermore, as activation of PI3Ka is known to suppress autophagy, its lack of activation by KRAS G12R further sensitizes cells to HCQ. The combination therapy MEK-inh-HCQ is therefore mechanistically-rationale and warrants the further investigation of KRAS G12R as an actionable biomarker.[Table: see text]
Genomic landscape and clonal evolution between adenocarcinoma and squamous components in adenosquamous carcinoma of the pancreas.
Authors: Wang Zheng , Guo Shiwei , Jiang Yina , WU Yinying , Wu Zheng , Ma Qingyong , Wang Yan , Zhang Liwen , You Dong 
Published: June 2022

e16265 Background: Adenosquamous carcinoma of the pancreas (ASCP) is a rare histological subtype of pancreatic cancer with high metastasis rate and poor prognosis, which is characterized by a variable proportion of adenocarcinoma and squamous carcinoma components with at least 30% of the tumor showing squamous differentiation. To get further insight into the tumorigenesis and progression, we profiled the genetic characterization and explored the evolutionary model of this subtype. Methods: A total of 10 patients with ASCP were enrolled. For each sample, glandular and squamous carcinoma tissues were separated by microdissection. Whole exome sequencing for 20 samples with matched peri-carcinomatous tissues were performed by next-generation sequencing. Results: Genetic profiling revealed that top 5 mutated genes of adenocarcinoma and squamous components were highly consistent including TP53 (100% vs 100%), KRAS (100% vs 90%), CDKN2A (40% vs 40%), KDM6A (20% vs 20%) and LRP1B (20% vs 20%). KEGG pathway analysis showed that PI3K-Akt, MAPK and FoxO signaling pathways were the most frequently mutated pathways in adenocarcinoma. In contrast, Apelin and Rap1 signaling pathways were highly mutated in squamous components, advocating that these pathways may play important roles in the transformation of squamous carcinomas. A higher proportion of indels were identified in adenocarcinoma than squamous components (12.1% vs 3%). The chromosome regions of 3p21.3, 9p21.3, 11p15.5, 16p13.11 and 21q22.3 were the most commonly deleted regions in the adenocarcinoma components, while losses of 1p36.21, 3p25.3, 3q13.13, 6p22.3 and 11p15.5 had been observed in the squamous components. Some of these regions had important effects on development and progression of cancer. For example, 9p21.3 had well-established impact on cell proliferation and apoptosis containing two crucial tumor suppressor genes, CDKN2A and CDKN2B. Additionally, the C > T mutation was predominant among the 6 types of single nucleotide variations. Most common signatures were related to aging (Single base substitutions, SBS1), BRCA1/2 mutations and responders to platinum therapy (SBS3), and defective DNA mismatch repair (SBS6). Tumor evolution analysis showed that the glandular and squamous components shared a common origin. There were two evolutionary scenarios in the early stages of tumor evolution, with a third of nine patients ware parallel evolution and the remaining patients were linear evolution. KRAS (100%), TP53 (66.7%) and TTN (33.3%) were frequently identified as clonal mutations. Conclusions: This is the first study to elucidate the genomic alteration as well as the clonal evolution using whole-exome sequencing in ASCP patients. It provides evidence for more comprehensive understanding of pathophysiology of ASCP at genomic level, which could contribute to the amelioration for ASCP patients’ management.
Real-world data comparing FOLFIRINOX versus gemcitabine nab-paclitaxel as first-line treatment of metastatic pancreatic ductal adenocarcinoma patients in the United States.
Authors: Klein-Brill Avital , Amar-Farkash Shlomit , Lawrence Gabriella , Collisson Eric Andrew , Fisch Michael Jordan , Aran Dvir 
Published: June 2022

e16271 Background: The common first-line therapies for metastatic adenocarcinoma of the pancreas (mPC) are FOLFIRINOX and gemcitabine plus nab-paclitaxel (Gem-Nab-P). However, these treatments have not been directly compared in a clinical trial and comparative real-world data analyses on their effectiveness are limited. Using real-world data, we evaluated the impact on overall survival and post-treatment hospitalizations of 1L FOLFIRINOX vs. Gem-Nab-P in individuals with mPC. Methods: We performed a retrospective cohort study of 1L treatment of patients with mPC between 1/2015 and 6/2020, utilizing administrative claims data from the Anthem Cancer Care Quality Program. Real-world overall survival (rwOS) was defined as time from diagnosis to death. Inverse probability of treatment weighting (IPTW) was used to adjust for age, ECOG, Socioeconomic index (SDI), comorbidity, metastatic sites and pre-treatment. Median rwOS was estimated using the weighted Kaplan-Meier method. Results: Our cohort included 1,102 1L mPC patients, 566 (51.4%) treated with FOLFIRINOX (F), and 536 (48.6%) treated with Gem-Nab-P (GNP). F-treated patients were generally younger, with better performance status (ECOG PS), fewer comorbidities and living in regions with higher socioeconomic index. Following adjustments, the Median rwOS was 9.28 and 6.82 months for F-initiated patients and GNP, respectively (p-value = 2.5e-07). This survival benefit of F was observed among all sub-groups, including different ECOG PS, ages, socioeconomic index and metastatic sites. F-treated patients also had fewer post-treatment hospitalizations (p-value=0.027) and lower post-treatment costs (p-value=0.00004). Conclusions: Our retrospective cohort study demonstrated that FOLFIRINOX is associated with improved survival of approximately 2 months over Gem-Nab-P and is also associated with fewer post-treatments complications. A randomized controlled trial comparing these first line treatments is warranted to test the survival and post-treatment complications benefit of FOLFIRINOX over Gem-Nab-P.[Table: see text]
Machine learning based detection of pancreatic tumors using the Dxcover cancer platform.
Authors: Baker Matthew , Sala Alexandra , Cameron James Munro , Christie Loren , Conn Justin , Palmer David 
Published: June 2022

e16275 Background: Pancreatic cancer is the 7th most deadly cancer worldwide with over 460,000 victims per year. In the current diagnostic pathway, carbohydrate antigen (CA) 19-9 serum test is the blood assessment used for detection of pancreatic cancer; although, with poor positive predictive values reported, it is not specific for pancreatic tumors as its levels can be raised in symptomatic patients with other benign comorbidities and/or because of other tumors in the surrounding area. Attenuated total reflection–Fourier transform infrared spectroscopy (ATR-FTIR) has demonstrated exceptional potential in human blood serum analysis for cancer diagnostics and its implementation in the clinical environment could represent a significant step forward in the early detection of pancreatic cancer. This proof-of-concept study aimed to investigate the use of the Dxcover cancer liquid biopsy as a novel approach for pancreatic cancer detection. Methods: The study was focused on the discrimination between both cancer (n = 100) versus healthy control samples (n = 100), and cancer (n = 35) versus symptomatic non-malignant control samples (n = 35) from patients with comorbidities and/or confounding diseases. Various machine learning algorithms were applied to discriminate between the classes: random forest (RF), partial least squares-discriminant analysis (PLS-DA) and support vector machine (SVM). Receiver operating characteristic (ROC) analysis was also employed to evaluate the classes’ degree of diagnostic separability. Permutation tests were performed for each classification in order to ensure their statistical significance. Results: Cancer (n = 100) and healthy control samples (n = 100) were distinguished with excellent results, achieving results up to a sensitivity of 91.0 %, specificity of 87.6 %, and accuracy of 89.3 % with PLS-DA. Moreover, an area under the curve (AUC) equal to 0.954 was obtained through ROC analysis. When discriminating between cancer (n = 35) and symptomatic control samples (n = 35), accuracy values were recorded in the range between 70.6 and 77.3 % with ROC analysis showing a balanced sensitivity and specificity over 75 % with an AUC of 0.844. Both discriminations were proven statistically significant. Conclusions: Pancreatic cancer detection in early stages would be key in improving prognosis and survival rates of patients, through targeted earlier surgery and treatments. The Dxcover cancer liquid biopsy could represent a powerful tool in the clinical environment as an easy-to-use, minimally invasive and reliable spectroscopic blood test for detection of pancreatic cancer.
Efficacy and the safety of endoscopic ultrasound guided radiofrequency ablation of pancreatic cancer: A systematic review and meta-analysis.
Authors: Ehsan Hamid , Masood Adeel , Wahab Ahsan , Ahmed Zahoor , Franco Diana , Rafae Abdul , Yousaf Muhammad Nadeem 
Published: June 2022

e16276 Background: Endoscopic ultrasound-guided RFA (EUS-RFA) is a minimally invasive emerging modality that may be an alternative to surgical resection for the management of unresectable pancreatic cancer (UPC). In this review, we highlighted the efficacy, clinical and technical success of the EUS-RFA for UPC. Methods: Studies were selected with a comprehensive search strategy for EUS-RFA and pancreatic cancer on PubMed, Google Scholar, and Embase databases as of October 2021. The primary outcomes were the technical (TS) and clinical success rate (CS) of the EUS-RFA procedure, while the secondary outcome was the adverse events (AEs) rate. Results: Twelve studies including 114 patients with 50% (57) females were included. Common pancreatic tumors were locally advanced pancreatic ductal adenocarcinoma (LAPDAC) 38.3% (49), followed by nonfunctional neuroendocrine tumor (NNET) 32% (41), pancreatic cystic neoplastic lesions 14.8% (19), insulinoma 12.5% (16) and others 2.3% (3). The most common site of the tumor was pancreatic head 45.7% (59) followed by body, neck, and tail 47.6% (61). The average number of ablation sessions per patient was 1.4 based on the total of 115 EUS-RFA sessions performed in 84 neoplastic lesions. The pooled TS rate of EUS-RFA calculated from the total number of procedures was 99.2% [95% CI = 0.90-0.98, I2 = 0%]. The pooled CS rate calculated from the total number of pancreatic lesions was 91.9% [95% CI = 0.77-0.92, I2 = 0%]. Clinical improvement in symptoms was reported in five studies whereas complete resolution or decrease in tumor size was reported in all studies. The pooled AEs rate was 24.6% [95% CI = 0.17-0.39, I2 = 30%]. Common AEs were abdominal pain 10.5% (12), and pancreatitis 3.5% (4). Conclusions: EUS-RFA is a promising and safe modality that can be used for the management of UPC in selected patients with a high TS (99.2%) and CS rates (91.9%). Large clinical trials are needed to identify safety, clinical outcomes, and overall survival benefits of EUS-RFA.[Table: see text]
Sensitive detection of pancreatic adenocarcinoma using plasma cell-free DNA methylomes.
Authors: Nie Peiyao , Lv Fang , He Shuying , Han Tiancheng , Yang Shunli , Suxing Li , Liu Dan , Yang Ying , LI Yulong , Huang Yu S. , Hong Yuanyuan , Chen Weizhi , Yu Jianing , Sun Yongkun 
Published: June 2022

e16277 Background: Cell-free DNA (cfDNA) methylation, fragmentation patterns, chromosome instability, and chromatin accessiblity have been previously shown to be valid plasma biomarkers for non-invasive cancer detection. However, conventional whole-genome bisulfite sequencing (WGBS) is unable to simultaneously profile all these biomarkers due to bisulfite-induced DNA damages. Here we developed a machine learning approach to comprehensively integrate multiple types of cancer genomic markers from enzyme-conversion-based low-pass whole-methylome sequencing (WMS) of plasma cfDNA to non-invasively detect pancreatic adenocarcinoma. Methods: Plasma cfDNA sampels from 139 cancer patients and 568 healthy individuals were collected and were split into the discovery and independent testing cohort. The discovery cohort includes 99 cancer patients and 398 healthy individuals and the independent testing cohort includes 40 cancer patients and 170 healthy individuals. Whole methylome sequencing (WMS) libraries were generated from enzymatically converted cfDNA and were subsequently paired-end sequenced at ̃2X coverage. The genome-wide methylation density, fragmentation fingerprints, chromosome instability, and chromatin accessibility were extracted from the WMS data and individually modelled via machine learning methods such as SVM, LR, GBDT, random forest. The final predictive model is an ensemble model integrating all uni-modal models. All models were trained and fitted on the discovery cohort. Results: Data of different modalities provide complementary information in separating the cancer patients from the healthy individuals. Unsupervised clustering of the individuals showed clear separation between cancer patients and healthy individuals. The final predictive model achieved AUC =0.982 in the discovery cohort and AUC =0.986 in the independent testing cohort. Under a specificity of 96.23% (CI: 87% - 88%), sensitivity was 95% (CI: 93% - 96%) in the independent testing cohort. Separating the cancer patients into different stages, we found that the detection power is usuaul lower for early-stage cancer patients. Conclusions: These results demonstrate the first proof of principle on the feasibility of integrating multiple genomic cancer markers to non-invasively detect pancreatic adenocarcinoma from WMS plasma cell-free DNA. A large prospective cohort study is planned to further validate its clinical performance.