bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pathogenic germline mutations prevalence in Saudi patients with pancreatic ductal adenocarcinoma.
Authors: Algarni Mohammed Ahmed , Alshammari Kanan , Al Olayan Ashwaq , Sabatin Fouad , Mabsout Nadine , Zaher Horya , Shehata Husam , Al Turki Saeed 
Published: January 2022

538 Background: While the majority of pancreatic ductal adenocarcinoma(PDAC) cases are sporadic, about 10% related to familial and hereditary component. Multiple studies have shown that germline genetic testing regardless of family history for patients with PDCA is feasible and more likely to identify the carrier of pathogenic mutations. There is no data about the prevalence of pathogenic germline mutations in Saudi population. We aimed to study the prevalence of these mutations in Saudi patient patients with PDAC regardless of the family history of cancer. Methods: By using our cancer genetics database, we analyzed all the confirmed cases of PDAC who were referred to the cancer genetic clinic at King Abdulaziz medical city in Riyadh, Kingdom of Saudi Arabia. Since November 2018, a comprehensive hereditary cancer gene panel (including 70 genes) is offered to all referred PDAC cases regardless of their family history of cancer after obtaining a genetic counselling assessment and an informed consent. Results: Between November 2018 and August 2021, a total of 88 patients with PDAC cases have been tested. The median age was 60 and the majority of patients were males (n=56, 64%). Most of the patients had stage IV disease (n=75, 85.23%). The genetic result was available for 86 patients. Pathogenic variant(PVs) was reported in 8.1% (n=7), variant of uncertain significance (VUSs) was reported in 15% (n=13) while no mutation reported in the rest of the patients. The PVs reported were BRCA2 (n=4), BRIP1 (n=1), PMS1(n=1) and MRE11 (n=1). All the carriers of the PVs had no documented family history of breast, ovarian or pancreatic cancers at the time of genetic counselling. Conclusions: This study confirms the importance of genetic testing in all patients with PDAC regardless of the family history. This is in line with previous studies from other populations. This is the first study from Saudi patients with PDAC and to the best of our knowledge, the first study in Arab population.
Initial observation of contrast profiles for 3D and 2D MRI sequences in MR-guided radiation therapy for locally advanced pancreatic cancer.
Authors: Gill Gobind S. , Hunt Brady , Zhang Rongxiao , Williams Benjamin B. , Thomas Charles R. , Zaki Bassem I. 
Published: January 2022

541 Background: MR-guided stereotactic body radiation therapy (MR-SBRT) is a novel method of treating mobile tumors with soft-tissue gating and on-table adaptive planning. In our experience using the ViewRay MRIdian system (VR) for treating locally advanced pancreatic cancer (PA) with MR-SBRT, the true-fast imaging with steady-state free precession (TRUFI) sequences on the VR impart differing intensities for relevant structures seen on the pre-treatment high resolution 3D MRI (3D MRI) versus the real-time 2D cine MRI (2D cine) used for target tracking. Since these variations can confound target tracking selection, we propose that an understanding of the differing contrast profiles could improve selection of tracking structures and optimize treatment delivery. Methods: We retrospectively reviewed both 3D MRI and 2D cine images for patients (pts) with PA (n =20) treated on the VR. At simulation, an appropriate tracking target was identified and contoured on a single 3mm sagittal slice of the 3D MRI. This sagittal slice was directly compared to the registered 7mm 2D cine to identify structures with notable discrepancies in signal intensity. The 3D MRI was then explored in additional planes to confirm structure identities. For quantitative verification of the clinically observed differences, the pixel intensity distributions of 3D MRI and 2D cine DICOM image datasets were statistically compared. Results: In all pts reviewed, arteries (aorta, celiac, SMA) appeared with similar contrast profiles on both images. However, veins (portal vein, SMV) appeared hypointense on 3D MRI but hyperintense on 2D cine. Biliary structures appeared hyperintense on 3D MRI but only mildly hyperintense on 2D cine. The pixel intensity distributions extracted from 3D MRI and 2D cine images were confirmed to differ significantly (two sample Kolmogorov-Smirnov test; test statistic =0.40; p < 0.001). Conclusions: There are significant variations in image intensity between the initial treatment planning 3D MRI and the immediate pre-treatment 2D cine obtained with the VR. Understanding these discrepancies can guide radiation oncologists in choosing optimal tracking targets. Future work will focus on identifying the particular causes and frequencies of target tracking failures and exploring alternative tracking algorithms using artificial intelligence which could ultimately allow for VMAT on the ViewRay system.
Randomized phase II trial of neoadjuvant chemotherapy with modified FOLFIRINOX versus modified FOLFIRINOX and PD-1 antibody for borderline resectable and locally advanced pancreatic cancer (the CISPD-4 study).
Authors: Chen Yiwen , Guo Chengxiang , Bai Xueli , Gao Shunliang , Shen Yan , Zhang Min , Wu Jian , Que Risheng , Li Xiang , Liang Tingbo , Wu Jian 
Published: January 2022

562 Background: Neoadjuvant chemotherapy is recommended for BRPC and LAPC planned resection. PD-1 antibody alone was failed in advanced pancreatic cancer, but chemotherapy combined with PD-1 antibody are promising. Methods: This is a randomized, controlled, open-label phase II study including patients with BRPC or LAPC. Modified FOLFIRINOX (mFFX) is used as neoadjuvant chemotherapy. Patients will be randomly allocated into two groups: mFFX group and mFFX plus PD-1 antibody group (PD-1 group). Imaging evaluation will be discussed by the MDT. Surgical resection will be performed if the MDT confirms the resectability. (NCT03983057). Results: From March 4, 2019 to August 1, 2021, 146 patients (62 BRPCs and 84 LAPCs) were enrolled. 115 patients received at least four cycles of therapy. In PD-1 group, irAEs happened in seven patients (9.7%), including rash (3 patients, Grade 1), hepatic AE (2 patients Grade 3, 1 patient Grade 2), renal AE (2 patients, Grade 2), and hyperglycemia (2 patients). Radiological PR were noted in 13.3% patients in mFFX group, and 26.9% in PD-1 group. For BRPC patients, the radiological PR was 13.0% and 36.3%, respectively. The resection rate was similar in two groups (47.4% and 51.7%). R0 resections were performed in 70.3% and 86.6% patients, respectively. For LAPC patients, PD-1 group has a higher resection rate (37.1% vs. 48.0%). The survival data are not mature at present. Conclusions: Modified FOLFIRINOX plus PD-1 antibody is feasible and well-tolerated for BRPC and LAPC patients. The study will be continued and the detailed data will be reported. Clinical trial information: NCT03983057.
A single-center analysis of 30- and 90-day post-pancreatectomy complications in patients undergoing neoadjuvant radiation with EBRT versus MRI-guided SBRT.
Authors: Saad Mariam , Clark Julie , Shah Rupen A. , Siddiqui Farzan , Parikh Parag , Gartrelle Kendyll , Natour Abdul Kader , Khan Gazala , Kwon David S. 
Published: January 2022

572 Background: Stereotactic MRI -guided adaptive radiation therapy (SMART) is being investigated for enhanced efficacy in locally advanced, borderline resectable and medically inoperable pancreatic cancer. Traditionally, conventionally fractioned chemoradiation (EBRT) has been used for operable patients. We sought to evaluate whether there would be differences in surgical complications and outcomes in the 30- and 90- day postoperative period in patients who received either neoadjuvant EBRT or SMART followed by definitive surgery. Methods: A retrospective single-center analysis of patients with either resectable, borderline resectable or locally advanced tumors of the pancreas or duodenum, treated with neoadjuvant radiation and surgical management between 2014 and 2021 was performed. Patient demographics and post-surgical complications were collected and stratified according to both treatment arms. The International Study Group of Pancreatic Surgery (ISGPS) classifications were used to define and grade postoperative pancreatic fistula (POPF), delayed gastric emptying (DGE) and postpancreatectomy hemorrhage (PPH). A univariate analysis was done followed by a multivariate analysis. Results: Among the 65 patients (mean age 62.6 years, 46% female) who underwent definitive surgical intervention, 44 (67.7%) received EBRT, and 21 (32.3%) received SMART. Baseline characteristics including age, sex, race, ASA, and Charlson comorbidity index (CCI) scores were found to be similar. On univariate analysis, PPH was significantly higher in SMART (OR, 6.6; 95% CI, 1.2 to 37.3; p = 0.034). After adjusting for confounders on multivariate analysis, it appears there is a trend towards higher PPH in the SMART cohort ( p = 0.052). Conclusions: Neoadjuvant SMART followed by definitive surgery is not associated with worse outcomes in the 30- and 90- day postoperative period vs. neoadjuvant EBRT. Although there was a trend towards PPH on multivariate analysis, further discussion is warranted involving vascular resection, vascular stents and anticoagulation.[Table: see text]
Phase II study of PEGPH20 plus pembrolizumab for patients (pts) with hyaluronan (HA)-high refractory metastatic pancreatic adenocarcinoma (mPC): PCRT16-001.
Authors: Zhen David Bing , Whittle Martin , Ritch Paul S. , Hochster Howard S. , Coveler Andrew L. , George Ben , Hendifar Andrew Eugene , Dragovich Tomislav , Green Steven , Dion Barbara , Stoll-D'Astice Amy C. , Lee Arthur , Thorsen Shelley M. , Rosenthal Adam , Hingorani Sunil R. , Chiorean E. Gabriela 
Published: January 2022

576 Background: Stromal HA poses a physical barrier and protects tumor cells from immune surveillance. PEGPH20 is a pegylated, human recombinant PH20 hyaluronidase that remodels tumor stroma. Preclinical studies of PEGPH20 showed improved infiltration of cytotoxic T-lymphocytes and delivery of chemotherapy and PD1/PD-L1 antibodies. This study aimed to evaluate the efficacy, safety, and translational biomarkers of PEGPH20 plus pembrolizumab in pts with HA-high refractory mPC. Methods: mPC pts with HA-high expression, ECOG PS 0-1, ≤ 2 prior therapies for metastatic disease, life expectancy ≥ 12 weeks were treated with PEGPH20 3 µg/kg iv on D1, D8, D15 and pembrolizumab 200 mg iv on D1 in 21-day cycles. Primary endpoint was progression-free survival (PFS). Secondary endpoints were safety, overall survival (OS), and objective response rate (ORR). Blood and tumor biopsies were collected at baseline and on-study. Translational endpoints included flow cytometry and IHC for immune subsets, T-cell receptor sequencing, immune transcriptome, circulating cytokines, and plasma and tumor HA levels. Assuming a one-sided α-level of 0.05 and power of 80%, 31 evaluable pts were needed to detect an improvement of median PFS from 3 to 6 months. Results: Between May 2019 to Nov 2019, 38 pts were screened for HA expression, and 8 pts were enrolled, with median age 68 years (range 60-73), 7 males, and median 2 prior therapies (range 1-4). The accrual was stopped early by Halozyme Pharmaceuticals due to lack of benefit from PEGPH20 added to chemotherapy in the HALO-301 study. Treatment exposure median was 2 cycles (range 1-6). Reasons for study discontinuation were disease progression (n = 4), termination by sponsor (n = 3), patient withdrawal to enroll in hospice (n = 1). Treatment related toxicities were musculoskeletal (n = 6, grade 1/2), edema (n = 2, grade 1), fatigue (n = 1, grade 3), dyspnea (n = 1, grade 2), hypothyroidism (n = 1, grade 2). Median OS was 7.2 months (95% CI 1.2-11.8), and median PFS was 1.5 months (95% CI 0.9-4.4). Best response was stable disease (n = 2, 25%) lasting 2.2 and 9 months, respectively, and no responses were noted. Patients with available molecular sequencing data had MSS tumors. Translational biomarkers will be presented. Conclusions: Pembrolizumab and PEGPH20 did not increase PFS compared to historical data among heavily pretreated mPC pts, but the median OS of 7.2 months is encouraging. Translational analyses will provide insights into immune modulatory effects from PEGPH20 that could inform future studies with stroma targeted therapies and immune checkpoint blockade in mPC. Clinical trial information: NCT03634332.
Impact of nuclear factor of activated T cells (NFAT) families as a poor prognostic factor in pancreatic cancer patients.
Authors: Kamioka Yuto , Hiroshima Yukihiko , Kawahara Shinnosuke , Murakawa Masaaki , Yamamoto Naoto , Tamagawa Hiroshi , Oshima Takashi , Miyagi Yohei , Rino Yasushi , Morinaga Soichiro ,   Department of Gastrointestinal Surgery, Kanagawa Cancer Center
Published: January 2022

584 Background: Pancreatic cancer microenvironment is crucial in cancer development, and cancer-stromal interactions have been recognized as important targets for cancer therapy. Nuclear factor of activated T-cells (NFAT) has been found in T cells as a transcriptional activator of IL-2, and known to be involved in various processes including the immune system. In cancer tissues, NFAT has been reported to be involved in metastasis. In breast and colorectal cancers, NFATc2 and NFAT5 have been reported to interact with integrins to promote cancer cell migration. On the other hand, in pancreatic cancer, NFAT5 has been reported to be a poor prognostic factor via regulation of PGK1 transcription. In the present study, we evaluated the expression of NFATc2 and NFAT5 in pancreatic cancer and examined their relationship with prognosis. Methods: One hundred and sixty five pancreatic cancer patients who underwent curative-intrent resection at our hospital between 2010 and 2020 were included in this study. We performed immunostaining for NFATc2 and NFAT5 using the tissue micro array. We evaluated the expression of NFATc2 and NFAT5 protein and examined their correlation with clinicopathological factors. Results: Of the 165 pancreatic cancer cases, we detected increased NFATc2 protein expression in cytoplasm of cancer cells in 53 cases (32.1%) and NFAT5 in 104 cases (63.0%), and NFATc2/NFAT5 co-expression in 43 cases (26.1%). NFATc2 expression was not correlated with any clinicopathological factors, NFAT5 expression was correlated with venous invasion (p = 0.047), and NFATc2/NFAT5 co-expression was slightly correlated with Stage (p = 0.054). Relapse free survival (RFS) was estimated in all 165 patients. There was no significant difference for RFS in either NFATc2-high group or NFAT5-high group (p = 0.314 or p = 0.574), however, NFATc2/NFAT5 co-expression group showed significantly poor RFS (p = 0.023). Overall survival (OS) was also estimated in all 165 patients. There was no significant difference for OS in either NFATc2-high group or NFAT5-high group (p = 0.146 or p = 0.529), however, NFATc2/NFAT5 co-expression group showed significantly poor survival (p = 0.006). In multivariate analysis, lymphatic invasion, curability and NFATc2/NFAT5 co-expression were independent prognostic factors for RFS, and lymphatic invasion, curability, presence of adjuvant therapy and NFATc2/NFAT5 co-expression were independent prognostic factors for OS. Conclusions: In pancreatic cancer, NFATc2/NFAT5 co-expression was suggested to be involved in the critical process of pancreatic cancer progression, and may be a novel therapeutic target.
Prognostic impact of common pathologic alterations in pancreatic ductal adenocarcinoma from the veterans health administration.
Authors: Mehlhaff Eric Glenn , Zafar Syed Nabeel , Lesnik Dyan M. , LoConte Noelle K. , Lubner Sam Joseph , Kratz Jeremy D. 
Published: January 2022

603 Background: The Veteran Health Administration’s (VHA) National Precision Oncology Program was established to provide comprehensive molecular profiling for US military veterans with advanced cancers. There is an urgent need for precision strategies in pancreatic ductal adenocarcinoma (PDAC), as it is a leading cause of cancer-related mortality. We hypothesized that contributions of molecular alterations in PDAC would fail to stratify overall survival (OS), as current strategies are largely dependent on the activity of cytotoxic chemotherapy. Methods: A retrospective, multicenter cohort of 342 veterans with PDAC were identified from January 2016 to March 2021 who underwent comprehensive next-generation sequencing of tumor using FoundationOne CDx (UW IRB#2020-0696). Subjects were stratified by localized (L) or metastatic (M) disease at the time of diagnosis. Molecular alterations were compared by disease presentation using chi-squared analysis, and the clinical outcomes of overall survival (OS) were evaluated using Student’s t-test. Results: Baseline characteristics were representative of the VA population across 80 independent sites. The cohort was male-dominant (97%) with a median age of 69 years at diagnosis. Of this sample, 55% had M disease (n=189) compared to 45% with L disease (n=153). Median OS for M PDAC was 8.9±10.2 months (mo) v. L PDAC with median OS 22.5±18.0 mo (p<0.00005). Primary driver alterations were representative of PDAC and comparable between L and M on presentation, respectively; these included KRAS (92% v. 91%), TP53 (73% v. 80%), CDKN2A (29% v. 32%), SMAD4 (18% v. 23%), ARID1A (15% v. 16%) and BRCA2 (9% v. 12%). Primary driver alterations did not confer differences in OS across the population when comparing mutant (mt) to wildtype (wt) for KRAS (10.7 v. 11.8 mo, n=312), TP53 (10.3 v. 11.8 mo, n=263), CDKN2A (10.2 v. 10.9 mo, n=105), ARID1A (10.8 v. 10.9 mo, n=53), SMAD4 (11.3 vs 10.7 mo, n=72), and BRCA2 (13.8 v. 10.7 mo, n=37). Conclusions: Using the largest report of molecular profiles in veterans with PDAC to date, current therapeutic strategies fail to differentiate clinical outcomes by common molecular alterations with cytotoxic chemotherapy. The molecular profiles of veterans are representative of PDAC and do not vary significantly between localized and metastatic disease. There remains a persistent unmet need for therapeutic strategies including ongoing investigations of novel metabolic and immune-based therapies.
Does detection of microsatellite instability-high (MSI-H) by plasma-based testing predict tumor response to immunotherapy (IO) in patients with pancreatic cancer (PC)?
Authors: Chakrabarti Sakti , Bucheit Leslie A. , Starr Jason S. , Innis-Shelton Racquel , Shergill Ardaman , Resta Regina , Wagner Stephanie Ann , Kasi Pashtoon Murtaza 
Published: January 2022

607 Background: Immunotherapy (IO) is known to have robust anti-tumor activity in patients with MSI-H solid tumors. However, clinical trials investigating IO activity have used tissue-based testing to determine MSI-H status. Pancreatic tumor biopsy often does not provide sufficient tumor tissue for MSI testing. We investigated if the MSI-H status detected by plasma-based circulating tumor DNA (ctDNA) testing predicts robust response to IO in patients with PC. Methods: Genomic results from a well-validated plasma-based ctDNA assay (Guardant360[G360]) performed as part of routine clinical care between October 1, 2018 and September 7, 2021 in patients with PC were queried to identify patients with MSI-H tumors. Patient characteristics, tumor characteristics, treatment details, and outcomes were reported by ordering clinicians where available. The data cut-off date was September 1, 2021. Results: A total of 52 patients with PC who had MSI-H tumors on G360 were identified. Clinical outcomes data were available for 10/52 (19%) patients who were included for analysis. This patient cohort had a median age of 68 years (range: 56-82); 80% were male and 80% of patients had metastatic disease. 9/10 patients received IO: 3 in the first-line, 3 in the second-line, 3 in the third-line setting; most received pembrolizumab (8/9) while 1 received ipilimumab plus nivolumab. The median duration of IO was 8 months (range: 1-24). The overall response rate was 77% (7/9) and 6 of the 7 responders continue to show response at the time of data cut-off after a median follow-up of 21 months (range:11-33). The median progression-free survival and overall survival were not reached in the IO-treated cohort. Tissue-based MSI testing results were concordant with plasma-based G360 results in 5 of 6 patients (83%) who had tissue-based test results available. The patient with the discordant result was MSI-H by G360 but had intact mismatch repair protein expression by immunohistochemistry. This patient received neoadjuvant IO followed by surgery and the resected specimen confirmed pathological complete response. Conclusions: The detection of MSI-H status by plasma-based ctDNA testing is highly concordant to tissue-based testing and predicts robust and durable response to IO in patients with PC. The use of a well-validated plasma-based ctDNA analysis may expand the identification of MSI-H tumors in patients with PC and enable treatment with IO resulting in improved outcomes.
Homologous recombination repair pathway alterations and their relationship to homologous recombination deficiency in advanced pancreatic cancer patients.
Authors: Patel Hitendra , Barrett Alex , Mauer Elizabeth , Kato Shumei , Leibowitz Benjamin D. , Singhi Aatur D. , Javle Milind M. , Lowy Andrew M. 
Published: January 2022

609 Background: Homologous recombination repair (HRR) is critical for limiting DNA damage arising from double strand breaks. Disrupting HRR has emerged as a therapeutic strategy in pancreatic cancer given the development of PARP inhibitors that can specifically target tumors with homologous recombination deficiency (HRD). While HRD is strongly associated with loss-of-function mutations in BRCA1/2, a broad range of pathogenic alterations have been identified in other HRR genes. Identification of pathogenic alterations that predict response to PARP inhibition remains a critical knowledge gap in the field. Methods: We retrospectively analyzed de-identified records from 895 patients with advanced pancreatic cancer that underwent next generation sequencing (NGS) with the Tempus|xT assay (DNA-seq of 648 genes at 500x coverage, matched normal, full transcriptome RNA-seq). HRD-positivity and genome-wide loss of heterozygosity (LOH) were compared across groups, which were defined based on alterations to BRCA1/2 or other HRR pathway genes. Results: We identified 293/895 (33%) pancreatic cancer patients to be HRD-positive. Among HRD positive patients, 23/895 (2.6%) tumors harbored two alterations in BRCA1/2 (BRCA++), 179/895 (20%) harbored a single alteration in BRCA1/2 (BRCA+), 25/895 (2.8%) harbored two alterations in at least one other non-BRCA HRR gene (other HRR++), 367/895 (41%) harbored a single alteration in one other HRR gene (other HRR+), and 143/895 (16%) had pathogenic alterations in neither BRCA1/2 nor other HRR genes. In terms of HRD status, 23/23 (100%) of BRCA++ cases, 179/337 (53%) of BRCA+ cases, 4/25 (16%) of other HRR++ cases, and 87/367 (24%) of other HRR+ cases were HRD-positive. We observed no cases that were HRD-positive without an alteration in either BRCA1/2 or other HRR gene. Within the other HRR+ group, we found that single alterations in CHEK1/2, FANCA/L, MRE11, PALB2, and RAD51B were all significantly associated with HRD-positivity whereas CDK12, for instance, was not (Table). Conclusions: Comprehensive genomic profiling demonstrates that approximately 1 in 4 patients without BRCA alterations may potentially benefit from PARP inhibition due to alterations in other HRR genes. Future studies may examine the role of PARP inhibition in this population of HRR+ pancreatic cancer patients.[Table: see text]