bluuebunny/crossref_metadata_2025_split huggingface dataset:
Changing the landscape of germline testing in patients with pancreatic adenocarcinoma.
Authors: Athens Aly , Amacker-North Lisa , Warsinske Kelly , Kadakia Kunal C. , Kim Edward S. , Salem Mohamed E. , Elrefai Sara 
Published: February 2020

676 Background: Results from the POLO trial demonstrated the benefits of PARP inhibition in patients (pts) with germline BRCA-mutated metastatic pancreatic cancer (PC). In 2018, ASCO and NCCN updated their guidelines to recommend that pts with a personal history of PC undergo germline testing. We examined referral patterns and frequency of germline pathogenic variants in pts with PC. Methods: A retrospective review was performed of PC pts seen at the Levine Cancer Institute (LCI) Center for Genetics between January 2010 and September 2019. Descriptive analyses were completed on demographics and appointment outcomes. Results: A total of 201 PC pts were referred; 20 canceled and 14 no-showed their appointment. The remaining 167 were seen and included in this analysis. Most pts (59%) were referred after July 2018. The median age was 65 years (range 32-90) and 19% were < 50 years. The majority of pts were female (61%). Race was most often reported as white (72%) followed by black (20%). Reported family histories were as follows: 28 (17%) claimed at least one first-degree relative with PC; 54 (32%) claimed a first, second, or third-degree relative with PC; 24 (14%) had no known family history of PC; and 95 (57%) claimed a first-degree relative with another cancer (breast [37], prostate [25], colon [18], ovarian [9], uterine [6], and gastric [2]). Germline testing was pursued by 138 (83%) pts: 25 (18%) were found to have a pathogenic variant and 50 (36%) a variant of uncertain significance. Pathogenic variants were most commonly identified in ATM (24%), BRCA2 (20%), PALB2 (12%), and CDKN2A (8%). Variants were also observed in DIS3L2, HOXB13, MITF, MUTYH (heterozygote), NTHL1 (compound heterozygote), RAD50, PRSS1, and SDHA. Among pts that had a pathogenic variant, cascade testing was performed in 11 families (44%) for 29 individuals. Conclusions: Our data suggest that the referral of PC pts to genetics has increased following updated ASCO/NCCN guidelines. However, improved adherence to genetic counseling is needed. ATM and BRCA2 were the most common germline mutations observed. More effort to increase awareness of genetic testing and its potential implications for pts and their families is warranted and might reduce cancellations and missed visits.
Case series examining somatic test results for patients with hereditary cancer syndromes associated with gastrointestinal cancer risk.
Authors: Pauley Kristen , Koptiuch Cathryn , Greenberg Samantha , Amanda Gammon , Nevala-Plagemann Christopher , Vagher Jennie , Espinel Whitney , Gilcrease Glynn Weldon , Kohlmann Wendy , Garrido-Laguna Ignacio 
Published: February 2020

680 Background: Somatic tumor testing may identify germline pathogenic variants (PV) associated with cancer predisposition syndromes. Labs differ whether they offer somatic only or paired germline analysis. Methods used by somatic testing labs, even those that include germline analysis, differ from designated germline labs that have optimized the identification of germline PV. Methods: Chart reviews were performed for patients who had testing through both somatic and designated germline laboratories. Cases with discrepant results in which germline PV were not detected by the somatic laboratory are summarized. Results: Nine cases with discrepant results. Five had paired germline testing and 4 somatic testing only. All 9 patients met the criteria to undergo designated germline testing, either for Lynch syndrome (3) or BRCA1/2 testing (6), based on personal and/or family history. Designated germline testing identified 4 MLH1, 1 BRCA1, 2 ATM, 1 MUTYH and 1 RAD50 PV not reported by the somatic labs’ tumor or germline analysis; 2 MLH1 PV were called variants of uncertain significance by somatic testing but classified as PV by ClinVar and designated germline labs. Three PV identified by designated germline labs are targets for PARP inhibitors and resulted in different treatment options. Three of the MLH1 PV were identified in patients meeting Lynch Syndrome test criteria while 1 was identified in a patient meeting BRCA1/2 criteria. Among the 5 other patients meeting BRCA1/2 test criteria, 3 had PV in breast cancer genes (2 ATM, 1 BRCA1) and 2 had PV in other cancer genes ( MUTYH and RAD50) not reported by the somatic labs, highlighting the importance of panel testing. Conclusions: Methods used by somatic labs, regardless of inclusion of germline analysis, are not equivalent to those of designated germline labs. Overlooked germline PV may miss identification of hereditary syndromes and targeted therapy opportunities (e.g. Anti-PD1 immunotherapy, PARP inhibitors). Patients meeting criteria for genetic evaluation should be referred for designated germline testing regardless of somatic testing outcomes.
Tumor downsizing following neoadjuvant therapy for borderline-resectable pancreatic adenocarcinoma.
Authors: Reza Joseph Arturo , Monreal Alberto , Meyer Patrick Hunter , Patel Swati , Zakari Ahmed , de la Fuente Sebastian 
Published: February 2020

690 Background: Downstaging of pancreatic adenocarcinoma in patients presenting with nonmetastatic, unresectable disease has proven to be associated with improved clinical outcomes. Efforts at rescuing these patients to become surgical candidates are commonly attempted with a combination of systemic and radiation strategies. In this study, we aimed to determine tumor downsizing in patients that underwent neoadjuvant systemic therapy followed by a curative-intended surgical resection. Methods: A retrospective review of consecutive patients that underwent surgical resection for pancreatic adenocarcinoma following a course of neoadjuvant therapy was performed. Basic demographics, endoscopic ultrasound (EUS) findings, chemotherapy regimens and duration, rates of radiotherapy, type of surgical procedure and pathologic results were recorded. Tumor response to neoadjuvant therapy was established by correlating EUS- to pathologic tumor dimensions. Analysis of the data was done using Mann-Whitney U test, Pearson correlation and Chi-square when indicated. Results: A total of 97 patients were analyzed; 40 underwent neoadjuvant chemotherapy (13 patients also received concurrent radiation therapy). In those 57 patients that were resected upfront, EUS tended to underestimate tumor sizes significantly compared to pathologic dimensions, with an average difference between dimensions of 0.66 cm (p = 0.0004). Within the group treated with neoadjuvant chemotherapy, 90% of patients had downsizing at an average of 8% of tumor size. There were no differences in rates of tumor downsizing between FOLFIRINOX or Gemcitabine/Nac-paclitaxel treated patients. In addition, there were no correlations in margin status (R0) based on chemotherapy used, with both regimens achieving a similar rate of R0 resections (mean 61%). The type of chemotherapy regimen used did not affect the ratio of positive lymph nodes harvested. Conclusions: In patients that present with borderline resectable pancreatic adenocarcinoma, a course of neoadjuvant therapy results in tumor downsizing in a significant number allowing for margin negative resections. These results were seen regardless of the chemotherapeutic regimens utilized.
The surgical outcomes of borderline resectable or locally advanced pancreatic cancer.
Authors: Okamura Yukiyasu , Sugiura Teiichi , Ito Takaaki , Yamamoto Yusuke , Ashida Ryo , Ohgi Katsuhisa , Uesaka Katsuhiko 
Published: February 2020

691 Background: Advances in multidisciplinary treatment for pancreatic cancer (PC) have increased surgical opportunities for initially unresectable locally advanced (UR-LA) or borderline resectable PC. In order to obtain a high rate of R0 resection, it is important to select an appropriate approach according to the infiltration site of the artery that can determine whether curative surgery is possible or not at early phase of the operation. Methods: From April 2012 to December 2018, 81 patients who were scheduled for curative resection for UR-LA or borderline resectable PC that contact the main artery (BR-A). In our institution, if a tumor is in contact with the superior mesenteric artery (SMA), we select the mesenteric approach. And if a tumor is in contact with the common hepatic artery (CHA) and/or celiac artery (CA), we open the lesser omentum and then dissect from the cranial side of pancreas to the diaphragm leg to judge the resectability before dividing the stomach. When arterial plexus infiltration is observed during surgery, we abandoned curative surgery or we performed combined resection of CHA and reconstruction if possible. Results: There were 69 BR-A and 12 UR-LA patients. Macroscopic curative resection was performed in 67 (83%) of 81 patients, and 14 patients were unresectable. Pancreatoduodenectomy was performed in 54 patients, distal pancreatectomy (DP) in 8, and DP with celiac axis resection in 7. There were 67 patients with vascular resection / reconstruction. R0 resection was obtained in 64 of 67 patients among curative resection. The median blood loss, operation time, and length of hospital stay were 714 mL, 439 minutes, and 19 days, respectively. The complications of Clavien-Dindo grade 3a or higher were observed in 18 patients (27%). There were no post-operative deaths. The 3-year survival rate after surgery was 70.3%, and there was no significant difference between BR-A and UR-LA (P = 0.701). The 3-year recurrence-free survival rate after surgery was 34.4%, which was not significantly different between the two groups (P = 0.816). Conclusions: A high R0 resection rate (96%) was obtained by an appropriate approach that can determine the resectability at early stage of operation, and high R0 rate leads to good outcomes.
Use of gastrin vaccine to increase gamma-delta and NKT cells and alter pancreas tumor microenvironment to improve survival.
Authors: Smith Jill P , Osborne Nicholas , Sundseth Rebecca , Cao Hong , Gay Martha D , Tucker Robin D. , Kroemer Alexander H , Sutton Lynda Youngpeter , Cato Allen 
Published: February 2020

696 Background: Pancreatic cancer (PC) has been called a “cold” tumor as it responds poorly to immune-based therapies. Strategies to render PC susceptible to immunotherapy are under investigation by methods that alter immune cell signatures such as increasing the population of double negative CD4-CD8-T-cells, or changing the polarization of tumor-associated macrophages (TAMs). Our current aim was to determine if a gastrin vaccine, Polyclonal Antibody Stimulator (PAS) influences double negative T-cell phenotype and polarization of TAMs to improve survival of PC. Methods: Two cohorts of C57BL/6 mice were injected either sc or orthotopically with syngeneic mT3 murine pancreatic cancer cells. After 1 week, groups were treated with PBS; PAS (100μg); PD-1 antibody (150μg); or the combination of PAS and PD-1 Ab. PAS was given ip at weeks 0, 1 and 3. Anti-PD-1 was given on days 0, 4, 8, 15 and 21. Spleens were collected from the sc experiment for T-cell surface analysis by flow cytometry. Orthotopic tumors were measured for growth rate, metastases, and stained for M1 (inos) and M2 (arginase) polarized TAMs, and mouse survival was analyzed. Results: PAS therapy increased expression of double negative T-cells. The percentage of gamma-delta T-cells in the (CD3+/CD4−/CD8−/CD44−/CD62L−) TEMRA subpopulation of mice treated with PAS or combinations of PAS with PD-1 Ab were increased approximately 40% compared to PBS-treated controls or PD-1 Ab-treated mice. NKT cells from PAS-vaccinated mice were 2.5-fold higher than controls. M2+ TAMS were significantly decreased in tumors of PAS treated mice compared to PBS treated mice (p = 0.017). PAS monotherapy resulted in a nearly 10-fold increase in M1 TAMs relative to controls (p = 0.002). PAS monotherapy decreased tumor metastases by 69% and prolonged survival. Primary tumor growth decreased with PAS in combination with PD-1 Ab (p=0.0025). Conclusions: PAS decreases PC tumor growth and metastases by increasing CD4-CD8-, gamma-delta, and NKT T-cell populations. Furthermore, PAS monotherapy significantly increases M1 and decreases M2 TAMs. These immune cell changes with PAS vaccination may render tumors more susceptible to other cancer therapies and improve survival.
Phase II study of preoperative chemotherapy with nab-paclitaxel and gemcitabine followed by chemoradiation for borderline resectable or node-positive pancreatic ductal adenocarcinoma.
Authors: Chen Emerson Yu-sheng , Tormoen Garth William , Kardosh Adel , Nabavizadeh Nima , Foster Bryan , Mayo Skye C. , Billingsley Kevin G. , Gilbert Erin W. , Lanciault Christian , Grossberg Aaron , Bensch Kenneth Gregory , Maynard Erin , Anderson Eric C. , Sheppard Brett C. , Thomas Charles R. , Lopez Charles D. , Vaccaro Gina M. ,   OHSU Gastrointestinal Cancer Disease Group
Published: February 2020

697 Background: Pre-operative therapy for resectable pancreatic ductal adenocarcinoma (PDAC) may eliminate micro-metastatic disease early and help achieve negative surgical margins. The present study is based on the hypothesis that gemcitabine/nab-paclitaxel chemotherapy followed by chemo-radiation with fluoropyrimidine is a feasible and efficacious pre-operative treatment for borderline resectable or node-positive PDAC. Methods: This is a single-arm phase II trial to evaluate pre-operative treatment with 2 cycles of gemcitabine 1000 mg/m2 and nab-paclitaxel 125 mg/m2 on days 1, 8, 15 every 28 days followed by 50.4 Gy of intensity-modulated radiation therapy over 28 fractions with concurrent 5-fluorouracil or capecitabine prior to pancreatic resection. Patients were eligible if they met borderline resectable criteria or had abnormal regional nodes visible on contrast CT. After surgery, they were eligible to receive up to 4 additional cycles of gemcitabine/nab-paclitaxel. The primary endpoint was the R0 resection rate. Secondary endpoints included response to pre-operative therapy, overall toxicities, relapse-free survival, and overall survival. Results: Nineteen of 24 screened patients have been enrolled. Median age was 68, 10 (53%) were female, and 4 (21%) were non-Caucasian. Eleven (78%) had head of pancreas cancers, 13 (68%) exhibited both arterial and venous involvement, and 12 (63%) had positive clinical nodes. All 19 patients received 2 months of gemcitabine/nab-paclitaxel, of which 17 patients continued to chemo-radiation (1 developed metastatic disease and 1 moved out of state). In the interval between chemo-radiation and surgery, 3 developed metastatic disease, 1 became unresectable, 1 withdrew from study, and 1 was deemed too frail for surgery. Nine have undergone successful pancreatic resection, and 2 are pending resection. Conclusions: Pre-operative gemcitabine/nab-paclitaxel followed by chemo-radiation with fluoropyrimidine is feasible in patients with borderline resectable PDAC and represents another strategy to FOLFIRINOX-based therapy. A planned interim analysis is ongoing. Clinical trial information: NCT02427841.
Phase II clinical trial of novel agent PBI-05204 in patients with metastatic pancreatic adenocarcinoma (mPDA).
Authors: Roth Marc Thomas , Cardin Dana Backlund , Borazanci Erkut Hasan , Steinbach Margaux , Picozzi Vincent J. , Rosemurgy Alexander , Wadlow Raymond Couric , Newman Robert A. , Berlin Jordan 
Published: February 2020

698 Background: Survival statistics for mPDA are dismal and with limited treatment options novel agents are needed to improve disease outcomes. PBI-05204 (Phoenix Biotechnology, Inc., San Antonio, TX) is a modified supercritical carbon dioxide extract of Nerium oleander leaves. Oleandrin, the extract’s major cytotoxic component, has demonstrated anti-tumor activity in various tumor cell lines. In a human PDA orthotopic model, this preparation reduced tumor burden as monotherapy. Pharmacodynamic studies suggest that PBI-05204’s mechanism of action is through inhibition of the PI3k/Akt/mTOR pathway. Methods: A phase II single-arm, open-label study to determine the efficacy of PBI-05204 in patients (pts) with mPDA refractory to standard therapy was conducted. The primary endpoint was overall survival (OS) with the hypothesis that 50% of pts would be alive at 4.5 months. Secondary objectives included safety, progression-free survival (PFS), and overall response rate. Pts received oral PBI-05204 daily until progressive disease (PD), unacceptable toxicity, or pt withdrawal. Radiographic response was assessed every two cycles. Results: Forty-one pts were enrolled; two never received treatment and one was found to have a neuroendocrine tumor after pathological re-evaluation, leaving 38 pts for analysis. Median age at time of enrollment was 65.0 years. The median time from initial diagnosis to treatment was 16.9 months. The primary reason for withdrawal was PD (45.2%). Ten pts were alive at 4.5 months (26.3%) with a mPFS of 56 days (corresponding to first restaging). One objective response (2.6%) was observed for 162 days. Grade ≥3 treatment-emergent adverse events occurred in 63.2% of pts with the most common attributed to drug (all grades) being fatigue (36.8%), vomiting (23.7%), nausea (18.4%), decreased appetite (18.4%), and diarrhea (15.8%). Conclusions: PBI-05204 did not meet its primary endpoint for OS in this study. Recent preclinical data indicate an efficacious role for PBI-05204 against glioblastoma multiforme when combined with chemotherapy, such as temozolomide, and radiotherapy. A randomized Phase II trial is currently being designed. Clinical trial information: NCT02329717.
Attenuated regimen of biweekly gemcitabine/nab-paclitaxel in patients aged > 65 years with advanced pancreatic cancer (APC).
Authors: Rehman Hasan , Chi Jeffrey , Hakim Nausheen , Goyal Shreya Prasad , Olazagasti Coral , Jose Jyothi , Moriarty Linda , Saif Wasif M. 
Published: February 2020

705 Background: Treatment with gemcitabine/nab-paclitaxel confers a survival benefit over gemcitabine monotherapy in APC. However, such treatment can be associated with significant toxicities especially in older patients and carries practical disadvantages related to a weekly schedule along with financial cost. We retrospectively analyzed patients > 65 years of age with APC who received a modified biweekly regimen of gemcitabine/nab-paclitaxel to evaluate efficacy and toxicity. Methods: Patients aged > 65 years with chemo-naive APC and ECOG PS < 2 were studied. Patients were treated with a modified regimen of gemcitabine 1000 mg/m2 and nab-paclitaxel 125 mg/m2 every 2 weeks on days 1 and 15 of a 28-day cycle. Patients were evaluated for progression-free survival (PFS) and overall survival (OS) with analyses performed using Kaplan-Meier method. Adverse events were recorded on the day of chemotherapy. CA19-9 was measured every cycle and restaging scans were performed every two cycles. Results: Seventy-three patients (median age: 73; range: 66 - 93) were treated with biweekly gemcitabine/nab-paclitaxel as first-line treatment. The median OS and PFS were 9.1 months and 4.8 months respectively. 66% of patients received growth factor support based on ASCO guidelines and no patients developed neutropenic fever. The incidence of grade > 3 toxicity for neutropenia, anemia, thrombocytopenia, and neurotoxicity were 2%, 7%, 3%, and 5% respectively. Dose reductions of gemcitabine/nab-paclitaxel were required in 10% and 4% patients respectively. Conclusions: In patients > 65 years of age with APC, a modified regimen of biweekly gemcitabine/nab-paclitaxel was found to be effective when compared with historical control from the MPACT study. This regimen allowed for less dose reductions, reduced healthcare costs from additional appointments, travel-related cost, as well as favorable side effect profile while maintaining efficacy. Though retrospective in nature, this study underlines the need for further investigation, particularly in elderly patients with APC and poor performance status. Better tolerability may allow for combination with a third agent, such as a targeted or immunotherapy.
Neoadjuvant therapy guideline adherence for locally advanced rectal cancers in a region with sociodemographic disparities.
Authors: Wong Denise , Hendrick Leah E. , Guerrero Whitney M. , Monroe Justin J. , Hinkle Nathan M. , Deneve Jeremiah Lee , Glazer Evan Scott , Shibata David 
Published: February 2020

71 Background: Quality and practice guidelines from the American College of Surgeons Commission on Cancer (CoC) and the National Comprehensive Cancer Network (NCCN) recommend neoadjuvant chemoradiation (NCR) for locally advanced rectal cancer (LARC). We examined guideline adherence in a healthcare system serving a region with significant socioeconomic disparities and poor cancer outcomes. Methods: We performed a retrospective analysis of patients from 2005-2014 with stage II and III rectal cancer in our local 5- hospital healthcare system in the Mid-South region of the US. We examined the associations between guideline adherence and patient demographic, socioeconomic, and clinicopathologic data. Results: Of 157 stage II/III RC patients, 96 (61.1%) received NCR. By univariate analysis, factors associated with receipt of NCR included white race versus non-white (OR = 2.14, p = 0.024), private insurance versus no or public insurance (OR = 2.70, p = 0.005), employed status versus unemployed (OR = 2.29, p = 0.031), age at diagnosis (OR = 0.74, p = 0.032), and appropriate local staging with EUS or MRI (OR = 6.67, p = < 0.0001). Those who were diagnosed and treated later in the study period were more likely to get NCR (OR per 1 year = 1.20, p = 0.006). In addition, receipt of NCR was protective against death at time of follow up (OR = 0.41, p = 0.009). By multivariate analysis, those with private insurance (OR = 2.51, p = 0.023), younger age at diagnosis (OR per 10 years = 1.39, p = 0.048) and with appropriate local staging (OR = 6.67, p < 0.0001) were more likely to have received NCR. Conclusions: Guideline adherence for LARC in our system, which serves a population with socioeconomic disparities, is relatively low. Sociodemographic factors such as employment and race influenced receipt of NCR, while insurance status and age were independent determinants. Despite some increase in compliance over time, adherence to NCR for LARC remains lower than expected and represents an important target for improvement efforts.