bluuebunny/crossref_metadata_2025_split huggingface dataset:
The impact of CDKN2A mutations on overall survival in pancreatic adenocarcinoma.
Authors: Doyle Allison , Kubler Manfred M , Harris Ashton C , López Alfredo , Govindaraj Prateek , Prins Petra , Weinberg Benjamin Adam 
Published: January 2019

278 Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a five-year survival rate of only 9%. Analyses based on tumor DNA mutations indicate the presence of specific molecular subtypes of PDAC. Tumor genomic profiling could result in better treatment selection and improved overall survival. We performed a single institution analysis of PDAC mutations and correlated them with clinical outcomes. Methods: PDAC samples from patients (pts) seen at the Lombardi Comprehensive Cancer Center between 2014 and 2018 were profiled using next generation sequencing including 592 whole-gene targets (Caris Life Sciences). Relevant clinical data was mined retrospectively and correlated with genomic data. Pt outcomes were correlated with the presence of mutations in KRAS, MSH2, MSH6, MLH1, PMS2, TP53, SMAD4, CDKN2A, BRCA1, and BRCA2. Results: Our cohort (N = 100) included 50% men and 50% women, 59% were Caucasian and 21% African-American. Thirty-two percent had stage II, 14% had stage III, and 38% had stage IV disease. Seventy-seven percent developed metastatic disease. Genetic mutations were found in KRAS 87% (N = 82), TP53 76% (N = 82), SMAD4 37% (N = 49), CDKN2A 29% (N = 66), and BRCA2 21% (N = 81). Sixty percent of pts with KRAS mutations also had TP53 mutations. Almost all pts with mutated SMAD4, CDKN2A, or BRCA2 also had mutated KRAS (89%, 84%, and 80%). Median overall survival (OS) for all pts from time of diagnosis was 31 months (m). Stratification of OS based on single gene mutations did not significantly impact OS except for CDKN2A. Patients with CDKN2A mutations had significantly reduced OS compared to wild type (22 m vs. 35 m; P = 0.018). OS based on presence of co-occurring mutations only showed a negative OS impact when CDKN2A mutations were present (14 m vs. 35 m; P = 0.021). Conclusions: Our data demonstrate that the presence of CDKN2A mutations is an independent negative prognostic OS indicator for patients with PDAC. This finding highlights the need to select PDAC pts for potential targeted therapies, including those that target the cell cycle pathway (e.g. cyclin-dependent kinase inhibitors).
A multi-institutional study assessing prevalence of deleterious germline mutations in pancreatic cancer.
Authors: Sadaps Meena , Funchain Pauline , Heald Brandie , Huether Robert , Pitt Jason , White Kevin , Khorana Alok A. , Sohal Davendra 
Published: January 2019

280 Background: Pancreatic cancer is being increasingly associated with germline implications. Some large single-center studies have reported results ranging from 3.9% to 19.8% of patients found to have germline variants [Shindo, JCO 2017; Lowery, JNCI 2018]. Due to this wide range, we aim to further delineate prevalence of deleterious germline mutations in pancreatic cancer using a multi-institutional data set. We also aim to analyze predictive factors such as mutant allele frequency (MAF, in %) in germline versus somatic calls. Methods: We sequenced 23 genes in DNA prepared from clinical tissue and blood specimens submitted to Tempus Labs. Germline variants and somatic variants were processed separately. Germline variants were determined to be deleterious through the sum effect of a combination of in silico predictors, population databases, and internal evaluations. Tumor-normal comparisons were used to define somatic versus germline, and MAFs were calculated for each. Results: A total of 234 patient samples from 17 institutions were analyzed. Of these, 12 (5.1%) had predicted deleterious germline variants involving 8 different genes: BRCA1 (n = 3), CHEK2 (n = 3), ATM (n = 1), MLH1 (n = 1), MUTYH (n = 1), PALB2 (n = 1), SMAD4 (n = 1), TP53 (n = 1). For most somatic alterations, the MAFs were found to be greater than the germline deleterious alterations, with the latter approaching ~50% in most cases (Table). Conclusions: This multi-institutional study identifies 5% of patients with pancreatic cancer to have deleterious germline alterations. Somatic variant testing, particularly when paired with germline, can be used as a screening method for genetic counseling referrals, especially with MAF analyses of paired tumor-normal samples. [Table: see text]
Pilot study of plasma KRAS as a prognostic biomarker in localized pancreas ductal adenocarcinoma (PDAC).
Authors: Krantz Benjamin A. , Gedvilaite Erika , Chou Joanne F. , Capanu Marinela , You Daoqi , Yu Kenneth H. , Varghese Anna M. , Iacobuzio-Donahue Christine A , Kelsen David Paul , Tsui Dana , O'Reilly Eileen Mary 
Published: January 2019

294 Background: Validated predictive and prognostic biomarkers are needed in PDAC. Such biomarkers could predict response and resistance early in treatment. As 95% of PDAC harbor KRAS mutations (mKRAS), plasma mKRAS has utility as a biomarker. We explored the prognostic value of mKRAS in a PDAC cohort at Memorial Sloan Kettering. Methods: 10 mL of whole blood was collected at diagnosis of localized PDAC and early interval CT scan (approx. 8 weeks). DNA was extracted with QIAamp DNA kits (Qiagen, Valencia, CA). Single locus, if tissue KRAS known, or multiplex (G12A, G12C, G12D, G12R, G12S, G12V, G13D) digital droplet PCR (ddPCR) was performed with QX200 (BioRad, Hercules, CA) ddPCR system. Disease status was determined by radiographic, CA19-9 and clinical evaluation. Results: N = 18 enrolled (median age: 65 [range 34-85]). Median time between baseline (B) and interval (I) blood was 2.53 months (range 0.9-6). One had locally recurrent disease, 2 AJCC stage IIa, 1 IIb and 14 III. Three had tissue KRAS G12D mutation, 6 G12V and 9 unknown. Eight had gemcitabine-based treatment, 10 5-FU-based and 5 radiation. See table. mKRAS and CA19-9 at B were not associated with progression free survival (PFS) or overall survival (OS). mKRAS detection at I was associated with shorter PFS/OS (P < 0.01), but CA19-9 was not. mKRAS change from B to I was also associated with PFS/OS. For every 1 copy/mL increase in the change of mKRAS from B to I, the risk of death or progression/death increased by nearly 2 fold after controlling for baseline value (p = 0.01 for OS, p = 0.03 for PFS). Four patients, all undetectable mKRAS at I, went to surgery; 2/4 resected. Conclusions: In this pilot, 59% of localized PDAC patients had detectable mKRAS at B. mKRAS detection at I and change from B to I were associated with PFS/OS supporting that mKRAS early in treatment may be a useful prognostic and predictive marker in localized PDAC. We have initiated a large prospective trial to evaluate the predictive and prognostic potential of plasma mKRAS in advanced PDAC. [Table: see text]
Phase I study of nivolumab (Nivo) + nab-paclitaxel (nab-P) + gemcitabine (Gem) in advanced pancreatic cancer (APC).
Authors: Wainberg Zev A. , Hochster Howard S. , Kim Edward Jae-Hoon , George Ben , Kalyan Aparna , Chiorean E. Gabriela , Waterhouse David Michael , Gutierrez Martin , Parikh Aparna Raj , Jain Rishi , Carrizosa Daniel R. , Soliman Hatem Hussein , Bhore Rafia , Banerjee Sibabrata , Lyons Larry , Louis Chrystal Ursula , Ong Teng Jin , O'Dwyer Peter J. 
Published: January 2019

298 Background: Chemotherapy may work synergistically with immune checkpoint inhibitors by increasing tumor antigen exposure. This 2-part phase I study assessed safety and efficacy of Nivo + nab-P + Gem in APC. Methods: Treatment-naive patients (pts) with APC (locally advanced or metastatic) received nab-P 125 mg/m2 + Gem 1000 mg/m2 on d 1, 8, and 15 + Nivo 3 mg/kg on d 1 and 15 of each 28-d cycle until disease progression (PD), unacceptable toxicity, or withdrawal. Pts could continue Nivo alone beyond initial PD. Part 1 assessed dose-limiting toxicities (DLTs) and determined the recommended Part 2 dose; Part 2 (expansion phase) further assessed safety. The primary endpoints were DLTs (Part 1) and safety and tolerability (Parts 1 and 2). Key secondary endpoints were response rates, progression-free survival (PFS), and overall survival (OS). Results: As of July 13, 2018, 50 pts with APC were treated: 6 in Part 1; 44 in Part 2. The median age was 67.5 years; 56% were male; 62% had an ECOG PS 1. Of 40 pts with available data, 12 (24%) had ≥ 1% and 6 (12%) had ≥ 5% PD-L1 expression at baseline (data missing for 10 pts). The median follow-up was 11.3 mo. In Part 1, 1 DLT (hepatitis, as evidenced by grade 3 elevated liver function tests; suspected to be related to nab-P + Gem) was reported. In Parts 1 and 2, 48 pts (96%) had ≥ 1 grade 3/4 TEAE; 7 (14%) discontinued treatment due to a TEAE. Most common (> 10%) grade 3/4 TEAEs of special interest were anemia (36%), neutropenia (36%), gastrointestinal events (24%), hepatic toxicity (22%), peripheral neuropathy (16%), thrombocytopenia (12%), and colitis (12%). One grade 5 TEAE, respiratory failure (most likely pneumonitis), was reported. The table shows treatment responses. Of 7 pts (14%) who continued Nivo beyond initial PD, 4 achieved disease control. The median PFS was 5.5 mo (6-mo PFS rate, 47%). The median OS was 9.9 mo (6-mo OS rate, 73%). Conclusions: Combining Nivo with nab-P + Gem is feasible in pts with APC: 1 DLT was reported, and no unexpected safety signals were detected. Clinical trial information: NCT02309177. [Table: see text]
Biliary tract cancers and the associated risk of venous thromboembolism.
Authors: Khanuja Jasleen , Bahrami Tabar Samira , Tsao-Wei Denice , Piatek Caroline Irene , Barzi Afsaneh 
Published: January 2019

304 Background: Venous thromboembolism (VTE) is a common cause of morbidity and mortality in cancer patients. Because biliary tract cancers (BTC) cholangiocarcinoma and gallbladder (GB) cancer are uncommon, the incidence of VTE in this population are not well-described. Methods: We conducted a retrospective study of patients with BTC identified by the cancer registry at the Los Angeles County-University of Southern California (USC) Medical Center, USC Norris Cancer Center, and USC Keck Hospital between January 2011 to December 2016 to describe the incidence of VTE. 330 BTC patients’ medical records were reviewed for demographics, tumor characteristics, treatment history, and VTE events. 41 patients were excluded due to incomplete records/follow-up. Overall survival (OS) was calculated from date of diagnosis to date of death or last follow-up. Logrank test was used to evaluate the association of VTE with OS. Results: 289 patients with BTC were identified (177 cholangiocarcinoma, 112 GB) with a median follow-up period of 16.7 (0.3-89.0) months (mo). 169 (58%) were women. The median age at diagnosis of 66 years (range 22-89). 144 (59%) underwent cancer surgery and 274 (95%) received chemotherapy. 65 (22%) patients had VTE events: 22 pulmonary embolism [PE] with or without lower extremity (LE) deep vein thrombosis [DVT], 15 with LE DVT alone, three with upper extremity DVT, and 30 with visceral thrombosis (27 portal vein thrombosis [PVT] with or without inferior vena cava thrombosis [IVC], 2 IVC thrombosis, two hepatic vein thrombosis). Five patients had both DVT/PE and visceral thrombosis. The median time from cancer diagnosis to VTE event was not met. Patients with a PVT or any visceral thrombosis had an inferior OS compared to those without (PVT: median OS 16.2 mo [95% CI 12.2-25.8] versus 7.5 [3.4-14.2], p = 0.10, visceral thrombosis: 17.0 mo [95% CI 11.8-25.9] versus 8.4 [95% CI 3.7-14.3], p = 0.30). There was a non-significant trend towards inferior OS in patients with any VTE event type (median OS 17.0 mo [95% CI 11.8-39.0] versus 11.4 [95% CI 7.2-18.4], p = 0.10). There was no difference in OS for patients with PE/DVT compared to those without. Conclusions: VTE is commonly observed in patients with BTC. Visceral thrombosis is associated with inferior survival in patients with BTC.
A phase I study of mesothelin-targeted immunotoxin LMB-100 in combination with nab-paclitaxel for patients with previously treated advanced pancreatic cancer.
Authors: Alewine Christine Campo , Hassan Raffit , Ahmad M. Iqra , Trepel Jane B , Peer Cody , Figg William Douglas , Pastan Ira 
Published: January 2019

307 Background: LMB-100 is a Pseudomonas exotoxin A-based immunotoxin that targets mesothelin (MSLN). MSLN is expressed by >75% of pancreatic adenocarcinomas (PDAC). LMB-100 kills MSLN-expressing cells by irreversibly modifying elongation factor-2 to halt protein synthesis. Phase I studies of LMB-100 defined the maximum tolerated dose (MTD) of 140 mcg/kg IV given on D1, 3 and 5 of a 21-day cycle. Development of anti-drug antibodies (ADAs) limited patient drug exposure beyond cycle 2. Our pre-clinical data showed that combination of LMB-100 with a taxane resulted in synergistic anti-tumor activity. Methods: We conducted a phase I single center study (standard 3+3 design) to determine the MTD of LMB-100 given with nab-paclitaxel in patients with previously treated advanced PDAC. LMB-100 was given on D1, 3 and 5 of a 21-day cycle, and nab-paclitaxel (125 mg/m2) on D1 and D8. Initial patients could receive a maximum of 4 cycles, but subsequently a 2-cycle maximum was employed. Results: Fourteen patients (median age 58) were enrolled. Two of 6 patients experienced DLTs at the 100 mcg/kg dose of LMB-100 (myalgia- 2 pts, fatigue- 1 pt, hypotension- 1 pt; all grade 3). One of 8 patients had DLT at the 65 mcg/kg dose (edema, urine output decrease- both grade 3). Other toxicities related to LMB-100 included hypoalbuminemia, edema-associated weight gain, hyponatremia, fatigue, drug fever, infusion-related reaction, hypophosphatemia, nausea and anorexia. One patient died on treatment from complications of bowel perforation attributed to cancer. All patients achieved detectable serum levels of LMB-100 during the first cycle, even those with pre-existing ADAs, and 5 of 8 did so during cycle 2. One patient receiving the 65 mcg/kg dose had a confirmed partial response, and CA 19-9 dropped by > 50% in 5 of 8 evaluable patients. Conclusions: MTD of LMB-100 is 65 mcg/kg given with nab-paclitaxel on this schedule. Anti-tumor activity was observed. A phase II cohort is currently being accrued. Clinical trial information: NCT02810418.
Adjuvant gemcitabine versus 5-fluorouracil/folinic acid based on hENT1 immunostaining in curative resected pancreatic adenocarcinoma: A biomaker stratified trial.
Authors: Shin Dong Woo , Kim Min Jae , Yang Se Yeol , Lee Jong-chan , Hwang Jin-Hyeok 
Published: January 2019

308 Background: The human equilibrating nucleoside transporter (hENT1) protein transports gemcitabine into the cell. However, role of hENT1 as a predictive biomarker for gemcitabine responsiveness in pancreatic adenocarcinoma (PDA) is still needed to be elucidated, although several studies had been conducted. We investigated whether hENT1 has a predictable role on adjuvant chemotherapy responsiveness in PDA according to stratification of hENT1 immunostaining. Methods: The 44 patients who underwent curative surgery (R0 or R1) due to PDA at Seoul National University Bundang Hospital from May 2015 to June 2017 were enrolled prospectively. The hENT1 expressions were measured by immunochemical staining (SP120-rabbit monoclonal antibody, Ventana). According to hENT1 immunostaing (≥ 50% vs. < 50%), higher hENT1 group received gemcitabine [1,000mg/m2 (day 1, 8, 15) q 4 weeks x 6 cycles] and lower hENT1 group received [5-FU 425mg/m2 (day 1-5) plus folinic acid 20 mg/m2 (day 1) q 4 weeks x 6 cycles]. Primary outcome was overall survival (OS) and secondary outcomes were toxicity and recurrence free survival (RFS). Results: Among 44 patients, 5 patients were excluded due to withdrew consent (3 patients) and toxicities (2 patients in 5FU/LV group). Eighteen patients in the higher hENT1 group and twenty-six patients in the lower hENT1 group were followed up for 24.1 months. Our data showed OS was 97.4% at 12 months and 86.4% at 24 months. Moreover, RFS was 76.8% at 12 months and 64.2% at 24 months. Although it is preliminary data, it showed better OS and RFS compared to previous study (Neoptolemos JP et al., JAMA 2010) (OS, 61.3% at 12 months, 30.7% at 24 months; RFS, 58.7% at 12 months and 30.1% at 24 months). Conclusions: Adjuvant chemotherapy based on hENT1 immunostaining stratification provides excellent survival in resected PDA. Therefore, hENT1 immunostaining should be used for making a decision for adjuvant chemotherapy remimen in PDA. Clinical trial information: NCT02486497.
Neoadjuvant chemotherapy versus upfront resection in ampullary adenocarcinoma stratified by stage: A retrospective analysis using the National Cancer Database.
Authors: Leonard-Murali Shravan , Shah Rupen A. , Ivanics Tommy , Han Xiaoxia , Steffes Christopher P. , Kwon David S. 
Published: January 2019

318 Background: Outcomes of a neoadjuvant therapy (NAT) strategy to treat ampullary adenocarcinoma (AAC) are unclear. Upfront resection (UR) (typically pancreaticoduodenectomy) with or without adjuvant therapy (AT) is currently the standard of care. We looked to assess outcomes of NAT followed by radical surgery for AAC. Methods: The NCDB was queried for ampullary carcinoma patients from 2004-2015. Patients with Stage I to III AAC who underwent radical surgery were included, and separated into NAT with surgery and UR groups. Demographic/clinical/pathologic data and their associations to survival were analyzed with univariate and multivariate cox proportional hazard models. Overall survival was estimated from time of diagnosis using Kaplan-Meier curves and compared using log-rank tests (LRT) (see table). Statistical analyses were performed using R version 3.5.1 with significance established at p < 0.05. Results: There was no difference in overall survival between the NAT (n = 47) and UR (n = 1521) groups, either as total groups (LRT p = 0.2), or when stratified by stage (stratified LRT p = 0.5). Rates of AT were higher in the UR group (p = 0.038). Receiving AT was significantly associated with improved survival (hazard ratio (HR) = 0.648), while positive nodal status (HR = 2.06), stage 3 disease (HR = 1.542), age > 65 (HR = 1.494), and male gender (HR = 1.241) were significantly associated with decreased overall survival by multivariate analysis. Conclusions: NAT does not offer a survival advantage over UR either overall or for stage-specific disease. This finding extended even to stage III disease, where NAT would theoretically offer greatest benefit. This study suggests that a NAT strategy is not preferable to UR for treatment of resectable AAC, regardless of stage. Higher powered study of NAT for AAC with controls for AT is warranted before discarding a NAT strategy. [Table: see text]
Multicenter retrospective analysis for efficacy and safety of liposomal irinotecan (nal-IRI) plus 5-FU/leucovorin (5-FU/LV) after progression on gemcitabine-based therapy in Korean patients (pts) with metastatic pancreatic ductal adenocarcinoma (mPDAC): A study by Korean Cancer Study Group (KCSG).
Authors: Yoo Changhoon , Im Hyeon-Su , Kim Kyu-Pyo , Oh Do-Youn , Lee Kyung-Hun , Chon Hong Jae , Kim Joo Hoon , Kang Myoung Joo , Kim Il-Hwan , Lee Guk Jin , Oh Sung Yong , Choi Younak , Choi Hye Jin , Kim Seung Tae , Park Joon Oh , Ryoo Baek-Yeol 
Published: January 2019

344 Background: Nal-IRI plus 5-FU/LV has demonstrated efficacy in mPDAC pts who previously received gemcitabine-based therapy in the pivotal NAPOLI-1 trial. Real-world data are helpful to measure the clinical outcomes and safety profile of this regimen in daily practice setting. Methods: Between January 2017 and April 2018, a Named Patient Program (NPP) was activated to provide controlled, pre-approval access of nal-IRI in Korea. This analysis is multicenter retrospective study for patients who received nal-IRI plus 5-FU/LV under the NPP. Results: A total of 86 patients entered into this NPP among 10 Korean institutions. Median age was 61 years (range, 37-79) and 52 pts (60%) were male. Liver (n=49, 57%), peritoneum (30, 35%), and lung (27, n=31%) were the most common metastatic sites. All patients had ECOG performance status 0-1 and previously received gemcitabine-based therapy. Prior to nal-IRI plus 5-FU/LV, 35 (41%) and 51 (59%) patients received <2 and ≥ 2 lines of chemotherapy for unresectable/metastatic disease, respectively. Best response was complete response (n=2, 2%), partial response (7, 8%), stable disease (38, 44%), and progressive disease (32, 37%), indicating overall response rates of 10% and disease control rate of 55%. With median follow-up duration of 6.4 months, median progression-free survival (PFS) was 3.5 months (95% CI, 1.3-5.7) and median overall survival (OS) was not yet reached. The 6-month PFS and OS rates were 37.5% and 65.1%, respectively. Most common grade 3-4 toxicities were neutropenia (n=32, 37%), nausea (9, 10%), vomiting (8, 9%), anemia (7, 8%), and diarrhea (4, 5%). Febrile neutropenia occurred in 7 patients (8%). Conclusions: Nal-IRI plus 5-FU/LV was well tolerated and effective for mPDAC patients who progressed on gemcitabine-based therapy. Despite heavily pretreated patients were included, efficacy and safety outcomes in our cohort were consistent with the results of previous NAPOLI-1 trial.
Adjuvant therapy is associated with improved survival in pT1N1 gastric cancer in a heterogeneous western patient population.
Authors: Porembka Matthew R. , Hester Caitlin , Augustine Mathew M , Mansour John C. , Polanco Patricio , Yopp Adam Charles , Zeh Herbert , Wang Sam C. 
Published: January 2019

36 Background: Two recent South Korean studies showed adjuvant therapy (AT) was not associated with improved survival in pT1N1 gastric adenocarcinoma (GAC). We aimed to establish the prognostic utility of lymph node status, determine the pattern of use of AT, and compare survival stratified by type of AT in pT1N1 GAC in a Western patient population. Methods: We identified patients with pT1N0 and pT1N1 GAC using the National Cancer Database from 2004 to 2012. Clinicopathologic variables, treatment regimens, and overall survival (OS) were compared. Results: We compared 4,516 (86.6%) pT1N0 to 696 (13.4%) pT1N1 patients. pT1N1 tumors were larger (median size 2.5 vs. 1.8 cm, p < 0.001), more often poorly differentiated (56.2% vs. 39.6%, p < 0.001), and had higher median retrieved lymph nodes (RLN) (14 vs. 12, p < 0.001) compared to pT1N0. pT1N1 was associated with worse median OS (6.9 years vs. 9.9 years for pT1N0, p < 0.001). pN1 was independently associated with worse OS (HR 2.17 95% CI 1.84-2.56). Increased RLN was associated with improved OS (HR 0.73, 95% CI 0.65-0.83). Among pT1N1 patients, 330 (47.4%) had observation (OBS), 77 (11.1%) received adjuvant chemotherapy (ACT), 68 (9.8%) received adjuvant radiation therapy (ART), and 221 (31.8%) received adjuvant chemoradiation therapy (ACRT). ACT and ACRT were independently associated with improved OS (HR 0.37, 95% CI 0.22-0.65 and HR 0.40, 95% CI 0.28-0.57). Conclusions: pN1 was associated with worse survival and RLN ≥ 15 was associated with improved survival in pT1 GAC. ACT and ACRT were independently associated with improved survival in pT1N1 gastric cancer suggesting a valuable role in Western patients.