bluuebunny/crossref_metadata_2025_split huggingface dataset:
Profiling of 3,634 cholangiocarcinomas (CCA) to identify genomic alterations (GA), tumor mutational burden (TMB), and genomic loss of heterozygosity (gLOH).
Authors: Javle Milind M. , Murugesan Karthikeyan , Shroff Rachna T. , Borad Mitesh J. , Abdel-Wahab Reham , Schrock Alexa Betzig , Chung Jon , Goyal Lipika , Frampton Garrett M. , Kelley Robin Kate , Miller Vincent A. , Ross Jeffrey S. , Bekaii-Saab Tanios S. , Ali Siraj Mahamed , Albacker Lee A. 
Published: May 2019

4087 Background: The management of CCA has evolved as targeted and immune checkpoint inhibitor (ICPI) therapies have emerged. We used comprehensive genomic profiling (CGP) to characterize the genomic alterations (GA) that have potential to personalize therapy for CCA. Methods: 3634 CCA underwent hybrid capture based CGP on 0.8-1.1 Mb of the coding genome to identify GAs in exons and select introns in up to 404 genes, TMB, microsatellite status (MSI) and % monoallelic genome (gLOH). PD-L1 expression was determined by IHC (Dako 22C3). Results: 52% of CCA were female with a median age of 62 years (range 16 - > 89). The most common biopsy sites were liver (74%), lymph node (4%), bile duct (3.3%), and lung (2%). MSI-high was rare (1%), 118 and 47 cases had TMB > 10 and > 20 mut/mb respectively. Of the latter, 51% (24/47) were MSI-H. PD-L1 amplification (AMP) was present in 0.27%. Of 490 CCA tested, 43 (9%) were positive for PD-L1 expression. 11% of cases had gLOH > 16%, only 2 cases had both TMB > 20 and gLOH > 16%. GA were most common in TP53 (31%), CDKN2A (29%), KRAS (20%) and ARID1A (17%). Potentially targetable GAs included FGFR2 (11%, 85% fusions), BRAF (5%, 50% V600E), ERBB2 (5%, 72% AMP), MET (2%, 90% AMP), EGFR (0.52%) and rarer ( < 0.5%) FGFR3, RET, FGFR1, ALK, and ROS1 fusions. The FGFR2 fusions had 128 unique 3’ partner genes including BICC1 (26%), CCDC6 (3.2%), AHCYL1 (2.6%) and KIAA1217 (2.6%). FGFR2 fusions occurred in a mutually exclusive fashion from high gLOH (p < 0.002), but not high TMB. GA in IDH1 (15%) were mutually exclusive of FGFR2 fusions (p < 1e-13), but co-occurred with PBRM1 GA (23%, p < 1e-21), ARID1A (26% p < 1e-10). IDH1 GA had gLOH similar to the overall CCA population but were enriched for low TMB (p < 1e-3). Conclusions: Nearly 20% of CCA cases harbor targetable kinase GA, half of which were FGFR2 fusions. Independently, an additional 10% (gLOH) and 1% (high TMB, MSI and/or PD-L1 AMP) may benefit from PARP inhibitors and ICPI respectively. Independently, co-mutation of IDH1 and PBRM1/ARID1A defines a class of CCA that warrants further investigation for sensitivity to PARP inhibitors and may serve as a paradigm for other tumors (ie. gliomas) with a similar co-occurrence landscape.
Novel staging system using carbohydrate antigen (CA) 19-9 in extrahepatic cholangiocarcinoma (ECCC) and its implications on overall survival (OS).
Authors: Tella Sri Harsha , Yadav Siddhartha , Kommalapati Anuhya , Mahipal Amit 
Published: May 2019

4091 Background: Optimal management of ECCA patients with elevated CA19-9 remains undefined. We hypothesized CA 19-9 elevation as a marker of aggressive biology in ECCA and that inclusion of CA 19-9 in the staging may improve OS discrimination. Methods: Patients with ECCA with CA 19-9 levels reported to the National Cancer Database (years 2004-2015) were included. The patients were classified based on their CA19-9 levels and a new staging system was proposed. Based on the current knowledge, we considered 37 U/ml as our cut off. Kaplan Meier method was used to compare OS between the groups. The net reclassification improvement (NRI) model was used to assess the predictive improvement in the proposed survival model. Results: A total of 2100 patients met the inclusion criteria: 601 (32%) and 1436 (68%) had normal and elevated CA19-9 levels, respectively. Rates of chemo (p=0.16) and radiation therapy (p=0.07) were similar between groups, but patients with elevated CA19-9 were less likely to undergo resection. Resected patients with CA19-9 elevation had higher 30-day mortality (p=0.02) and lower median OS (p<0.01). Patients with elevated CA 19-9 levels had decreased stage-specific survival in all stages (p<0.01). On adjusted analysis, CA19-9 elevation independently predicted poor OS (HR: 1.67 [1.42-1.97]) with impact resembling nodal metastasis, positive resection margin, lymphovascular invasion, and non-receipt of surgery or chemotherapy (p<0.01). CA 19-9 included proposed staging system (Table) had a better OS discrimination over AJCC 7th edition. The new staging system had a concordance of 60% as opposed to 58% for the AJCC staging, leading to an improvement of 2% (p<0.01). NRI of 46% (95% CI: 39-57) indicates that the new staging system is substantially effective at re-classifying events at 12 months as compared to AJCC staging. Conclusions: Elevated CA19-9 was found to be an independent risk factor for mortality in ECCA and its inclusion in the newly proposed staging system markedly improved OS discrimination.[Table: see text]
Clinical and prognostic significance of serum levels of fatty acid binding proteins in hepatocellular carcinoma (HCC).
Authors: Abugabal Yehia I. , Kaseb Ahmed Omar , Rashid Asif , Pestana Roberto , Abdel-Wahab Reham , Xiao Lianchun , Qayyum Aliya , Girard Lauren , Raghav Kanwal Pratap Singh , Morris Jeffrey , Wolff Robert A. , Yao James C. , Amin Hesham M. , Hassan Manal 
Published: May 2019

4099 Background: Limited data are available about the prognostic effect of fatty acid binding proteins (FABP) in viral and non-viral-related hepatocellular carcinoma (HCC). Previous studies suggested that selected FABP could be a potential target markers for HCC chemotherapy response and may correlated with presence of cirrhosis and poor outcome. We aimed to test the association between plasma levels of Liver (L)-FABP, Heart (H)-FABP, and Adipose (A) FABP and HCC. Methods: we enrolled 767 HCC patients from MD Anderson Cancer Center. Under IRB approval, baseline patients’ characteristics were retrieved from medical records and blood samples were collected and tested form plasma levels of L-, A-, H-, FABPs. Descriptive statistics were performed and the median values of FABPs among 200 normal controls (NC) were used as cutoff values of FABPs. Overall survival (OS) was estimated by Kaplan Meier curve and log rank test. Results: FABPs were highly expressed in HCC cases than controls. Mean values (±SE) of AFABP, HFABP, and LFABP were significantly higher in cases [25.6 (.7), 10.8 (.5), and 47.8 (1.9)] than controls [19.1 (.8), 7.7 (2), 22. 9 (.5)], P < .001. All FABPs were significantly associated with cirrhosis, higher Child Pugh Score (CTP), advanced stage in Barcelona clinic liver cancer stage (BCLC), higher AFP levels, vascular invasion and thrombosis, and tumor nodularity. Median OS (months) (95%CI) were significantly short in patients with higher level of AFABP, HFABP, and LFABP [9.3 (6.8-11.9), 9.4 (6.8-11.9), and 11.1 (8.8-13.3)] as compared to patients with low levels [16.4 (13.8-18.9), 16.4 (14.2-18.6), and 17.9 (14.9-20.9) respectively (P < .01). The significance was observed in non-viral related HCC for LFABP and HFABP, but not AFBABP. Conclusions: To the best of our knowledge, we describe the largest study correlating FABPs levels with clinical and prognostic characteristics of HCC. Higher levels were associated with poor survival. These findings suggest that LFABP and HFABP may be used as potential prognostic biomarkers for non-viral-related HCC.
An open label, single-arm, two-stage, multicenter, phase II study to evaluate the efficacy and safety of TLC388 as second-line treatment in subjects with poorly differentiated neuroendocrine carcinomas (TCOGT1Z14).
Authors: Chen Ming-Huang , Chou Wen-Chi , Hsiao Chin-Fu , Liu Yi-Chang , Hsu Chiun , Yanshen Shan , Hung Yi-Ping , Hsieh Chia-Hsun , Chiu Chao-Hua , Liu Ta-Chih , Cho Shih-Feng , Liu Tsang-Wu , Chao Yee 
Published: May 2019

4101 Background: Therapeutic options for metastatic poorly differentiated neuroendocrine carcinoma (NEC) after prior platinum‐based chemotherapy are unknown. Camptothecin analogs, like topotecan and irinotecan, are approved chemotherapy in small cell lung cancer (SCLC). NEC is considered to have similar biological behavior to SCLC. The aim of this study was to analyze the efficacy of TLC388 (Lipotecan) Hydrochloride, which is a novel camptothecin analog, in pretreated metastatic NEC patients. Methods: This single-arm, 2-stage, phase 2 clinical trial was conducted at 4 community and academic centers in Taiwan. Patients aged 20 years or older enrolled between July 2015 to May 2018 had confirmed metastatic NEC with prior systemic therapy with etoposide plus cisplatin. Patients received intravenous 40 mg/m2 of TLC388 on Days 1, 8 and 15 of a 28-day cycle until disease progression or unacceptable toxic effects. Results: twenty-three patients with a median age of 61 (range, 44-73) years, including 18 men (78%), were enrolled. Patients received a median of 2 (range, 0-6) treatment cycles. Among 20 evaluable patients, three patients showed a stable disease and no patient a complete or partial remission, resulting in a disease control rate of 15%. Median PFS was 1.8 (95% CI, 0.4-15) months and median OS was 4.3 (95% CI, 1.7-15) months. The most common treatment-related hematologic adverse events at grade 3 or higher were leukopenia (22.7%), anemia (31.8%), and thrombocytopenia (18.2%), respectively. Conclusions: TLC388 shows modest antitumor activity in metastatic NEC. Clinical trial information: NCT02457273.
Surgery and peptide receptor radionuclide therapy: An effective multimodal approach for metastatic neuroendocrine tumors.
Authors: Frilling Andreja , Clift Ashley , Al-Nahhas Adil , Baum Richard P. , Kaemmerer Daniel 
Published: May 2019

4113 Background: Neuroendocrine neoplasia (NEN) of the pancreas (PanNEN) or small bowel (SBNEN) frequently present with metastases at initial diagnosis, undermining the efficacy of surgical treatment. Peptide receptor radionuclide therapy (PRRT) with radiolabelled somatostatin analogues, 90Y-DOTATOC and 177Lu-DOTATATE, has been shown to achieve prolonged progression-free survival (PFS) and overall survival (OS) in a substantial number of non-surgical patients with advanced NEN. Our aim was to prospectively determine the efficacy of a combination of radical loco-regional surgery and 177Lu PRRT in patients with metastasised NEN. Methods: A set of inclusion criteria was defined (e.g. PanNEN or SBNEN, G1/G2 NEN, initial tumour diagnosis, treatment naïve patient, stage IV NEN, positivity on 68Ga DOTATATE or DOTATOC PET/CT, eligibility for surgery and PRRT). Patients underwent PRRT within 3 months following surgery. Follow-up included biochemistry and imaging. Outcome measures included 1-, 3-, and 5-year OS and PFS from initial diagnosis. Results: Forty-one patients met eligibility criteria and were included. There were 26 males (63.4%) and median age at surgery was 58.8 years (range 32.1-78.3). All patients with SBNEN underwent right hemicolectomy, terminal ileal resection and mesenteric lympadenectomy. In PanNEN patients either Whipple procedure or distal pancreatectomy and peripancreatic lymphadenectomy were performed. The median number of PRRT cycles was 4 (range 2-6). Post-treatment mortality was 0%. Surgical morbidity was 12% (all grade 1 according Clavien-Dindo) and transient grade 1 toxicity occurred post PRRT in 40%. There was no grade 3 toxicity. Median follow-up was 5.48 years (range 0.53 – 11.98). Median PFS and OS were 3.33 years and 9.07 years, respectively. Progression-free survival (with 95% CI) was at 1-, 3-, and 5-years 80% (68.7-92.6), 60.9% (45.9-75.9) and 43.3% (27.4-59.3), respectively. Overall survival (with 95% CI) at 1-, 3-, and 5-years was 97.6% (93-100), 97.6% (93-100), and 95% (87-100), respectively. Conclusions: Radical loco-regional surgery for primary tumours combined with PRRT provides a novel, highly efficacious approach in metastasised NEN.
Variation in the surgical management of locally advanced pancreatic cancer.
Authors: Reames Bradley Norman , Blair Alex , Krell Robert Wallace , Padussis James , Thayer Sarah P. , Falconi Massimo , Wolfgang Christopher Lee , Weiss Matthew J. , Are Chandrakanth , He Jin 
Published: May 2019

4122 Background: Recent reports suggest patients with locally advanced pancreatic cancer (LAPC) may become candidates for curative resection following neoadjuvant therapy, with encouraging survival outcomes. Yet the optimal management approach for LAPC remains unclear. We sought to investigate surgeon preferences for the management of patients with LAPC. Methods: An extensive electronic survey was systematically distributed by email to an international cohort of pancreas surgeons. Data collected included surgeon practice characteristics, preferences for staging and management, and 6 clinical vignettes (with detailed videos of post-neoadjuvant arterial and venous imaging) to assess attitudes regarding eligibility for surgical exploration. Results: A total of 150 eligible responses were received from 4 continents. Median duration in practice was 12 years (IQR 6-20) and 75% respondents work in a university setting. Most (84%) are considered high volume, 33% offer a minimally-invasive approach, and 48% offer arterial resection in selected patients. A majority (70%) always recommend neoadjuvant chemotherapy, and 62% prefer FOLFIRINOX. Preferences for duration of neoadjuvant therapy varied widely: 39% prefer ≥2 months, 41% prefer ≥4 months, and 11% prefer 6 months or more. Forty-one percent frequently recommend neoadjuvant radiation, and 51% prefer standard chemoradiotherapy. Age ≥80 years and CA 19-9 of ≥1000 U/mL were commonly considered contraindications to exploration. In 5 clinical vignettes of LAPC, the proportion of respondents that would offer exploration following neoadjuvant varied extensively, from 15% to 54%. In a vignette of oligometastatic pancreatic liver metastases, 32% would offer exploration if a favorable biochemical and imaging response to therapy is observed. Conclusions: In an international cohort of high volume pancreas surgeons, there is substantial variation in attitudes regarding staging preferences and surgical management of LAPC. These results underscore the importance of coordinated multi-disciplinary care, and suggest an evolving concept of “resectability.” Patients and their oncologists should have a low threshold to consider a second opinion for the surgical management of LAPC, if desired.
A phase Ib dose-escalation and cohort-expansion study of safety and activity of the transforming growth factor (TGF) β receptor I kinase inhibitor galunisertib plus the anti-PD-L1 antibody durvalumab in metastatic pancreatic cancer.
Authors: Melisi Davide , Hollebecque Antoine , Oh Do-Youn , Calvo Emiliano , Varghese Anna M. , Borazanci Erkut Hasan , Mercade Teresa Macarulla , Simionato Francesca , Park Joon Oh , Bendell Johanna C. , Faivre Sandrine J. , Zhao Yumin , Gueorguieva Ivelina , Man Michael , Estrem Shawn , Benhadji Karim Adnane , Lanasa Mark , Guba Susan C. , Garcia-Carbonero Rocio 
Published: May 2019

4124 Background: Pancreatic cancer (PC) is characterized by a highly immunosuppressive microenvironment, and immune checkpoint inhibitors as monotherapy have been ineffective to date. TGFβ is commonly viewed as a powerful immunosuppressive cytokine, and inhibition of its signaling reverses this suppression and activates adaptive immune responses. A combination of TGFβ and PD-L1 inhibition may act synergistically to induce immune restoration and to improve antitumor responses. This Phase 1b study (NCT02734160) evaluated the combination of galunisertib plus durvalumab in recurrent or refractory metastatic PC. Methods: Eligible patients (pts) were ≥18 years old, had ECOG status ≤1, and had not received treatment with anti-PD-1, anti-PD-L1, or TGFβ R1 kinase inhibitors. The primary objective was to assess the safety and the recommended dose of galunisertib given 14 days on/14 days off in combination with durvalumab 1500 mg every 4 weeks. Four dose levels of galunisertib were tested in the dose escalation portion of the study: 50 mg QD, 50 mg BID, 80 mg BID and 150 mg BID, followed by the cohort expansion portion of the study at the recommended Phase 2 dose (RP2D). Secondary objectives included preliminary assessment of activity by response rate, (RECIST v1.1), median PFS (mPFS), and OS (mOS). Results: 42 pts (25F/17M) were treated in the study (median age 56.5 y; 71.4% had received ≥2 prior systemic regimens). There was no dose limiting toxicity and galunisertib 150 mg BID was chosen as the RP2D. In the 32 pts treated at this dose, Grade ≥3 related AEs included AST and GGT elevations (2 pts each), and ALT and alkaline phosphatase elevations, and neutropenia (1 pt each). One partial response and 7/32 stable diseases were observed (disease control rate 25%); mPFS was 1.9 months (95% CI: 1.5, 2.2) and mOS was NR (95% CI: 3.6, NR). Biomarker data will be presented at the meeting. Conclusions: The combination of galunisertib plus durvalumab had an acceptable tolerability and safety profile. The activity of this combination in second and third line PC patients warrants further consideration. Clinical trial information: NCT02734160.
NEONAX trial: Neoadjuvant plus adjuvant or only adjuvant nab-paclitaxel plus gemcitabine for resectable pancreatic cancer, a phase II study of the AIO pancreatic cancer group (AIO-PAK-0313)—Safety interim analysis.
Authors: Uhl Waldemar , Ettrich Thomas Jens , Reinacher-Schick Anke C. , Algül Hana , Friess Helmut , Kornmann Marko , Koenig Alexander , Ghadimi Michael , Wittel Uwe A , Gallmeier Eike , Wille Kai , Geissler Michael , Schimanski Carl Christoph , Prasnikar Nicole , Tannapfel Andrea , Perkhofer Lukas , Berger Andreas W. , Seufferlein Thomas 
Published: May 2019

4128 Background: Survival in pancreatic cancer (PDAC) is still poor even after curatively intended resection. Perioperative treatment approaches improve outcome in various tumor entities. Data on perioperative treatment in resectable PDAC are limited and there is a debate whether neoadjuvant treatment might impair subsequent surgery by adding perioperative morbidity or mortality. Methods: NEONAX is a randomized phase II study (planned 166 patients) of perioperative gemcitabine/nab-paclitaxel (Arm A: 2 pre- and 4 post-operative cycles, Arm B: 6 cycles adjuvant) for patients with primarily resectable PDAC. Primary objective is DFS at 18 months after randomization. Secondary objectives are 3-year OS-rate and DFS-rate, progression during neoadjuvant therapy, R0/R1 resection rate and QoL. Results: NEONAX was initiated in March 2015 in 26 centers for PDAC surgery in Germany. The data represent the safety interim analysis (IA) of the first 48 patients. 25 patients were randomized to Arm A and 23 to Arm B. Patients’ median age was 65.3 years (56.3% males, 43.8% females, 85.4% ECOG 0). Out of 25 patients in Arm A 20 patients (80%) underwent surgery, compared to 21 of 23 patients (91.3%) in Arm B with upfront surgery. Reasons for no resection were intraoperatively determined small liver metastases (2 cases, Arm A), withdrawal of informed consent (2 cases in each arm) and 1 patient with uncontrolled cholestasis (arm A). Postoperative complications occurred in 45% of arm A and 42.8% of arm B. (pancreatic fistula: 15% in arm A and 9.5% in arm B, infections: 10% in arm A and 9.5% in arm B) All resected patients were alive 60 days after surgery. At least 1 adverse event (AE) NCI-CTCAE ≥ grade 3 occurred in 60% of the perioperative and 39.1% of adjuvant treatment arm. Most common AEs were neutropenia (16.7%), fatigue (10.4%) and infections (10.4%). Conclusions: There was an increase in NCI-CTCAE ≥ grade 3 events in the perioperative arm, but this was manageable and did not result in increased peri- or postoperative mortality. 8% of patients in the perioperative arm did not get resected due metastases detectable during surgery, but not on preoperative imaging immediately prior to surgery. Therefore, it cannot be determined whether these metastases were preexistent or developed during neoadjuvant treatment. In conclusion, the first interim analysis of the NEONAX trial shows that this protocol can be safely applied to patients with resectable PDAC in a perioperative setting. Clinical trial information: NCT02047513.
Association of BRCA-mutant pancreatic cancer with high tumor mutational burden (TMB) and higher PD-L1 expression.
Authors: Seeber Andreas , Puccini Alberto , Xiu Joanne , Goldberg Richard M. , Grothey Axel , Shields Anthony Frank , Salem Mohamed E. , Battaglin Francesca , El-Deiry Wafik S. , Tokunaga Ryuma , Philip Philip Agop , Marshall John , Kocher Florian , Hall Michael J. , Korn Wolfgang Michael , Lenz Heinz-Josef , Spizzo Gilbert 
Published: May 2019

4133 Background: In the U.S. 56,000 Americans are expected to be diagnosed with pancreatic cancer in 2019. Prognosis in pancreatic cancer is poor. Therefore, new treatment strategies are urgently needed to improve survival. BRCA1 and BRCA2 mutations have been described to be the most common genetic mutations involved in familial pancreatic cancer. The optimal treatment regimen to use in BRCA-mutant pancreatic cancer has still to be established. Moreover, no data are available on association of BRCA mutation with immune-associated markerssuch as tumor mutational burden (TMB), microsatellite instability (MSI) or PD-L1 expression. Methods: Tumor samples of 2824 patients with pancreatic ductal adenocarcinoma were analyzed for BRCA mutation by NGS and for other genes (MiSeq on 47 genes, NextSeq on 592 genes) at Caris Life Sciences, Phoenix, AZ. TMB was calculated based on somatic nonsynonymous missense mutations, and MSI was evaluated by NGS of known MSI loci. PD-L1 expression was evaluated using immunohistochemistry. Results: In 4.4% (N = 124) of all pancreatic adenocarcinoma samples BRCA mutations were detected. BRCA2 mutations were more common: 3.1% (N = 89) vs 1.1% BRCA1 mutations (N = 35). BRCA mutations were associated with younger age ( BRCA1: 61 yrs for mutated vs. 64 for wild-type, p = 0.07; BRCA2: 61 yrs vs. 64, p = 0.002; both: p < 0.001). BRCA mutations were associated with higher MSI-H frequency (4.8% vs. 1.2%, p = 0.002), elevated PD-L1 expression (22% vs. 11%, p < 0.001) and higher TMB (mean 8.7 mut/MB vs. 6.5, p < 0.001); the differences remain significant in MSS tumors (p < 0.05). BRCA-mutant pancreatic carcinomas showed a significantly lower mutation frequencies in TP53 (59% vs 73%, p = 0.001), CKDN2A (13% vs 25%, p = 0.006), but higher frequencies in APC (6.5% vs 2.2%), KMT2A (1.9% vs 0.2%), AMER1 (1.9 vs 0.5%) and SETD2 (3.7% vs 0.4%) mutations (p < 0.05 for all comparisons). Conclusions: BRCA mutations are found in a significant subgroup of pancreatic ductal adenocarcinoma and these carcinomas are associated with an immunogenic tumor profile. These data suggest evaluating PARP inhibitors in combination with immunotherapy in patients with BRCA-mutant pancreatic adenocarcinoma especially in tumors that are MSS.