bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical value of atezolizumab + bevacizumab for first-line unresectable hepatocellular carcinoma (HCC): A network meta-analysis.
Authors: Vogel Arndt , Rimassa Lorenza , Sun Hui-Chuan , Abou-Alfa Ghassan K. , El-Khoueiry Anthony B. , Pinato David James , Daigl Monica , Sanchez Alvarez Javier , Orfanos Panos , Leibfried Michael , Blanchet Zumofen Marie-Hélène , Gaillard Vincent , Merle Philippe 
Published: May 2020

4585 Background: The IMbrave150 pivotal study in unresectable HCC showed superiority of atezolizumab + bevacizumab (atezo + bev) vs sorafenib for OS and PFS. Based on these data supporting first-line atezo + bev for HCC, we conducted a network meta-analysis (NMA) to compare the efficacy of atezo + bev with other systemic and local therapies approved for HCC. Methods: A systematic literature review identified randomized controlled trials in adults with locally advanced or metastatic HCC and no prior systemic therapy for HCC. Studies of therapies now approved for any line of HCC treatment with data reported for first-line treatment since sorafenib approval in 2007 were eligible. Screening of 8783 records yielded 55 trials for inclusion; 9 studies were eligible for the evidence network. Reported hazard ratios (HRs) for OS and PFS were extracted from published studies. The IMbrave150, REFLECT and CheckMate-459 study populations were considered sufficiently similar to compare. A generalized linear model with random effects was used to estimate indirect treatment effects. Informative priors for the heterogeneity of treatment effects across trials were adopted given the limited number of trials to inform each pairwise comparison. HRs with 95% credible intervals (CrIs) and Bayesian posterior probability of atezo + bev being superior to other treatments were calculated for each treatment comparison. The base case NMA compared the relative efficacy of atezo + bev vs sorafenib observed in the IMbrave150 study with the relative effect of other therapies. Sensitivity analyses were performed to compare subgroup results as appropriate based on disease etiology, extrahepatic spread and geography. Results: NMA results suggested improved OS with atezo + bev vs lenvatinib (HR, 0.63; 95% CrI: 0.32, 1.25; probability of atezo + bev being superior to lenvatinib: 93.7%) or nivolumab (HR, 0.68; 95% CrI: 0.35, 1.38; probability of atezo + bev being superior to nivolumab: 90.3%) and improved PFS with atezo + bev vs lenvatinib (HR, 0.91; 95% CrI: 0.23, 3.65; probability of atezo + bev being superior to lenvatinib: 61.5%) or nivolumab (HR, 0.63; 95% CrI: 0.16, 2.59; probability of atezo + bev being superior to nivolumab: 85.5%). Conclusions: This NMA suggested greater OS and PFS benefits with first-line atezo + bev treatment vs other therapies approved for treatment of unresectable HCC.
Predictive value of changes in plasma vascular endothelial growth factor at eight weeks after lenvatinib administration in patients with unresectable hepatocellular carcinoma.
Authors: Tsuchiya Kaoru , Kurosaki Masayuki , Kaneko Shun , Yasui Yutaka , Kirino Sakura , Sekiguchi Shuhei , Inada Kento , Yamashita Koji , Hayakawa Yuka , Higuchi Mayu , Takaura Kenta , Maeyashiki Chiaki , Tamaki Nobuharu , Nakanishi Hiroyuki , Itakura Jun , Izumi Namiki 
Published: May 2020

4594 Background: Lenvatinib (LEN) has been used in patients with unresectable hepatocellular carcinoma (u-HCC) and there is no established predictive biomarker. Previously it was reported that a plasma vascular endothelial growth factor (VEGF) concentration decrease at 8 weeks after starting sorafenib might predict favorable overall survival (OS) in patients with u-HCC (Tsuchiya, et al. Cancer, 2013). We aimed to investigate the value of changes in plasma VEGF at 8 weeks after LEN administration in patients with u-HCC. Methods: Forty-six patients with u-HCC who received LEN between April 2018 and August 2019 at our institution were enrolled. Plasma concentrations of VEGF and serum α-fetoprotein (AFP) levels were measured at baseline, 4 and 8 weeks after administration of LEN. A VEGF decrease was defined as > 5% decrease during 8 weeks after the beginning of LEN therapy. AFP response was defined as > 20% decrease during 8 weeks according to the previous reports. Results: Median overall survival (OS) was not reached and progression-free survival (PFS) was 5.9 months. Median observation period and treatment duration were 10.1 and 6.3 months. The objective response rate and disease control rate by mRECIST criteria were 43.5% and 82.6%. Median PFS in patients who had a VEGF decrease at week 8 (n = 29) was significantly longer than those who did not have a VEGF decrease (n = 17; 7.1 months vs 5.0 months; p = 0.014). AFP response was not associated with PFS. There were no significant differences in baseline VEGF, AFP, ALBI score, and extrahepatic metastasis between the patients with and without a VEGF decrease. A VEGF decrease was significantly associated with radiological objective response (p = 0.001) and 18 of 20 patients who achieved CR (n = 3) or PR (n = 17) had a VEGF response in LEN therapy. Conclusions: A decrease of plasma VEGF level at 8 weeks in patients with u-HCC on LEN was significantly associated with PFS. Changes in plasma VEGF could become a new biomarker for molecular targeted therapies including VEGF inhibitors in patients with unresectable HCC.
Immediate post-thermal ablation biopsy of colorectal liver metastases to predict oncologic outcomes.
Authors: Vasiniotis Kamarinos Nikiforos , Vakiani Efsevia , Gonen Mithat , Kemeny Nancy E. , Covey Anne M. , Brown Karen T. , Brody Lynn A , Deipolyi Amy R , Camacho Juan , Boas F. Edward , Yarmohammadi Hooman , Erinjeri Joseph , Petre Elena N , Kingham T. Peter , D'Angelica Michael Ian , Saltz Leonard B. , Solomon Stephen Barnett , Sofocleous Constantinos T. 
Published: May 2020

4602 Background: Thermal ablation (TA) is used as a local cure for selected colorectal liver metastases (CLM) with minimal risk. A critical limitation of TA has been early local tumor progression (LTP). The goal of this study is to establish the role of ablation zone (AZ) biopsy in predicting LTP. Methods: This institutional review board-approved prospective study included patients with CLM of 5cm or less in maximum diameter, with confined liver disease or stable, limited extrahepatic disease. Both radiofrequency(RF) and microwave(MW) ablation modalities were used. A biopsy of the center and margin of the AZ was performed immediately after ablation. The applicators were also examined for the presence of viable tumor cells. All samples containing morphologically identified tumor cells were further interrogated with immunohistochemistry to determine the proliferative and viability potential of the detected tumor cells. Ablation margin size was evaluated on the first CT scan performed 4–8 weeks after ablation and was confirmed by 3D assessment with Ablation Confirmation Software (Neuwave™). Variables were evaluated as predictors of time to LTP with the competing-risks model (uni- and multivariate analyses). Results: Between November 2009 and February 2019, 102 patients with 182 CLMs were enrolled. Mean tumor size was 2.0 cm (range, 0.6–4.8 cm). MW was used in 95/182 (52%) tumors and RF in 87/182 (48%). Median follow-up was 19 months. Technical effectiveness was evident in 178/182 (97%) ablated tumors on the first contrast material–enhanced CT at 4–8-weeks post-ablation. The cumulative incidence of LTP at 12 months was 19% (95% confidence interval [CI]: 14, 27). Samples from 64 (35%) of the 178 technically successful cases contained viable tumor. At univariate analysis, tumor size, minimal margin size, and biopsy results were significant in predicting LTP. In a multivariate model, margin size of less than 5 mm (P < .001; hazard ratio [HR], 4.3), and positive biopsy results (P = .02; HR, 1.8) remained significant. LTP within 12 months after TA was noted in 3% (95% CI: 1, 6) of tumor-negative biopsy CLMs with margins of at least 5 mm. Conclusions: Biopsy and pathologic examination of the AZ predicts LTP regardless of TA modality used. This can optimize ablation as a potential local cure for patients with limited CLM.
Safety of 177Lu-DOTATATE in patients with advanced neuroendocrine tumors: Data from a U.S. expanded access program.
Authors: Auerbach Martin S. , Wolin Edward M. , Nassiri Val , Broberg Per , El-Haddad Ghassan 
Published: May 2020

4604 Background: The NETTER-1 clinical trial showed that peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE increased progression-free survival in patients with somatostatin-receptor-positive advanced midgut neuroendocrine tumors (NETs) compared with high-dose octreotide long-acting repeatable, and was associated with few serious adverse events (AEs). To assess the safety profile of 177Lu-DOTATATE in a real-world population, we analyzed safety data from a US expanded access program (NCT02705313). Methods: Patients had inoperable, histologically proven, somatostatin-receptor-positive, locally advanced or metastatic GEPNETs (Ki-67 index ≤ 20%) that progressed after somatostatin analog therapy. Exclusion criteria were: surgery, radiotherapy or chemotherapy in the last 12 weeks; treatment with an interferon, mTOR inhibitor, or other systemic therapy in the last 4 weeks; or ongoing octreotide therapy that could not be interrupted for PRRT. Patients with impaired renal function (serum creatinine > 1.7 mg/dL or creatinine clearance < 50 mL/min) or serious coexisting conditions were excluded. The analysis included patients who received ≥ 1 cycle of 177Lu-DOTATATE between July 5, 2016 and December 21, 2018. Data were collected from the first cycle to the latest data collection point (up to October 7, 2019). Results: 299 patients received a mean 177Lu-DOTATATE cumulative dose of 552 mCi (20.4 GBq) (standard deviation [SD]: 220 mCi [8.1 GBq]) over a mean of 2.8 cycles (SD: 1.1). Mean age was 60.8 years (SD: 11.7); 38.5% of patients were men. Over a mean follow-up of 131 days (SD: 87), 48.8% of patients reported treatment-related AEs (TRAEs), with a maximum severity of grade 1, 2 and 3 for 26.8% (n = 80), 18.1% (n = 54) and 4.0% (n = 12) of patients, respectively; there were no grade 4–5 TRAEs. The most common TRAEs of any grade (≥ 5.0% of patients) were nausea (31.1%), vomiting (13.7%), fatigue (9.4%) and thrombocytopenia (6.0%). The most prevalent grade 3 TRAEs were lymphocyte count decrease (1.0%) and thrombocytopenia (0.7%). Serious TRAEs occurred in 1.0% of patients (carcinoid crisis, dehydration, syncope and vomiting). AEs led to dose modification in 1.7% of patients, dose delay in 6.4% (most commonly due to nausea [2.0%] or thrombocytopenia [2.0%]) and discontinuation in 1.3% (due to thrombocytopenia [1.0%] and extravasation [0.3%]). Conclusions: In a real-world population of US patients with advanced GEPNETs, 177Lu-DOTATATE treatment was well tolerated with few TRAEs, consistent with the safety profile in the NETTER-1 trial. Clinical trial information: NCT02705313 .
Multicenter analysis of treatment outcomes for well differentiated grade 3 neuroendocrine tumors (NET G3).
Authors: Apostolidis Leonidas , Dal Buono Arianna , Merola Elettra , Jann Henning , Jaeger Dirk , Wiedenmann Bertram , Winkler Eva Caroline , Pavel Marianne 
Published: May 2020

4607 Background: Well differentiated grade 3 neuroendocrine tumors (NET G3) have been distinguished from poorly differentiated neuroendocrine carcinomas (NEC) in the most current WHO classifications from 2017 and 2019. Retrospective data suggest that commonly applied first-line chemotherapy protocols with cisplatin or carboplatin in combination with etoposide (PE) are less effective in NET G3 than NEC. Therefore, current treatment guidelines suggest alternative first-line treatment protocols like temozolomide-based (TEM), streptozotocin-based (STZ) and FOLFOX which have only been studied in second-line so far. The aim of this multicenter analysis was to evaluate treatment outcomes for NET G3 with a focus on the efficacy of different first-line regimens. Methods: We performed retrospective analysis of all patients with NET G3 in the NEN databases of 3 German cancer centers. All histopathological findings were reviewed by the investigators in order to comply with the most current WHO classification. Results: A total of 131 patients could be identified. Median Ki67 was 30 %, primary tumors were located in the pancreas in 71 % of cases, 20 patients had a history of prior NET G1/G2 diagnosis. Median overall survival (OS) was 138.1 months with a median follow-up of 20.4 months. 125 patients received palliative first-line therapy: PE n = 34, FOLFOX n = 36, TEM (mostly temozolomide+capecitabine) n = 21, STZ n = 19, other (including targeted agents, somatostatin analogues, PRRT and multimodal combination approaches) n = 15. Overall response (ORR) and disease control rate was 35.3 % and 67.6 % for PE, 52.8 % and 80.6 % for FOLFOX, 28.6 % and 66.7 % for TEM, 47.4 % and 68.4 % for STZ, 20.0 % and 73.3 % for other respectively. Median progression-free survival for PE was 5.2 months. Compared to PE, PFS in the other treatment groups was 6.0 months for FOLFOX (p = 0.164), 12.0 months for TEM (p = 0.059), 5.7 months for STZ (p = 0.519), 14.1 months for other (p = 0.003). All non-PE patients combined showed a significantly prolonged PFS vs. PE (9.0 vs. 5.2 months; p = 0.011). 89 patients received second-line systemic therapy with a median PFS of 5.3 months. Conclusions: In this first multicenter analysis of different treatment strategies for NET G3, patients receiving upfront treatment with non-PE regimens had a significantly prolonged PFS. Of the single defined protocols, FOLFOX showed the highest ORR, and TEM the longest PFS. Further prospective evaluation of the optimal therapeutic strategy for this newly defined tumor entity is needed.
Landscape of DNA-damage-repair/homologous recombination deficiency (DDR/HRD) in hepatopancreaticobiliary (HPB) cancers.
Authors: Park Wungki , Sokol Ethan , Chen Jiapeng , Yu Kenneth H. , Khalil Danny , Harding James J. , El Dika Imane H. , Riaz Nadeem , Abou-Alfa Ghassan K. , Kelsen David Paul , Iacobuzio-Donahue Christine A , O'Reilly Eileen Mary 
Published: May 2020

4620 Background: Biallelic HR-gene mutations (HRm) confer HRD and sensitivity to DDR-targeted therapies including platinum and PARPi in pancreatic cancer (PDAC). The landscape of DDR/HRD phenotypes in HPB cancers and their clinical implication is yet to be evaluated, the subject of this effort. Methods: Hybrid capture-based comprehensive genomic profiling was performed in a CLIA-certified, CAP-accredited lab (Foundation Medicine, Inc.) on up to 395 genes, including the HR-genes ( BRCA1/2, PALB2, RAD50/51B/C/D, MRE11, ATRX, ATR, ATM, BAP1, BRIP1, CHEK2, NBN, and FANCA). Putative DDR/HRD phenotype was assessed using percent genome under LOH (gLOH) (PMID: 28916367). Variant zygosity was assessed as previously described (PMID: 29415044). From an independent PDAC subgroup among HPB cancers, we evaluated their outcomes on first-line platinum. Results: From a total of 11,174 tumors, pathogenic DDR/HRm were identified in 18% (1980/11174) of HPB cancers, 15% (863/5941) of PDAC, 25% (744/2998) of cholangiocarcinoma, 15% (141/958) of hepatocellular carcinoma, and 17% (152/873) of gallbladder carcinoma. We observed a majority (63%) of DDR/HRm with LOH. Rigorous filtering for tumor purity and copy number quality metrics yielded 34% (4051/11774) cases evaluable. The median gLOH of any biallelic DDR/HRm was 12.9% compared to 8.8% in no DDR/HRm (p=5.7E-33). Strength of the association varied by gene, with the strongest association in BRCA1 (22.3, p=1.5E-10), BRCA2 (20.1, p=1.7E-35), RAD51C (16.7, p=7.8E-4), PALB2 (16.4, p=1.4E-5), BRIP1 (14.3, p=0.02), RAD51B (13.7, p=0.02), and ATM (13.6, p=7.7E-12) (Table). Most other DDR/HR-genes and monoallelic DDR/HRm had weak gLOH. PDAC accounted for 60% of this HPB dataset. In an independent dataset of PDAC at MSK (n=262), biallelic DDR/HRm patients (n=29, 11%) had mostly germline mutations and had significantly improved median PFS on first-line platinum vs. non-platinum (13.3 [95%CI: 9.57-NR] vs 3.8 [95%CI: 2.79-NR] months, p<0.0001). Conclusions: Biallelic DDR/HRm is a distinct population of HPB cancers beyond PDAC and may confer better phenotype in DDR-targeted treatment. Further independent validation is underway. [Table: see text]
Enrichment of alterations in targetable molecular pathways in KRAS wild-type (WT) pancreatic cancer (PC).
Authors: Philip Philip Agop , Xiu Joanne , Hall Michael J. , Hendifar Andrew Eugene , Lou Emil , Hwang Jimmy J. , Gong Jun , Khushman Moh'd M. , Sohal Davendra , Lockhart A. Craig , Weinberg Benjamin Adam , Marshall John , Grothey Axel , Shields Anthony Frank , Korn Wolfgang Michael 
Published: May 2020

4629 Background: Genomic profiling has identified KRAS mutations in 88-90% of PC. KRAS WT tumors represent a molecularly heterogeneous group that may harbor targetable alterations (TA). We studied KRAS WT PC using NextGen sequencing (NGS) and whole transcriptome sequencing (WTS) to characterize the molecular landscape of this unique group and to assess the prevalence of TA. Methods: A total of 1164 PC tumors were tested at Caris Life Sciences by NGS (592 genes), WTS (NovaSeq), IHC and fragment analysis. Comparison of KRAS WT vs. mutant (MT) was done by Fisher-Exact or Chi2 and was corrected for multiple tests. Results: The KRAS WT cohort included 144 tumors (12.4%). No differences were seen in gender (female: 46% in both WT & MT) and age (median: 66 & 67) compared to KRAS MT. In KRAS WT tumors, targetable fusions tested by WTS and pathogenic mutations by NGS were seen in 22% (32 of 144) and 52% (75 of 144) respectively; potentially targetable amplifications (amp) were seen in 5 additional tumors. No TA were seen in 22% of WT tumors. Key alterations are in Table. Alterations inducing MAPK activation, including BRAF, RAF1, NF1 and GNAS changes were seen in 38 (26%) tumors. Frequent alterations were seen in FGFR genes (11 tumors), MET (4, including 1 exon 14 skip), and ERBB receptor and ligands (10). Fusions in ALK, ROS1, RET and NOTCH1 were seen (8), largely exclusive of other drivers. Wnt, PI3K, chromatin remodeling (CR) and DDR changes were common and sometimes seen concurrent with other alterations. Compared to KRAS MT, no difference of PD-L1 or TMB-H was seen. BRAF, APC, PBRM1, CTNNB1 mutations, MDM2 amp, gene fusions and MSI-H/dMMR were all more frequent in KRAS WT tumors (corrected p < 0.05). Conclusions: KRAS WT PC is enriched with TA (e.g., BRAF, ALK, ROS1, NRG1, MSI-H). The use of WTS in combination with NGS identifies activated molecular pathways in the majority of KRAS WT tumors. Based on our findings, comprehensive profiling of PC at the DNA and RNA level is recommended to provide patients with therapeutic opportunities beyond standard treatments. [Table: see text]
Outcomes and Immunogenicity of pancreatic cancer stratified by the HRDetect score.
Authors: O'Kane Grainne M. , Jang Gun Ho , Denroche Rob , Zhang Amy , Picardo Sarah Louise , Grant Robert C , Allen Michael , Wang Yifan , Dodd Anna , Ramotar Stephanie , Hutchinson Shawn , Tehfe Mustapha , Biagi James Joseph , Lam Bernard , Wilson Julie , Notta Faiyaz , Fischer Sandra , Zogopoulos George , Gallinger Steven , Knox Jennifer J. 
Published: May 2020

4630 Background: The HRDetect score uses whole genome sequencing (WGS) to incorporate patterns of substitution base signatures and structural variation to identify tumours deficient in homologous recombination repair (HRD). HRD-tumours, with a higher mutational burden, may be more immunogenic. Methods: We applied HRDetect to 182 resected pancreatic cancers (PDA) and 233 advanced PDA enrolled on the COMPASS trial; both cohorts underwent WGS after tumour enrichment. Patients were classified as high(hi) or low(lo) according to the published score threshold of 0.7; clinical characteristics and survival outcomes were determined. Immunogenicity of the cohorts was explored by analyzing cytolytic activity (CYT) as measured by RNA expression of perforin and granzyme A. Results: 14% of resected (25/182) and 14% of advanced cases (32/233) were considered HRDetecthi . The median age at PDA diagnosis was younger in HRDetecthi vs HRDetectlo (61 vs 66 years, p = 0.005), with no difference in sex between groups. Of the 57 cases identified, 37 (65%) were considered true HRD-PDA with inactivation of BRCA1, BRCA2, PALB2, RAD51C and XRCC2. The remaining 20 cases, were considered false positives for HRD; of these 7 had evidence of a tandem duplicator phenotype with duplications ranging from 10Kbp to 1Mbp in size and 13 had no defining genomic characteristics of the HRD-subtype. In resected PDA, the HRDetect score after adjusting for stage, was not prognostic. In contrast in a multivariable analysis of advanced cases, both HRDetect (HR 0.51, 95% CI 0.30-0.87, p = 0.01) and the Moffitt RNA classifier were highly prognostic (HR 1.99, 95% CI 1.32-3.00, p = 0.0001) with improved survival in HRDetecthi and classical PDA. Of patients receiving platinum in advanced disease (n = 128) HRDetecthi PDA had longer survival compared to the HRDetectlo (15.6 vs. 9.9 months, p = 0.02) although the interaction term between chemotherapy regimen (gemcitabine vs. platinum) and HRDetect score was not significant in this cohort. HRDetecthi tumours had increased cytolytic activity than HRDetectlo PDA; furthermore, within the cohort of HRDetecthi PDA, higher CYT scores were evident in primary lesions compared to metastatic sites sequenced. Conclusions: A high HRDetect score is prognostic in advanced PDA where patients treated with platinum have longest survival. HRDetecthi tumours have increased cytolytic activity with differences observed between primary and metastatic lesions.