bluuebunny/crossref_metadata_2025_split huggingface dataset:
Early nutritional risk assessment by NRS 2002 to predict survival in patients with advanced biliary tract cancer.
Authors: Oh Se Eung , Jeung Hei-Cheul 
Published: February 2020

505 Background: Biliary tract cancer (BTC) has heterogenous disease with dismal prognosis. We investigated the predictors of overall survival (OS) among Korean patients with advanced BTC according to their baseline nutritional risks estimated by Nutritional Risk Screening (NRS) 2002 score. Methods: From September 2006 to July 2017, we retrospectively reviewed the data of 601 patients with BTC. Data on demographic and clinical parameters were collected from electronic medical records, and overall survival (OS) and progression-free survival (PFS) was estimated using the Kaplan–Meier method. Stepwise Cox regression analysis was used to determine the factors associated with survival. Patients with a NRS 2002 score ≤2 were classified as “no-risk; ” those with a score of 3 were classified as “moderate-risk; ” and those with a score of ≥4 were classified as “high-risk.” Results: Following nutritional screening at baseline, 333 patients (55%) were classified as the “no risk” group; 109 patients (18%), as the “moderate risk” group; and 159 patients (27%) as the “high risk” group. Survival analysis showed significant differences in the median OS according to the NRS 2002 groups: “no risk” group: 12.6 months (95% CI: 11.5–13.7); “moderate risk” group: 6.1 months (95% CI: 4.3–8.0); and “high risk” group: 3.9 months (95% CI: 3.2 – 4.6) (p<0.001). On the Cox’s regression analysis, NRS 2002 score came out as the most independent factor for OS (for “moderate-risk” HR 1.610, 95% CI 1.288-2.027, p<0.001; for “high-risk”, HR 2.121, 95% CI 1.728-2.612, p<0.001), compared with other prognostic factors including liver metastasis, peritoneal seeding, white blood cell count, platelet count, neutrophil-to-lymphocyte ratio, cholesterol, CEA, and CA19-9. Conclusions: Our study demonstrated OS of advanced BTC was strongly related to their baseline nutritional status assessed by NRS 2002. Constitutional nutritional assessment can help to improve patient prognosis through proactive and individualized nutritional intervention. Baseline nutritional status should be integrated for implementing prognostic scoring system, which can provide more sophisticated risk stratification of patients with metastatic BTC.
Updated efficacy and safety of KEYNOTE-224: A phase II study of pembrolizumab (pembro) in patients with advanced hepatocellular carcinoma (HCC).
Authors: Kudo Masatoshi , Finn Richard S. , Edeline Julien , Cattan Stéphane , Ogasawara Sadahisa , Palmer Daniel H. , Verslype Chris , Zagonel Vittorina , Fartoux Laetitia , Vogel Arndt , Sarker Debashis , Verset Gontran , Chan Stephen Lam , Knox Jennifer J. , Daniele Bruno , Gurary Ellen B , Siegel Abby B. , Jain Lokesh , Cheng Ann-Lii , Zhu Andrew X. ,   for the KEYNOTE-224 Investigators
Published: February 2020

518 Background: Pembro received accelerated approval in pts with advanced HCC in the second-line setting based on results of the KEYNOTE-224 trial. Results of a 2 y follow-up analysis of the efficacy and safety in this trial are presented here. Methods: Eligible pts had histologically confirmed HCC, radiographic progression on/intolerance to sorafenib and disease not amenable to curative treatment, Child Pugh A, ECOG PS 0-1 and BCLC stage C or B. Pts received pembro 200 mg IV Q3W for 2 y or until disease progression, unacceptable toxicity, consent withdrawal or investigator decision. Response was assessed every 9 wk. Primary endpoint was ORR (RECIST v1.1, central review). Secondary endpoints were DOR, DCR, PFS, OS and safety. Results: Efficacy and safety were assessed in 104 pts. The median time from randomization to data cutoff (Jun 05, 2019) was 31.2 mo (27.5-35.5 mo). Pt characteristics were: median age 68 y (43-87), 21.2% HBV+, 25% HCV+, 94.2% Child Pugh A, 79.8% had PD on sorafenib, 17.3% had MVI and 64.4% had extrahepatic disease. ORR was 18.3% (95% CI 11.4-27.1) and was similar across subgroups. Median DOR was 21.0 mo (3.1-28+ mo); 77% had responses lasting ≥12 mo (Kaplan Meier). Best overall responses were 4 (3.8%) CRs, 15 (14.4%) PRs, 45 (43.3%) SDs and 34 (32.7%) PDs; DCR was 61.5%. The median PFS (95% CI) was 4.9 mo (3.5-6.7) and OS was 13.2 mo (9.7-15.3). PFS 24 mo rate was 11.3% and OS 24 mo rate was 30.8%. ORR was shown to be a predictor of longer OS by landmark analysis. Treatment-related AEs occurred in 76 (73.1%) pts; the most common AEs were fatigue, increased aspartate aminotransferase, pruritus and diarrhea observed in ≥10% pts. Grade ≥3 treatment related AEs occurred in 27 (26.0%) pts. Immune-mediated hepatitis occurred in 3 (2.9%) pts; no cases of HBV/HCV flare were identified. Conclusions: At 2 y follow-up, pembro continued to provide durable anti-tumor activity and prolonged survival (30.8% OS, 24 mo rate), further supporting its use in previously treated pts with advanced HCC. With longer follow-up, increases in ORR (18.3% vs 17.0%), DOR ≥12 mo (77.0% vs 61.4%) and CR rates (3.8% vs 1%) were seen. The safety profile was similar to the primary analysis. Clinical trial information: NCT02702414.
Baseline liver function and outcomes in the phase III REFLECT study in patients with unresectable hepatocellular carcinoma (uHCC).
Authors: Vogel Arndt , Frenette Catherine , Sung Max W. , Daniele Bruno , Baron Ari David , Chan Stephen Lam , Blanc Jean-Frédéric , Tamai Toshiyuki , Ren Min , Lim Howard John , Palmer Daniel H. , Takami Yuko , Kudo Masatoshi 
Published: February 2020

524 Background: Lenvatinib (LEN) is approved for first-line treatment of uHCC. Baseline (BL) liver function (Child-Pugh score [CPS] and albumin-bilirubin grade [ALBI]) was prognostic in uHCC patients (pts) who received sorafenib (SOR) but has not been assessed with LEN in uHCC. Here, we report post hoc analysis of BL liver function and efficacy/safety outcomes from the phase 3 REFLECT study. Methods: Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and safety were stratified by BL ALBI or CPS. OS and PFS were estimated by Kaplan–Meier method. Independent radiologic review utilized mRECIST criteria for ORR. Safety was assessed using NCI-CTCAE, version 4.0. Results: Liver function measured by ALBI and CPS seemed to be prognostic for OS and ORR. Median OS was longer in ALBI grade 1 (ALBI-1) vs grade 2 (ALBI-2) pts or for CPS-5 vs CPS-6 on either treatment arm and was longer for LEN vs SOR. ORR was higher in pts with better ALBI or CPS and for LEN vs SOR. Rates of treatment-emergent adverse events grade ≥3 were lower with better BL liver function (ALBI-1 vs ALBI-2: 70% vs 86%; CPS-5 vs CPS-6: 72% vs 86%). Study-drug withdrawal, dose reduction, and dose interruption occurred more often in pts with worse BL liver function. Conclusions: This post hoc analysis suggests ALBI (by OS, PFS and ORR) and CPS (by ORR) may be prognostic in uHCC pts and that BL liver function may be linked with efficacy/safety outcomes. This analysis also found that LEN provided benefit vs SOR for uHCC, regardless of BL liver function. The benefit of LEN may be underestimated, as more ALBI-2 pts and fewer ALBI-1 pts received LEN vs SOR. Clinical trial information: NCT01761266. [Table: see text]
Postoperative adjuvant transarterial infusion chemotherapy with FOLFOX could improve outcomes of hepatocellular carcinoma patients with microvascular invasion: A preliminary report of a phase III, randomized, controlled clinical trial.
Authors: Li Shaohua , Wei Wei , Wang Qiaoxuan , Guo Zhixing , Mei Jie , Lu Lianghe , Ling Yihong , Xu Li , Chen Minshan , Lin Wenping , Zou Jingwen , Wen Yuhua , Guo Rongping 
Published: February 2020

527 Background: Microvascular invasion (MVI) is a risk factor for recurrence after hepatectomy for hepatocellular carcinoma (HCC) patients. This study aimed to investigate to efficacy and safety of postoperative adjuvant transarterial infusion chemotherapy (TAI) with FOLFOX regimen for HCC patients with MVI. Methods: In this prospective, phase III, randomized, open-labeled, controlled clinical trial, HCC patients with histologically confirmed MVI were randomly assigned (1:1) after hepatectomy to receive either 1-2 cycles adjuvant TAI (AT group) or follow-up without any adjuvant treatment (FU group). The primary endpoint was disease-free survival (DFS), the secondary endpoints are overall survival (OS) and safety. Results: Between June, 2016 and April 2019, 127 patients were randomly assigned to AT group (n=63) or FU group (n=64). Clinicopathological characteristics were balanced between the two groups. The 6-, 12-, and 18-month OS rates for AT group were 100.0%, 97.7%, and 97.7%, and were 94.5%, 89.6%, and 78.5% for FU group, respectively. The 6-, 12-, and 18-month DFS rates for AT group were 84.7%, 61.8%, and 58.7%, and were 62.9%, 48.1%, and 38.6% for FU group, respectively. The OS and DFS were significantly better in AT group than in FU group (p=0.037 and 0.023, respectively). No patients in AT group experienced grade 3 or more severe adverse events (AEs). Conclusions: Adjuvant TAI after hepatectomy may bring survival benefits of OS and DFS for HCC patients with MVI. Clinical trial information: NCT03192618.
Cisplatin plus irinotecan versus cisplatin plus gemcitabine in the treatment of advanced or metastatic gallbladder or biliary tract cancer: Results of a randomized phase II trial (NCT01859728)– the Gambit trial.
Authors: dos Santos Lucas Vieira , Pinto Gustavo Sanches Faria , Ferraz Mauricio Wagner Souto , Bragagnoli Arinilda , Santos Florinda , Haddad Sarah , Barros Ana , Cordeiro Dias Isadora Clarissa , Lima Joao Paulo SN , Abdalla Kathia C 
Published: February 2020

529 Background: The combination of gemcitabine-cisplatin (GC) is the current standard of care chemotherapy for metastatic/unresectable biliary tract cancer (BTC). However, the prognosis remains poor. This randomized trial aimed to evaluate the efficacy and safety of irinotecan plus cisplatin (IP) versus GC in advanced or metastatic BTC. Methods: Patients with biopsy-proven, chemo-naïve, unresectable or metastatic BTC, ECOG 0-2, measurable disease per RECIST 1.1, adequate organ function and written informed consent were stratified by ECOG (0 or 1 vs 2) and distant metastases and randomized to receive irinotecan 65 mg/m² IV D1 and D8 plus cisplatin 60 mg/m² D1 repeated every 3 weeks (IP) or gemcitabine 1000 mg/m² IV D1 and D8 plus cisplatin 25 mg/m² IV D1 and D8 repeated every 3 weeks, until disease progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR). Results: Between January 2013 and April 2018, 47 pts were randomized (1:1) to receive IP (N = 24) or GC (N = 23). Overall, groups were well balanced according to prognostic factors. The ORR was 35% (complete response 5%, partial response 30%) and 31.8% in IP and GC arms, respectively. Median progression-free survival were 5.3 vs 7.8 months (HR = 1.165, 95%CI 0.628-2.161, p = 0.628) and median overall survival were 11.9 and 9.8 months (HR = 0.859, 95%CI 0.431 – 1.710, p = 0.665) for IP and GC, respectively. Adverse events were not statistically different between arms, and results were consistent with previous experiences with these regimens. No therapy-related death were reported. Conclusions: Irinotecan-cisplatin combination is active in BTC, with similar ORR, PFS and OS when compared to gemcitabine-cisplatin. Irinotecan-cisplatin were well tolerated, and adverse events were manageable. Irinotecan-cisplatin could be considered as an alternative to gemcitabine-cisplatin. Clinical trial information: NCT01859728.
In vitro and in vivo efficacy and safety of tumor treating fields (TTFields) and sorafenib combination in hepatocellular carcinoma.
Authors: Davidi Shiri , Tempel-Brami Catherine , Munster Mijal , Gotlib Karnit , Zeevi Einav , Schneiderman Rosa S , Voloshin Tali , Giladi Moshe , Kinzel Adrian , Kirson Eilon D. , Weinberg Uri , Palti Yoram 
Published: February 2020

551 Background: Hepatocellular carcinoma (HCC) is a leading global cause of cancer-related mortality. Sorafenib (oral multikinase inhibitor) is approved in patients with advanced HCC, yet survival benefit is limited. Tumor Treating Fields (TTFields) are an effective, anti-neoplastic treatment modality delivered via noninvasive, low intensity (1-3 V/cm), intermediate frequency (100-500 kHz), alternating electric fields. The study aim was to explore in vitro and in vivo effects of TTFields alone and combined with sorafenib for HCC treatment. Methods: HCC (HepG2 and Huh-7D12) cells were TTFields treated with at frequencies of 100-400 kHz for 72 hr using the inovitro system. Efficacy of TTFields and sorafenib combined treatment was tested at optimal frequency with various sorafenib concentrations. Cell counts, apoptosis induction, and clonogenic potential were determined. Healthy rats were used to assess safety of TTFields applied to the abdomen. N1S1 HCC cells were injected into the left hepatic lobe of Sprague Dawley rat; after 1 week, TTFields (1.2 V/cm) and sorafenib (10 mg/kg) were applied for 6 days. Tumor growth was evaluated using MRI. Results: The optimal TTFields frequency was 150 kHz in HepG2 and Huh-7D12 HCC cells. TTFields 150 kHz treatment (1.0 - 1.7 V/cm, 72 hr) led to cell count reductions (53-55%) and further decreases in clonogenic potential (65-69%). TTFields and sorafenib combination treatment led to a significant reduction in cell count (2-way ANOVA, P < 0.05) vs either treatment alone. Also, tumor growth was significantly reduced in the combined treatment group vs the control group (student t test, P < 0.01). Tumor volume (fold increase) in the combination treatment group (1.6) was significantly lower vs control (5.9, P < 0.0001), TTFields alone (3.3, P < 0.01), and sorafenib alone (2.3, P < 0.05) groups. Safety studies did not reveal any TTFields related adverse events with delivery to the rat abdomen. Conclusions: In vitro and in vivo data demonstrated efficacy and safety of TTFields in HCC; and improved efficacy in combination with sorafenib. A phase 2 study (HEPANOVA; NCT03606590) will explore the clinical potential of TTFields 150 kHz plus sorafenib.
Clinical characteristics and outcomes of patients with advanced hepatocellular carcinoma treated with immunotherapy: A real-world retrospective study.
Authors: Chergui Adel , Gadde Eswar , Tolu Seda Serra , Acuna-Villaorduna Ana , Kabarriti Rafi , Goel Sanjay , Kaubisch Andreas 
Published: February 2020

557 Background: Advanced HCC is an aggressive malignancy with dismal prognosis. Newer agents, including immunotherapy (IT), have been granted accelerated approval. Information outside clinical trials is scarce. This study is aimed to describe the clinical characteristics and outcomes of HCC patients treated with IT. Methods: Patients with HCC treated with IT were identified using the institutional data-mining software, Clinical Looking Glass. Patient demographics, clinical, and treatment characteristics were collected. Progression-free survival (PFS) was defined as time from treatment initiation to disease progression or death, and overall-survival (OS) as time from diagnosis of advanced disease to death. PFS and OS were plotted using Kaplan-Meier curves. Results: A total of 52 patients; median age 64 years; male predominance (38, 73.1%) were identified. There were 24 (54.5%) Hispanics, 9 (20.5%) Non-Hispanic Blacks, 7 (15.9%) Non-Hispanic White and 4 (9.1%) Asians. Cirrhosis was seen in 41 (83.7%), and median MELD score was 8 (IQ: 7-10). Hepatitis B and C infection were encountered in 12 (24.5%) and 22 (44%) patients, respectively. Imaging evidence of intravascular invasion was seen in 16 (34.8%) and extrahepatic metastases in 7 (14.9%) cases. Local treatment was provided to 29 (59.2%) and radiation treatment to 14 (28.6%) patients. Nivolumab was used in all the cases, as first-line treatment in 17 (32.7%) and as ≥ second line in 35(67.3%). The median PFS was 6.2 (3.1-10.6) months and was similar in first-line and ≥ second line treatment (8 vs 5.9 months, p=0.90). The median OS was 24.2 (18-28) months; there was a tendency towards higher survival rates in patients that were treated in ≥ second line (16.8 vs 25.2 months, 0=0.07). Conclusions: In this multiethnic cohort, the “real world” experience of the benefit of IT in HCC is encouraging, with a median OS exceeding two years. Expanded data may elucidate the differences if any, between use of IT as front vs. second line therapy, in PFS and OS.
Intensity-modulated proton therapy using dose-painting pencil beam scanning for high-risk hepatocellular carcinoma.
Authors: Schaub Stephanie K. , Bowen Stephen R. , Nyflot Matthew J. , Apisarnthanarax Smith 
Published: February 2020

558 Background: High rates of local control are achievable with hypofractionated proton therapy with passive techniques for hepatocellular carcinoma (HCC), but may have limitations when tumors are adjacent to organs-at-risk (OARs), which may result in tumor underdosage and lead to inferior local control. We present the first reported series of HCC patients treated with pencil beam scanning (PBS) intensity-modulated proton therapy (IMPT) using a simultaneous-integrated boost and protection (SIB/SIP) technique to escalate tumor dose while protecting adjacent OARs. Methods: Twenty-five HCC patients were treated between 2015-2019 with a 15-fraction regimen using IMPT SIB/SIP. SIB/SIP dose levels generally ranged from 36.0-67.5 GyRBE to minimize dose to OARs at their respective dose-limiting thresholds (e.g. luminal gastrointestinal organs, chest wall). Radiation-induced liver disease (RILD) was defined by a Child-Pugh (CP) score increase of 2 or greater and/or any RTOG grade 3 enzyme elevation. Other toxicities were graded by CTCAEv5.0. Overall survival (OS), progression-free survival (PFS), and local control were calculated using the Kaplan-Meier method. Results: Patients most commonly had BCLC stage B or C disease (84%) and CP-A (80%) and ALBI grade 2 (60%) liver function. Median gross tumor volume (GTV) size and volume were 12.3 cm (range 2.17-20.57) and 461 cc (range 4.68-2439), and 32% had gross vascular invasion. Median mean and minimum dose delivered to the gross tumor volume (GTV) was 64.0 GyRBE (EQD2 76.1, BED 91.3, range 54.3-69.6) and 45.1 GyRBE (EQD2 48.9, BED 58.7, range 33.4-67.7), respectively. Median mean dose to liver minus GTV was 15.0 GyRBE (range, 8.2-19.6). 1-year OS, PFS, and local control were 66%, 32%, and 84%, respectively. No isolated local failures occurred. Two patients experienced RILD with no RILD-related deaths. Two grade 3 non-GI toxicities occurred: 1 rib fracture and 1 pneumonitis. No acute or late GI grade ≥2 occurred. Conclusions: In our series of HCC patients with large tumors near OARs, IMPT SIB/SIP allows for tumor dose escalation while sparing of OARs and results in favorable local control and acceptable toxicities.
Phase Ib study of regorafenib (REG) plus pembrolizumab (PEMBRO) for first-line treatment of advanced hepatocellular carcinoma (HCC).
Authors: El-Khoueiry Anthony B. , Kim Richard D. , Harris William P. , Sung Max W. , Waldschmidt Dirk , Iqbal Syma , Zhang Xiaojing (Amily) , Nakajima Keiko , Galle Peter R. 
Published: February 2020

564 Background: REG is a multikinase inhibitor with immunomodulatory activity and PEMBRO is an anti-PD-1 monoclonal antibody. Both are approved as monotherapy for patients (pts) with HCC previously treated with sorafenib. Based on their potential synergistic effects, we conducted a phase 1b study of REG plus PEMBRO for first-line treatment of advanced HCC. Methods: This is an ongoing, open-label, dose-escalation study in pts with advanced HCC who had no prior systemic therapy. In the first cohort, pts received REG 120 mg/day PO for 3 weeks on/1 week off plus PEMBRO 200 mg IV q 3 weeks. In later cohorts, the REG dose could be escalated (160 mg) or reduced (80 mg) based on the modified toxicity probability interval design; the PEMBRO dose is fixed. The primary objective is safety and tolerability. Secondary objectives are to define the maximum tolerated dose (MTD) and recommended phase 2 dose, and to assess antitumor activity. Results: As of August 23, 2019, 29 pts have been treated at the REG 120 mg level. Median age is 65 years (range 32–81); 41%/55% of pts are BCLC stage B/C; 100% are Child–Pugh A; ECOG status 0/1 is 72%/28%. Dose-limiting toxicities occurred in 4/18 evaluable pts: grade (Gr) 3 increased ALT/AST with Gr 2 increased bilirubin (n = 2); Gr 3 rash (n = 2). The MTD of REG in the combination was 120 mg. Most common Gr 3 or 4 treatment-emergent adverse events (TEAEs) are shown (n = 29). There were no Gr 5 TEAEs. 59%/31% of pts had REG/PEMRO-related Gr 3 or 4 TEAEs. Dose modifications (reductions or interruptions) of REG/PEMBRO for drug-related TEAEs occurred in 59%/31% of pts. Of 23 evaluable pts, 7 (30%) had a partial response (PR) and 14 (61%) had stable disease (RECIST v1.1); 1 additional pt had PR by mRECIST. Conclusions: The combination of REG plus PEMBRO for first-line treatment of advanced HCC showed no unexpected safety signals and encouraging antitumor activity. Accrual is continuing at REG 120 mg dose and an expansion cohort evaluating REG 80 mg plus PEMBRO is planned. Clinical trial information: NCT03347292. [Table: see text]
Circulating levels of soluble urokinase plasminogen activator receptor (suPAR) to predict outcome after resection of biliary tract cancer.
Authors: Loosen Sven H , Breuer Annemarie , Tacke Frank , Alizai Patrick Hamid , Ulmer Tom Florian , Trautwein Christian , Longerich Thomas , Roderburg Christoph , Neumann Ulf Peter , Luedde Tom 
Published: February 2020

572 Background: Surgical resection is the only curatively intended therapy for patients with biliary tract cancer (BTC), but 5-year survival rates after tumor resection have remained below 30%, corroborating the need for better preoperative stratification tools to identify the ideal surgical candidates. The soluble urokinase plasminogen activator receptor (suPAR) represents a mediator of inflammation and has recently been associated with cancer. In this study, we evaluated a potential role of suPAR as a novel biomarker in patients undergoing resection of BTC. Methods: Tumor expression of uPAR, the membrane bound source of suPAR, was analyzed by IHC in 108 BTC samples. Serum levels of suPAR were analyzed by ELISA in a training and validation cohort comprising a total of 117 BTC patients and 76 healthy controls. Results: A high tumoral uPAR expression was associated with an adverse outcome after BTC resection. In line, circulating levels of suPAR were significantly elevated in BTC patients compared to healthy controls and patients with primary sclerosing cholangitis (PSC). Using a small training set, we established an optimal prognostic suPAR cut-off value of 3.72ng/ml for BTC patients. Importantly, preoperative suPAR serum levels above this cut-off value were associated with significantly impaired overall survival in both the training and validation cohort. Multivariate Cox-regression analysis including clinicopathological parameters such as the tumor stage, markers of systemic inflammation or organ dysfunction and established tumor markers revealed suPAR as an independent prognostic marker following BTC resection. Finally, high preoperative suPAR levels were indicative for acute kidney injury after tumor resection. Conclusions: Circulating suPAR represents a previously unrecognized biomarker in patients with resectable BTC, which might be useful to preoperatively identify the ideal candidates for tumor resection.