bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase Ib study of lenvatinib (LEN) plus nivolumab (NIV) in patients (pts) with unresectable hepatocellular carcinoma (uHCC): Study 117.
Authors: Kudo Masatoshi , Ikeda Masafumi , Motomura Kenta , Okusaka Takuji , Kato Naoya , Dutcus Corina E. , Hisai Takashi , Suzuki Mayumi , Ikezawa Hiroki , Iwata Takeyuki , Kumada Hiromitsu , Kobayashi Masahiro 
Published: February 2020

513 Background: LEN, a multikinase inhibitor of VEGFR 1–3, FGFR 1–4, PDGFRα, RET, and KIT with immunomodulatory activity, is approved in multiple countries for first-line treatment of uHCC. NIV is an anti-PD-1 monoclonal antibody approved in multiple countries as a second-line treatment for HCC. We report early results from a phase 1b trial of LEN + NIV in pts with uHCC. Methods: In this open-label study, pts with uHCC, BCLC stage B (not eligible for transarterial chemoembolization) or C, Child-Pugh class A, and ECOG PS ≤ 1 received LEN (bodyweight ≥ 60 kg: 12 mg/day; < 60 kg: 8 mg/day) PO QD and 240 mg NIV IV Q2W. The primary endpoint was tolerability and safety of the combination. Objective response rate (ORR; mRECIST by investigator) was a secondary endpoint. Tolerability was evaluated by assessing dose-limiting toxicities (DLTs) during the first cycle in pts for whom no other appropriate therapy was available (Part 1). Once tolerability was confirmed, additional pts with no prior systemic therapy for uHCC were enrolled (Part 2). Results: At data cutoff (May 17, 2019), 30 pts had received LEN + NIV (Part 1: n=6; Part 2: n=24). Pts had BCLC stage B (n=17) or C (n=13) and Child-Pugh scores of 5 (n=23) or 6 (n=7). 4 pts in Part 1 (66.7%) had received prior anticancer medications (3 pts had 1; 1 pt had ≥3). No DLTs were reported in Part 1. TEAEs leading to discontinuation of LEN were reported in 2 (6.7%) pts; 4 (13.3%) pts had TEAEs leading to discontinuation of NIV. TEAEs occurred in all 30 pts; the most common were palmar-plantar erythrodysesthesia (56.7%) and dysphonia (53.3%). Adverse events were manageable. Efficacy outcomes are reported (Table). Conclusions: LEN + NIV was well tolerated with encouraging anti-tumor activity in pts with uHCC. Clinical trial information: NCT03418922. [Table: see text]
Optimal timing of radiotherapy for incomplete transarterial chemoembolization in BCLC stage B hepatocellular carcinoma.
Authors: Byun Hwa Kyung , Kim Nalee , Seong Jinsil 
Published: February 2020

521 Background: Numerous studies have reported on the efficacy of radiotherapy (RT) after incomplete transarterial chemoembolization (TACE). However, the optimal timing of RT remains unclear. This study investigated the optimal time of initiating RT for incomplete TACE in patients with BCLC stage B hepatocellular carcinoma (BCLC-B HCC). Methods: Between 2001 and 2016, 116 lesions in 104 patients with BCLC-B HCC were treated with RT after TACE. The time interval between the last session of TACE and initiation of RT was obtained from medical records and analyzed retrospectively. The optimal cut-off time-interval that maximized the difference in local failure-free rate (LFFR) was determined using maximally selected rank statistics. Results: The median duration between TACE and RT was 26 (range: 2–165) days. Median number of TACE treatments on the target lesion before RT was 2; median tumor size was 7 cm. At a median follow-up of 18 (range: 3–160) months, the median overall survival was 18 months. The probability of local control increased as the time interval between TACE and RT decreased. The optimal cut-off value of the time interval was 5 weeks. With the cut-off of 5 weeks, 65 and 39 patients were classified into early and late RT groups, respectively. The early RT group had significantly poorer Child-Pugh class and higher alpha-fetoprotein levels. Most characteristics including tumor size (7 cm vs. 6 cm; P = .144) were not significantly different between the groups. One-year LFFR was significantly higher in the early RT group (94.6% vs. 70.8%; P = .005). On multivariate analysis, early RT was an independent predictor of favorable LFFR (hazard ratio: 3.82, 95% confidence interval: 1.64–8.88, P = .002). Conclusions: The optimal time for the administration of RT for incomplete TACE is within 5 weeks following TACE. Early administration of RT within 5 weeks after TACE was associated with better local control.
Regorafenib in patients with unresectable hepatocellular carcinoma (uHCC) in routine clinical practice: Interim analysis of the prospective, observational REFINE trial.
Authors: Lim Ho Yeong , Merle Philippe , Finn Richard S. , Frenette Catherine , Masi Gianluca , Ikeda Masafumi , Zebger-Gong Hong , Fiala-Buskies Sabine , Ozgurdal Kirhan , Kudo Masatoshi , Qin Shukui 
Published: February 2020

542 Background: Regorafenib significantly improved overall survival (OS) versus placebo in patients (pts) with uHCC who progressed on prior sorafenib therapy in the phase 3 RESORCE trial. The multicenter, international REFINE trial was designed to evaluate the safety and effectiveness of regorafenib in uHCC in the real-world setting. Methods: This prospective, observational trial aims to recruit 1000 pts with uHCC for whom a decision to treat with regorafenib has been made by the treating physician prior to enrollment according to the local health authority approved label. The primary endpoint is the incidence of treatment-emergent adverse events (TEAEs) and dose modifications due to TEAEs (NCI-CTCAE v4.03). Secondary endpoints are OS, progression-free survival, time to progression, best overall tumor response, and duration of treatment. Tumor response and progression are assessed per investigator according to local standard. An interim analysis includes the first 500 pts observed for ≥4 months. We report baseline characteristics, starting dose, and treatment duration for the interim analysis. Results: Of 498 pts evaluable for analysis, median age was 67 years (range: 22–91) and 84% were male. 59% were from Asia. Proportions of pts with ECOG performance status 0–1/≥2 were 82%/5% (missing 13%); 67% and 11% of pts had Child–Pugh A and B liver function, respectively (missing/not evaluable 21%). 60% of pts had metastases and 33% had vascular invasion. HCC etiology included hepatitis B 37%, alcohol use 26%, hepatitis C 23%, and NASH 7%. Baseline alpha-fetoprotein levels were < 400/≥400 ng/mL in 44%/26% of pts (missing 31%). The initial regorafenib dose was 160 mg/day (d) in 58% of pts, 120 mg/d in 13%, and 80 mg/d in 28% (8 pts initiated at 40 mg/d). The mean (SD) initial daily dose was 131 mg/d (37). Median duration of treatment was 3.7 months (IQR: 1.9–8.5). Conclusions: In this interim analysis of the observational REFINE study, some differences were observed in the characteristics of pts treated with regorafenib from the phase 3 RESORCE trial, reflecting less stringent inclusion criteria in a real-world study. Efficacy and safety analyses are ongoing. Clinical trial information: NCT03289273.
The efficacy and safety of lenvatinib in patients with intermediate-stage hepatocellular carcinoma: A nationwide multicenter study in Japan.
Authors: Tsuchiya Kaoru , Kurosaki Masayuki , Sakamoto Azusa , Marusawa Hiroyuki , Ogawa Chikara , Kondo Masahiko , Joko Kouji , Tsuji Keiji , Kimura Hiroyuki , Wada Shuichi , Kobashi Haruhiko , Uchida Yasushi , Furuta Koichiro , Akahane Takehiro , Kusakabe Atsunori , Yoshida Hideo , Matsushita Tomomichi , Abe Takehiko , Sohda Tetsuro , Izumi Namiki 
Published: February 2020

548 Background: Lenvatinib (LEN) has been used in patients with unresectable hepatocellular carcinoma (u-HCC) since Mar 2018 in Japan. We conducted a nationwide multicenter study and especially focused on the efficacy and safety in the patients with intermediate-stage u-HCC. Methods: A total of 240 patients received LEN from March 2018 at 15 sites in Japan was enrolled. Tumour assessments in accordance with modified RECIST were done using dynamic CT or MRI within 4-8 weeks and every 6-8 weeks thereafter. Results: In this study, 88 of 240 (36.7%) patients were BCLC stage B. Among them 76 (86.3%) patients received TACE before LEN and the median number of TACE was 2 (1-10). Only 4 patients were TKI experienced and other 84 (95.5%) patients received LEN as a 1st line therapy. The median pretreatment ALBI score was -2.35 and 75 (85.2%) patients were Child-Pugh A. In this cohort, 73 (83.0%) patients were beyond up-to-seven criteria and the median pretreatment AFP was 38.2 (2-12870) ng/mL. The median observation time was 8.5 months and 16 patients died. The median progression free survival was 8.7 months, and the median overall survival (OS) was not reached. Objective response rate (ORR) and disease control rate (DCR) were 48.5% and 80.3%. AFP decrease ( > 20%) after 1 month was observed in 52 (59.0%) patients. Child-Pugh B patients (n = 13) had significantly shorter OS than Child-Pugh A (p = 0.02) and median OS in Child-Pugh B patients was 8.8 months. The patients received > 6 times TACE before LEN had significantly shorter OS than patients received ≤ 6 times TACE (p = 0.02). Additional TACE was performed in 8 patients and The median time of restarting LEN was 19 days. The median ALBI score before additional TACE, Day 1 after TACE and Day 28 after TACE were -2.38, -2.07, and -2.36.There was no severe adverse event associated with additional TACE. The median duration of LEN in patients treated with LEN and additional TACE was 8.5 months. Conclusions: The ORR and DCR of LEN in Child-Pugh A patients with intermediate-stage HCC were 46.6% and 79.3%. The therapeutic strategies for intermediate-stage HCC should be discussed based on the liver function, tumor states, and treatment course about TACE.
Hyperprogressive disease during PD-1 blockade in patients with advanced hepatocellular carcinoma.
Authors: Chon Hongjae , Kim Chang Gon , Yoon Sangeun , Kim Chan , Kang Beodeul , Choi Hye Jin , Lim Ho Yeong 
Published: February 2020

550 Background: Immune checkpoint blockade with PD-1 inhibitors has shown promising clinical efficacy in patients with hepatocellular carcinoma (HCC). However, emerging evidences show that PD-1 blockade can sometimes lead to a flare-up of tumor growth with rapid clinical deterioration (hyperprogressive disease, HPD). This study aimed to evaluate the incidence and pattern of HPD in a multicenter, real-world cohort of East Asian patients with advanced HCC treated with PD-1 blockade. Methods: We enrolled 148 advanced HCC patients treated with nivolumab between March 2016 and December 2018 in Korea. Clinicopathologic variables, tumor growth dynamic, and treatment outcomes were comprehensively analyzed. Progressive disease was assessed using tumor growth kinetics (TGK), tumor growth rate (TGR), and time to treatment failure (TTF), and patient with HPD were defined as those who met the criteria of progressive disease by both TGK and TGR. Results: In this large cohort of HCC patients, the median age was 60 years and the majority were male (85%) and HBV-infected (72%). The objective response rate was 17.6% including two complete responders (1.4%). Ongoing responses were seen in 46% of responders at data cut-off. The incidence of HPD after PD-1 blockade was 23%. HCC patients with HPD had dismal prognosis with worse progression-free survival (PFS) and overall survival (OS) (HR, 1.947; 95% CI, 1.226-3.093 and HR, 1.839; 95% CI, 1.108-3.055, respectively) than progressive disease without HPD. Among various baseline clinicopatholgic parameters, elevated neutrophil-to-lymphocyte ratio (NLR) was only significantly associated with HPD. The optimal cut-off value of NLR for HPD prediction was 3.74 determined by ROC curves, and NLR > 3.74 was associated with worse PFS and OS. Conclusions: The real-world efficacy of PD-1 blockade in HCC patients was consistent with previous studies. However, there was also a corresponding risk of HPD as well as a clinical benefit. Therefore, careful patient selection using immunologic biomarkers, such as NLR, could enhance the therapeutic benefit of PD-1 blockade in clinical trials and real-world practice of HCC
A meta-analysis of the accuracy of a neuroendocrine tumor mRNA biomarker (NETest) in the blood.
Authors: Oberg Kjell E. , Califano Andrea , Strosberg Jonathan R. , Ma Steven M. , Pape Ulrich-Frank , Bodei Lisa , Kaltsas Gregory , Toumpanakis Christos , Goldenring James , Frilling Andreja , Paulson Andrew Scott , Modlin Irvin Mark 
Published: February 2020

606 Background: There is no accurate blood biomarker of neuroendocrine tumor (NET) disease. The inability to effectively assess disease in real-time has hindered management. The advance of genomic medicine and the development of molecular biomarkers has provided a strategy – liquid biopsy – to facilitate management. We reviewed the role of a blood mRNA-based NET biomarker, the NETest, as an in vitro diagnostic (IVD) to assess clinical utility. Methods: A systematic review of the literature using PRISMA guidelines was undertaken. The methodological quality was evaluated using the QUADAS-2 tool. We identified 10 original scientific papers, which met inclusion criteria. These were assessed by qualitative analysis, and thereafter meta-analysis. Data were pooled and median (95% CI) diagnostic odds ratio (DOR), positive likelihood ratio (+LR) and negative likelihood ratio (–LR) calculated. For the meta-analysis, a generic inverse variance method was undertaken using the accuracy and AUC data. Results: The ten studies exhibited moderate to high methodological quality. They evaluated NETest usage both as a diagnostic and as a monitoring tool. Meta-analysis identified the diagnostic accuracy of the NETest to be 94.9-96% with a median DOR of 400, +LR of 164 and–LR of 0.05. The NETest was 85.5-86% accurate in differentiating stable from progressive disease. As a marker of natural history, the accuracy was 90-94%. As an interventional/ response biomarker, the accuracy was 94-97%. The pooled AUC for the NETest was 0.954±0.005, with a z-statistic of 175.06 ( p< 0.001). Conclusions: The NETest is an accurate biomarker suitable for clinical use in NET disease management. The meta-analysis supports the utility of the NETest as an IVD to establish a diagnosis and monitor therapeutic efficacy. The use of a multianalyte genomic test as a biomarker provides information relevant to NET management consistent with observations regarding the utility of liquid biopsy in other oncological disciplines.
Socioeconomic disparities and outcomes in midgut neuroendocrine tumors.
Authors: Manguso Nicholas , Crystal Jessica , Cox Brian , Paski Shirley C , Hendifar Andrew Eugene , Gong Jun , Gangi Alexandra 
Published: February 2020

613 Background: Demographic and socioeconomic disparities have been shown to effect cancer specific outcomes in numerous malignancies but the effect in midgut neuroendocrine tumors (mNETs) is unknown. We sought to investigate whether these factors are associated with survival in mNETs. Methods: The NCDB was queried to identify patients with mNETs between 2004 and 2015. Only patients treated at a single hospital with complete data were included. Overall Survival (OS) was compared based on demographic data, socioeconomic factors, insurance status and place of living. Results: A total of 14,083 patients were identified with a mean age of 72 years (range 18-90). The majority of patients were Caucasian (83.9%) and male (50.9%). Most patients had private insurance (50.5%) or medicare (41.3%). Patients typically lived in larger metropolitan areas (51.5%) and 60.7% lived in zip codes with median household incomes > $48,000. Only 14.7% lived in zip codes where > 20% did not graduate high school (no HSD). The majority were treated at community comprehensive cancer centers (43.8%) or academic/research centers (35.2%). Overall, 3358 (24.5%) presented with metastasis at diagnosis. The 5-year OS for the entire cohort was 78.5%. The 5-year survival was worse in patients with lower median income (73.8% [ < $38,000] vs 81.5% [ > $63,000],p < 0.0001), lower education (74.9% [ > 20% no HSD] vs 80.7% [ < 7% no HSD], p < 0.0001), those not living in proximity to a metro area (73.8% [not metro adjacent] vs 78.7% [metro/adjacent], p = 0.0004) and those treated at a community cancer center (73.6% [community] vs. 80.1% [academic], p < 0.0001). Factors predictive of worse OS were lower income ( < $38,000) (HR 1.16, 95% CI 1.04-1.28), lower education ( > 20% no HSD) (HR 1.14, 95% CI 1.02-1.26), no insurance (HR 1.66, 95% CI 1.33-2.06) and not living in proximity to a metro area (HR 1.27, 95% CI 1.10-1.47). Conclusions: Socioeconomic factors shown to have worse OS in patients with mNETs were lower median income, lower education, treatment at a community cancer center and not living in proximity to a metro area. Patient demographic and socioeconomic factors play an important role in OS for patients with mNETs and access to care must be considered in this subpopulation of cancer patients.
Long-term safety and efficacy of lanreotide treatment in Japanese patients with neuroendocrine tumors: Final analysis of a phase II open-label extension study.
Authors: Ito Tetsuhide , Hisamatsu Seiichi , Nakajima Akihiro , Shimatsu Akira 
Published: February 2020

621 Background: Lanreotide autogel 120mg (lanreotide) was approved in Japan in July 2017 for the treatment of gastroenteropancreatic neuroendocrine tumors (NETs) based on the results from an international phase III study (CLARINET study) and a Japanese single-arm phase II study. The CLARINET extension study demonstrated long-term efficacy and safety of lanreotide treatment; however, no Japanese patients were included in the study. To describe the safety and efficacy of long-term lanreotide treatment for NETs in Japanese patients, the final analysis of the Japanese phase II study and its extension study was performed. Methods: This open-label extension study (Study 002, JapicCTI-142698) enrolled patients who completed 48 weeks of treatment with 4-weekly subcutaneous lanreotide in an open-label phase II study in Japanese patients with NETs (Study 001, JapicCTI-132375). Study 002 had the same design as Study 001. Results: Of the 32 patients who started treatment with lanreotide, 17 completed Study 001 and enrolled in Study 002. In the safety analysis set (n = 17), 16 patients (94.1%) developed adverse events (AEs) that were considered drug-related (adverse drug reactions; ADRs), most commonly faeces pale (n = 5; 29.4%), injection site induration (n = 4; 23.5%), flatulence and diabetes mellitus (both n = 3; 17.6% each). No patient permanently discontinued lanreotide or died as a result of an AE. Four patients had a total of eight serious AEs; of these, two events of bile duct stones were considered to be ADRs. In the efficacy analysis set (n = 28), the median lanreotide exposure over Studies 001 and 002 was 52.7 weeks (range: 12–181 weeks). The best overall response was partial response in 2 patients (7.1%; reached at 60 and 108 weeks), stable disease in 20 patients (71.4%) and progressive disease in 6 patients (21.4%). Conclusions: No unexpected serious AEs developed during prolonged use of lanreotide. Lanreotide was effective over long-term treatment in Japanese patients with NETs. Clinical trial information: JapicCTI-132375, JapicCTI-142698.
Treatment outcomes of patients with G3 neuroendocrine neoplasms.
Authors: Jann Henning , Kayser Antonin , Wiedenmann Bertram , Tacke Frank , Roderburg Christoph 
Published: February 2020

622 Background: Extra-pulmonary neuroendocrine carcinomas (NEC) and neuroendocrine tumors (NET) G3 are aggressive neoplasia that are associated with a limited prognosis. Data on this entity is scarce and optimal treatments are only poorly defined. Methods: 105 patients (♀ = 46; 43.8% and ♂ = 59; 56.2%) with histologically confirmed neuroendocrine carcinoma (NEC; n = 83) or neuroendocrine tumor G3 (NET G3; n = 12) or mixed neuroendocrine non-neuroendocrine neoplasms G3 (MiNEN G3; n = 10) were included into this study. Clinical and pathological characteristics at diagnosis, therapies, outcomes and survival data were recorded. Results: Primary tumor localizations included esophagus/stomach (n = 9; 8.7%), pancreas/duodenum (n = 29; 27.9%), appendix/colon/rectum (n = 25; 24.0%), the genitourinary tract (n = 9; 8.7%) and CUP (n = 32; 30.8%). Median Ki-67 across all patients was 70% (range 25-95) with a statistically significant difference in NEC G3 vs. NET G3 (74%, range 25-95 vs. 33.5%, range 25-69; p < .001). Median overall survival (mOS) was 19.2 (±1.6)months and was significantly higher in NET G3 (38 vs. 16.8 months in NEC; p = .012). First-line therapy in most patients was cisplatin or carboplatin in combination with etoposide (n = 64; 61.0%), followed by FOLFOX (n = 29; 27.6%). Twelve Patients (11.4%) received other chemotherapies. Best overall response to first-line chemotherapy was CR (5.7%), PR (52.4%) SD (17.1%) and PD (21%). In patients with Ki-67 < 55% (n = 40) no significant difference between the different regimens was found. In analyzing median PFS (mPFS) in patients with Ki-67 > 55% (n = 65) the combination of cis- or carboplatin with etoposide (mPFS 6.1±0.5 months) was superior to FOLFOX (mPFS 2.8±1.4 months; p = 0.038). Strikingly, in patients with small-cell NEC (n = 28) the combination of cisplatin/etoposide (mPFS 12.3±3months) showed a superior outcome compared to carboplatin/etoposide (mPFS: 6±1.4months; p = .022). Conclusions: Patients with non resectable NEN G3 should be treated with chemotherapy. In cases with proliferative index > 55% the 1st-line regimen of choice should be platinum in combination with etoposide. The difference in efficacy between carboplatin and cisplatin in our data should be evaluated in a prospective setting.
Comprehensive genomic sequencing of high-grade neuroendocrine neoplasms.
Authors: Sun Thomas Yang , Van Hummelen Paul , Martin Brock , Xia Charlie , Lee Hojoon , Zhao Lan , Hornbacker Kathleen , Ji Hanlee , Kunz Pamela L. 
Published: February 2020

624 Background: Grade 3 neuroendocrine neoplasms (G3 NENs), if poorly differentiated, have a median survival of only 10-19 months. Little is known regarding their underlying genomics. Methods: We applied multiomics analysis to 46 cases of G3 NEN that included copy number analysis, whole exome, and transcriptomic sequencing. Results: Of the 46 unique cases, 17 were lung, 16 gastroenteropancreatic (GEP), 13 other; 5 well-differentiated, 39 poorly differentiated and 2 mixed. Using a multivariate Cox model, we found histology characteristics (including differentiation, Ki67 and mitotic index) did not correlate with changes in overall survival (OS). The clinical variables that did correlate with OS included: number of lines of treatment (hazard ratio for death [HR], 0.72; p < 0.05), GEP primary site (HR, 5.36; p < 0.005), and non-resected primary tumor (HR, 14.52; p < 0.001). Two copy number changes were associated with worse prognosis: focal deletion 22q13 (HR, 10.23; p < 0.005), and arm amplification 19q (HR, 7.09; p < 0.01). The median OS of the top quartile compared to the rest for 22q13 deletion carriers was 9.9 months vs. 24 months, and for 19q amplification carriers was 8.7 months vs. 36.7 months. We estimated a median tumor mutation burden (TMB) of 3.7 mutations/Mb, with 20% (8/40) of patients showing high TMB ( > 10 mutations/Mb). The top five mutated genes were USH2A, RB1, APC, TP53, and MUC16. We also observed high transcriptomic similarity across all NENs regardless of their site of origin. Conclusions: We identified two copy number changes that can serve as predictive biomarkers in G3 NENs, as they confer an increased risk of death by as high as 10x to the carriers. Further, G3 NENs are characterized by a distinct group of somatic mutations, and a significant number have high tumor mutation burden. Lastly, G3 NENs across different organs were relatively homogeneous in expression profile.