bluuebunny/crossref_metadata_2025_split huggingface dataset:
Randomized dose comparison phase II study of the oral transforming growth factor-beta (TGF-ß) receptor I kinase inhibitor LY2157299 monohydrate (LY) in patients with advanced hepatocellular carcinoma (HCC).
Authors: Faivre Sandrine J. , Santoro Armando , Kelley Robin Katie , Merle Philippe , Gane Ed , Douillard Jean-Yves , Waldschmidt Dirk , Mulcahy Mary Frances , Costentin Charlotte , Minguez Beatriz , Papappicco Pasqua , Gueorguieva Ivelina , Cleverly Ann , Desaiah Durisala , Lahn Michael M. F. , Murray Nicola , Benhadji Karim A. , Raymond Eric , Giannelli Gianluigi 
Published: March 2020

4118 Background: TGF-ß signaling is associated with HCC progression in moderate to poorly differentiated tumors overexpressing alpha-fetoprotein (AFP) levels. We report here the safety and antitumor activity of LY in HCC patients with elevated AFP in this ongoing study. Methods: Patients with advanced HCC who progressed on sorafenib (SF) or are ineligible to receive SF, advanced Child-Pugh A/B7 HCC, AFP ≥1.5x ULN, ECOG PS ≤1, measurable disease (RECIST 1.1), and ≤1 prior systemic regimen were eligible. LY was administered as intermittent dosing of 14 days on/14 days off (28 days =1 cycle). Patients were randomized to either 160 mg/day (Arm A) or 300 mg/day (Arm B) LY. Primary endpoints were time-to-progression (TTP) and biomarker changes (serum AFP, TGF-ß and E-cadherin) for each dose. Secondary endpoints included toxicity (CTCAE, V 4.0) and pharmacokinetics (PK). Results: 106 patients were enrolled (Arm A=37; B=69), including 92% non-Asians. Baseline characteristics were (Arm A/B): median age 61/66 years; PS=0 60/51%; Child-Pugh A 97/86%; etiology: hepatitis C 30/33%, hepatitis B 24/25%, alcohol 22/22%. Overall, 78/83% of patients had received prior SF; 64/58% of patients had AFP ≥400 ng/mL. Median TTP was 12.0 weeks (90% CI: 7.1, 12.6) in the overall population (Arm A, 12.6 weeks; Arm B, 10.9 weeks). In SF-naïve patients, TTP was 18.3 weeks (90% CI: 6.3-non-estimable). TTP was higher in the non-alcohol compared to alcohol-only etiology group (median 12.1 vs. 6.1 weeks). Median baseline serum TGF-ß1 was 3.4 ng/mL (range: 1.4-3.7) and E-cadherin was 6.1 mg/mL (range: 1.9-17.3). AFP decline of >25% occurred in 21/106 patients (20%). Four patients discontinued treatment due to a drug-related AE. Most common grade 3/4 related AEs in patients were: neutropenia (n=3), GI bleeding (n=2), fatigue (n=2), and anemia (n=2). Preliminary PK analysis (51 patients) demonstrated moderate interpatient exposure variability (42%). Conclusions: Based on the manageable toxicity profile, the evidence for biomarker/TTP responses, and an analysis of the aggregate PK/PD data, the 300 mg/day dose was chosen for future studies in HCC. Clinical trial information: NCT01246986.
Prognostic delineation of papillary cholangiocarcinoma based on the invasive proportion.
Authors: Onoe Shunsuke , Shimoyama Yoshie , Ebata Tomoki , Yokoyama Yukihiro , Igami Tsuyoshi , Sugawara Gen , Nakamura Shigeo , Nagino Masato 
Published: March 2020

4119 Background: Intraductal papillary neoplasm of the bile duct (IPNB) is a presumed precursor lesion in biliary carcinogenesis, clinicopathologically overlapping with papillary cholangiocarcinoma (PCC); however, as IPNB has no standardized definition, this relationship remains equivocal. Here, we aimed to develop a new PCC prognostic model, focusing on the invasive proportion. Methods: Among 605 patients with surgically resected cholangiocarcinoma in Nagoya University Hospital between 2000 and 2011, 173 (29%) had intraductal exophytic papillary lesions. These were divided into four subsets based on the invasive component: non-invasive (PCC-1, n = 13), ≤10% (PCC-2, n = 30), 11-50% (PCC-3, n = 55), and >50% (PCC-4, n = 75). Results: Invasion beyond the ductal wall was observed in 83% of PCCs and 99% of non-papillary cholangiocarcinomas (NPCC, n = 432; P < 0.001). Regional lymph node metastases were more frequent in NPCC (48%) than PCC (32%; P < 0.001). Five-year survival was better for PCC (52%) than NPCC (37%; P < 0.001), indicating the papillary component to be a significant independent prognosticator. PCC-4 and NPCC had similar clinicopathological features and overlapping survival curves: 32% and 37% at 5 years (P = 0.877), both lower than those of PCC-1, PCC-2, and PCC-3 (respectively, 91%, 71%, and 60% at 5 years; P < 0.01 in all combinations). Multivariate analysis in PCC showed >50% invasive component, nodal metastasis, and positive surgical margin as independent predictors. Conclusions: The presence of an intraductal papillary component was an important determinant of better survival in cholangiocarcinoma. PCC exhibited a more aggressive histologic character and worse survival with progression of the invasive component. PCC with >50% invasive component was morphologically and prognostically similar to NPCC. Therefore, we propose that IPNB should be nosologically applied only for PCC cases with ≤50% invasive component.
Correlation between VEGF and VEGF-R polymorphisms, toxicity, and clinical outcome in HCC patients receiving sorafenib.
Authors: Faloppi Luca , Scartozzi Mario , Bianconi Maristella , Loretelli Cristian , Svegliati Baroni Gianluca , De Minicis Samuele , Mandolesi Alessandra , Giampieri Riccardo , Bittoni Alessandro , Del Prete Michela , Maccaroni Elena , Cecchini Luca , Bearzi Italo , Benedetti Antonio , Cascinu Stefano 
Published: March 2020

4123 Background: The introduction of sorafenib for the treatment of advanced HCC radically changed patients’ clinical outcome. However response to treatment as well as toxicity are still largely unpredictable in the single patient. We previously reported that VEGF and VEGFR polymorphisms may have a predictive and prognostic role in this setting, but little is known about the possible correlation with toxicity. The aim of our study was to evaluate whether VEGF and VEGFR genotyping was able to correlate with toxicity in HCC patients receiving sorafenib. Methods: 73 histological samples of HCC patients receiving sorafenib were tested for VEGF-A, VEGF-C and VEGFR-1,2,3 single nucleotide polymorphisms (SNPs). Patients time to progression (TTP), overall survival (OS) and toxicities were analysed. Results: VEGF-A rs833061 T>C, rs699947 C>A and rs2010963 C>G polymorphisms were statistically significant associated with any grade global (respectively: p=0.031; p=0.018; p=0.003) and cutaneous toxicities (respectively: p=0.043; p=0.019; p=0.025). Furthermore patients with any grade global and cutaneous toxicities showed a better progression free survival and overall survival (global toxicity PFS: 7.0 vs 5.0 months, p=0.016; OS: 26.8 vs 13.0 months, p=0.023) (cutaneous toxicity PFS: 7.6 vs 5.1 months, p=0.033; OS: 22.7 vs 13.3 months, p=0.014) Conclusions: In our analysis patients with polymorphism T at rs833061, C at rs699947 and C at rs2010963 showed a higher rate of toxicities and, accordingly to our previous report, this correlates with a better PFS and OS. Analysis of VEGF and its receptor genes polymorphisms represents a clinical tool to identify patients with favourable response to sorafenib presumably related to a more efficient control of tumour growth. The occurrence of toxicity could be an interesting clinical surrogate during sorafenib treatment and may help clinicians in a more cautious and aware management of HCC patients.
Postoperative nomogram for predicting survival after resection for intrahepatic cholangiocarcinoma.
Authors: Ribero Dario , Rosso Stefano , Pinna Antonio Daniele , Nuzzo Gennaro , Guglielmi Alfredo , Aldrighetti Luca , Leone Francesco , Aglietta Massimo , Giulini Stefano Maria , Gerunda Giorgio Enrico , Tomatis Mariano , Berloco Pasquale , Calise Fulvio , Opocher Enrico , Gruttadauria Salvatore , Torzilli Guido , Capussotti Lorenzo 
Published: March 2020

4129 Background: Conventional staging systems have limited value for survival estimation in individual patients because of the multiple predictors of outcome. Nomograms may overcome these limitations. Thus we developed and internally validated a postoperative nomogram to predict survival after resection of intrahepatic cholangiocarcinoma (IHC) and compared its predictions to those obtained using the 7th Ed. AJCC/UICC stage groupings. Methods: Prospective clinicopathologic data from 574 patients who underwent hepatic resection at 12 tertiary hepatobiliary centres (1995-2011) were used. After inputting missing values with regression imputation, the nomogram was developed from a Cox regression model with overall survival (OS) as the primary end-point. Calibration and internal validation were performed calculating the agreement between observed and predicted outcomes in terms of percentage of predicted errors (PE). Discrimination was quantified with the concordance index (CI). Both CI and PE were then corrected for over-optimism using bootstrapping with 100-fold cross-validation sampling. Credibility intervals around 3- and 5-year predicted survival were estimated from an empirical Bayesian model. Results: At last follow-up (median duration 27.6 months) 243 patients had died. Three and five-years OS were 52% and 39%. The predictive accuracy of the nomogram (CI: 66.5), which includes 7 variables (tumour size and number, lymph-node metastases, vascular invasion, perineural invasion, CA19.9 level, and radicality of resection), was good and superior to that of the current AJCC/UICC staging system (CI: 58.4). Percentage of PE for the AJCC/UICC staging system were 24%, while the studied model offered a PE slightly under 20%. Heterogeneity was observed in the distribution of nomogram-predicted survival probabilities within stage groups. Conclusions: The nomogram developed in this study overcomes some of the prognostic limitations associated with simple models by including all prognostic variables excluded from the AJCC/UICC staging system and may serve as an instrument for future refinements in determining individual patient prognosis necessary for accurate patients stratification.
Neutrophil/lymphocyte ratio (NLR) as a prognostic factor in biliary tract cancer (BTC).
Authors: McNamara Mairead Geraldine , Templeton Arnoud J. , Maganti Manjula , Walter Thomas , Horgan Anne M , McKeever Elizabeth , Min Trisha , Knox Jennifer J. 
Published: March 2020

4130 Background: BTCs include intrahepatic (IHC), hilar, distal bile duct (DBD), and gallbladder carcinoma (GBC). Risk factors include conditions associated with chronic inflammation. NLR, an inflammatory marker, is prognostic in several cancers but has not been reviewed in large BTC series, hilar or GBC. Methods: Baseline demographics and NLR at diagnosis were evaluated in 864 patients (pts) with BTC from 01/87 - 12/12 treated at Princess Margaret Cancer Center. Their prognostic significance for overall survival (OS) was determined using a Cox proportional hazards model. Results: High NLR ≥3.0 was associated with poor survival using univariable analysis as was stage/site of primary (P<0.05), age >65yrs, lymphocytes ≤1.6 (P<0.01), neutrophils ≥5.0, platelets ≥280, hemoglobin (Hb) < 110 g/L (P<0.001). Median OS in pts with NLR<3.0 was 21.6 mo, 12.0 mo with NLR ≥3.0 (P<0.001). NLR retained its significance as a prognostic marker on multivariable analysis (Table), along with GBC (P<0.05), age>65yrs, DBD primary (P<0.01), stage and Hb <110g/L (P<0.001). NLR was prognostic for OS on multivariable analysis for hilar: overall (Table) and advanced grp (n=102) (HR 1.68, 95%CI 1.07-2.64, P<0.05) and in advanced DBD (n=102) (HR 1.63, 95%CI 1.03-2.57,P<0.05). On subgrp analysis, NLR was prognostic for OS in advanced BTC (ABTC) (n=538) (P<0.01) but not in surgical grp. NLR did not predict RECIST response to first line palliative chemotherapy in ABTC. Conclusions: Baseline NLR is prognostic in BTC, specifically ABTC and hilar subgrp, suggesting the importance of systemic inflammation influencing outcome in pts with ABTC, thus providing a simple inexpensive prognostic biomarker while also possibly identifying pts that may benefit from antiinflammatory mediation. NLR was not predictive for response in BTC. [Table: see text]
Everolimus in combination with octreotide LAR as the first-line treatment for advanced neuroendocrine tumors: A phase II trial of the I.T.M.O. (Italian Trials in Medical Oncology) group.
Authors: Bajetta Emilio , Catena Laura , Fazio Nicola , Pusceddu Sara , Biondani Pamela , Blanco Giusi , Ricci Sergio , Aieta Michele , Pucci Francesca , Valente Monica , Bianco Nadia , Bellomo Fernanda , Mauri Chiara , Buonandi Pasquale , Roberto Vincenza 
Published: March 2020

4136^ Background: Everolimus has shown antitumor activity in patients (pts) with advanced pancreatic neuroendocrine tumors (NETs). We aimed to assess efficacy and safety of everolimus in combination with octreotide long-acting repeatable (LAR) in patients with well differentiated NETs of gastroenteropancreatic and of lung origin. Methods: We performed a phase II, multicenter trial using a Simon two-stage minmax design. Pts with advanced well differentiated, previously untreated NETs of the gastroenteropancreatic tract and of the lung received octreotide LAR 30 mg every 28 days in conjunction with everolimus 10 mg per day continuously. The primary endpoint was objective response rate (ORR). Results: A total of 50 pts (58% males) were enrolled. The median age was 60.5 years (range 25-76). Primary tumor site was pancreas in 14 (28%), unknown in 14 (28%), lung in 11 (22%), ileum in 9 (18%) and jejunum and duodenum in 2 (4%) of pts. 13 (26%) pts had carcinoid syndrome. The ORR, calculated on the ITT population, was 20.0% (95% CI 8.9-31.1): 2 patients (4%) had a complete response (CR), 8 (16%) a partial response (PR). Thirty-six patients (72%) achieved stable disease (SD). All CR and all PR as well as 91.7% of SD had a duration ≥ 6 months. Clinical benefit (CR+PR+SD) was 92%. At a median follow-up of 277 days, the median time to progression (TTP) was 16.3 months (95% CI 10.7-20.1). Overall survival could not be assessed. Treatment-related adverse events (AEs) were mostly of grade 1 or 2; the only grade 4 AE was mucositis in 1 patient, while grade 3 AEs included skin rash in 1 case, stomatitis in 4 cases (8%) and diarrhea in 11 cases (22%). Conclusions: Everolimus in combination with octreotide LAR has shown to be active and well tolerated in advanced NETs and, in this study, not only in primary pancreatic tumors. Compared to other clinical trials with everolimus in NETs, the observed ORR in this study was higher. Aknowledgements: The Authors thank the Italian Trials in Medical Oncology (I.T.M.O.) group and Novartis Pharma for the support provided. Clinical trial information: 2008-007153-13.
Study on activation of the IGF-1R mTOR pathway in neuroendocrine tumours (NETs).
Authors: Casanovas Oriol , Teule Alex , Villabona Carles , Serrano Teresa , Fabregat Joan , Salazar Ramon 
Published: March 2020

4139 Background: NETs are a heterogeneous group of rare neoplasms. Preclinical studies have shown that IGFR overestimulation can lead to constitutional activation of mTOR pathway. The main objective of this study is to describe the activation status of IGF1R-mTOR pathway by immunohistochemistry in a series of NETs and to assess the association with IGF1R expression. Methods: We studied 69 paraffin tumour blocks: 28 pancreatic NETs (pNETs) (2 gastrinomas, 1 glucagonoma, 4 insulinomas and 21 non-functioning (nf) pNETs), 32 GI NETs (4 stomach, 8 colorectum, 18 ileum and 2 dudodenum) and 9 NETs from other origins (2 anterior mediastinum, 2 ovary, 3 bile duct and 2 kidney). The expression of IGF1R, phosphorylated (p) mTOR and (p)S6 has been determined by immunohistochemistry using anti-IGF1Rβ (sc-713), anti-Phospho-mTOR (S2448) (49F9, Cell Signaling) and anti-Phospho-S6 Ribosomal Protein (S235/336)(91B2, Cell Signaling). Results: Expression of IGF1R has been observed in 46 of 69 (66%) samples with the highest expression in 2/4 (50%) insulinomas, 5/21 nf pNETs (23%) and 3/18 ileum (17%). We have observed activation of the mTOR pathway by immunodetection of (p)mTOR in 14 of 69 samples (20%): 2/21 nf pNETs (9.5%), 1/8 colorectum (12.5%), 8/18 ileum (44%), 1/2 anterior mediastinum, 1/2 ovary, 1/3 biliar tract. We haven’t detected any (p)S6 activation in these samples. Consistent IGF1R-mTOR pathway activation was detected in 11/14 (78%) samples with mTOR positivity that also showed expression of IGF1R. The most relevant finding is that all of the 8 samples from ileum with activation of mTOR showed some degree of expression of IGF1R. Conclusions: 2/3 of NETs show varying levels of expression of IGF1R, but only 16% demonstrate activation of the IGF1R-mTOR pathway. While the positivity of (p)mTOR in pNETs is lower than expected, we have identified a subgroup of ileal NETs with consistent activation of both IGF1R and (p)mTOR which could help stratify patients in clinical trials involving modulation of this pathway. In contrast, none of the 69 samples studied was positive for (p)S6 which suggests this marker is not valid to be used in the clinic. Further validation studies are required to help clinical stratification for therapies against IGF1R mTOR pathways.
Tivozanib in patients treatment-naive for metastatic renal cell carcinoma: A subset analysis of the phase III TIVO-1 study.
Authors: Sternberg Cora N. , Eisen Tim , Tomczak Piotr , Strahs Andrew Louis , Esteves Brooke , Berkenblit Anna , Motzer Robert John 
Published: March 2020

4513 Background: Tivozanib (T) is a potent, selective inhibitor of all three VEGF receptors with a long half-life of 4.5–5.1 days. Superior progression-free survival (PFS) and overall response rate (ORR) with T versus sorafenib (S) were demonstrated in a Phase III trial (TIVO-1) in patients (pts) with metastatic renal cell carcinoma (mRCC) (in ITT population, PFS: 11.9 vs 9.1 months HR=0.797, 95% CI 0.639–0.993; P=0.042; ORR: 33% vs 23%, P=0.014). Hypertension was more common with T, while lower rates of certain off-target AEs and fewer dose adjustments relative to S were reported (J Clin Oncol 2012;30[suppl]:Abstract 4501). Here we present efficacy and safety analyses for the pre-specified subset of pts who received no prior systemic therapy for mRCC. Methods: In the ITT population (N=517), pts were treatment-naïve or had received no more than 1 prior systemic therapy for metastatic disease; pts receiving prior VEGF- or mTOR-targeted therapy were excluded. Pts were randomized 1:1 to T 1.5 mg/d (once daily, 3 weeks on, 1 week off) or S 400 mg/d (twice daily, continuously). Of these, 181 pts (70%) in each treatment arm had not received prior systemic therapy for mRCC. Results: In pts who received no prior systemic therapy for mRCC, demographics were well balanced between the 2 arms. Median PFS was 12.7 for T vs 9.1 months for S (HR=0.756, 95% CI 0.580–0.985, P=0.037). ORR was 34% for T vs 24% for S (P=0.038). The most common adverse event (AE; All grades/Grade ≥3) for T was hypertension (T: 40%/25% vs S: 35%/18%), suggesting “on-target” biological activity and was manageable medically, while the most common AE for S was hand-foot syndrome (T: 11%/2% vs S: 52%/16%). Other common AEs were diarrhea (T: 22%/2% vs S: 32%/7%), fatigue (T: 19%/6% vs S: 15%/3%), and weight decrease (T: 18%/1% vs S: 17%/2%). Dose reduction (T: 12% vs S: 42%) and interruption (T: 18% vs S: 35%) rates were lower in the T arm and similar to the ITT population. Conclusions: T demonstrated significant improvement in PFS and ORR compared with S in pts who had received no prior systemic therapy for metastatic RCC. T was generally well tolerated, with low rates of treatment-related reduction/interruption in this pre-specified subgroup of pts. Clinical trial information: NCT01030783.
Gemcitabine, paclitaxel, and doxorubicin as first-line therapy for patients with advanced urothelial carcinoma and renal insufficiency: A phase II study.
Authors: Pagliaro Lance C. , Munsell Mark F. , Harris Deborah , Carolla Robert L. , Siefker-Radtke Arlene O. 
Published: March 2020

4528 Background: The role of cisplatin-based chemotherapy for the treatment of locally advanced or metastatic urothelial carcinoma is well established. For patients (pts) who cannot receive cisplatin owing to renal insufficiency, substitution with carboplatin was associated with inferior response rate and overall survival (OS). To address this unmet need, we conducted a phase II study of gemcitabine (Gem), paclitaxel (Tax), and doxorubicin (Adria) in this group. Methods: The primary endpoint was overall response rate (ORR); secondary endpoints were toxicity, OS, and the safety and efficacy of pegfilgrastim 6 mg (G-CSF) given immediately after chemotherapy on Day 1. A Simon 2-stage design was chosen to detect ORR of 40% and to reject ORR of 25%. Eligible pts had metastatic or unresectable urothelial carcinoma, no prior chemotherapy, performance status ≤ 2, glomerular filtration < 60 ml/min, and no need for dialysis; all gave informed consent. Brain metastases were excluded, as were clinically significant heart disease, peripheral neuropathy, and liver or bone marrow dysfunction. Treatment consisted of 900 mg/m2 Gem (fixed rate of 10 mg/m2/min), 135 mg/m2 Tax, and 40 mg/m2 Adria administered with same-day GCSF every 14 d to a maximum of 9 cycles. Tumors were evaluated after every 3 cycles. Results: Forty pts were enrolled January 2008 through November 2011, and 39 could be assessed for response. Median age was 72 (range, 51–89) and 11 pts (28.2%) were women. There were 7 complete and 15 partial responses, for an ORR of 56.4% (95% CI 39.6-72.2). Notable grade 3 and 4 nonhematologic toxicities in the first 2 cycles were dyspnea and mucositis (1 pt each). There were no treatment-related deaths and no toxicity attributed to same-day G-CSF. Median OS was 14.4 mo with median follow-up of 12.6 mo for all pts, 15.6 mo for 10 who were alive. Conclusions: Gem-Tax-Adria is effective as first-line treatment for metastatic or locally advanced urothelial carcinoma, and it can safely be given to pts with renal insufficiency. Same-day G-CSF also appears to be safe and effective in this setting. Phase III study is warranted. Clinical trial information: NCT00478361.