tbuckley/cabot-search huggingface dataset:
Contribution of eukaryotic translation initiation factor 3B to the pathogenesis of hepatocellular carcinoma via targeting EGFR and ZAK.
Authors: Jian-Feng Zheng, Xiao-he Jiang, Yu Chen, Li-li Cai, Xiao-zhong Wang, Wu-hua Guo, Ji-xiang Zhang
Journal: Journal of Clinical Oncology (2016)

e15587 Background: Eukaryotic initiation factor was reported to be dysregulated in human cancers. However, how it is potentially oncogenic remains elusive. Here we investigate the role of eukaryotic initiation factor 3B in the pathogenesis of hepatocellular carcinoma. Methods: Eukaryotic initiation factor 3B expression in hepatocellular carcinoma lesions and the cancer cell lines was measured by quantitative real-time polymerase chain reaction and immunohistochemistry analyses. Lentivirus-mediated RNA inference was utilized to silence Eukaryotic initiation factor 3B expression in SMMC-71cells, thereafter, cell proliferation, cell colony formation, and cell cycle phase distribution were examined. Eukaryotic initiation factor 3B-silenced hepatocellular carcinoma cells were implanted into nude mice to examine tumor biobehavior in vivo. Microarray gene expression analysis and Western blotting validation were used to determine global gene expression following eukaryotic initiation factor 3B silencing. Results: A significant overexpression of eukaryotic initiation factor 3B was found in hepatocellular carcinoma lesions compared to the matching adjacent non-tumor tissues. High expression of eukaryotic initiation factor 3B was significantly correlated with advanced tumor-node-metastasis stage and poor survival rates. Knockdown of eukaryotic initiation factor 3B significantly decreased proliferation and clonability of tumor cells in vitro and inhibited tumor growth in vivo; Eukaryotic initiation factor 3B silencing markedly downregulated expressions of epithelial growth factor receptor and zipper sterile-α-motif kinase. Conclusions: up-regulated Eukaryotic initiation factor 3B is associated with malignant transformation in hepatocellular carcinoma, and may contribute to hepatocarcinogenesis via targeting EGFR and ZAK, which could serve as a novel therapeutic target for hepatocellular carcinoma.
Upfront isolated limb perfusion (ILP) in untreated patients with unresectable non-metastatic primary soft-tissue sarcomas (STS) of the limb: The Gustave Roussy experience.
Authors: Tarek Assi, Andrea Cavalcanti, Axel Le Cesne, Matthieu Faron, Jean Francois Honart, Ashraf Hadiji, Olivier Camuzard, Tony Ibrahim, Cecile Le Pechoux, Olivier Mir, Julien Adam, Sarah Naomie Dumont, Philippe Terrier, Charles Honoré
Journal: Journal of Clinical Oncology (2018)

11569 Background: Options for limb-preserving surgery in locally advanced (LA) STS include chemotherapy and/or radiotherapy (RT), or ILP with tumour necrosis factor-alpha (TNFa) + melphalan, if the tumour is confined to an extremity. The aim of this study is to evaluate the benefit of upfront ILP in untreated unresectable patients (pts). Methods: All pts with unresectable non-metastatic primary LA STS of the limb treated at Gustave Roussy with exclusive ILP as induction treatment between 2003 and 2016 were included in this study. Demographic, clinical and long-term characteristics were obtained from the electronic medical records and retrospectively analyzed. Results: 41 pts were identified, with a median age of 51 yrs [range: 21-76]. Liposarcoma and undifferentiated pleomorphic sarcoma were the most common subtypes (27% and 22 % respectively) with tumors classified as FNLCC grade 3 in 11 pts, grade 2 in 16 and grade 1 in 13. Acute regional toxicities after ILP (Wieberdink classification) were grade 2 in 35 pts (85%), and grade 3 in 2 (5%). No grade IV-V were observed. Objective response rate and disease stabilization were observed in 22% (including 2 CR) and 65% respectively. 8 pts were not operated (4 had exclusive RT, 1 pt progressed, 2 pts were in CR and 1 pt died after 3 months after ILP of a massive pulmonary embolism). 1 patient had early amputation due to PD after ILP. Out of 41 pts, 32 patients had conservative resection (78%). 2 pts (6%) experienced pathological CR, 17 (53%) had pathological PR (≥ 50% necrosis) while 13 (41%) were considered refractory ( < 50% necrosis). All but 5 pts (84 %) received post-operative RT. After a median follow-up (FU) of 43 months 18 pts (47%) relapsed; one locally, 13 at distance (62% in the lung) and 4 in both sites. Median disease-free survival after surgery was 6.7 yrs. The 1-yr, 5-yrs and 10-yrs DFS rates were 75%, 50% and 45% respectively. Median overall survival (OS) was not reached after median FU of 6.3 yrs.1-yr, 5-yrs and 10-yrs OS rates were 90%, 63% and 55%. Conclusions: This study suggests that upfront ILP in unresectable STS pts is a potentially curative limb saving procedure and is well tolerated without affecting OS.
Safety of influenza vaccination in patients undergoing immunotherapy treatment for advanced cancer.
Authors: Curtis Robert Chong, Vivian Park, James J. Harding, Jennifer Brite, Jedd D. Wolchok, Mini Kamboj
Journal: Journal of Clinical Oncology (2018)

e15073 Background: Cancer patients (pts) are at a higher risk for developing influenza related complications. It is unclear if vaccination against influenza exacerbates adverse events in patients undergoing immune checkpoint blockade (immunotherapy). Methods: We conducted an IRB-approved retrospective review of advanced cancer pts who received the inactivated influenza vaccine and immunotherapy to define the safety and tolerability of concomitant administration. The Memorial Sloan Kettering Cancer Center pharmacy database was queried for all advanced cancer pts who received the influenza vaccination within 60 days of treatment with an FDA-approved immune checkpoint inhibitor during the 2015-16 influenza season. Clinicopathologic parameters were extracted, including any grade immune-related adverse events (irAEs) by Common Terminology Criteria for Adverse Events version 4.0. Results: 147 pts were identified: Median age, 77 years (5-87); main tumor types, 52% lung cancer, 11% melanoma, 7% primary CNS; treatment, 12% anti-PD-1 and ipilimumab (combination), 88% antiPD-1 only. irAE occurred in 18% of pts treated with an anti-PD1 and in 41% of pts treated with combination. No grade 4 or 5 irAE were observed, and 7% of pts treated with an anti-PD1 and 12% of pts treated with a combination experienced grade 3 toxicity. The most common irAE were hypothyroidism (5% anti-PD-1, 0% combination), transaminitis (0% anti-PD1, 18% combination), pneumonitis, arthritis, pancreatitis, and rash (each 2% anti-PD-1, 6% combination). Treatment was held in 5% of anti-PD-1 pts and in 29% of combination pts because of an irAE. Mean ± standard error (SE) time between vaccination and an irAE was 16 ± 3 weeks for patients treated with an anti-PD-1, and 10 ± 6 weeks for patients treated with a combination. No adverse events attributable to influenza vaccination were observed. Conclusions: The incidence of irAE were similar to results previously reported in clinical trials of immune checkpoint inhibitors, indicating that co-administration of influenza vaccination with FDA-approved immune checkpoint inhibitors is safe and effective.
ATLANTIS: Global, randomized phase III study of lurbinectedin (L) with doxorubicin (DOX) vs<i>.</i> CAV or topotecan (T) in small-cell lung cancer after platinum therapy.
Authors: Anna F. Farago, Luis G. Paz-Ares, Tudor-Eliade Ciuleanu, Andrea Fülop, Alejandro Navarro, Laura Bonanno, Jose Antonio Lopez-Vilariño, Rafael Nuñez, Carmen Maria Kahatt, Gabor Kos, Arturo Soto-Matos
Journal: Journal of Clinical Oncology (2018)

TPS8587 Background: Lurbinectedin (L), a synthetic analog of marine-based tetrahydroisoquinolone, blocks active transcription, produces DNA breaks and apoptosis, and affects the inflammatory microenvironment. L showed promising activity in combination with DOX in a phase I cohort of relapsed small cell lung cancer (SCLC) patients (pts) (overall response rate (ORR) = 67%, n = 21, ASCO 2015, abstract 7509). Most common toxicities were hematologic. Lower dose improved safety and confirmed activity in an expanded cohort (ORR = 37%, n = 27 SCLC pts). Methods: We present an ongoing multinational (20 countries), multicenter (154 sites), open-label, randomized phase III study of L/DOX vs. control arm (investigator choice of either cyclophosphamide, DOX and vincristine (CAV) or topotecan (T)). 600 pts will be randomized (1:1) and stratified according to ECOG performance status (PS), central nervous system (CNS) involvement, previous treatment with antiPD1/antiPD-L1, chemotherapy-free interval, and investigator´s choice of control arm. Interim safety analysis by an independent data monitoring committee (IDMC) is planned when the first 150 pts are randomized. The most relevant inclusion criteria are: age ≥18 years; confirmed SCLC diagnosis (if primary site unknown, Ki-67 expression > 50%); previous platinum-containing line (additional immunotherapy allowed); ECOG PS 0-2; adequate major organ function (including LVEF > 50%). Main exclusion criteria include chemotherapy-free interval < 30 days; prior treatment with L DOX or T; symptomatic or steroids-requiring CNS involvement. The primary objective is to determine a difference in progression-free survival (RECIST v.1.1) by independent review committee. Secondary endpoints include overall survival, survival rates at 12/18/24 months, antitumor response, duration of response, quality of life, safety, and pharmacokinetics. The first patient was randomized in August 2016. The pre-planned interim safety analysis was done on November 2017 and the IDMC recommended to continue the trial unmodified. Trial recruitment is expected to be completed in Q2 2018. Clinical trial information: NCT02566993.
Quantification of circulating tumor cells as a biomarker for surveillance in oligometastatic patients after definitive radiation therapy.
Authors: Daniel Paul Lindsay, Dominic Himchan Moon, Zahra Mahbooba, Sin-jung Park, Michael Poellmann, Jiyoon Bu, Seungpyo Hong, Andrew Wang
Journal: Journal of Clinical Oncology (2018)

e24106 Background: Circulating tumor cells (CTCs) have been demonstrated as a biomarker in certain advanced cancers. Additionally, there has been increasing recognition that definitive treatment, including radiotherapy (RT), may lead to cure or significantly increased time to progression in oligometastatic solid malignancies. However, differentiating between patients with truly oligometastatic disease and those who will develop systemic disease is difficult. In most cases, secondary to a lack of reliable biomarker, surveillance often relies heavily on imaging. We hypothesized that CTCs are a sensitive biomarker in post-treatment surveillance after metastasis-directed definitive RT in oligometastatic patients. Methods: Patients with oligometastatic solid-tumor malignancies with up to 3 metastases undergoing definitive RT to all known metastatic sites were enrolled on a prospective study. Peripheral blood (7 mL) was drawn prior to initiation of RT, 1-3 time points during RT, and at subsequent follow up appointments. CTCs were quantified using CapioCyte, a nanotechnology based CTC capture system that takes advantage of biomimetic cell rolling and dendrimer-mediated strong multivalent binding. Results: 33 patients were enrolled with a median follow-up of 12.4 months. All patients had detectable CTCs on enrollment with a median of 24 CTCs/mL (range 3-120). Pre-treatment CTCs did not predict subsequent recurrence (p = 0.94). 20 patients (67%) subsequently had progression of disease, with an overall median PFS of 4.6 months. Of those who recurred, 10 patients had CTCs quantified at or near the time of progression, with 8 of these patients showing a corresponding increase in CTCs (2.5-28.7 fold increase). Out of 6 patients who were started on systemic therapy after progression, CTCs declined or were stable in all 5 patients with a partial response or stable disease, and increased in 1 patient who progressed. Conclusions: Our data suggests CTCs as quantified by the CapioCyte technology correspond with disease status and are a reliable biomarker for post-treatment surveillance in oligometastatic solid-tumor malignancies.
The relationship between coping strategies and quality of life (QOL) in patients with chronic graft-versus-host disease (cGVHD).
Authors: Netana Markovitz, Lara Traeger, Sarah Fishman, Lauren Waldman, Julie Vanderklish, Thomas R. Spitzer, Yi-Bin Albert Chen, Jennifer S. Temel, Areej El-Jawahri
Journal: Journal of Clinical Oncology (2018)

e19016 Background: Allogeneic stem cell transplant survivors with moderate to severe cGVHD experience substantial impairment in their QOL. However, the impact of patients’ physical functioning, symptom burden, and coping strategies on their QOL trajectory over time is currently unknown. Methods: We conducted a longitudinal study of patients with moderate to severe cGVHD recruited from a single institution. We assessed patient-reported QOL (Functional Assessment of Cancer Therapy- General [FACT-G]), physical functioning (Human Activity Profile), cGVHD symptom burden (Lee Symptom Scale), and coping (Coping Inventory for Stressful Situations] at baseline, 3 months, and 6 months. Using mixed linear effects models, we longitudinally examined the relationship between patients’ QOL with their physical functioning, cGVHD symptoms, and coping strategies. Results: We enrolled 53 patients with moderate (71.7%, 38/53) or severe (28.3%, 15/53) cGVHD. Patients reported impaired QOL at baseline [FACT-G: mean = 70.33, SD = 18.96] which did not change significantly over time [β = -0.66, SE = 1.11, P = 0.550]. Higher physical functioning was associated with better QOL over time [β = 0.17, SE = 0.05, P = 0.001], while higher symptom burden was associated with worse QOL over time [β = -0.38, SE = 0.06, P < 0.001]. The use of emotion-oriented coping was associated with lower QOL over time [β = -0.70, SE = 0.14, P < 0.001]. In contrast, the use of avoidance-oriented coping was associated with higher QOL over time (β = 0.38, SE = 0.10, P < 0.001). Task-oriented coping was not significantly associated with patients’ QOL trajectory. Conclusions: Patients with moderate or severe cGVHD report persistently impaired QOL over time. Higher physical function and lower symptom burden are associated with improvement in patients’ QOL over time. The use of certain coping strategies impacts patients’ QOL trajectory. These data underscore the need for supportive care interventions to promote effective coping and enhance physical functioning in patients with cGVHD.
Real-world dose adjustment study of first-line afatinib in pts with <i>EGFR</i> mutation-positive (<i>EGFR</i>m+) advanced NSCLC.
Authors: Balazs Halmos, Eng-Huat Tan, Min Ki Lee, Pascal Foucher, Te-Chun Hsia, Maximilian J. Hochmair, Frank Griesinger, Toyoaki Hida, Edward S. Kim, Barbara L. Melosky, Angela Maerten, Enric Carcereny Costa
Journal: Journal of Clinical Oncology (2018)

e21060 Background: Tolerability-guided dose adjustment of afatinib reduced the incidence and severity of adverse drug reactions (ADRs) without affecting efficacy in the LUX-Lung (LL) studies in EGFRm+ NSCLC. We report the impact of afatinib dose modifications on efficacy and safety in a real-world setting. Methods: This non-interventional, observational, multi-country/site study used medical records of TKI-naïve pts with EGFRm+ (Del19/L858R) NSCLC treated with first-line afatinib. Primary outcomes were % pts with ADRs by severity, time on treatment, and time to progression (TTP; where reported), relative to LL3. Secondary outcomes were % pts with/reasons for modified starting dose. Results: 228 pts from 13 countries were included. Baseline characteristics were in line with LL3, but with more Del19 pts (78% vs 49%); 12% had ECOG PS 2–3. 31% started with <40 mg, mainly due to the pt's condition. Dose modifications were more frequent in females, older pts, Eastern Asian pts, and lower body weight pts. 51% of pts were still on treatment; main reason for discontinuation was PD (33% overall). 67% of ≥40 mg starters underwent dose reductions, with 86% of those occurring in the first 6 mos. 12% (28) pts increased dose. The main reason for dose modification was ADRs. In ≤30 mg starters, overall ADR incidence was similar to ≥40 mg starters, with fewer G3 (17% vs 25%) and no G4 ADRs. There were no new safety signals, and fewer ≥G3 ADRs and SAEs than in LL3 (25% vs 49% and 5% vs 14%). >60% of the pts received medications to treat diarrhea and manage skin AEs. Median time on treatment and TTP was 18.7 mos and 20.8 mos respectively and was not impacted by reduced starting dose or dose modification (19.4/17.7/19.5 and 25.9/20.0/29.0 mos for pts who started on ≤30 mg/reduced to <40 mg/remained on ≥40 mg). Conclusions: As in LL trials, real-world afatinib dose adjustments reduced the frequency and intensity of ADRs without impacting efficacy. Time on treatment/TTP were similar regardless of dose adjustment or reduced starting dose, confirming the efficacy of this regimen with an acceptable safety profile. The results highlight the benefit of tailoring afatinib dose based on individual pt characteristics and ADRs to optimize outcomes. Clinical trial information: NCT02751879.
Ixazomib plus lenalidomide-dexamethasone (IRd) vs placebo-Rd in patients (pts) with relapsed/refractory multiple myeloma (RRMM): China continuation of TOURMALINE-MM1.
Authors: Jian Hou, Jie Jin, Yan Xu, Depei Wu, Xiaoyan Ke, Zhou Daobin, Jin Lou, Xin Du, Xiequn Chen, Junmin Li, Jing Liu, Bingxia Wang, Xiaoquan Zhang, Hui Wang, Helgi Van De Velde, Paul G. Richardson, Philippe Moreau
Journal: Journal of Clinical Oncology (2016)

8036 Background: The global, randomized, double-blind, placebo-controlled, phase 3 TOURMALINE-MM1 study (NCT01564537) demonstrated 35% improvement in PFS (HR 0.74, p = 0.012) with IRd vs placebo-Rd in pts with RRMM (Moreau et al, ASH 2015). This continuation study assessed the efficacy and safety of IRd vs placebo-Rd in pts with RRMM in China as a separate regional expansion of the global study. Methods: Eligibility criteria and study design were per the global study, except high-risk cytogenetic and patient-reported outcome endpoints were not assessed. The primary endpoint was PFS, assessed by the same IRC. Pts were analyzed separately from the global study. Sample size was not based on a formal statistical hypothesis. Results: 115 pts were randomized (57 IRd, 58 placebo-Rd). Compared to the global study, pts had more advanced disease (63% ISS stage II/III vs 46% in the global study), were more heavily pretreated (60% vs 41% had 2 or 3 prior therapies), and more frequently had refractory MM (43% vs 11%). At data cut-off (12 July 2015; median follow-up 8.0 vs 7.8 mos), PFS was significantly improved with IRd vs placebo-Rd: median 6.7 vs 4.0 mos; HR 0.598; p = 0.035. This benefit was seen across prespecified subgroups. Median TTP was 7.3 vs 4.1 mos with IRd vs placebo-Rd; HR = 0.583. Overall survival data were not yet mature; 6 (11%) IRd and 16 (28%) placebo-Rd pts have died. Overall response ( ≥ VGPR) rates were 56% (25%) vs 31% (12%). Pts had received a median of 7 and 5 cycles of IRd and placebo-Rd, and 59% and 41% of pts remained on treatment; 56% vs 62% had grade ≥ 3 AEs, 23% vs 26% had SAEs, 5% vs 12% discontinued treatment due to AEs, and 4% vs 5% died on treatment. Common grade ≥ 3 AEs with IRd vs placebo-Rd included thrombocytopenia (23% vs 13%), neutropenia (23% vs 19%), anemia (12% vs 26%), and pneumonia (16% vs 10%). 18% vs 19% of pts had rash (no grade ≥ 3 events); 7% of pts in each group had peripheral neuropathy (no grade ≥ 3 events). Conclusions: In Chinese pts with RRMM, IRd was associated with a significant improvement in PFS, with limited additional toxicity, demonstrating the consistent relative benefit of IRd vs placebo-Rd in this distinct Chinese population and the global study Clinical trial information: NCT01564537.
TCT-499 Prognostic Implications of Pre-procedural TIMI Flow in Patients with STEMI Undergoing PCI with Drug-Eluting Stent Implantation
Authors: Mordechai Golomb, Rafal Wolny, Yangbo Liu, Pieter Smits, Clemens von Birgelen, Bjorn Redfors, Mahesh Madhavan, Ori Ben-Yehuda, Roxana Mehran, Martin Leon, Gregg Stone
Journal: Journal of the American College of Cardiology (2018)
Final phase Ib data for the oral c-Met inhibitor tepotinib in patients with previously treated advanced hepatocellular carcinoma.
Authors: Sandrine J. Faivre, Jean-Frédéric Blanc, Philippe Merle, Angelica Fasolo, Angelo Iacobellis, Thomas Decaens, Erica Villa, Jorg Trojan, Véronique Grando, Barbara Ellers-Lenz, Charles Zhao, Eric Raymond
Journal: Journal of Clinical Oncology (2017)

e15676 Background: The prognosis for patients (pts) with advanced hepatocellular carcinoma (HCC) after failure of sorafenib is poor, with few systemic therapy options. c-Met is a receptor tyrosine kinase implicated in the progression of HCC. Tepotinib, a highly selective c-Met inhibitor, has shown activity first-line in patients with c-Met+ HCC. We report final results of a phase Ib study of tepotinib in pts with advanced HCC after failure of first-line sorafenib. Methods: Eligible pts were ≥18 years with advanced HCC, Child-Pugh Class A, ECOG PS 0-1, and progression after ≥4 weeks of sorafenib. Tepotinib doses of 300 and 500 mg/day on a 21-day cycle were explored to establish the recommended phase II dose (RP2D) of tepotinib. Secondary objectives included antitumor activity by RECIST v1.1, biochemical response, and safety. Results: Seventeen pts were enrolled: 4 pts received tepotinib 300 mg/day and 13 pts 500 mg/day, confirmed as the RP2D. Fourteen pts experienced treatment-related adverse events (TRAEs), the most frequent being peripheral edema (n = 5, 2 grade 3), lipase increase (2, 1 grade 3), acute kidney injury (2, 1 grade 3), renal impairment (2, 1 grade 3), fatigue (2), nausea (2), asthenia (2). One pt with peripheral edema permanently discontinued treatment. No grade ≥4 TRAEs and no dose-limiting toxicities (DLTs) were reported. The best overall response was partial response (PR) in 2 pts and stable disease (SD) in 4 pts. The duration of the PRs was 57 and 91 weeks. In the first of these pts, tumor size decreased by 55% and serum alfa-fetoprotein (AFP) levels had decreased from 15,923 μg/L at baseline to &lt; 3,000 μg/L by day 15 of cycle 2 and remained at this level until progression. In the second pt, tumor size decreased by &gt; 60% from baseline. No consistent change in AFP was seen in pts with SD. Median overall survival was 7.2 months (range 0.7–22.9 months). Conclusions: The RP2D of tepotinib as second-line therapy for pts with advanced HCC who progress after sorafenib treatment is 500 mg/day. Tepotinib was well tolerated at this dose and showed signs of activity. The ongoing phase II part of this trial is investigating the efficacy and safety of tepotinib 500 mg/day in pts with c-Met+ HCC. Clinical trial information: NCT02115373.