tbuckley/cabot-search huggingface dataset:
Axitinib treatment in advanced RAI-resistant differentiated thyroid cancer (DTC) and refractory medullary thyroid cancer (MTC).
Authors: Jaume Capdevila, Jose Manuel Trigo Perez, Javier Aller, Jose Luis Manzano, Silvia Garcia Adrian, Carles Zafon, Òscar Reig, Uriel Bohn, Elena Cillan, Manuel Duran, Beatriz Gonzalez Astorga, Ana Lopez, Medina Javier, Ignacio Porras, Juan J Reina, Nuria Palacios, Enrique Grande, Juan J. Grau
Journal: Journal of Clinical Oncology (2014)

6027 Background: Multikinase inhibitors (MKI) have demonstrated significant activity in advanced thyroid cancer. Axitinib is a potent oral MKI targeting the three known receptors of VEGF. Methods: Patients (pts) with advanced RAI-refractory DTC or unresectable MTC in documented disease progression were included in a compassionate use program of axitinib 5 mg bid. Primary end point was response rate (RR) by RECIST, and secondary objectives included progression-free survival (PFS), toxicity profile and biomarker correlation analysis. The program was validated by regulatory authorities and all patients signed informed consent form. Results: 41 pts were enrolled (med age: 54; male: 51%; 29 DTC, 12 MTC). Axitinib was first-line MKI therapy in 39%, second-line in 36% and 24% in subsequent lines. One level dose reduction (5 mg qd) was required in 24% of pts to manage toxicity. Main side effects were grade 1-2, including fatigue (46%), mucositis (24%), diarrhea (24%) and hypertension (19%). Grade 3-4 side effects included anorexia, diarrhea and cardiac toxicity in less than 5% of pts. 32 pts were evaluable for efficacy. In DTC, RR was 41%, stable disease (SD) 18% and progression disease (PD) 41%. In MTC, RR was 30%, SD 40% and PD 30%. Regarding treatment lines, RR in first-line was 69% and SD 31%; in second and third-lines, RR was 20%, SD 30% and PD 50% (p<0.05). No differences in median PFS were observed between DTC and MTC (p=0.509). However, significant differences were found regarding treatment lines: first-line 12.6 months, second-line 8.6 months and successive lines 3.9 months. 15 pts were evaluated for biochemical response. The Kappa index correlation observed between biomarker reduction >30% and tumor growth control (RR + SD) was for thyroglobulin 0.21 (0.30-0.72), CEA 0.22 (0.19-0.64) and calcitonin 0.087 (-0.62-0.79). No correlation was observed in this small number of pts. Conclusions: Axitinib has showed meaningful activity and a safety toxicity profile in refractory and progressive thyroid cancer regardless tumor histology in first and second-line therapy. Efficacy significantly decreases in successive lines suggesting cumulative resistance to MKIs.
Frontline bortezomib and rituximab for the treatment of newly diagnosed high tumor burden (HTB) indolent non-Hodgkin lymphoma (iNHL): A multicenter phase II study.
Authors: Andrew M. Evens, Mitchell Reed Smith, Izidore S. Lossos, Michael Mark Millenson, Jane N. Winter, Steven T. Rosen, Leo I. Gordon
Journal: Journal of Clinical Oncology (2014)

8545 Background: There is a deficiency of published data examining non-cytotoxic options for the frontline treatment of HTB iNHL. In addition, few HTB iNHL series have reported outcomes with long-term follow-up (ie, >3-4 years). Methods: All patients (pts) were required to have HTB by GELF criteria. Treatment in this multicenter phase II study consisted of 3 induction cycles of bortezomib (1.6 mg/m2 weekly x 4) and rituximab (4 weeks cycle 1; 1 dose cycles 2 + 3) administered q35 days. This was followed by an abbreviated consolidation (ie, each drug once q 2 months x 4). All outcomes were analyzed by intent-to-treat. Results: 42 pts were enrolled and all were evaluable. Histologies were follicular lymphoma (FL) (n=33, 79%), marginal zone lymphoma (n=6, 12%), small lymphocytic lymphoma (n=2, 7%), and Waldenstroms (n=1, 2%). Pt characteristics included median age 62 years (40-86); 38% bulky disease (>7cm); 19% malignant effusions; 91% advanced-stage; and the median FLIPI was 3. Therapy was well tolerated with few grade 3/4 toxicities and minimal neurotoxicity. Grade 3 adverse events (AE) were fever (5%), infusion reaction (5%), infection (5%), cardiac (5%), fatigue (5%), diarrhea, hypokalemia and bowel obstruction (2% each); the only grade 4 AEs were neutropenia (5%) and thrombocytopenia (2%). There was no motor neuropathy noted, no grade 3 or 4 sensory neuropathy, and the rates of grade 1 and 2 sensory neuropathy were 14% and 2%, respectively. Overall response rate (ORR) at end of therapy was 70% with a 40% complete remission (CR) rate (FL: ORR 76%, CR 44%). With 50 month median follow-up, 4-year progression-free survival (PFS) was 44% with 4-year overall survival (OS) of 87% (FL: 44% and 97%, respectively). Four-year PFS for FLIPI 0-2 vs 3-5 were 60% vs 26%, respectively (P=0.02), with corresponding OS rates of 92% and 81%, respectively (P=0.16). Interestingly, 4-year OS was superior for FL compared with non-FL histologies (97% vs 43%, respectively, P=0.003). Conclusions: Altogether, bortezomib/rituximab is a targeted therapeutic regimen that was very well tolerated and resulted in long-term survival rates approximating prior HTB FL rituximab/chemotherapy series. Clinical trial information: NCT00369707.
Imatinib Inhibits Proteasomal Activity in CML Cells.
Authors: Stefanie A.E. Held, Katharina M. Brauer, Thomas Rückrich, Daniela Werth, Karin von Schwarzenberg, Anita Bringmann, Lothar Kanz, Frank Grünebach, Christoph Driessen, Peter Brossart
Journal: Blood (2007)
Double-blind randomized trial of aflibercept versus placebo with docetaxel and prednisone for treatment of metastatic castration-resistant prostate cancer (mCRPC).
Authors: Ian Tannock, Karim Fizazi, Sergey Ivanov, Camilla Thellenberg-Karlsson, Aude Flechon, Iwona Anna Skoneczna, Francisco Jorquera Orlandi, Gwenaelle Gravis, Vsevolod Matveev, Sevil E. Bavbek, Thierry Gil, Luciano S. Viana, Osvaldo Aren, Oleg Karyakin, Tony Elliott, Alison J. Birtle, Emmanuelle Magherini, Daniel Peter Petrylak, Bertrand Tombal, Mark Rosenthal
Journal: Journal of Clinical Oncology (2013)

5002 Background: Docetaxel/prednisone is standard first-line chemotherapy for men with mCRPC. Aflibercept is a recombinant human fusion protein that binds A and B isoforms of Vascular Endothelial Growth Factor and Placental-derived Growth Factors, thereby inhibiting angiogenesis. Methods: We performed an international double-blind randomized trial (known as VENICE) which recruited men with mCRPC, adequate organ function and no prior chemotherapy. Men were treated with docetaxel (75mg/m² intravenously every 3 weeks) and oral prednisone (5mg twice daily) and randomized 1:1 to receive aflibercept (6 mg/kg) or placebo, intravenously every 3 weeks. The primary endpoint was overall survival: 873 deaths were required to detect a hazard ratio (HR) of 0.8 with 90% power. Results: A total of 1,224 men were randomized, 612 in each arm. Median age was 68 years and baseline characteristics were well balanced between arms. Participants received a median of 8 (aflibercept) and 9 (placebo) cycles of therapy. Median relative dose intensity was &gt;0.93 for aflibercept, placebo and docetaxel. At final analysis, median follow-up was 35 months and 873 pts had died. Median survival was 22.1 months (95.6% CI: 20.3-24.1 months) in the aflibercept arm and 21.2 months (95.6% CI: 19.6-23.8 months) in the placebo arm (stratified HR = 0.94; 95.6% CI: 0.82-1.08, p=0.38). Pre-defined secondary endpoints for aflibercept and placebo arms were similar, including PSA response rate (68.6% and 63.5%), time to first skeletal-related event (median: 15.3 and 15.0 months), and progression-free survival (median: 6.9 and 6.2 months). Quality of Life analysis using FACT-P and a trial-specific module will be reported. Higher incidence of grade 3-4 gastrointestinal disorders, hemorrhagic events, hypertension, fatigue, infections and fatal adverse events (5.6% vs. 3.3%) was observed in the aflibercept arm. Conclusions: Aflibercept in combination with docetaxel/prednisone given as first-line chemotherapy for men with mCRPC did not lead to an improvement in survival and added toxicity. Trial Registration: NCT00519285. Funding: Sanofi and Regeneron Pharmaceuticals, Inc. Clinical trial information: NCT00519285.
ELABELA-APJ axis protects from pressure overload heart failure and angiotensin II-induced cardiac damage
Authors: Teruki Sato, Chitose Sato, Ayumi Kadowaki, Hiroyuki Watanabe, Lena Ho, Junji Ishida, Tomokazu Yamaguchi, Akinori Kimura, Akiyoshi Fukamizu, Josef M. Penninger, Bruno Reversade, Hiroshi Ito, Yumiko Imai, Keiji Kuba
Journal: Cardiovascular Research (2017)

Elabela/Toddler/Apela (ELA) has been identified as a novel endogenous peptide ligand for APJ/Apelin receptor/Aplnr. ELA plays a crucial role in early cardiac development of zebrafish as well as in maintenance of self-renewal of human embryonic stem cells. Apelin was the first identified APJ ligand, and exerts positive inotropic heart effects and regulates the renin-angiotensin system. The aim of this study was to investigate the biological effects of ELA in the cardiovascular system.Continuous infusion of ELA peptide significantly suppressed pressure overload-induced cardiac hypertrophy, fibrosis and impaired contractility in mice. ELA treatment reduced mRNA expression levels of genes associated with heart failure and fibrosis. The cardioprotective effects of ELA were diminished in APJ knockout mice, indicating that APJ is the key receptor for ELA in the adult heart. Mechanistically, ELA downregulated angiotensin-converting enzyme (ACE) expression in the stressed hearts, whereas it showed little effects on angiotensin-converting enzyme 2 (ACE2) expression, which are distinct from the effects of Apelin. FoxM1 transcription factor, which induces ACE expression in the stressed hearts, was downregulated by ELA but not by Apelin. ELA antagonized angiotensin II-induced hypertension, cardiac hypertrophy, and fibrosis in mice.The ELA-APJ axis protects from pressure overload-induced heart failure possibly via suppression of ACE expression and pathogenic angiotensin II signalling. The different effects of ELA and Apelin on the expression of ACE and ACE2 implicate fine-tuned mechanisms for a ligand-induced APJ activation and downstream signalling.
Chronic Graft-Versus-Host Disease: Lessons From a Randomized Trial on GvHD Prophylaxis with or without Anti-T-Cell Globulin ATG-Fresenius (ATG-F) In Allogeneic Hematopoietic Cell Transplantation (HSCT) From Matched Unrelated Donors
Authors: Gérard Socié, Claudia Schmoor, Wolfgang Andreas Bethge, Hellmut Ottinger, Matthias Stelljes, Axel R. Zander, Liisa Volin, Dominik Heim, Rainer Schwerdtfeger, Hartmut Bertz, Olga Grishina, Jurgen Finke
Journal: Blood (2010)
Reply to Zhang et al.
Authors: Saowanee Ngamruengphong, Mouen Khashab
Journal: Endoscopy (2017)

We are grateful for the opportunity to respond to the Letter to the Editor entitled “Prevention of stent migration: Which option would patients prefer?” by Zhang et al. The authors suggested that endoscopic clips, rather than endoscopic suturing, should be the first-line option for stent fixation in consideration of procedure time, safety, and cost-efficacy [1] [2].
Regular Prophylactic Donor Lymphocyte Infusion Is Effective and Safe to Prevent Relapse after Hematopoietic Cell Transplantation in High-Risk Patients
Authors: Yi Luo, Yamin Tan, Yongxian Hu, Jimin Shi, Weiyan Zheng, Yanmin Zhao, Yuanyuan Zhu, Jian Yu, Jiasheng Wang, He Huang
Journal: Blood (2016)
A phase II clinical trial of tumor-treating field (TTF) therapy concomitant to pemetrexed for advanced non-small cell lung cancer (NSCLC).
Authors: Miklos Pless, Daniel C. Betticher, Cornelia M. Droege, Marc Oliver Salzberg, Roger Von Moos
Journal: Journal of Clinical Oncology (2012)

e18012 Background: TTF therapy is a novel, non-invasive treatment modality for solid tumors recently approved by FDA for recurrent GBM. It uses intermediate frequency alternating electric fields to inhibit tumor growth, by mitotic spindle and plasma membrane integrity disruption during cytokinesis. Pemetrexed is a folate antimetabolite used as a first/second line and as a maintenance therapy for non-squamous NSCLC patients. Preclinical studies in NSCLC models demonstrated that TTF therapy and pemetrexed had additive efficacy, with no increase in toxicity. The current trial tested TTF therapy concomitant to pemetrexed in NSCLC patients. Methods: A single arm, multi-center, prospective trial was performed in 42 stage IIIB (with pleural effusion) and IV NSCLC patients, following progression after at least one prior chemotherapy. Patients received continuous 150 KHz TTF therapy (12 h/day) using the NovoTTF-100L system (NovoCure, Israel), concomitant to pemetrexed (Alimta™, Eli Lilly) q3w, until progression. Pemetrexed was in use for squamous histology when the study opened. Results: The trial included 35 patients with non-squamous histology and 7 patients with squamous histology. TTF Therapy was well tolerated by all patients enrolled in the trial, with high compliance (11 h/day). No TTF-related adverse events were reported apart from dermatitis caused by the application of transducer arrays. Median progression free survival was 22.7 and 10.3 weeks for non-squamous and squamous histology, respectively. Median overall survival was 12.4 and 13.8 months for nonsquamous and squamous histology, respectively. One- and two- year-survival was 53% and 27%, respectively. Conclusions: TTF therapy concomitant to pemetrexed was well tolerated and safe for patients with advanced NSCLC, of all histologies. Efficacy indices are promising, in view of the poor outcome previously reported for similar populations. This first clinical trial involving TTF as a treatment for NSCLC patients suggests that it should be further studied in larger clinical trials for squamous and nonsquamous NSCLC.
Validation of the NSABP neoadjuvant rectal score (NAR) in a prospective phase II study evaluating an experimental regimen and a standard chemoradiation cohort with molecular genotyping.
Authors: Theodore S. Hong, Jackie Szymonifka, Greg Yothers, Lawrence Scott Blaszkowsky, Andrea Lyn Russo, Jennifer Yon-Li Wo, Harvey J. Mamon, Eunice Lee Kwak, Andrew X. Zhu, Jill N. Allen, Jeffrey W. Clark, David P. Ryan
Journal: Journal of Clinical Oncology (2014)

3599 Background: NSABP recently proposed replacing pCR with a new neoadjuvant rectal score (NAR) based on clinical downstaging from pre to post-treatment, pathologic (yp) stage. The NAR formula yields values from 0-100; higher scores indicate poor prognosis. In NSABP R04 (n=1479), the mean NAR = 15.61 with SD of 14.37, and OS hazard ratio/unit (HR) = 1.04 (p<0.0001). NAR showed a stronger association with OS than pCR, and was proposed as a new endpoint for phase II trials. We sought to evaluate the prognostic significance of NAR in two previously published datasets. Methods: Patient (pt) data from 2 IRB approved, previously published studies were used. Study 1 was a phase I/II study evaluating bevacizumab (bev) and erlotinib (erl) with neoadjuvant chemoradiation (CRT) (Ann Oncol 2014;25:121-6). Study 2 was a retrospective review of pts receiving 5-FU/RT (J Gastrointest Canc epub 2013, PMID24006244), with mutational analysis. All pts had pretreatment M0 and T3/4 or node + disease by MRI. Study 1 had 32 pts, with a pCR rate of 33%. Study 2 had 79 pts, with a pCR rate of 21.5%. NAR = [ 5pN- 3(cT-pT) + 12]2/ 9.61 where pN = yp nodal stage (0,1,2), cT = clinical T-stage (1,2,3,4), and pT= yp T stage (0,1,2,3,4). The NAR score’s association with DFS was tested as a pseudocontinuous variable in a Cox model, and is reported as a HR/unit. Results: In study 1, the mean NAR = 12.67 (SD =12.20): DFS HR 1.12 (1.04, 1.21, p=0.004). In study 2, mean NAR = 16.85 (SD = 16.17), DFS HR = 1.07 (1.03, 1.12, p=0.001). Mutational frequency in study 2 was KRAS 43%, APC 17%, BRAF 4%, NRAS 4%, PIK3CA 4%, TP53 11%. For study 2 pts with any mutation, mean NAR = 18.90 (SD =15.66): DFS HR 1.07 (1.01, 1.14, p=0.025). For study 2 pts with NO mutation, mean NAR = 13.85 (SD =16.69): DFS HR 1.07 (1.01, 1.13, p=0.004). Conclusions: Higher NAR was associated with worse DFS in a standard CRT cohort and an experimental phase II cohort, confirming the findings in NSABP R04. The mean NAR of 12.67 in the bev/erl study compares favorably to both NSABP R04 (15.61) and the retrospective CRT cohort (16.85). In study 2, pts with no mutation had a lower NAR than those with a mutation (13.85 vs 18.90), suggesting more favorable prognosis.
Molecular profiling of metastatic castration-resistant prostate cancer (mCRPC): Preliminary results from the SU2C/PCF/AACR West Coast Prostate Cancer Dream Team (WCDT).
Authors: George Thomas, Jack Youngren, Charles J. Ryan, Tomasz M. Beer, Martin Edwin Gleave, Christopher P. Evans, Josh Stuart, Matthew Rettig, Alexandria Toschi, Adam Foye, Joshi J. Alumkal, Christopher L. Corless, Tanaya Neff, Robert Baertsch, Jiaoti Huang, Kim N. Chi, Kit S. Lam, Theodore C. Goldstein, Owen Witte, Eric Jay Small
Journal: Journal of Clinical Oncology (2014)

5088 Background: The molecular basis of mCRPC has not been well characterized because of its bone tropism and difficulties in obtaining adequate tissue to evaluate. Bringing next-gen sequencing into clinical (CLIA-licensed) laboratories is an important step in the advancement of personalized cancer care in these patients (pts). As part of the WCDT project, we are conducting next-gen, semiconductor-based sequencing using the GeneTrails®Solid Tumor Panel, which covers 37 commonly mutated cancer genes. Methods: mCRPC pts, both abiraterone and enzalutamide naive and resistant, underwent biopsy (bx) at one of 5 WCDT clinical sites. Oncogenic mutations or amplifications in 37 genes were detected in formalin-fixed, paraffin embedded (FFPE) bone and soft issue bx using amplicon + semiconductor-based sequencing within a CLIA-certified laboratory. PTEN status was also examined by immunohistochemistry. Results: 60 of 300 planned mCRPC pts have undergone a metastasis bx. FFPE tissue has been evaluated by sequencing in 26 of these bx. Bx sites were: bone (n=8), lymph node (n=9) liver (n=7) lung (n=1), and adrenal (n=1). Mutations were found in 16 (62%) of the samples, with a greater rate of mutations in soft tissue (13/18) vs. bone (3/8). The most frequent mutations were in TP53 (N = 11, 42%), followed by PTEN (N = 4, 15%), RB1 (N = 4, 15%), PIK3CA (N = 2, 7.6%). Single instances of mutations were observed for AKT1, DDR2, EGFR, KIT, NOTCH1, TSC1, TSC2 and HRAS (3.2% each). Amplification of EGFR and FGFR1 were also noted. 90% of these alterations are known to result in either gain or loss of function. PTEN loss by IHC and/or mutation was seen in 12 of 26 (46%) of pts. Overall, 13 pts (50%) demonstrated at least one alteration in the PTEN/PI3K/AKT axis. Conclusions: Bx from mCRPC pts, including bone, can be used for prospective molecular profiling of tumor biopsy specimens. The most common alterations were found in the PTEN/PI3K/AKT pathway (50%), p53 (11%) and RB1 (15%). Combining amplicon + semiconductor-based next-gen sequencing provides a fast, cost-effective and reliable approach to potentially clinically actionable targeted sequencing data from mCRPC sites.
Multiarm, nonrandomized, open-label phase IB study to evaluate FP1039/GSK3052230 with chemotherapy in NSCLC and MPM with deregulated FGF pathway signaling.
Authors: Pilar Garrido Lopez, Enriqueta Felip, Jean-Pierre Delord, Luis Paz-Ares, Juneko E. Grilley-Olson, Michael S. Gordon, Fabrice Barlesi, Hendrik-Tobias Arkenau, Primo Lara, Paul K. Paik, Daniel Morgensztern, Shirish M. Gadgeel, Karen L. Reckamp, Erin Marie Bertino, Sergey Orlov, Eugeny Levchenko, Ignacio Delgado, Jose Manuel Trigo Perez, Teresa Moran, Ulrik Niels Lassen
Journal: Journal of Clinical Oncology (2014)

TPS8120 Background: FP1039/GSK3052230 (GSK230) is a soluble fusion protein that acts as a ligand trap by sequestering fibroblast growth factors (FGFs) involved in tumor growth. FGF ligand-dependent signaling plays an important role in cancer development and growth through autocrine production of FGFs from cancer cells, or paracrine production of FGFs from local stroma, or by tumor overexpression of FGF receptors (FGFRs) or amplification of FGFR genes. FGFR1 amplification has been identified in ~15-20% of squamous non-small cell lung cancers (NSCLC) and is associated with shorter disease-free and overall survival. Efficacy was observed with GSK230 + chemotherapy in FGFR1 amplified in NSCLC xenograft models and in xenograft models of malignant pleural mesothelioma (MPM) where FGF2 mRNA levels were overexpressed. In a phase I study, no maximum tolerated dose (MTD) was identified and 20 mg/kg weekly was the maximum feasible dose (MFD) achieving the desired target concentration. Toxicities associated with small-molecule FGFR inhibition, namely hyperphosphatemia and retinal, nail, and skin changes, were not observed. Methods: This is a multi-arm, nonrandomized, open-label phase IB study designed to evaluate the safety and preliminary efficacy of GSK230 in combination with paclitaxel + carboplatin in previously untreated FGFR1 amplified metastatic squamous NSCLC (Arm A), in combination with docetaxel in FGFR1 amplified metastatic squamous NSCLC that has progressed after 1 line of chemotherapy (Arm B), or in combination with pemetrexed + cisplatin in patients with untreated and unresectable MPM (Arm C). Approximately 70 patients will be enrolled. Each arm involves a dose escalation phase utilizing the 3+3 design, followed by a cohort expansion phase of at least 12 patients treated at either MTD or MFD. GSK230 will be administered as a 30-minute intravenous infusion once a week in a 21-day cycle. The starting dose is 5 mg/kg and will be dose escalated until MTD or MFD in combination with chemotherapy is reached. Endpoints include the combination dose of GSK230 with chemotherapy, safety, response rates and their duration, and translational objectives (NCT01868022). Clinical trial information: NCT01868022.