tbuckley/cabot-search huggingface dataset:
90 yttrium-ibritumomab tiuxetan consolidation of first remission in advanced-stage follicular non-Hodgkin lymphoma: Updated results after a median follow-up of 8.5 years from the GOTEL trial.
Authors: Mariano Provencio-Pulla, Fernando Franco, Jose Gómez-Codina, Cristina Quero, Marta Llanos, Francisco Ramon Garcia Arroyo, Luis De la Cruz-Merino, Josep Guma, Juan Ramón Delgado, Ruth Alvarez, Jose Ignacio Chacon, Ana Royuela, Antonio Rueda
Journal: Journal of Clinical Oncology (2018)

7550 Background: Relapse is the main cause of therapeutic failure in follicular lymphoma (FL). We report updated long-term efficacy and toxicity results of a multicenter phase II study (GOTEL-Provencio et al, Leuk Lymphoma 2014) to evaluate the role of consolidation with Yttrium-90 ibritumomab tiuxetan in patients with intermediate- and high-risk FL after 4 cycles of CHOP-R (cyclophosphamide, doxorubicin, vincristine, prednisone, rituximab) and 2 cycles of CHOP, without Rituximab. Methods: Patients older than the age of 18 with biopsy-proven, untreated, two-dimensionally measurable bulky stage II, III or IV FL (grade 1, 2 or 3) expressing the CD20 antigen were eligible for this trial. Patients were treated with standard CHOP-R immunochemotherapy every 21 days for 4 cycles, and 2 cycles of CHOP without rituximab. All patients achieving at least an unconfirmed partial response after four cycles of CHOP-R chemotherapy received treatment with two cycles of CHOP, without R. Consolidation treatment was with Yttrium-90 ibritumomab tiuxetan in a single dose. Results: Thirty patients were included. The overall response rate after consolidation therapy was 93%. The complete clinical response rate was 76.6%. With a median follow-up of 102 months ( > 8-y). Twenty-three patients (77%) are alive without disease. 6 patients died (2 progressions, 1 AML, 3 others cause). The means for progression-free survival (PFS) and overall survival (OS) were not reached. OS at 5-year was 90% (IC 95%; 72-96%); PFS at 5-years was 70% (IC 95%, 50-83%). Conclusions: Our data support consolidation with Yttrium-90 ibritumomab tiuxetan as an effective treatment, which provides long progression-free and overall survival, in first line after a response to induction treatment in patients with intermediate- and high-risk FL. Updates on the long-term follow-up of these studies are needed because of the natural history of FL.
P01.145 Tumor growth dynamics in serially-imaged low-grade glioma patients
Authors: J F Megyesi, C Gui, S Kosteniuk, J Lau
Journal: Neuro-Oncology (2018)

Diffuse low-grade gliomas (LGGs) are infiltrative, slow-growing primary brain tumors that remain relatively asymptomatic for long periods of time before progressing into aggressive and fatal high-grade gliomas. We retrospectively identified LGG patients with numerous (>= 8) serial magnetic resonance imaging (MRI) studies. Tumor volumes were measured by manual segmentation on serial imaging to study the natural history and growth of the lesion. Patient demographic information, tumor characteristics, and histological data were collected from electronic medical records and paper charts. Out of 74 LGG patients, 10 patients (13.5%) were identified to meet the study criteria with number of MRIs acquired ranging from 8 to 18 (median, 11.5) over a median of 79.7 months (range, 39.8–113.8 months). Tumor diameter increased at a median of 2.17 mm/year in a linear trajectory. Cox regression analysis revealed that initial tumor volume was an independent predictor of time to clinical intervention, and Mann-Witney U test found that patients younger than 50 years old had significantly slower-growing tumors. Clinical intervention was more likely for tumors above a volume threshold of 73.8 mL. We retrospectively analyzed the natural history of LGGs of patients managed at a single institution with numerous serial MRI scans. Comparisons of our cohort to the literature suggest that this is a subset of particularly slow-growing and low-risk tumors.
Abstract 13834: Changes in Treatment Patterns and Incremental Healthcare Utilization Due to P2Y12 Associated Disorders in Patients With Acute Coronary Syndrome
Authors: Ami Vyas, Lori D Bash, Mehul D Patel, Ross J Simpson
Journal: Circulation (2016)

Introduction: Data on the effect of P2Y12 associated disorders on adherence to antiplatelet therapy (APT) in acute coronary syndrome (ACS) patients are sparse. We describe the characteristics, trea...
Safety and efficacy of combination of temozolomide and pazopanib in patients with advanced pancreatic neuroendocrine tumors (PNET).
Authors: Halla Sayed Nimeiri, Sachin Gopalkrishn Pai, E. Gabriela Chiorean, Alfred Rademaker, Sheetal Mehta Kircher, Mary Frances Mulcahy, Steven J. Cohen, Crystal Shereen Denlinger, Vaibhav Sahai, Mark Zalupski, Jordan Berlin, Al Bowen Benson
Journal: Journal of Clinical Oncology (2016)

e15662 Background: Pazopanib (Pazo) is an angiogenesis tyrosine kinase inhibitor(TKI) targeting VEGFR-1, -2, and -3; PDGFR-α, -β; and c-Kit. Pazo has shown activity in a single arm phase II study in PNET with ORR 17%, 6mo PFS rate 80%. Temozolomide (tem) is an oral alkylating agent, which has shown promising activity (ORR70%) in combination with capecitabine in small retrospective PNET trial. In the preclinical setting, the combination of tem and VEGF TKI acts synergistically altering tumor micro environment enhancing tem activity, hence the rationale for our trial. This phase I study evaluates safety, and clinical benefit of tem+pazo in advanced PNET pts. Methods: Eligible pts have advanced well differentiated PNET, 0-4 prior therapy, prior tem was allowed, ECOG PS 0, 1, 2. Pts were enrolled into 3 sequential cohorts of tem(1) 150, (-1) 100, (-2) 75 mg/m2 PO QD(D1-7,15-21) + Pazo 400mg PO QD every 28 days. Endpoints included incidence DLT, MTD, adverse events (AE), PK of tem + its metabolite, and ORR. Results: As of 1/2016, 18 pts enrolled (cohort1=7; cohort-1=5, cohort-2=6). 7 females. Median (range) age=52 (21-71); 11(61%), 6(33%), 1(5%) had ECOG scores 0, 1 and 2. All received ≥1 28D cycle, median (range) number cycles=6 (1-41), median (range) time on treatment = 24 (4-164) weeks. There were 3 DLT: 2 (dose level 1) = grade 4 thrombocytopenia, and neutropenia, 1 (dose level-1) = grade 3 liver toxicity. MTD was tem 75/m2 QD (D1-7,15-21) + pazo 400 QD. 7 (39%) pts had grade 3-4 AE, most common being neutropenia (15%), thrombocytopenia (11%), liver toxicity (11%), and diarrhea (9%). Best ORR by RECIST:7 (39%) PR, 8 (44%) SD, 2 (11%) PD. Median PFS = 9.7 mo, 1 year OS rate = 94%. Conclusions: Pazo+tem combination at MTD dose is well tolerated, and has promising clinical activity in advanced PNET. PK cohort at MTD dose is ongoing. A single arm phase II trial is planned. This study was approved and funded by the National Comprehensive Cancer Network (NCCN) Oncology Research Program from general research support provided by Novartis Pharmaceuticals Corporation (formerly GlaxoSmithKline, LLC). Clinical trial information: NCT01465659.
Safety data from a phase II randomized trial of radium-223 dichloride (Ra-223) plus enzalutamide (Enza) vs. Enza alone in men with metastatic castration refractory prostate cancer (mCRPC).
Authors: Benjamin Louis Maughan, John M. Hoffman, Kathryn Morton, Bhasker Koppula, Julia Anne Batten, Jared Thorley, Josiah Hawks, Kenneth Boucher, Neeraj Agarwal
Journal: Journal of Clinical Oncology (2018)

5057 Background: Ra-233, a bone targeting alpha radiopharmaceutical, and Enza, are approved for mCRPC. Per SWOG0421, the subset of men with mCRPC with the highest bone metabolism marker levels had improved survival with concomitant decrease in these markers on treatment (Rx) with atrasentan, a bone targeting agent (Lara P et al, JNCI, 2014). Our hypothesis was that Rx with Ra-223+ Enza will be safe and feasible, and decrease bone metabolism markers compared to Enza alone. Methods: In this phase 2 trial (NCT02199197), men with progressive CRPC on continuous androgen deprivation therapy were included. Ra-223 was administered at standard dose of 55 kBq/kg IV Q4 weeks x 6, and Enza at 160 mg orally daily until disease progression or unacceptable toxicities. Primary objectives: 1) Safety and feasibility of combining Ra-223+Enza, 2) changes in the bone metabolism markers with Rx. Secondary objectives included time to progression, skeletal events, percent change in opioid use. The pre-specified primary safety endpoint was the proportion of patients treated with the combination who experienced grade 3+ cytopenias relative to historic controls (21%) from the phase 3 ALSYMPCA trial using an exact binomial test with a one-sided 0.05 significance level. All adverse events between arms were compared using Fisher’s Exact Test. Results: Safety data are presented. 49 patients were accrued between 2014-2017. 35 men received Rx with Ra-223+Enza and 14 men with Enza alone. The primary safety endpoint occurred in 3 patients in the combination arm (incidence 8.6%, n = 35 patients), and in 0 patients in the Enza only arm (n=14). These were similar to historic data (ALSYMPCA trial) of monotherapy with Ra-223 (P = 1.00), and not different between arms (P=0.55). Serious adverse events (SAEs), “regardless” of attribution were similar in both arms (P=0.66). Conclusions: Combining Ra-223+Enza is safe and feasible in men with progressive mCRPC with no difference observed in SAEs regardless of attribution between two arms. Specifically, there was no incidence of skeletal related events in either arm. Safety data will be elaborated during the meeting. Clinical trial information: NCT02199197.
Altered vascular remodeling in the mouse hind limb ischemia model in Factor VII activating protease (FSAP) deficiency
Authors: J. Herold, C. Deffge, S. Nowak, M. Wagner, R. C. Braun-Dullaeus, Sawa Kostin, J. M. Daniel, A. Francke, S. Subramaniam, S. M. Kanse
Journal: Cardiovascular Research (2016)
Discovery and Therapeutic Exploitation of Mechanisms of Resistance to MET Inhibitors in Glioblastoma
Authors: Nichola Cruickshanks, Ying Zhang, Sarah Hine, Myron Gibert, Fang Yuan, Madison Oxford, Cassandra Grello, Mary Pahuski, Collin Dube, Fadila Guessous, Baomin Wang, Ciana Deveau, Karim Saoud, Isela Gallagher, Julia Wulfkuhle, David Schiff, See Phan, Emanuel Petricoin, Roger Abounader
Journal: Clinical Cancer Research (2018)

Glioblastoma (GBM) is the most common and most lethal primary malignant brain tumor. The receptor tyrosine kinase MET is frequently upregulated or overactivated in GBM. Although clinically applicable MET inhibitors have been developed, resistance to single modality anti-MET drugs frequently occurs, rendering these agents ineffective. We aimed to determine the mechanisms of MET inhibitor resistance in GBM and use the acquired information to develop novel therapeutic approaches to overcome resistance.Experimental Design: We investigated two clinically applicable MET inhibitors: crizotinib, an ATP-competitive small molecule inhibitor of MET, and onartuzumab, a monovalent monoclonal antibody that binds to the extracellular domain of the MET receptor. We developed new MET inhibitor-resistant cells lines and animal models and used reverse phase protein arrays (RPPA) and functional assays to uncover the compensatory pathways in MET inhibitor-resistant GBM.We identified critical proteins that were altered in MET inhibitor-resistant GBM including mTOR, FGFR1, EGFR, STAT3, and COX-2. Simultaneous inhibition of MET and one of these upregulated proteins led to increased cell death and inhibition of cell proliferation in resistant cells compared with either agent alone. In addition, in vivo treatment of mice bearing MET-resistant orthotopic xenografts with COX-2 or FGFR pharmacological inhibitors in combination with MET inhibitor restored sensitivity to MET inhibition and significantly inhibited tumor growth.These data uncover the molecular basis of adaptive resistance to MET inhibitors and identify new FDA-approved multidrug therapeutic combinations that can overcome resistance.
Intensive multi-modality therapy for extra-ocular retinoblastoma (RB): A Children's Oncology Group (COG) trial (ARET0321).
Authors: Ira J. Dunkel, Mark D. Krailo, Guillermo L. Chantada, Anuradha Banerjee, Sherif Abouelnaga, Jeffrey Buchsbaum, Thomas E. Merchant, Meaghan Granger, Rima Fuad Jubran, Michael Kellick, Joanna Weinstein, David H. Abramson, Carlos Rodriguez-Galindo, Murali M. Chintagumpala
Journal: Journal of Clinical Oncology (2017)

10506 Background: Metastatic RB is associated with a poor prognosis. Previous small series suggested that intensified systemic chemotherapy with or without radiation therapy (RT) may improve outcomes in this population. COG opened this prospective, multi-institutional, international trial to study the effectiveness of this approach. Methods: Patients with regional extra-ocular RB (stage 2 or 3) were treated with 4 cycles of intensive conventional chemotherapy (vincristine 0.05 mg/kg/day, cisplatin 3.5 mg/kg/day, cyclophosphamide 65 mg/kg x 2 days, etoposide 4 mg/kg x 2 days) followed by involved-field RT (4500 cGy). Two strata of patients with metastatic RB [stage 4a: distant metastases not involving the central nervous system involvement (CNS); and stage 4b (CNS metastases)/trilateral RB)] were treated with 4 cycles of the same chemotherapy. Patients with ≥ partial response then received 1 cycle of high-dose carboplatin (Calvert formula with AUC = 7/day, maximum 16.7 mg/kg/day) on days -8 to -6, thiotepa (10 mg/kg/day), &amp; etoposide (8.3 mg/kg/day) on days -5 to -3 with autologous hematopoietic stem cell rescue on day 0. Patients with metastatic RB who did not achieve an adequate response to chemotherapy also received RT. Results: Sixty subjects (20 in each stratum) were enrolled; 57 were eligible and included in the analyses (based on data current to June 30, 2016). Toxicity was significant as expected and there were 2 therapy related deaths. Event-free survival (EFS) at 36 months was 87.7% (90% CI 65.4 to 96.0%) for subjects with stage 2 or 3 disease, 79.3% (90% CI 54.2 to 91.6%) for subjects with stage 4a disease and 8.0% (90% CI 1.0 to 25.1%) for subjects with stage 4b/trilateral disease. The observed results significantly improved the EFS in each stratum compared with historical results used for planning the study. Conclusions: This is the first prospective, multi-institutional, international study to show that intensive multi-modality therapy is highly effective for patients with regional extra-ocular RB and metastatic RB not involving the CNS. More effective therapy is required for patients with CNS RB. Clinical trial information: NCT00554788.
The appropriateness of flow cytometry testing: A single institution retrospective analysis.
Authors: Danny Landau, Talia Zahra, Annette Sturtz, Amy Rich
Journal: Journal of Clinical Oncology (2016)

e18149 Background: Flow cytometry is tool used for analysis of abnormal cells. Such testing assists in establishing a diagnosis or to identify residual disease. Flow cytometry can be expensive and requires effort on the part of pathologist. A poor understanding of the use of flow cytometry leads to over ordering and increasing healthcare costs. We opted to look at the results of flow cytometry ordering on peripheral blood samples to determine the appropriateness. Methods: Flow cytometry results on peripheral blood samples were collected over a six month time period. We opted to focus on peripheral blood testing as this could be ordered by multiple providers. Results were broken into: - Ordering physician; hematologist or non-hematologist - Normal or abnormal results - Diagnoses: - Leukemia - Lymphoma - Abnormal complete blood count (CBC) (includes neutropenia or anemia) - Not otherwise explained elsewhere - Chronic lymphocytic leukemia (CLL) - Paroxysmal nocturnal hemoglobinuria (PNH) - Other Results: Hematology physicians ordered 71 out of 127 evaluated cases. Results proved abnormal in 38 cases (53%). Associated diagnoses were as follows: - Leukemia: 25/71: 35% - Lymphoma: 16/71: 22% - CLL : 11/71: 15% - PNH: 9/71: 13% - Abnormal CBC: 6/71: 8% - Other: 4/71: 6% Non hematology physicians ordered flow cytometry 58 out of 127 evaluated cases. The results were abnormal in 25 cases (45%). Associated diagnoses were as follows: - Leukemia: 17/58: 29% - Lymphoma 7/58: 12% - CLL: 2/58: 3% - PNH: 12/58: 21% - Abnormal CBC: 12/58: 21% - Other: 6/58: 10% Flow cytometry ordered due to abnormal CBCs, showed no abnormal findings. Testing for PNH resulted in only one abnormal result (1/21). Review of ordered flow cytometry showed rational for all ordered tests. Conclusions: When ordered by a hematology physician, flow cytometry on peripheral blood samples were more likely to be associated with abnormalities. Flow cytometry testing for abnormal CBCs were more commonly ordered by non-hematology physicians and showed no abnormalities. PNH testing was often done with reason, although this is a known low yield test. A better understanding of the appropriateness for flow cytometry will be essential to reduce frequency of inappropriate ordering.
PerTe: Pertuzumab for the neoadjuvant treatment of HER2-positive breast cancer patients—Efficacy and safety of pertuzumab in “real life" setting.
Authors: Daniela Cianniello, Antonella Prudente, Roberta Caputo, Michela Piezzo, Maria Riemma, Beatrice Savastano, Stefania Cocco, Ivana Cerillo, Rossella Lauria, Mario Giuliano, Cinzia Cardalesi, Giuseppe Buono, Grazia Arpino, Giovanni Iodice, Francesca Di Rella, Carmen Pacilio, Salvatore Del Prete, Sabino De Placido, Michelino De Laurentiis
Journal: Journal of Clinical Oncology (2018)

e12654 Background: Standard preoperative systemic therapy for HER2+ breast cancer (BC) patients (pts) includes chemotherapy (CT) and Trastuzumab (T). Two randomized phase II trials, NeoSphere and TRYPHAENA, showed that the addition of Pertuzumab (P) to a T–based neoadjuvant therapy improves the pathologic complete response (pCR) rate, with no evidence that P increased the rate of cardiac dysfunction. Based on these two trials, on June 2015, European Medicine Agency (EMA) approved dual HER2 blockade with T+P for the neoadjuvant treatment of HER2+ BC. PerTe is an observational study, aimed to evaluate the efficacy and safety of P+T as neoadjuvant treatment of HER2+ BC in a real practice setting. Methods: 65 pts treated with P+T+CT as neoadjuvant therapy were identified by 3 Italian Institutions since July 2015. Based on clinical practice of belonging institution, pts were treated with 3 different CT regimens: 1) ECx4 followed by P+T+weekly paclitaxel for 12, 2) ECx4 followed by P+T+docetaxel for 4 cycles and 3) P+T+docetaxel for 6 cycles. The primary objective is to evaluate the pCR rate, defined as the absence of any residual invasive cancer on hematoxylin and eosin evaluation of the resected breast specimen and all sampled ipsilateral lymph nodes. The secondary objective is to evaluate the safety profile of dual HER2 blockade. Results: To date, 48 pts completed the study treatment and underwent surgery, 2 experienced disease progression at the end of neoadjuvant treatment, while 16 pts are still on treatment. Of all evaluable pts, 28 (56%) had a HER2+, Luminal B, ductal infiltrating carcinoma (DCI) and 22 (44%) had a HER2+, Hormone Receptor-negative (HR-) DCI. pCR was achieved in 36 (72%) pts, 12 pts (24%) had residual disease at histologic examination. The highest pCR rate was observed in pts with high level of ki-67 and HR- (86%). No difference was observed among treatment regimens. No significant cardiac toxicity was detected. Conclusions: Neoadjuvant treatment with P+T+CT in a real practice setting is highly effective and does not raise cardiac safety concerns, regardless of the chemotherapy regimen used. We are going to involve more institutions in order to collect a larger sample.
Identifying the prognostic significance of genomic alterations in a real-world, EHR-derived clinico-genomic database (CGDB).
Authors: Vineeta Agarwala, Daniel Backenroth, Gaurav Singal, Claire O'Connell, Gerald Li, Garrett Alpha Cobb, Gaurav Kaushik, Kenneth Robert Carson, Vincent A. Miller, Amy Pickar Abernethy
Journal: Journal of Clinical Oncology (2018)

e24319 Background: A central goal of precision oncology is to relate genomic alterations in a patient’s tumor to prognosis and therapy response. Today, variant interpretation is based on functional studies in model systems, retrospective case series, and prospective clinical trials. As more patients undergo tumor sequencing to guide care, ongoing real-world clinical annotation at scale using the electronic health record (EHR) presents an opportunity to identify new clinico-genomic associations. Methods: We retrospectively studied non-small cell lung cancer (NSCLC) patients treated in the Flatiron Health network ( > 265 US practices) from Jan 2011 to Dec 2016, who underwent FoundationOne tumor sequencing as part of routine care. Clinical data from EHRs (dates of diagnosis, death) were linked in a HIPAA-compliant manner with genomic findings (short variants, deletions, and amplifications across 395 genes). We calculated per-gene hazard ratios (HRs) using a Cox model to compare overall survival (OS) from advanced diagnosis in patients with and without alterations in each gene. Covariates included age, gender, smoking status, and histology. P-values were adjusted for multiple comparisons using false discovery rate (FDR) control. Results: The cohort included 1404 patients with NSCLC whose tumor samples were collected < 90 days after advanced diagnosis. When restricting to variants predicted to be functional, EGFR alterations were associated with lower mortality (HR = 0.7; 95% CI 0.5 - 0.8, adj-p = 0.03); this was expected given available targeted therapy. Variants in KEAP1 (HR = 2.0; CI 1.5 - 2.6, adj-p = 0.0004), SMARCA4 (HR = 1.7; CI 1.3 - 2.3, adj-p = 0.01), CTNNA1 (HR = 16; CI 3.8 - 63.8, adj-p = 0.01) and CREBBP (HR = 3.0; CI 1.6 - 5.6, adj-p = 0.03) were associated with higher mortality. In KEAP1, variants of unknown significance (VUS) were also associated with lower OS (HR = 1.6, CI 1.3-2.0, adj-p = 0.007). Conclusions: A continuously growing linked CGDB can reveal prognostic biomarkers for OS, and provide evidence to inform VUS annotation. Future work is needed to account for co-mutation patterns, divergent variant effects in the same gene, and unmeasured factors influencing treatment and outcome.