tbuckley/cabot-search huggingface dataset:
Evaluation of safety, efficacy, and other clinical endpoints of delta-9-tetrahydrocannabinol in older patients with hem/onc malignancies.
Authors: Damien Mikael Hansra
Journal: Journal of Clinical Oncology (2017)

e21671 Background: Dronabinol, synthetic delta-9-tetrahydrocannabinol (Δ-9-thc), is the active compound &amp; natural occuring component of Cannabis Sativa L(Marijuana). Dronabinol is used as an appetite stimulant &amp; treatment of chemo induced nausea/vomiting in cancer patients (pts). Here we evaluate the efficacy, safety, &amp; other clinical endpoints in older cancer pts. Methods: Survey study administered to cancer pts prescribed Dronabinol w/ 7 questions (yes/no/n/a): Did Dronabinol increase appetitie? decrease nausea/vomiting? improve mood? decrease insomnia? decrease anxiety? have any side effects? improve quality of life (QOL)? Also pts were asked if they preferred sythetic meds vs natural plant based meds (oil, capsule, liquid, etc). Inclusion: age &gt; 60, hem/onc malignancy, prescribed Dronabinol. Exclusion: death, altered mental status, not taking Dronabinol, off label use. Unpaired t-test w/ two sided P value used to compare differences. Results: N = 28 pts enrolled, 12 pts excluded, 16 pts meeting study criteria. Mean age 70 (range 61-78). 100% white pts w/ 94% Latin 6% non-Latin. 50% male 50% female. 81% Onc vs 19% Heme malignancy. Dose given: 2.5 mg QD (25%), 2.5 mg BID (62.5%), 5mg BID (12.5%). Significant improvements in appetite (87.5% vs 12.5% p = &lt; 0.0001), anxiety (75% vs 25% p = 0.0128), QOL (81.3% vs 18.7% p = 0.0001) observed. No side effects seen in 87.5 % vs 12.5% (dizziness) p = &lt; 0.0001 of pts. 100% vs 0%, p = &lt; 0.0001 of pts preferred natural plant based meds vs synthetics. Non significant improvements in mood (61.5% vs 38.5% p = 0.2567), insomnia (61.5% vs 38.5% p = 0.2567), nausea/vomiting (71.4% vs 28.6% p = 0.1263) observed. Conclusions: This unique study shows Dronabinol significantly improved appetite, anxiety, &amp; QOL in older cancer pts w/ most pts having no side effects. Also non significant improvements in mood, nausea/vomiting, insomnia observed. 100% of pts preferred natural plant based meds vs. synthetics. Further investigations examining the clinical benefits &amp; safety of Dronabinol &amp; Cannabis Sativa L are warranted in older cancer patients.
Pre-cancer cardiovascular risk factors and anthracycline-related cardiotoxicity among non-Hodgkin lymphoma survivors.
Authors: Talya Salz, Peter Brown, Emily Craig Zabor, Susanne Oksbjerg Dalton, Nirupa Jaya Raghunathan, Matthew J. Matasar, Richard Steingart, Andrew J. Vickers, Kevin C. Oeffinger, Christoffer Johansen
Journal: Journal of Clinical Oncology (2016)

e19031 Background: Anthracycline-based therapy is associated with an increased risk of late-onset heart failure (HF). We investigated whether this association is potentiated by pre-existing cardiovascular (CV) risk factors. Methods: Using Danish nationwide population-based registries, we identified all adults diagnosed with primary aggressive non-Hodgkin lymphoma from 2000-2010 who were alive 9 months after diagnosis, using the lymphoma registry. Outcomes were followed through 2012. The patient registry contains ICD codes for all specialist visits; we used ICD codes to assess HF diagnosed at hospitalization or death, at least 9 months after diagnosis. Pre-cancer CV risk factors (hypertension, dyslipidemia, and diabetes) were identified algorithmically using prescription data, specialist visit ICD codes, and the diabetes registry; they were coded as 0, 1, or ≥ 2 risk factors. Anthracycline dose was coded continuously. Controlling for age, sex, and pre-existing CV disease (ischemic heart disease, cerebrovascular accident, and cardiomyopathy, identified from the patient registry), we used Cox multivariate regression to test the interaction between CV risk factors and anthracyclines on subsequent HF. Results: Among 2649 patients with NHL, the median follow-up time was 3.2 years. During this time, 115 were diagnosed with HF. Before lymphoma diagnosis, 31% of the entire cohort had at least 1 CV risk factor and 11% had ≥ 2; 93% of patients were treated with anthracyclines. Anthracycline dose was associated with increased HF risk (HR = 1.3 [95% CI = 1.1-1.5]). Those with more CV risk factors had an increased risk of HF compared to those without CV risk factors (HR for 1 risk factor = 1.7 [95% CI = 1.1-2.6], HR for ≥ 2 risk factors = 2.7 [95% CI = 1.5-4.6], overall p < 0.01). No significant interaction was found between the number of CV risk factors and anthracycline dose on HF (p = 0.4). Conclusions: In a large, well-characterized cohort of lymphoma survivors with minimal loss to follow-up, anthracyclines and CV risk factors were independently associated with later HF. Notably, underlying CV risk factors did not appear to heighten the cardiotoxic effect of anthracyclines.
First-in-child trial of celyvir (autologous mesenchymal stem cells carrying the oncolytic virus ICOVIR-5) in patients with relapsed and refractory pediatric solid tumors.
Authors: Manuel Ramirez, David Ruano, Lucas Moreno, Álvaro Lassaletta, Francisco José Bautista Sirvent, Maitane Andión, Carmen Hernández, África González-Murillo, Gustavo Melen, Ramón Alemany, Javier García-Castro, Luis Madero
Journal: Journal of Clinical Oncology (2018)

10543 Background: Outcome for relapsed/refractory pediatric solid tumors is dismal so there is an urgent need for new therapies. Immunotherapy with oncolytic viruses show great promise in adult cancers but have scarcely been explored in children. The results of a first-in-man, first-in-child trial (NCT01844661) using Celyvir, autologous mesenchymal stem cells (MSC) carrying an oncolytic adenovirus are presented. Methods: Patients (1-18 yrs) with advanced relapsed/refractory solid tumors, adequate organ function and performance status were included. Autologous MSCs were collected from a bone marrow aspirate (BMA). Celyvir was manufactured within 6 weeks from BMA and then given IV weekly for 6 weeks at doses from 2x106 cells/Kg and 2x104 viral particles (vp) per cell. Dose was based in a previous compassionate use program (Melen et al. 2016;371:161). Primary objective was to determine safety and toxicity. Secondary objective was preliminary antitumor activity. Biomarker studies included oncolytic viral replication and immune response. Results: Fifteen patients had BMA performed, 6 progressed before treatment could be started, 9 received Celyvir and completed the planned 6 weeks treatment and were evaluable. The total number of cells administered ranged from 89 to 468 million, 1,78 – 8,36x1012 vp. Celyvir was well tolerated showing no grade 3/4 toxicities. Most frequent adverse event was pyrexia (37,5% patients). Adenoviral replication detected by PCR was found in all but two patients and humoral antiadenoviral response was detected in all but one patient. Circulating T lymphocytes numbers raised with Celyvir administration, mostly CD8 effector cells. No radiological responses were seen. Two patients with neuroblastoma showed disease stabilization per RECIST, one of them continued on treatment for up to 6 additional weeks. Conclusions: Celyvir, the combination of MSCs and oncolytic adenovirus is safe and warrants further evaluation in the pediatric phase 2 setting. The use of MSCs may be a strategy to increase the amount of oncolytic virus administered to patients, minimizing toxicities and avoiding direct tumor injections. Clinical trial information: NCT01844661.
A cloud-based virtual tumor board to facilitate treatment recommendations for patients with advanced cancers.
Authors: Subha Madhavan, Edik Matthew Blais, R Joseph Bender, Vincent M. Chung, Andrew Eugene Hendifar, Sameh Mikhail, Maeve Aine Lowery, Davendra Sohal, Paula Raffin Pohlmann, Kathleen N. Moore, Kai He, Bradley J. Monk, Robert L. Coleman, Thomas J. Herzog, Emanuel Petricoin, David Charles Halverson, Michael J. Pishvaian
Journal: Journal of Clinical Oncology (2018)

6508 Background: A deficiency in current approaches in Precision Oncology is the sole focus on gene mutations while overlooking the patient context, including medical and treatment history, as well as other multi-omic data, such as proteomics, germline, and phosphoprotein assays. Optimally every patient facing a molecular treatment decision will benefit from an expert tumor board, but it is impossible to convene this for every patient. Methods: We developed a cloud-based, asynchronous virtual tumor board (VTB) that integrates multi-modal patient data to formulate, discuss, and rank treatments. The VTB utilizes 8 linked databases, a treatment scoring model based on the AMP/ASCO variant interpretation guidelines and an AI-based treatment recommender. Molecular and clinical data including past medical history, molecular and pathology reports were aggregated from 1342 cases from > 300 community and academic hospitals. A preliminary list of therapy options and trials were prepared by the VTB which integrates variant annotations, biomarker implications, trial eligibility criteria, outcomes, and literature. Medical and scientific experts reviewed each case, discussed through an asynchronous chat room, modified, and ranked treatment options delivered as a report to the treating oncologist. Results: Automation through VTB, increased the volume of cases reviewed per month by twofold. The VTB also led to a larger set of options compared to a lab report alone. Across 642 patients, the VTB enabled genomic-based therapy options in 503 (78.6%) patients. Additionally, proteomic data strengthened on-label treatment recommendations in 229 (36%), and off-label treatment recommendations in 80 (12%) patients. Importantly, by considering patients’ previous treatment histories, the VTB omitted treatment options in 64% of patients to which patients had developed resistance. Conclusions: The VTB provides a scalable platform for integration and asynchronous team communication for facilitating case review with no geographical and time/attendance restrictions. We anticipate that further development of such decision support tools will be important for widespread adoption of cancer precision medicine.
TRIB3: A new transcriptional target gene of rapalogs, modulating their effects on splicing
Authors: B. Stefanovska, C. Vicier, V. Scott, I. Bouakka, A. Rocca, F. André, O. Fromigué
Journal: Annals of Oncology (2018)

Background: The mTOR pathway has a key role in regulating cell growth and is altered in 70% of cancers. Rapalogs have become standard of care in patients with metastatic breast, kidney and neuroendocrine cancers. Nevertheless, tumor escape occurs after several months in most patients, highlighting the need to understand the mechanisms of action and resistance. Thus, we aim to identify new target genes of rapalogs that could be used as biomarkers to predict the treatment efficacy, or as therapeutic targets, to overcome resistance. Methods: Expression levels of target genes were evaluated in a panel of cancer cell lines by transcriptomic analyses, real-time qPCR and western blot. Transcriptional regulation was investigated by in silico analyses of the promoter region, gene reporter assays using site-directed mutagenesis, and ChIP. Stably modified cell lines were established by lentiviral transduction. The analysis of the putative interacting partners was performed by LC-MS/MS followed by functional classification using the bioinformatics tool DAVID. The interactions between proteins were investigated by co-IP. Splicing efficiency was assessed by double-gene reporter assay. Results: Using a panel of eight cancer cell lines, we showed that rapamycin down-regulates only one gene, named TRIB3, in common in all cell lines. These data were confirmed in vivo in patients treated with rapalogs for cancer. Transcriptional repression of TRIB3 by rapalogs was mediated by the interaction of FKBP3/LRRFIP1 with the promoter, suggesting an inhibitory effect of rapalogs independent of mTOR targeting. Furthermore, we identified TRIB3 as a component of the splicing machinery necessary for pre-mRNA splicing disturbance by rapalogs. In addition, we observed that, the overexpression of TRIB3, abolished the inhibitory effects of rapalogs on cancer cell viability. Conclusions: These results identify TRIB3 as a new transcriptional target gene of rapalogs, and evidence it as a key component of spliceosome machinery. Thus, TRIB3 may be considered as a suitable biomarker to assess the efficacy of rapalogs treatment. Moreover, TRIB3 could also be suitable as a therapeutic target to synergize with rapalogs treatment. Legal entity responsible for the study: Gustave Roussy. Funding: INSERM, Gustave Roussy (taxe d'apprentissage), Opération Parrains Chercheurs, Odyssea, Dassault Foundation, Breast Cancer Research Foundation, and La Ligue contre le Cancer (Rhone-69, and Allier-03). Disclosure: F. André: Research grant from Novartis. All other authors have declared no conflicts of interest.
IMRT-induced acute hepatic toxicity and analysis of the dose-volume effects in gastric cancer patients treated with postoperative radiation.
Authors: Yu Jing, Fuxiang Zhou, Yang Wen-juan, Dai Jing, Xia Ling, Wang Wen-bo
Journal: Journal of Clinical Oncology (2017)

e15542 Background: To investigate the postoperative-IMRT-induced hepatic toxicity in gastric cancer, and analyze the correlations between liver dose-volumetric parameters and acute hepatic toxicity, so as to give a dose-limitation suggestion for postoperative-IMRT in gastric cancer patients. Methods: Between June 2013 and June 2016, 67 patients with gastric cancer treated with post-operative adjuvant IMRT were reviewed. Prescribed dose was from 45Gy to 54Gy, in a daily fraction of 1.8–2.0 Gy. Dose constraints included: liver V30 &lt; 40%, liver V40 &lt; 30%, a mean dose of two kidneys &lt; 18Gy and one kidney V6 &lt; 50% if a mean dose of another kidney is more than 18Gy or another kidney has been resected. The following clinical and dose-volumetric parameters were examined: age, gender, concurrent chemotherapy, chemotherapy cycles before IMRT, chemotherapy cycles after IMRT, total chemotherapy cycles, Dmean (mean dose to liver), V5, V10, V15, V20, V25, V30, V35, and V40. Acute hepatic toxicity was evaluated between 1 and 4 months after radiation, according to the Common Terminology Criteria for Adverse Events(CTCAE), version 3.0. Results: 46 patients developed grade 1 hepatic toxicity, and 8 patients developed grade 2 hepatic toxicity after radiation, while there was no grade 3 or more severe hepatic toxicity. On univariate analysis, chemotherapy cycles after radiation, total chemotherapy cycles, Dmean, V20, V25, V30, V35 and V40 show correlations with Grade 2 acute hepatic toxicity (p = 0.009, 0.004, 0.015, 0.040, 0.005, 0.001, 0.001, 0.001, respectively). On multivariate analyses, V40 was the only significant parameter correlated with the risk of Grade 2 acute hepatic toxicity (P = 0.002). Using ROC curves, we find that to avoid grade 2 acute hepatic injury, the dose-volumetric limitations would be: Dmean of 22.4Gy, V20 of 42.3%, V25 of 38%, V30 of 27%, V35 of 17%, and V40 of 13%. Conclusions: IMRT is safe for gastric cancer treated with postoperative-radiotherapy as to liver. The grade 2 acute hepatic toxicity could be avoided by restricting dose-volumetric parameters of liver.
Targeted genomic profiling of blood from patients with NSCLC after classification with a poor prognosis.
Authors: Hestia S. Mellert, Leisa Jackson, Kristina Koch, Westen Hahn, Gary Anthony Pestano
Journal: Journal of Clinical Oncology (2016)

e23051 Background: Proteomic signatures have clinical utility, with one example, VeriStrat (VS), measuring acute phase reactant proteins in blood. Patients with EGFRwt tumors and a POOR (VS-P) prognostic classification have worse clinical outcomes relative to those with a GOOD (VS-G) status. A VS-P prognostic result limits standard of care therapeutic options, thus clinical trials may be a good option. A global Phase II study, FOCAL is being conducted that examines the addition of ficlatuzumab to erlotinib for first line EGFR sensitizing mutation positive, VS-P patients. In contrast, treatment options for patients with NSCLC and EGFR wildtype, VS-P status are limited. From this latter group we profiled cell-free DNA (cfDNA) with a targeted NGS panel to identify actionable somatic variant mutations. Methods: Plasma samples previously determined to be EGFRwt by ddPCR and VS-P by MALDI-ToF were analyzed by NGS with a targeted 15-gene panel. Screening of cfDNA isolated from the plasma of 11 VS-P patients with advanced stages of NSCLC are presented. Results: As expected, EGFR sensitizing variants were detected only in the positive control but not among any of the EGFRwt pre-screened VS-P cohort. Six of the 11 plasma samples contained TP53 mutations, which included missense, splice-site and frame-shifts. Although targeted therapies for p53 are not currently approved by the FDA, several pre-clinical and clinical trials are underway with either compounds such as the p53 re-activating agent APR-246 (a PRIMA-1 analogue), or with wild-type p53 gene-therapy such as SGT-53. Conclusions: Targeted profiling using NGS on cfDNA from plasma can identify actionable mutations in patient samples with a poor prognosis as determined by the VS-P status. This is the first study to profile EGFRwt/VS-P patient samples. It is likely that other targets associated with current therapy may be uncovered with additional profiling. Additional profiling of EGFRwt/VS-P patients with a 35-gene NGS panel that measures additional somatic variants, indels and amplifications is warranted. We expect that these studies will yield targets that could provide options for patients with NSCLC and a poor prognosis.
Increasing the duration and efficacy of intravenous chemotherapy using a patient-centered digital education program: Navigating Cancer’s program for patients receiving pemetrexed for lung cancer.
Authors: Scott C. Howard, Timothy Joseph Yeatman, Mark Layton Watson, Catherine Lam
Journal: Journal of Clinical Oncology (2017)

e18025 Background: Adherence to therapy improves survival in cancer patients. Patient education interventions have effectively improved adherence to oral drugs, but have not been studied for intravenous drugs. Methods: We assessed impact of a pemetrexed educational program for lung cancer patients from 58 oncology practices delivered from 2014-2016 via the Navigating Cancer (www.navigatingcancer.com) patient portal. After online registration, the program provided sequential messages about pemetrexed therapy and management of side effects. Access to each component of the education program was tracked and de-identified data provided to the study team for analysis. Results: Of 944 patients, 441 (47%) accessed pemetrexed-specific educational materials, and were more likely to be Caucasian (p=0.01) and to have never smoked (p=0.05). Patients who accessed educational materials received a mean of 286 days of pemetrexed versus 236 days (p&lt;0.01); their one-year survival was 66% (SE 2.8%) versus 53% (SE 2.9%) (p&lt;0.01). In multivariable analysis, survival was predicted by accessing education (p&lt;0.01), but not race or smoking status (p&gt;0.1). Conclusions: Drug-specific patient education delivered via a patient portal and email reached 47% of registered patients and was associated increased duration of therapy and improved survival. [Table: see text]
TCT-869 Two years outcomes in elderly patients planned for one-month DAPT after PCI: subanalysis of the SENIOR trial
Authors: Olivier Varenne, Stephane Cook, Georgios Sideris, Sasko Kedev, Didier Carrie, Thomas Hovasse, Philippe Garot, Christian Spaulding, Gerard Helft, Salvatore Brugaletta, Eduardo Pinar Bermudez, Josepa Mauri, Philippe Commeau, Emmanuel Teiger, Kris Bogaerts, Manel Sabate, Marie-Claude Morice, Peter Sinnaeve
Journal: Journal of the American College of Cardiology (2018)
Phase II study of bipolar androgen therapy (BAT) in men with metastatic castration-resistant prostate cancer (mCRPC) and progression on enzalutamide (enza).
Authors: Benjamin A. Teply, Hao Wang, Rana Sullivan, Irina Rifkind, Ashley Bruns, Morgan Decarli, Victoria J. Sinibaldi, Caroline F. Pratz, Jun Luo, Michael Anthony Carducci, Channing Judith Paller, Emmanuel S. Antonarakis, Mario A. Eisenberger, Samuel R. Denmeade
Journal: Journal of Clinical Oncology (2017)

5017 Background: Androgen receptor (AR) overexpression is a common adaptive resistance mechanism in mCRPC. High dose testosterone in this setting may induce tumor responses and restore normal AR expression. To evaluate BAT, we enrolled men with mCRPC progressing on enza to assess (1) responses to BAT and (2) enza re-challenge after BAT. Methods: Eligible men had minimally symptomatic mCRPC with progression on enza. Subjects received testosterone cypionate 400mg IM every 28d and continued gonadal suppression, until progression. Subjects were evaluated with PSAs each cycle, and CT/bone scans every 3 cycles. Upon progression on BAT, men were re-challenged with enza. The co-primary endpoints were &gt; 50% PSA responses (PSA 50 ) to BAT and PSA 50 to enza re-challenge. The null hypothesis was a PSA 50 rate of 5% for both endpoints, with alternative hypotheses of 20% to BAT and 25% to enza. 30 subjects were required for 90% and 83% power, respectively, with overall type 1 error of 0.1. Secondary endpoints were safety, objective response, progression-free survival (PFS), and effect on circulating tumor cell-based AR and AR-V7 expression. Results: 30 eligible subjects were accrued (2014-2016). No dose limiting toxicities were seen. 2 subjects had transient pain flares after BAT initiation. Common grade 1-2 adverse events (AE) were musculoskeletal pain (40%), increased hemoglobin (37%), breast tenderness (17%) and rash (17%). 3 Grade 3-4 AE potentially attributable to BAT occurred (pulmonary embolism, NSTEMI, and urinary obstruction). 9/30 men (30% [95% CI: 17-48%]) achieved a PSA 50 to BAT. 5/14 men (36%) with measurable disease had an objective response by RECIST 1.1. The median clinical/radiographic PFS on BAT was 8.6 months. 21 subjects proceeded to enza re-challenge, yielding 15 PSA 50 responses (54% by intention to treat [95% CI: 34-69%]), with a PFS of 4.8 months. 1/3 AR-V7+ subjects responded to BAT, and all had decreased AR-V7/AR ratios (2 converted to AR-V7-) after 3 cycles. Conclusions: The study met its primary endpoints, demonstrating preliminary efficacy of BAT in men with progressive mCRPC after enza. A randomized study comparing BAT to enza in mCRPC is ongoing. Clinical trial information: NCT02090114.