tbuckley/cabot-search huggingface dataset:
Real-time clinical application of next-generation sequencing (NGS): Results from a multicenter program.
Authors: Aaron Richard Hansen, Andrew M. K. Brown, Philippe L. Bedard, Sebastien J. Hotte, Eric Winquist, Glenwood D. Goss, Dimitrios Vergidis, Hal W. Hirte, Stephen Welch, Tong Zhang, Lincoln D. Stein, Vincent Ferretti, Stuart Watt, Wei Jiao, Karen Ng, Teresa Petrocelli, Lillian L. Siu, John D. McPherson, Suzanne Kamel-Reid, Janet Dancey
Journal: Journal of Clinical Oncology (2013)

11016 Background: NGS techniques enable the identification of actionable mutations in clinical tumor samples. The objective of this study is to assess feasibility and explore the impact of real-time targeted NGS on therapeutic decision-making. Methods: Patients (pts) with advanced solid tumors underwent a biopsy of a metastatic lesion. The first phase was performed with Sequenom MassARRAY somatic genotyping and Pacific Biosciences RS-targeted NGS. The second phase broadened genomic coverage in both Sequenom and Illumina MiSeq. All pts had a molecular profiling (mp) report issued after identified actionable mutations were verified by Sanger sequencing in a CLIA-lab and reviewed by an expert panel. “Actionability” was defined as having prognostic, predictive or diagnostic implications on patient management. Details of clinical outcomes and subsequent matched therapy, if applicable, were captured. Referring physicians were surveyed on the impact of mutation results on their treatment recommendations. Results: These are summarized in the Table. Conclusions: Broader mp platforms resulted in more identified actionable mutations which required a longer time for verification prior to reporting, but may yield a greater impact on clinical decision-making. However, the matching of pts to drugs based on their molecular profiles depends highly on drug access. For mp to be clinically relevant, it must be coupled with access to approved drugs or to investigational agents on clinical trials. Clinical trial information: NCT01345513. [Table: see text]
An integrative approach to personalized cancer survivorship care at an academic medical center.
Authors: Louis S. Constine, Nancy K. Termer, David Holub, Chunkit Fung, M. Jacob Adams, Sughosh Dhakal, Lauren B. Bruckner, Bethany Marsh, Sarah L. Kerns, Katia Noyes, AnnaLynn Williams, Susan Fritsch, Carol Lustig, Claire Lynch, Susan Nelson, Heather L. Menchel, Olle Jane Sahler, Michael T. Milano, Eva Galka, Michelle Shayne
Journal: Journal of Clinical Oncology (2017)

37 Background: Quality cancer survivorship care has multiple missions 1) develop personalized disease-specific treatment summaries (TS) and evidence-based survivorship plans (SPs), 2) foster recognition amongst Primary Care Providers (PCPs) of the consequences of cancer and its therapy, 3) coordinate care amongst providers, 4) use technology to foster communication and mining data, 5) train residents/fellows, 6) determine knowledge gaps for research, 7) engage community health providers, 8) publicize and raise funds, and 9) develop metrics to assess outcomes. Here we describe initial steps toward these goals. Methods: The University of Rochester Judy DiMarzo Cancer Survivorship program is a multidisciplinary effort across 7 centers involving oncologists, PCPs, social workers, integrated oncology, legal/financial services, and survivors. Survivors are identified at two critical time points: after (1) completion of primary curative therapy = transition visit, (2) discontinuation of routine oncologic follow-up and transition of care to their PCP = shared care visit. These visits are staffed within each cancer discipline. Trainees (15-20/year) probe existing evidence and draft TS/SP templates that are vetted by that cancer discipline. Patient needs are surveyed; institutional and community resources are identified. Results: In 3 years, 1037 patients had survivorship visits - 859 transition visits, 178 shared care visits. Cancers include breast (31%), head &amp; neck (17%), lymphoma (15%), GI (15%), GU (11%), GYN (7%), lung (3%), melanoma and sarcoma (1%) with continuing refinement of systematic patient identification. Visits by year were: 120 in 2013, 266 in 2014, and 470 in 2015. Amongst the 1037 patients, the 6 most common needs were exercise, emotional, return to work, nutrition, financial, and pain. Conclusions: Our program is systematically embracing challenges to deliver evidence-based, individualized TS/SPs for survivors, as well as train future oncology providers in survivorship care. Current areas of focus are better engaging PCPs, ensuring program sustainability, improving technology use to mine data, measuring outcomes, establishing rural outreach, and fostering survivorship research.
A phase I, first-in-human dose study of the dual PI3K/mTOR inhibitor LY3023414 (LY) in patients (pts) with advanced cancer.
Authors: Kathleen N. Moore, Anna M. Varghese, David Michael Hyman, Sophie Callies, Ji Lin, Volker Wacheck, Shubham Pant, Todd Michael Bauer, Johanna C. Bendell
Journal: Journal of Clinical Oncology (2015)

11075 Background: The phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway is dysregulated in many malignant diseases. LY3023414 (LY) is an oral ATP competitive inhibitor of the class I PI3K isoforms, mTOR and DNA-PK. Based on preclinical results, we investigated LY in patients with advanced solid tumors. Methods: In this 3+3 dose escalation phase I study, patients with solid tumors refractory to standard therapies received LY once daily (QD) or twice daily (BID). The primary objective was to determine a recommended phase II dose (RPTD). Additional objectives were to assess LY dosing safety, pharmacokinetic/pharmacodynamic (PK/PD) profiles, drug-drug interaction with midazolam, and to document anecdotal antitumor activity. Results: As of September 2014, 47 pts have received LY either QD (at 20, 40, 80, 150, 225, 325, 450 mg) or BID (at 150, 200, 250 mg). Dose-limiting toxicities (DLTs) have been observed for LY QD only at 450 mg and consisted of grade [G] 4 thrombocytopenia, G4 hypotension, G3 hyperkalemia in 3/3 patients treated. For BID dosing, DLTs were observed in 3/4 patients at 250 mg (G4 hypophosphatemia, G3 fatigue, G3 mucositis) and in 1/15 patients at 200 mg (G2 nausea). Common treatment-related adverse events (all grades) included nausea (38%), fatigue (31%), vomiting (27%), and diarrhea (17%). PK analyses showed a dose-proportional increase in LY exposures (AUC) at tolerated dose levels with a half-life of 1.9 hours and a body clearance of 85 L/hr. Midazolam PK data indicated that LY is a weak inhibitor of CYP3A4. Biomarker assessment demonstrated dose-related target inhibition in peripheral mononuclear cells at LY doses ≥ 150 mg. Durable partial response according to RECIST was observed in an endometrial cancer patient harboring PIK3R1 and PTEN mutations and 22 additional patients (47%) had stable disease as their best response. Conclusions: LY appears to be safe when administered as single agent up to 325 mg QD or 200 mg BID. The RPTD of single-agent LY is 200 mg BID based on safety, tolerability, and PK/PD data. LY is currently studied in tumor-specific expansion cohorts for mesothelioma, breast cancer, indolent Non-Hodgkin Lymphoma and squamous NSCLC. Clinical trial information: NCT01655225.
The GAIN-C study (BP25438): Randomized phase II trial of RG7160 (GA201) plus FOLFIRI, compared to cetuximab plus FOLFIRI or FOLFIRI alone in second-line KRAS wild type (WT) or mutant metastatic colorectal cancer (mCRC).
Authors: Andres Cervantes-Ruiperez, Ben Markman, Salvatore Siena, Carles Pericay, Giuseppe Aprile, John A. Bridgewater, Antonio Cubillo, Ashita Marie Waterston, Rocio Garcia-Carbonero, Mark Kozloff, Joseph James McKendrick, Leslie M. Samuel, Jose Alejandro Perez-Fidalgo, Andrew H. Strickland, Katia Bencardino, Irene Moya, Stefania Eufemia Lutrino, Christoph Mancao, Luigi Manenti, Josep Tabernero
Journal: Journal of Clinical Oncology (2012)

TPS3637 Background: GA201 is a novel, dual-acting, humanized, glycoengineered IgG1 anti-EGFR monoclonal antibody, with enhanced antibody-dependent cellular cytotoxicity (ADCC) activity in combination with signal inhibition. GA201 demonstrates significantly enhanced in vitro/vivo activity compared to cetuximab (cet) both as a single agent and in combination with irinotecan, in both KRAS mutant and BRAF mutant models and promising clinical activity in ph I and neo-adjuvant trials (Paz Ares et al, JCO 2011) including KRAS mutant mCRC. A randomized ph II program was launched: one study in NSCLC and GAIN-C in mCRC (NCT01326000), which is presented here. Methods: Main inclusion criteria are progression on 1L containing oxaliplatin, ECOG 0-1, and adequate hematological and liver function. Main exclusion criteria: prior anti-EGFR treatment. A total of 160 patients in 2L mCRC (stratified for EGFR expression, disease progression before or after 6 months after starting 1L, prior treatment with bevacizumab Y vs N) will be randomized to receive either GA201 (day 1, 8 of cycle 1 then q2W) or cet (qW) + FOLFIRI q2W (KRAS WT) or to receive GA201+ FOLFIRI or FOLFIRI alone (KRAS mutant). Collection of archival tumor plus a mandatory fresh tumor biopsy at baseline were implemented because ph I data showed that EGFR expression is not concordant between the two specimen types and to optimize assessment of potential immune related biomarkers. The fresh tumor biopsy will be centrally analyzed for EGFR (immunohistochemistry) and KRAS status. Primary objective is progression free survival; secondary endpoints are to define objective response rates, the safety profile, pharmacokinetics and pharmacodynamics. A comprehensive biomarker program (blood and tumor), mainly immune-phenotyping, immunohistochemistry in tumor samples (Ventana) and immune functional tests (including adaptive responses) were set up to investigate potential predictive biomarkers and the mode of action of GA201. Study is ongoing worldwide in 9 countries with the safety run-in phase completed in Nov 2011. Recruitment is planned to be completed by end of April 2012.
A phase I/IIa study evaluating the safety, efficacy, pharmacokinetics, and pharmacodynamics of lucitanib in advanced solid tumors.
Authors: Jean-Charles Soria, Filippo G. De Braud, Ratislav Bahleda, Barbara Adamo, Roberta Cereda, Maria Gabriella Camboni, Renata Robert, Jeffrey D. Isaacson, Jason B. Litten, Andrew R. Allen, Lindsey Rolfe, Josep Tabernero
Journal: Journal of Clinical Oncology (2014)

2500 Background: Lucitanib is a potent, oral inhibitor of the tyrosine kinase activity of FGFR1/2, VEGFR1-3 and PDGFRA/B. These well-described signaling pathways are essential for tumor growth, survival, migration, and angiogenesis. Further, several tumor types, including carcinoma of the breast, demonstrate amplification of FGF-related genes. Currently, there are no approved drugs for patients (pts) with molecularly defined FGF-aberrant (FGFR1 or FGF3/4/19 amplified) tumors. Methods: The first in human 3-part study is evaluating oral lucitanib monotherapy. Part 1 employed a 3+3 ascending cohort design in pts with advanced solid tumors to establish a recommended dose for further study. Parts 2 and 3 evaluated safety and efficacy of lucitanib in pts with FGF aberrant or angiogenesis sensitive tumors using continuous (part 2) or intermittent schedules (part 3) of administration. Results: 109 (part 1 n=17; part 2 n=59; part 3 n=33) pts were treated. Median age was 55 yrs [range 34-80]; 59 female; 105 stage IV; 29 breast cancer, 16 colon, 13 thyroid and 51 other tumor. Doses from 5 mg to 30 mg were evaluated with dose limiting toxicities (DLTs) dominated by VEGF-inhibition related toxicity at the 30 mg dose level. The most common adverse events (all grades, all cohorts, continuous and intermittent dosing schedules) were hypertension (86%), asthenia (73%) and proteinuria (69%). Exposure increased with dose and a t1/2 of 25-40 hours, deemed suitable for once daily administration. Clinical activity was observed at all doses tested with durable RECIST PRs in a variety of tumor types. In evaluable FGF-aberrant breast cancer pts, 50% (6 of 12) achieved RECIST PR with a median PFS of 9.4 months for all treated patients. Additionally, 1 of 3 pts with advanced squamous NSCLC experienced SD for 8 months with lucitanib therapy. Conclusions: Lucitanib demonstrated promising clinical activity and a tolerable side-effect profile in pts with advanced solid tumors, including those with FGF pathway aberrations. A phase 2 program in FGF aberrant breast and squamous NSCLC is underway in US and Europe. Clinical trial information: NCT01283945.
A multinational phase III adjuvant study of immediate (I) versus deferred (D) chemotherapy (C)/hormone therapy (HT) after radical prostatectomy (RP): TAX-3501.
Authors: Mario A. Eisenberger, Michael W. Kattan, Cora N. Sternberg, Ronald De Wit, Jonathan I Epstein, Evelyne B Ecstein-Fraïssé, Adam Stuart Kibel
Journal: Journal of Clinical Oncology (2012)

4570 Background: TAX 3501 was designed to test I or D C/HT after RP. No adequately designed prospectively randomized surgical systemic adjuvant studies have ever been successfully completed. Methods: TAX-3501 was a randomized phase III study. Eligibility included post-operative predicted probability of 5-year freedom from progression of &lt;60% (Kattan et al) after central pathology review, no prior C/HT, undetectable PSA, M0, normal hematology/chemistries, signed consent. Pts were randomized within 120 days after RP to I or D (at 1 st progression) Rx with HT (leuprolide acetate 22.5mg S.C. q.3 months x 6 ) +/- C (docetaxel 75mg/m 2 q.3wks x 6). F/U included a physical exam, PSA, CBC/chemical profile, serum T, scans yearly or at progression (PSA≥ 0.4ng/ml, clinical or radiographic and death). Main objectives comparing PFS and 5-year progression-free rates after systemic treatment (2 × 2 factorial design, 4 arms). 1,696 subjects would provide 90% power to detect the targeted treatment effect at a 5% 2-sided type I error level. Results: From 12/2005-9/2007399 pts were registered, 228 randomized after central path review ICHT=55, IHT=55, DCHT=56, DHT=62, median age 62 (41-76), pre-op PSA (ng/ml) 9.38 (2.2 - 90.0), Gleason score- 8,T3a (19.6%),R+(65%),S.V.+(50%),N+(19.7%%), all had undetectable post op PSA. Predicted probability of no progression was 21% on 228pts. Study was terminated by sponsor (9/2007) due to poor accrual F/U continued from 2007-2010. Small sample size precludes reliable analyzes 37/118 (31.3%) on the D arms received CHT/HT (all PSA progressions); ICHT 10/55, IHT 14/55, DCHT 9/56, DHT 8/62 met progression endpoint after I/D Rx (1/31 bone). AEs were characteristic and reversible (no grade 5). Leading causes of accrual impediment were inadequate site selection, no consensus regarding patient and treatment selection for this pt population, physician and patient bias re: treatment and evolving changes in the adjuvant treatment landscape during follow-up time (adjuvant RT). Conclusions: The role of adjuvant systemic treatment after RP remains undefined. Clinical trials in this pt population are challenging. Supported by Sanofi NCT000283062.
Abstract P278: Fibroblast Growth Factor 21 Mediated Protection of Ischemic Myocardium
Authors: Shu Q Liu, Brandon Tefft, Alexei Kharitonenkov, Yupeng Ren, Li-Qun Zhang, Yu H Wu
Journal: Circulation Research (2011)

Myocardial ischemia is a prevalent disorder causing heart failure. As cardiomyocyte death is the principal cause of cardiac functional deficits, a recognized treatment is to minimize cardiomyocyte death post myocardial ischemia. While extensive investigations have been conducted, few effective cardioprotective agents have been developed for clinical applications. The goal of this investigation is to test and establish a cardioprotective agent based on fibroblast growth factor 21 (FGF21), a secretory protein participating in innate cardioprotective responses. In myocardial ischemia induced by LAD coronary artery ligation in the mouse, hepatocytes upregulated FGF21 mRNA by 11 folds at 12 hrs, followed by an increase in the FGF21 protein level in hepatocytes and the serum. Administration of recombinant FGF21 to mice immediately post MI (50 ng/gm, IV, twice/day for 3 days) resulted in a significant reduction in the fraction of myocardial infarction (MI) with reference to the LV wall volume below the LAD ligation (38+/−5 and 21+/−4%, n=7, vs. albumin administration 51+/−8 and 31+/−5%, n=6, at day 1 and 10, respectively, p&lt;0.05 for both times) in association with improved LV dp/dt. In FGF21 overexpressing mice, the volume fraction of MI (36+/−6%, n=6) was significantly lower than that in wildtype mice (48+/−6%, n=5, p&lt;0.05) at day 1 post MI. Furthermore, FGF21 administration to normal mice induced phosphorylation of FGFR1, PI3K, Akt, and BAD in cardiomyocytes within 10 – 30 min. These molecules were also phosphorylated in cardiomyocytes within 1 day post MI. Injection of siRNA specific to FGFR1, PI3K, or Akt to the LV anterior wall at 6 locations about 2 mm apart (diffusion range of FITC-siRNA tested by fluorescence microscopy) 3 days prior to MI resulted in a reduction in the protein level of FGFR1, PI3K, or Akt by 65+/−9, 71+/−11, or 68+/−12%, respectively (n=3), within the region of siRNA injection at 1 day post MI in association with a reduction in BAD phosphorylation and an increase in the fraction of MI by 9+/−3, 8+/−2, or 11+/−3%, respectively (n=3). These observations suggested that FGF21 contributed to myocardial protection possibly via the FGFR1-PI3K-Akt-BAD signaling mechanisms and recombinant FGF21 may be potentially used as a cardioprotective agent.
Patient distress assessment in a VA oncology clinic: A quality improvement project.
Authors: Reena Jayani, Geetika Kumar, Ronald Markert, Amy Heard
Journal: Journal of Clinical Oncology (2017)

203 Background: Distress in oncology patients (pts) has a negative impact on quality of life, survival, and healthcare satisfaction. Higher distress is related to lower compliance with treatment and follow-up. The 2012 American College of Surgeons Commission on Cancer (CoC) standard of care for oncology pts included an assessment for distress. A screening process for distress allows the healthcare team to address these issues early and refer to appropriate resources. This project was initiated to meet National Comprehensive Cancer Network (NCCN) and CoC standard of care; identify distress in veterans with cancer; and address these concerns. Presented here are preliminary results. Methods: Pts who attended the Tuesday oncology clinic at the Dayton VAMC were given the NCCN Distress Thermometer (DT) during triage. The treating physician addressed problems identified. The Wilcoxon Signed Rank Test and the Friedman Test were used. Results: DTs were completed by 232 pts from March to September 2016. Mean age was 68, 93% male, 83% white, 54% married, and 93% without PTSD. The distress level was not different from T1 through T3. Number of problems decreased over three time periods, and Referrals to nutrition, mental health, and social work services increased over time (see Table). Conclusions: Although over time periods we found no decrease in distress scores, there was a decline in number of problems. The mean distress score at all but Time 4 was &lt;4, which is considered mild distress. The mean distress score at T4 was 4.36 (n=14), suggesting that the few pts who return to clinic more than three times may be experiencing more difficult personal and environmental circumstances. This pt sample ranged from those undergoing intensive cancer treatment (e.g., chemotherapy) to less intensive treatment (e.g., hormone injections) to those who completed treatment. As this tool was implemented only on one clinic day, some time points were missed if a pt was seen on a different day. [Table: see text]
Frequency of EGFR mutations in leptomeningeal metastasis of lung adenocarcinoma.
Authors: Ben-Yuan Jiang, Jinji Yang, Jian Su, Zhihong Chen, Yi-Long Wu, Weibang Guo
Journal: Journal of Clinical Oncology (2015)

e19066 Background: Along with recent advances in systemic treatment and neuroimaging, leptomeningeal metastasis (LM) is being diagnosed more frequently in lung adenocarcinoma and has become a matter of concern for thoracic oncologists. Methods: We retrospectively reviewed the cases of 102 lung adenocarcinoma patients diagnosed with LM between September 2008 and December 2014 at Guangdong Lung Cancer Institute (GLCI). The diagnosis of LM was based on the presence of malignant cells in the cerebrospinal fluid (CSF) or the detection of leptomeningeal enhancement on gadolinium-enhanced MRI. Results: Of the 102 patients diagnosed with LM, 46 were male (50%), the median age was 56.0 years (range, 32–80 years). 86 patients (84.3%) had a conclusive driver gene mutation (80 were EGFR mutation, 4 were ALK rearrangement, 1 was k-ras mutation and 1 was MET amplification), 7 patients had a gene status with wild type and another 9 patients were unknown. The median overall survival (mOS) of mutant patients was much longer than those with wild type and unknown (9.0 vs. 4.4 months, Х2= 4.11, P= 0.043). 38 patients with cytologically proven LM had a worse outcome than those with radiologic evidence of LM, the mOS were 7.5 months and 9.7 months respectively (Х2= 4.64, P= 0.031). 65 patients(63.7%) suffered from LM after tyrosine kinase inhibitor (TKI) treatment, the median interval time from TKI treatment to LM was 12.0 months(1.0-39.4 months), and the mOS was 7.5 months (5.8-9.2 months). 41 patients received whole brain irradiation(WBI) after diagnosed with LM , patients who received WBI had improved survival compared to patients who did not receive WBI (10.0 vs. 7.5 months, Х2= 2.67, P= 0.101). 84 patients(81.8%) were diagnosed with a symptomatic LM, which had a worse prognosis than those without symptoms( 7.5 vs. 12.4months, Х2= 4.40, P= 0.036). A multivariate analysis showed that positive symptom were associated with a worse prognosis in lung adenocarcinoma patients when diagnosed with LM（Х2 = 4.90, P= 0.027. Conclusions: Lung adenocarcinoma patients harboring EGFR mutation were more prone to develop LM; patients without symptom at the time of LM diagnosis might confer a survival benefit.
Palmitic acid mediates hypothalamic insulin resistance by altering PKC-θ subcellular localization in rodents
Authors: Stephen C. Benoit, Christopher J. Kemp, Carol F. Elias, William Abplanalp, James P. Herman, Stephanie Migrenne, Anne-Laure Lefevre, Céline Cruciani-Guglielmacci, Christophe Magnan, Fang Yu, Kevin Niswender, Boman G. Irani, William L. Holland, Deborah J. Clegg
Journal: Journal of Clinical Investigation (2010)

In the Methods section titled "Fatty acid infusion," the dose of fatty acids delivered centrally was given incorrectly.The correct sentence appears below.The cannula was connected via a polyethylene catheter to a subcutaneous osmotic minipump (Alza Corporation) filled with either palmitic or oleic acid (equimolar concentrations, 50 μmol/l; Sigma-Aldrich) or vehicle (PBS) for continuous infusion over 3 days.The authors regret the error.