tbuckley/cabot-search huggingface dataset:
Pediatric preclinical testing program (PPTP) efficacy and pharmacodynamic evaluation of the Hsp90 inhibitor 17-DMAG
Authors: M. A. Smith, J. M. Maris, S. T. Keir, R. B. Lock, H. Carol, R. Gorlick, E. A. Kolb, N. Keshelava, C. P. Reynolds, C. Morton, P. J. Houghton
Journal: Journal of Clinical Oncology (2007)

3575 Background: 17-DMAG is a small-molecule inhibitor of the protein chaperone HSP90 that is being developed as an anticancer agent because of the multiple HSP90 client proteins involved in cancer cell growth and survival. Methods: The PPTP includes an in vitro panel (n=27) as well as panels of xenografts (n=61) representing most of the common types of childhood solid tumors and childhood ALL. 17-DMAG was tested against the in vitro panel at concentrations from 1 nM to 10 microM and was tested against the in vivo tumor panels by IP administration using a 50 mg/kg BID twice weekly x 6 weeks dose and schedule. The PPTP’s 3 measures of antitumor activity were used (Houghton et al. Ped Blood Cancer 2006): 1) an objective response measure; 2) treated to control (T/C) tumor volume at day 21; and 3) a time to event (EFS T/C) measure. HSP70 induction was was used as a pharmacodynamic measure of HSP90 inhibition and was determined in tumor and liver tissue at 8 and 24 hours following the second of two doses of 17-DMAG (50 mg/kg IP) administered at 12 hour intervals. Results: 17-DMAG had an EC 50 of 62 nM against the PPTP’s in vitro panel, with a trend for lower EC 50 values for the rhabdomyosarcoma panel (median EC 50 31 nM) compared to the remaining PPTP in vitro cell lines (p=0.06) and for higher EC 50 values for the neuroblastoma lines (median EC 50 396 nM, p=0.01). 17-DMAG induced significant differences in EFS distribution in 15 of 30 of the solid tumor xenografts, and in 4 of 6 of the evaluable ALL xenografts. Using the time to event activity measure, 17-DMAG had intermediate or high activity against 4 of 28 evaluable solid tumor xenografts (1 of 2 rhabdoid tumor and 3 of 4 alveolar rhabdomyosarcoma). The only objective response (a PR) observed was for an alveolar rhabdomyosarcoma xenograft. HSP70 induction was observed in both liver and tumor tissue, with robust induction (up to 450% increase versus control) occurring in both responding and non-responding tumors. Conclusions: 17-DMAG produced its greatest antitumor activity against alveolar rhabdomyosarcoma xenografts. Robust HSP70 induction was observed in both responding and non-responding xenografts, suggesting that tumor-specific downstream effects of HSP90 inhibition are primary determinants of response. (Supported by NCI NO1CM42216) No significant financial relationships to disclose.
Beliefs and behavior regarding e-cigarettes in a large cross-sectional survey.
Authors: Sebastien Couraud, Alexis B. Cortot, Chantal Touboul, Xavier B. Pivot, François Eisinger, Jean F. Morere, Jerome Viguier, Jean-Yves Blay, Christine Lhomel, Laurent Greillier
Journal: Journal of Clinical Oncology (2015)

1570 Background: The use of e-cigarettes has developed dramatically in recent years. However, the role of e-cigarettes in helping cigarette cessation or in lowering social stigma of tobacco use remains controversial. It is therefore useful to assess beliefs and behavior about e-cigarettes. Methods: The 4th French nationwide observational survey, EDIFICE 4, was conducted among a representative sample of 1602 subjects aged 40 to 75 years, using the quota method, from June 12 to July 10, 2014. Profile, beliefs and behavior were assessed by phone interviews of the general population with no history of cancer (n = 1463), and compared with those of cigarette smokers and e-cigarette users (eC+). Results: Of the 1463 individuals analyzed, 93 (6%) were e-cigarette users (74 current and 19 former cigarette smokers), with a mean daily consumption of 9.9 (±11.0); 88% used nicotine-based e-liquid. Among cigarette users (C+), current C+/eC+ were more likely to be men, to have a lower socioeconomic status (56% vs 39%), and to be more dependent on nicotine according to the Fagerström test (58% vs 46%), in comparison with cigarette smokers alone (C+/eC-). In the general population, 58% believed that e-cigarettes are potentially useful in helping to reduce cigarette smoking, and for 31%, they can help to quit smoking. In contrast, these proportions were 24% and 69% respectively, among e-cigarette users (C+/eC+). In the general population, 42% and 54% believed that e-cigarette smoke is less toxic than cigarette smoke for the user and for passive smokers, respectively. These figures were both greater among e-cigarette users (C+/eC+), reaching 68% and 87% respectively. Of the total population, 12% felt that e-cigarettes are likely to be effective for controlling lung cancer mortality (18% among current smokers vs 9% and 12% in former- and never-smokers), compared to 33% of e-cigarette users (C+/eC+). Lastly, current C+/eC+ smokers believed they have a higher risk of lung cancer than that of current C+/eC- smokers. Conclusions: Current cigarette smokers and current e-cigarette smokers both tend to have a lower awareness of e-cigarette toxicity and to emphasize the potential benefit of e-cigarettes for quitting smoking.
Should US doctors mourn for Obamacare?
Authors: Adam Gaffney, Zackary D Berger, Saurabh Jha
Journal: BMJ (2017)

Any changes to the Affordable Care Act are likely to result in fewer people being insured, worry <b>Adam Gaffney</b> and <b>Zackary D Berger</b>, but <b>Saurabh Jha</b> thinks reform could prioritise market forces and really make care affordable
A phase I trial of GBS-01 for advanced pancreatic cancer refractory to gemcitabine.
Authors: Masafumi Ikeda, Akihiro Sato, Nobuo Mochizuki, Kayo Toyosaki, Chika Miyoshi, Rumi Fujioka, Shuichi Mitsunaga, Satoshi Shimizu, Izumi Ohno, Hideaki Takahashi, Hiroyuki Okuyama, Hiromi Hasegawa, Shogo Nomura, Toshiki Ohkubo, Satoshi Yomoda, Satoshi Kishino, Hiroyasu Esumi
Journal: Journal of Clinical Oncology (2013)

2559 Background: Arctigenin, which is abundant in the seeds of Arctium lappa Linné, was found by a novel strategy to attenuate cancer cells’ tolerance to glucose deprivation (antiausterity) and showed antitumor activity in mouse xenograft models. GBS-01 is an orally administered drug and contains rich arctigenin extracted from Arctium lappa Linné, which is one of the traditional herbal medicine. This study investigated the maximum-tolerated dose of GBS-01 based on the frequency of dose-limiting toxicities (DLT) in patients with refractory advanced pancreatic cancer, which is considered as one of the hypoxic cancer. Methods: Histologically or cytologically proven advanced pancreatic adenocarcinoma patients refractory to gemcitabine were enrolled. GBS-01 was administered orally at escalating doses from 3g to 12g qd. DLT was defined as grade 4 hematological toxicities and grade 3 or 4 non-hematological toxicities during first 28 days of the treatment. Response evaluation based on RECIST criteria and progression-free survival were set as secondary endpoint for efficacy evaluation. Results: Fifteen patients (GBS-01 3g: 3 patients, 7.5g: 3 patients, 12g: 9 patients) were enrolled in this trial. All patients were refractory to S-1 as well as gemcitabine. All patients at the three dose levels did not demonstrate any sign of DLT. The main adverse events of this agent were increased γGTP, hyperglycemia, and increased total bilirubin, but all toxicities were extremely mild. Of all 15 enrolled patients, 1 patient showed a partial response and 4 patients had a stable disease. The median progression-free and overall survival time for all patients were 1.05 months and 5.68 months, respectively. Conclusions: The recommended dose of GBS-01 was 12 g qd (4 g as a extract of Arctium lappa Linné), and favorable clinical responses were obtained. A multicenter phase II trial is being planned to evaluate the efficacy and safety of this agent. Clinical trial information: 000005787.
HSG-MLF1IP axis as potential targets for lung adenocarcinoma treatment.
Authors: Yuqing Lou, Rong Li, Jielin Liu, Yanwei Zhang, Wei Zhang, Xueyan Zhang, Bo Jin, Ya Liu, Zuoguang Wang, Hua Zhong, Shaojun Wen, Baohui Han
Journal: Journal of Clinical Oncology (2015)

e13591 Background: Hyperplasia suppressor gene (HSG) encodes a mitochondrial protein associated with mitochondrial fusion process. HSG was initially identified as a hypertension-associated gene and then implicated in the pathogenesis of variant types of cancer. However, the involvement of HSG in lung adenocarcinoma and underlying mechanisms remain elusive. Methods: HSG protein level in 30 pair lung adenocarcinoma/adjacent normal lung samples was examined with immunohistochemistry staining. Then HSG was knockdown in human lung adenocarcinoma cell line A549 with lentiviral siRNA and the impact of this on cell proliferation, cell cycle process and invasion was determined. Gene expression changes in A549 cells treated with HSG siRNA were further explored with microarray. High Content Screening was performed to determine the downstream factors involved in HSG-associated lung adenocarcinoma progress. The expression of downstream factors were then further determined in 15 lung adenocarcinoma samples by real-time PCR. Results: HSG expression was significantly higher in lung adenocarcinoma tissues as compared to adjacent normal lung tissues, with positive HSG signals in 90% (27/30) tumor tissues and only in 26.7% (8/30) normal tissues. HSG knockdown led to impaired cell proliferation, cell cycle arrest and impaired invasion behavior in A549 cells. Microarray analysis revealed that multiple genes and signaling pathways were deregulated in HSG-knockdown A549 cells. Out of these deregulated genes, MLF1 interacting protein (MLF1IP) was implicated in cell proliferation regulation as High Content Screening revealed that MLF1IP knockdown led to significantly reduced cell proliferation rate in A549. Furthermore, MLF1IP expression was significantly higher in lung adenocarcinomas as compared to adjacent normal lung tissues (fold change = 2.50, P < 0.05), with higher MLF1IP expression in 66.7% (10/15) samples and lower in only 20% (3/15) samples. Conclusions: We confirmed the involvement of HSG in the pathogenesis of lung adenocarcinoma and revealed that MLF1IP might be the downstream factor responsible for HSG-mediated lung adenocarcinoma progress. HSG-MLF1IP axis might be the potential targets for lung adenocarcinoma treatment.
Guideline: The USPSTF recommends low- to moderate-dose statins to prevent CVD in selected adults 40 to 75 years of age
Authors: Neha J. Pagidipati, Christopher B. Granger
Journal: Annals of Internal Medicine (2017)

Source Citation US Preventive Services Task Force, Bibbins-Domingo K, Grossman DC, et al. Statin use for the primary prevention of cardiovascular disease in adults: US Preventive Services Task Force recommendation statement. JAMA. 2016;316:1997-2007. 27838723
Retrospective analysis on the factors related with lower response rates to second-line chemotherapy after failure of adjuvant/front-line chemotherapy for colorectal cancer.
Authors: Ke-Feng Ding, Jun Li, Yue Liu, Ye-Ting Hu, Ying Yuan, Han-Guang Hu, Liu-Hong Wang, Ya Wang
Journal: Journal of Clinical Oncology (2015)

e14537 Background: To assess the factors influence the response rates to the second-line chemotherapy after failure of adjuvant chemotherapy or front-line chemotherapy for colorectal cancer. Methods: The patients with colorectal cancer diagnosed from June 2008 to May 2014 in SAHZU were reviewed. Inclusion criteria: 1)Group 1, patients with initial stage II-IVa colorectal cancer received R0 resection, adjuvant chemotherapy and recurred during adjuvant chemotherapy or within 12 months completing adjuvant chemotherapy, and then received second-line chemotherapy; 2)Group 2, patients with initial unresectable stage IV colorectal cancer who had disease progression during front-line chemotherapy or within 6 months completing front-line chemotherapy, and then received second-line chemotherapy. Responses were assessed by RECIST Version 1.1. The endpoint was failure of the second-line chemotherapy which was defined as disease progression 3±1 months after initiation of second-line chemotherapy. We analyzed 79 covariates including characteristics of patient, characteristics of tumor and information of treatment. Logistic regression was analyzed by using STATA 12. Results: 125 patients were analyzed, including 53 in Group 1 (Ages 55.8±9.8 years, 43.4% patients failed second-line chemotherapy) and 72 in Group 2 (Ages 55.5±11.3 years, 51.4% patients failed). For group 1, we found that younger patients ( ≤ 55 years old vs. > 55 years old, OR = 3.71, 95% CI 1.02-13.55) and patients with early recurrence after adjuvant chemotherapy (Duration from initial diagnosis to recurrence ≤ 300 days vs.> 300 days, OR = 6.18, 95% CI 1.69-22.56) had lower response rates to second-line chemotherapy. The logistic regression equation was logit(Probability of failure) = -1.92+1.31×Age+1.82×Duration to Recurrence. The Area Under the Curve of Receiver Operating Characteristic was 0.77. For Group 2, we failed to build a model. Conclusions: Patients who younger than 55 years old at initial diagnosis and recurred in 300 days after initial diagnosis had lower response rate to second-line chemotherapy.
The impact of interventions on provider and treatment delays in head and neck cancer patients.
Authors: Dominic W. Lai, June Kim, Ariel Marciscano, Sarah A Buckley, Brian L. Schmidt, Richard F. Cohen, Mary Lynn R. Nierodzik, David Myssiorek, Mark D. DeLacure, Nicholas Sanfilippo, Nagashree Seetharamu
Journal: Journal of Clinical Oncology (2012)

e16052 Background: Diagnosis and management of squamous cell carcinoma of head and neck (SCCHN) involves a multidisciplinary approach. Navigation at a public hospital can be difficult and lead to delays. In a previous study, we reported English-speaking and employed patients having longer provider delays (Lai 2011). In July 2010, we instituted the use of patient navigators, bimonthly management conferences, and improved inter-disciplinary communication in order to improve the patient experience. Aims: 1. Study differences in “provider delay” (time between first contact with health care provider and positive biopsy) between patients in cohort A (diagnosed between 1/2007 and 6/2010) and cohort “B” (diagnosed between 7/2010 and 6/ 2011). 2. Study differences in “treatment delay” (time between biopsy and initiation of treatment) between the two cohorts. 3. Determine what factors influence delays in both cohorts. Methods: The delays of the two cohorts were compared using the student t-test. Independent t-test and chi-square tests were used to examine associations between delays and the following characteristics: language, employment, presence of partner, gender, ethnicity, age, cancer sub-site, staging, number of co-morbidities, tobacco use, and alcohol use. The likelihood ratio test was used for multivariate analysis. Results: 133 patients in cohort A and 20 patients in cohort B were evaluable. Both provider and treatment delays in cohort B (50.5 and 39.3 days, respectively) were shorter than cohort A (60.2 and 41.6 days), but this was not statistically significant. The standard deviations of both delays were lower in cohort B, pointing towards a greater consistency in this group. In cohort A, provider delay was significantly shorter (p-value=0.003) for non-English speakers than English speakers on univariate and multivariate analysis. Other trends were not observed. Conclusions: Simple interventions can reduce provider and treatment delays. Our observations suggest that these interventions can mitigate the effect of patient factors on provider and treatment delay. However, our results may be affected by small sample size and demographic shifts. With time, we will accrue more patients to address these issues.
Pharmacogenetic study in metastatic colorectal cancer (CRC) patients receiving third-line panitumumab-irinotecan: A GERCOR ancillary study.
Authors: Marie-Christine Etienne-Grimaldi, Laurence Llorca, Patricia Formento, Benoist Chibaudel, Christophe Tournigand, May Mabro, Jean-Baptiste Bachet, Helene Blons, Pierre Laurent-Puig, Jean-Louis Formento, Aimery De Gramont, Thierry Andre, Gerard A. Milano
Journal: Journal of Clinical Oncology (2012)

2537^ Background: Test the predictive value of gene polymorphisms potentially linked to panitumumab and irinotecan pharmacodynamics. Methods: 45 patients with metastatic CRC refractory to standard therapy were enrolled in this ancillary pharmacogenetic study as part of a phase II trial that included 63 patients. Inclusion required wild-type KRAS tumor status (codons 12-13, analyses performed in each center). After inclusion, central KRAS re-assessment was performed (codons 12-13-59-61) and 9 patients over 45 were found to carry a KRAS mutation. Patients received panitumumab (6 mg/kg, day 1) associated with irinotecan (180 mg/m 2 , day 1), Q2W until disease progression or unacceptable toxicity. Analyzed polymorphisms on blood DNA were : EGFR (CA repeats in intron 1, -216G&gt;T, -191C&gt;A), EGF (61A&gt;G), CCND1 (870A&gt;G), UGT1A1 (*28). Results: Cutaneous toxicity imputable to panitumumab i.e. folliculitis and paronychia was not linked to EGFR, EGF or CCND1 polymorphisms. Diarrhea (12 grade 1, 13 grade 2, 8 grade 3) was linked to CCND1 polymorphism: 22% grade 2-3 in AA patients vs 63% in AG+GG patients (p = 0.007). As expected, neutropenia (6 grade 1, 4 grade 2, 5 grade 3) was more frequent in patients bearing the *28 allele of UGT1A1 gene (33% grade 2-3 vs 5% in *1/*1, p = 0.020). In these 45 patients, response rate, progression-free survival and overall survival (OS) were only significantly related to re-assessed KRAS status. Of note, a tendency for a longer OS was observed in patients bearing the *28 allele of UGT1A1 gene (p = 0.091, analysis adjusted for KRAS). Interestingly, the frequency of KRAS mutation was higher in patients with long CA repeats in EGFR gene intron 1: 54.5% i.e. 6 mutated patients among the 11 patients with both alleles ≥17 vs 10.5% i.e. 2 mutated patients among the 19 patients with intermediary alleles vs. 6.7% i.e. 1 mutated patient among the 15 patients with both alleles &lt;17 (p = 0.004). Conclusions: Present data indicate that A870 allele of CCND1 gene (40% AA patients) may protect from diarrhea induced by panitumumab-irinotecan. Also, these results report an original relationship between EGFR polymorphism in intron 1 and KRAS mutation status that merits further confirmation.
Impact of surgery and radiation of the primary among women with de novo stage IV breast cancer.
Authors: Shaheenah S. Dawood, Rebecca Alexandra Dent, Sudeep Gupta, Jennifer Keating Litton, Rashid Mustafa, Javier Cortes, Elizabeth Ann Mittendorf, Ana M. Gonzalez-Angulo, Thomas A. Buchholz
Journal: Journal of Clinical Oncology (2012)

1032 Background: The aim of this retrospective study was to determine the impact of surgery(S) and radiation(R) therapy to the primary tumor among patients (pts) with stage IV denovo breast cancer. Methods: The SEER registry was used to identify pts with denovo stageIV breast cancer diagnosed between 1988 and 2008. Pts were divided into 4 groups based on type of treatment to primary tumor: both S+R, S alone, R alone, or no treatment of primary (no S/R). Breast cancer specific survival (BCS) was calculated from the date of diagnosis of breast cancer to the date of death from breast cancer or last follow up. Survival outcomes were estimated by the Kaplan-Meier method, and Cox models were fit to determine the association between treatment of primary and survival after adjusting for potential confounders (e.g age, grade, hormone receptor and race). Results: 25903 pts were identified; 4640 (17.9%) S+R, 6556 (25.3%) S, 4467 (17.2%) R, and 10240 (39.5%) no S/R. 1183 (4.6%) had surgery to sites other than the primary. Median age was 63 years. Median follow-up was 14 months. Median BCS was 23 months. Median BCS among pts who underwent S+R, S, R and no S/R was 36 months, 31 months, 18 months and 15 months respectively (p&lt;0.0001). Among pts who underwent S+R, median BCS among pts who did and did not have surgery to sites other than primary was 50 months and 41 months respectively (p=0.029). Of the pts treated with S+R 10-year BCS was 18%. In the multivariable model compared to women who were in the no S/R group those who underwent S (HR= 0.59, 95%CI 0.55- 0.62,p&lt;0.0001) and S+R (HR=0.51, 95%CI 0.47-0.55,p&lt;0.0001) had decreased risk of death from breast cancer and those who underwent R (HR=1.13, 95% CI 1.04-1.21, p=0.002) had an increased risk of death from breast cancer. Pts who had surgery to sites other than the primary tumor had decreased risk of death from breast cancer compared to those who did not (HR=0.80, 95%CI 0.72-0.89,p&lt;0.0001). Conclusions: Our results indicate that S+R of the primary breast tumor among pts with denovo stage IV breast cancer maybe associated with a decreased risk of death from breast cancer. A select subgroup of pts who undergo S+R may also benefit from surgery to sites other than the primary which may afford them maximum survival advantage.
Randomized phase II trial of intravenous RO5137382/GC33 at 1600 mg every other week and placebo in previously treated patients with unresectable advanced hepatocellular carcinoma (HCC; NCT01507168).
Authors: Chia-Jui Yen, Bruno Daniele, Masatoshi Kudo, Philippe Merle, Joong-Won Park, Paul J. Ross, Jean-Marie Peron, Oliver Ebert, Stephen Lam Chan, Ronnie Tung Ping Poon, Massimo Colombo, Takuji Okusaka, Baek-Yeol Ryoo, Beatriz Minguez, Takayoshi Tanaka, Toshihiko Ohtomo, Olga Rutman, Ya-Chi Chen, Reuy-min Lee, Ghassan K. Abou-Alfa
Journal: Journal of Clinical Oncology (2014)

4102 Background: RO5137382/GC33 (GC33) is a humanized monoclonal antibody against GPC3 that is frequently expressed in HCC. GC33 interacts with CD16/FcγR3 and triggers antibody-dependent cytotoxicity. GC33 was compared with placebo in a randomized phase II study in advanced HCC patients (pts) who had failed prior systemic therapy. Methods: Pts with advanced HCC who had failed prior systemic therapy, ≥18 years, ECOG 0-1, Child-Pugh A were randomized in a 2:1 ratio to GC33 1600 mg Q2W after two weekly doses versus placebo. Prior to randomization, pts were assigned into 3 cohorts based degree of GPC3 immunohistochemical expression: A (GPC3 2-3+), B (GPC3 1+) and C (GPC3 no expression). Primary endpoint was progression free survival (PFS). Secondary endpoints include overall survival (OS), time to progression (TTP), tolerability, and pharmacokinetics (PK). Tumor assessment was based on RECIST1.0 criteria and safety on CTCAE 4.0. Results: Between February 2012 to March 2013, 185 pts were enrolled: 121 received GC33 and 64 placebo: Median age 64/63, 85/75% male, 46/42% Asian, ECOG 0 65/63%, 74/77% having vascular invasion and/or extra-hepatic metastasis. 49/41% had prior single agent sorafenib. Drug exposure was 98.6% of planned dose, with an identical adverse events profile between the 2 groups. The median PFS, OS, and TTP in the GC33 vs placebo groups in months were: 2.6 vs 1.5 (HR 0.97, p=0.87), 6.8 vs 6.7 (HR 0.99, p=0.97), and 2.9 vs 1.7 (HR 0.96, p=0.85). A subsequent exposure-efficacy analysis showed that increased exposure based on projected Ctroughat cycle 3 day 1 was associated with prolonged PFS and OS. Median PFS for high GC33 exposure group (n=60) was 4 vs 1.5 months for placebo (n=60), and OS 9.7 vs 6.7 months, respectively. Combining higher exposure with FcγR3A-158V polymorphism or CD16 expression intensity may correlate with improved PFS and OS. Conclusions: GC33 did not show a clinical benefit in this advanced, previously treated HCC population, potentially due to suboptimal dosing. Further studies are needed to investigate whether higher GC33 drug exposure and a favored CD16/FcgR3 immune environment may help. Clinical trial information: NCT01507168.
Stearoyl CoA Desaturase 1 (SCD1) Is Upregulated in Rapidly Growing Myeloma Cells and Is Required for Cell Proliferation,
Authors: Sathisha Upparahalli Venkateshaiah, Sharmin Khan, Wen Ling, Linda Saint John, Rakesh Bam, Xin Li, Shmuel Yaccoby
Journal: Blood (2011)