tbuckley/cabot-search huggingface dataset:
Compliance to chemoradiation (CRT) using mitomycin (MMC) or cisplatin (CisP), with or without maintenance 5FU/CisP chemotherapy (CT) in squamous cell carcinoma of the anus (SCCA) according to radiotherapy (RT) dose, overall treatment time (OTT) and chemotherapy (CT) and their impact on long-term outcome: Results of ACT II.
Authors: Robert Glynne-Jones, Helen Margaret Meadows, Andre Lopes, Richard A. Adams, David Sebag-Montefiore
Journal: Journal of Clinical Oncology (2015)

3518 Background: Concurrent CRT is standard treatment for patients with SCCA. We explored CRT compliance in ACT II, which compared 5FU/CisP with 5FU/MMC (wks 1 & 5) of a uniform RT dose (50.4Gy, 28 daily fractions (F) of 1.8Gy). Methods: We investigated the association between poor compliance and baseline factors (age, sex, site, T & N stage), type of CT (MMC/CisP) with progression free survival (PFS). Compliance was categorized as follows: RT, 5 groups: A = per protocol (50.4Gy in 28F in 38-42 days), B = ≤ 40Gy, C = 40-48.6Gy in 23-27F, D = 50.4Gy in > 42 days, E > 52.2Gy. CT, 2 groups: 1 = wks1 & 5 & 2 = wk1 only. Results: 933 and 862 of 940 pts were evaluable for RT & CT compliance respectively. Median follow-up was 5.1 yrs. Baseline characteristics of evaluable patients were similar to all 940 ACT II patients. Canal tumors, CisP, GFR<60 & WBC < 11 were borderline significant predictors of poor wk5 CT compliance (p 0.09, 0.07, 0.06 & 0.08 respectively). Poor CT compliance at wk5 impacted significantly on PFS (treatment adjusted HR: 1.63 (95% CI: 1.23-2.17), p = 0.001). No baseline factors analyzed, or chemotherapy type, were significant independent predictors of poor RT compliance. Conclusions: In ACT II poor CT & RT compliance (lower dose/prolonged OTT) adversely impacted on PFS. Treatment interruptions should be minimized and prolonged OTT compensated by hyperfractionation or possibly additional dose. Intensity Modulated RT may improve compliance. Patients with poor compliance to RT/CT may need closer monitoring following treatment. Clinical trial information: 26715889.Impact of RT compliance on PFS (N=933). Group Total events/ No of pts 3 y PFS rate % Treatment-adjusted HR (95% CI) P-value A 221/786 76 1.00 0.0001 B 11/18 44 3.71 (2.01-6.82) C 11/21 56 2.26 (1.23-4.14) D 39/93 62 1.62 (1.15-2.28) E 6/15 59 1.60 (0.71-3.61)
Liam West #PioneeredUndergraduateSEMSocieties
Authors: Johann Windt
Journal: British Journal of Sports Medicine (2017)

My energy and drive have helped me overcome hurdles within SEM. My policy of strategic volunteering has been key. For instance, I am 27 years old and I have been to over 45 SEM conferences already. That provides a network that provides a lot of wisdom. At about 75% of the conferences I have gone for free (as I could not afford them) by serving drinks, cleaning floors, packing delegate bags or acting as an MSK model—I will do whatever it takes!



Take life less seriously, spend more quality time with my family and travel at every opportunity. Try to find the optimum work–life balance (something I still struggle with). I would also write that it is okay to say no to opportunities—aim for quality over quantity!

I am only just beginning my sport and exercise medicine (SEM) journey, but most rewarding to date was serving as team doctor for the England U16 Football Team at the 2015 Montaigu International Tournament in France—we won!

I cycle or run to work, and since moving to Melbourne, Australia, where coffee is ingrained into the culture, I must start with at least one latte! Then more paperwork than I would like.

I think being at Old Trafford to watch Eric Cantona come back from his ‘Kung Fu Kick’ 8-month ban to score a penalty against Liverpool FC. I was sitting …
A phase I study of ARQ 197 in combination with temsirolimus in patients (Pts) with advanced solid tumors.
Authors: Amy M. Braden, Kari Braun Wisinski, Jens C. Eickhoff, William R. Schelman, Howard Harry Bailey, Daniel Mulkerin, Jennifer Heideman, Jill Kolesar, Glenn Liu
Journal: Journal of Clinical Oncology (2014)

2555 Background: Disregulated c-Met activity is implicated in tumor progression and metastasis. Phosporylation of c-Met leads to activation of the PI3K/AKT/mTOR pathway. Preclinical studies demonstrate that combined inhibition of c-Met and mTOR is effective. ARQ 197 (tivantinib) is an inhibitor of c-Met and Temsirolimus selectively inhibits mTOR. This study is designed to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), adverse events (AEs), clinical activity, and pharmacokinetic (PK) parameters of this combination. Methods: This open label phase I study utilizes a 3+3 dose escalation of ARQ 197 (120mg-480mg bid) and Temsirolimus (20-25mg IV weekly) followed by dose expansion at MTD. ARQ 197 is primarily metabolized by CYP2C19. Separate cohorts for dose escalation are incorporated for poor and extensive metabolizers. Cycles are 28 days, except cycle 1 which is 35 days, to evaluate PK interactions. Results: 14 pts (median age 60.5 [range 29-71]; 8 male:6 female) were enrolled. The most common malignancies were colorectal (4 pts), ovarian (2 pts) and renal cell carcinoma (2 pts). 3 pts were unevaluable per protocol. 11 evaluable patients were on study a median of 55.5 days (range 15-296). After 3 evaluable subjects there was no DLT at dose level (DL) 1. At DL2, there were 2 DLTs. 1 pt received <75% of drug due to grade (gr) 3 hypophosphatemia and gr 3 diarrhea but had baseline diarrhea. A 2ndpt had gr 4 neutropenia and gr 3 mucositis. DL 1 was expanded with 3 additional pts without DLT. An amendment with stricter eligibility criteria was approved by CTEP and dose was re-escalated to DL2. 2 additional pts have been treated without DLT. Dose escalation will continue if 1 additional pt at DL2 does not have DLT. The most common AEs at least possibly related to therapy included: fatigue (gr 1-2 in 9 pts), anemia (gr 2 in 7 pts, gr 3 in 1 pt), nausea (grade 1-2 in 8 pts) and diarrhea (gr 1-2 in 6 pts, and gr 3 in 1 pt). 1 pt with ovarian cancer had a confirmed partial response, a decline in CA 125 and remained on study for > 9 months. Conclusions: ARQ 197 in combination with Temsirolimus appears to be well-tolerated at biologically active doses. Dose escalation and PK analysis is ongoing. MTD expansion is planned. Clinical trial information: 9145.
Final results of a phase I study of wild-type oncolytic reovirus administered intravenously to patients with advanced cancer
Authors: J. F. Spicer, L. Vidal, H. Pandha, T. Yap, C. White, M. Coffey, B. Thompson, S. Kaye, K. Harrington, J. De Bono
Journal: Journal of Clinical Oncology (2007)

3572 Background: Reovirus has minimal pathogenicity in humans but selectively replicates in cells with activated Ras, which inactivates the anti-viral effects of double stranded RNA-activated protein kinase. Wild-type reovirus serotype 3 Dearing has selective antitumor activity in pre-clinical models. Methods: Wild-type reovirus serotype 3 Dearing was administered as a 1-hr IV infusion every 4 weeks, initially for 1 day, then for 3 and then 5 days every 4 weeks. The starting dose was 1 x 10^8 tissue culture infectious dose (TCID50), increasing in successive cohorts until the observation of grade 2 toxicity. Endpoints were safety, detection of viral replication, viral shedding, immune response and antitumor activity. Results: A total of 33 patients (25 males, median age 61; ECOG performance status 0/1/2 = 15/17/1) were treated. 8 cohorts were treated at dose levels of 1x10^8 TCID50 for 1 day, 1x10^8 for 3 days, and 1x10^8, 3x10^8, 1x10^9, 3x10^9, 1x10^10 and 3x10^10 for 5 days. Maximum tolerated dose (MTD) was not reached and toxicities were mild (grade 1 or 2), including chills, fever, headache, rhinorrhea, fatigue and myelosuppression. Reverse transcription polymerase chain reaction (RT-PCR) studies of blood, urine, stool and sputum post reovirus administration and every week thereafter were negative for viral shedding for all treated patients. Anti-reovirus antibodies were present at baseline in most patients, and titres increased after cycle 1 by between 1- and 4-log. Intratumoral reovirus replication was detected by electron microscopy in tumor biopsies. PSA decreased by 50% in a patient with metastatic prostate cancer treated at 3x10^9 TCID50, with evidence of tumor necrosis on CT scanning. 2 patients with metastatic colorectal cancer treated at 3x10^8 and 3x10^9 TCID50 had CEA reductions of 60% and 27%, and received 6 and 3 cycles respectively. 1 patient with metastatic bladder cancer treated at 1x10^9 TCID50 had a minor response and received 4 cycles. Conclusions: Wild-type reovirus serotype 3 Dearing is well tolerated, with minimal toxicity, and MTD has not been reached. Despite a vigorous host response to virus, tumor necrosis associated with intratumoral viral replication was observed. Clinical indications of anticancer activity were seen and phase II studies are planned. [Table: see text]
NovoTTF-100A alternating electric fields therapy for recurrent glioblastoma: An analysis of patient registry data.
Authors: Eric T. Wong, Herbert H Engelhard, David Dinh Tran, Yvonne Kew, Maciej M. Mrugala, Robert Cavaliere, John L. Villano, Daniela Annenelie Bota, Jeremy Rudnick, Ashley Love Sumrall, Jay-Jiguang Zhu
Journal: Journal of Clinical Oncology (2014)

e13033 Background: The NovoTTF-100A is a first-of-a-kind anticancer device, approved by the Food and Drug Administration in 2011, for the treatment of recurrent glioblastomas. It emits alternating electric fields, at an intensity of 1 V/cm and a frequency of 200 kHz, that mimic the cytotoxic effect of chemotherapy by disrupting charged cytoplasmic proteins involved in the tightly orchestrated process of mitosis. Past phase III trial demonstrated equivalent efficacy when the device was compared to conventional cytotoxic chemotherapies and bevacizumab, but without their systemic side effects. Methods: The NovoTTF-100A device has been available by prescription at 91 oncology centers in the United States since November 2011. We retrospectively analyzed the outcome and toxicity data from patients who were prescribed the device from October 2011 to November 2013 as treatment for their recurrent glioblastomas. Results: There were 147 female and 310 male patients (n=457) who were treated with this device. The median age was 55 (range 18 to 86) years. The Kaplan-Meier median OS was 9.6 (95% confidence interval [CI] 8.0 to 13.7) months and the median treatment duration was 4.1 (95% CI 3.5 to 4.8) months. The most common device-related adverse events include skin reaction (24.3%), neurological disorders (10.4%), heat sensation (8.9%), electric sensation (7.7%) and headache (5.7%). Conclusions: Treatment with NovoTTF-100A, as prescribed in the general clinical setting to patients with recurrent glioblastomas, offers favorable outcomes compared to historical patient data. The adverse event profile of the device remains benign with no new unexpected toxicities.
Heterogeneous populations driven by clinical practice: A case example comparing enzalutamide (ENZA) and bicalutamide (BIC).
Authors: Ruth Kim, M. Alan Brookhart, Scott Flanders, Neil M. Schultz, Jon Fryzek, Arie Barlev
Journal: Journal of Clinical Oncology (2017)

e571 Background: Comparative real-world insurance claims data (RWD) analysis can be used to compare homogeneous cohorts (to avoid selection bias). Since the National Comprehensive Cancer Network guidelines recommend ENZA for metastatic castration-resistant prostate cancer (PC) and BIC for localized PC, it was of interest to evaluate these 2 heterogeneous cohorts as the ENZA cohort, being further advanced in the disease, has a worse prognosis than the BIC cohort. Here, we describe the results of a post hoc analysis on the ENZA and BIC cohorts to confirm the heterogeneity of demographics presented in a published study (Behl A et al. J Clin Oncol. 2016;34:235). Methods: The RWD captured enrollees with PC, claims for ENZA or BIC from 09/01/2012–12/31/2014, and at least 6 mo of continuous enrollment prior to the index date. After replicating methods from Behl et al using Truvan, we explored the balance of demographics in baseline periods greater than 6 mo. Differences in demographics and the post hoc analysis were compared. Results: Behl et al reported balanced age between the ENZA (73.1±10.0 y) and BIC (71.4±10.5 y) cohorts. However, 90% (531/592) of the ENZA cohort were metastatic vs 35% (1917/5524) of the BIC cohort. The Quan-Charlson comorbidity index was higher for the ENZA (5.6±2.1 y) than BIC (3.2±2.1 y) cohort. In the ENZA cohort, abiraterone acetate (ABI) or BIC utilization in the baseline period was higher (53%) than in the BIC cohort (0%). When the baseline period was greater than 6 mo, per our post hoc analysis, prior use of ABI or BIC increased to 68% for the ENZA cohort and remained unchanged in the BIC cohort. Conclusions: Despite results from the Behl analysis, the ENZA and BIC cohorts were dissimilar; ENZA patients had more advanced disease (metastatic disease; received ≥ 1 therapy) than BIC patients. Comparison of such heterogeneous populations can lead to biased estimates of treatment effects. Analyses lacking appropriate measures of prognostic variables that guide treatment decisions should be cautiously interpreted. Further analysis is required to identify best practices for using RWD and to address confounding driven by clinical practice.
Mortality risk disparities in children receiving chronic renal replacement therapy for the treatment of end-stage renal disease across Europe: an ESPN-ERA/EDTA registry analysis
Authors: Nicholas C Chesnaye, Franz Schaefer, Marjolein Bonthuis, Rebecca Holman, Sergey Baiko, Esra Baskın, Anna Bjerre, Sylvie Cloarec, Elisabeth A M Cornelissen, Laura Espinosa, James Heaf, Rosário Stone, Diamant Shtiza, Ilona Zagozdzon, Jérôme Harambat, Kitty J Jager, Jaap W Groothoff, Karlijn J van Stralen
Journal: The Lancet (2017)
Frequent expression of MAGE tumor antigens in bronchial epithelium of chronic smokers without lung cancer
Authors: Ashutosh Pathak, Manisha Bhutani, Diane Liu, Jack Lee, Hongli Tang, You-Hong Fan, Jonathan Kurie, Rodolfo Morice, Waun Hong, Li Mao
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

1692 

Background : Melanoma antigens ( MAGE ) type 1are considered tumor-specific antigens and potential targets for cancer management. We have earlier shown that MAGE -A1, -A3, and -B2 genes frequently express in patients of non-small cell lung cancers (NSCLCs). Importantly, these genes also expressed in the adjacent normal lungs of these patients raising the possibility that activation of MAGE occurs in carcinogen-exposed bronchial epithelial cells. The purpose of current study was to test the hypothesis that MAGE activation is an important event in lung carcinogenesis and occurs early enough in the bronchial epithelium to be used as a potential biomarker for lung cancer prevention studies.

Methods: We tested MAGE -A1, -A3, and -B2 genes expression profiles in bronchial brush samples from chronic smokers, enrolled on a lung chemoprevention clinical trial, by reverse transcription- PCR (RT-PCR). Bronchial brush samples were obtained from six different sites per individual. We analyzed the expression profiles with clinicopathologic parameters using both patients (expression index of six bronchial brush sites of each patient) and the bronchial brush sites as separate analytic units.

Results: The median age of the 66 subjects was 54 yr (range 32-73 yr), including 17 former smokers (who stopped smoking for more than 12 months) and 49 current smokers, and had a median of 38 pack-years smoking history. Among the 66 chronic smokers, 37 (56%), 50 (76%), and 25 (38%) had detectable MAGE -A1, -A3, and -B2 expression, respectively in at least one of the bronchial brushing sites. Of the total 391 bronchial brush specimens tested, MAGE -A1, -A3, and -B2 expression was detected in 61 (16%), 103 (26%), and 43 (11%) respectively. More importantly, as compared to former smokers, significantly higher proportion of current smokers had positive expression of MAGE A1 (35% Vs 63%, P = 0.045). On further analysis with GEE model on MAGE expression, using the site (nested in participant) as a unit, we found that significantly higher proportion of sites in current smokers ( P = 0.04) had positive expression of MAGE - A1 adjusted for age and MAGE B2 ( P = 0.02) adjusted for pack-years. Conclusions: MAGE -A1, -A3, and -B2 genes are frequently expressed in bronchial epithelium of chronic smokers without the evidence of lung cancer, suggesting that smoking activates MAGE genes. Smoking cessation might reduce the incidence of expression of these genes. These findings, together with the fact that such genes are not expressed in normal lungs and have an important role in lung cancer growth regulation, suggest that these molecules may serve as biomarkers in early detection and/or surrogate endpoints for lung chemoprevention trials.
Key considerations on nebulization of antimicrobial agents to mechanically ventilated patients
Authors: J. Rello, J.J. Rouby, C. Sole-Lleonart, J. Chastre, S. Blot, C.E. Luyt, J. Riera, M.C. Vos, A. Monsel, J. Dhanani, J.A. Roberts
Journal: Clinical Microbiology and Infection (2017)
Outcomes of ERCC1 high locally advanced esophageal cancer patients treated with non-platinum vs platinum based CRT.
Authors: Meera Yogarajah, Chipman Robert Geoffrey Stroud, Aparna Madhukeshwar Hegde, Paul R. Walker
Journal: Journal of Clinical Oncology (2017)

192 Background: ERCC1 is a DNA excision repair enzyme which repairs the DNA adduct damage caused by platinum and hence high levels of ERCC1 has been associated with platinum resistance. Thus utility of platinum as a first line chemotherapy in esophageal cancers with high ERCC1 levels is controversial. SWOG S0356 trial noted a significantly low 2 year overall survival of 37% for platinum based CRT in ERCC1 high esophageal carcinomas, yet no studies have identified the alternative first line chemotherapy. Our Program utilized combined irinotecan 65mg/m 2 on D1 and D8 and nab-paclitaxel 100mg/m 2 with concurrent radiation therapy of 50.4Gy for ERCC1 high esophageal cancers at the treating physician’s discretion. We compared the differences in survival with non-platinum versus platinum CRT. Methods: Retrospective analysis from 2011 to 2016 identified 25 locally advanced esophageal cancer patients in whom ERCC1 levels were checked. Out of this 25 patients 23 had high ERCC1 levels and 2 had low ERCC1 levels. Patients with low ERCC1 were excluded. Patients with high ERCC1 levels received either non-platinum or platinum CRT as neo-adjuvant, adjuvant or definitive chemotherapy. Results: Patient characteristics: Male 69.5%, female 30.5%, squamous 43.4%, adenocarcinoma 52.1%, other 4.5%, operable 39%, non-operable 61%. Non-platinum therapy was utilized for 69.5% and platinum based therapy for 30.5% of the patients. Kaplan-Meier analysis for survival showed clear separation of the curves around 2 years. Median overall survival of non-platinum doublet was not reached during a median follow up of 22 months. Overall survival at 2 years was 57%. The median overall survival for the platinum doublet was 22 months and the 2 year overall survival was 42%. (p = 0.22). Hazard ratio (HR) 0.48(95% CI 0.14-1.58 p = 0.23) .This statistical non significance was due to small sample size. Conclusions: Abraxane and irinotecan showed improved overall survival in the ERCC1 high group when compared with platinum based therapy demonstrated both in our population and the SWOG 0356 trial. [Table: see text]
A phase I/II randomized trial using GM-CSF-producing and CD40L-expressing bystander cell line (GM.CD40L) vaccine in combination with CCL21 in stage IV lung adenocarcinoma: Preliminary results.
Authors: Jhanelle Elaine Gray, Alberto Chiappori, Charles C. Williams, Mary Colleen Pinder, Eric B. Haura, Jongphil Kim, Germaine Gonzalez, David Noyes, Scott J. Antonia
Journal: Journal of Clinical Oncology (2013)

3091 Background: Our GM.CD40L vaccine (an allogeneic tumor cell-based vaccine generated from human bystander cell line) recruits and activates dendritic cells, which then migrate to regional lymph nodes, where T cell activation occurs, leading to systemic tumor cell killing. The CCL21 chemokine helps to recruit T cells and leads to enhanced T cell responses. The GM.CD40L.CCL21 combination has demonstrated additive effects in NSCLC mouse models. Methods: We initiated a phase I/II randomized study to evaluate GM.CD40L (Arm A) vs. GM.CD40L.CCL21 (Arm B) in patients with lung adenocarcinoma who had failed first-line therapy. Primary endpoints were safety and tolerability of Arm B in phase I and progression-free survival (PFS) in phase II; secondary endpoints included anti-tumor immune responses/T-cell responses by ELISpot assay on PBMC. Immune-related response criteria as determined by the investigator served to determine discontinuation from study treatment. Intradermal vaccines were administered every 14 days for 3 doses and then monthly X3. A two-stage minimax design was used. Results: In phase I, 3 patients received GM.CD40L.CCL21; no dose-limiting toxicities occurred. Between 4/2012 and 12/2012, Arm A enrolled 11 and Arm B enrolled 16 patients, including those in phase I (median age: 70/67.5 years, females: 45.5%/37.5%, PS1: 54.5%/75%, median prior regimens: 3/5 for Arm A vs. Arm B, respectively). Most common toxicities for Arm A vs. Arm B were injection site reaction (45.5%/43.8%), fatigue (9.1%/37.5%), anorexia (0%/12.5%), and pain in extremity (0%/12.5%). Median PFS for Arm A vs. B was 4.4 vs. 4.4 months (p=0.37). Of the 6 patients who remained on study post RECIST v1.1 progression, all demonstrated further progression on subsequent scans and were removed from the study. Of patients evaluable for efficacy, stable disease was 3/7 and progressive disease was 6/7 for Arm A vs. Arm B, respectively. Analyses of ELISpot assay on the PBMC are underway. Conclusions: GM.CD40L.CCL21 vaccine is well tolerated; thus far, median PFS results are similar to GM.CD40L vaccine. Updated results of the phase II trial will be presented. Clinical trial information: NCT01433172.
Erratum: Corrigendum: Trans-presentation of IL-6 by dendritic cells is required for the priming of pathogenic TH17 cells
Authors: Sylvia Heink, Nir Yogev, Christoph Garbers, Marina Herwerth, Lilian Aly, Christiane Gasperi, Veronika Husterer, Andrew L Croxford, Katja Möller-Hackbarth, Harald S Bartsch, Karl Sotlar, Stefan Krebs, Tommy Regen, Helmut Blum, Bernhard Hemmer, Thomas Misgeld, Thomas F Wunderlich, Juan Hidalgo, Mohamed Oukka, Stefan Rose-John, Marc Schmidt-Supprian, Ari Waisman, Thomas Korn
Journal: Nature Immunology (2017)