tbuckley/cabot-search huggingface dataset:
Evaluation of an intervention to improve communication about phase I/II trials.
Authors: L. Fallowfield, I. Solis-Trapala, C. I. Langridge, V. A. Jenkins
Journal: Journal of Clinical Oncology (2011)

6028 Background: Communicating well with patients and families about early phase cancer trials presents many challenges. Studies examining the informed consent process show deficiencies including failure to check understanding about prognosis, a lack of clarity about the experimental nature of trials and inadequate discussion of palliative care options (Jenkins et al, JCO, 2010). We evaluated a one-day facilitator led, modular program combining DVD review and group discussion with exercises and evidence-based didactic presentations. DVDs were based on real scenarios with breast, melanoma, colorectal and lung cancer patients and were presented as 4 modules dealing with standard chemotherapy plus novel agents, monoclonal antibodies, standard dose escalation studies and phase II targeted treatment trials. Methods: Objective and subjective assessments were made pre (T1) and post (T2) workshop. We tape-recorded 47 participants conducting Phase I/II trial interviews with simulated patients. Coders blinded to time-point rated tapes for inclusion and omission of key areas. Patient simulators at T1 and T2 rated presence and comprehensiveness of communication needed to elicit informed consent. Finally participants completed assessments of self-confidence. Results: Significant improvements in communication behaviours were found post course. Objective analysis comparing taped interviews at T1 and T2 showed positive shifts in issues such as:- establishing knowledge of prognosis (p=0.005), discussing symptomatic care options (p=0.002), and the experimental nature of trials (p=0.009). Patient simulator ratings showed overall improvements in key areas including awareness of palliative/symptom control options (p=0.004), voluntariness of participation (p=0.004), opportunity to ask questions (p=0.044) and time to consider participation (p=0.009). Participants own self confidence increased significantly in all 13 areas probed (p≤0.008). Conclusions: This short, but intensive, educational workshop changed the communication skills and self efficacy of healthcare professionals in ways likely to promote better understanding and valid, ethically informed consent from patients contemplating early phase trial entry.
Bevacizumab (Bev) with or without erlotinib as maintenance therapy, in patients (pts) with metastatic colorectal cancer (mCRC): Exploratory analysis according to KRAS status in the gercor DREAM phase III trial.
Authors: Benoit Samson, Christophe Tournigand, Werner Scheithauer, Gérard Lledo, Frédéric Viret, Thierry André, Jean François Ramée, Nicole Tubiana-Mathieu, Jérôme Dauba, Olivier Dupuis, Yves Rinaldi, May Mabro, Nathalie Aucoin, Ahmed Khalil, Jean Latreille, Christophe Louvet, David Brusquant, Franck Bonnetain, Benoist Chibaudel, Aimery De Gramont
Journal: Journal of Clinical Oncology (2013)

448 Background: In the GERCOR-DREAM trial, maintenance therapy (MT) with bev + EGFR tyrosine kinase inhibitor erlotinib (E) after a first-line Bev-based induction therapy (IT) in pts with mCRC significantly improved PFS compared with bev alone. Here we explore the influence of KRAS status on erlotinib efficacy. Methods: Pts with previously untreated and unresectable mCRC were eligible. After a Bev-based IT with FOLFOX or XELOX or FOLFIRI, pts without disease progression were randomized to MT between Bev alone (Bev 7.5 mg/kg q3w; arm A) or Bev+E (Bev 7.5 mg/kg q3w, E 150 mg/day continuously; arm B). KRAS determination was established by local assessment in each center. Results: Among the 452 randomized patients, KRAS status was available in 403 pts (89%): 234 pts (58%) KRAS wt and 169 pts (42%) KRAS mut. Clinical characteristics were similar between both populations. For the whole population of randomized patients (n=452), median PFS from inclusion were 9.33m and 10.55m in arm A and B, respectively (HR=0.76 [0.61-0.94], p=0.011). For KRAS wt population, median PFS from inclusion was 9.66 m and 10.94 m in arm A and B, respectively (HR=0.80 [0.59-1.08], p=0.141). For KRAS mut population, median PFS from inclusion was 9.79 m and 9.79 m in arm A and B, respectively (HR=0.86 [0.61-1.22], p=0.393). In KRAS wt pts treated with erlotinib, cutaneous toxicity was predictive of PFS: mPFS was 9.66m in pts with grade 0 (n=101) and 10.91m in pts with grade ≥1 (n=114) (HR=0.69 [0.51-0.95], p=0.0186). Conclusions: The addition of erlotinib to bevacizumab as maintenance treatment in first-line metastatic colorectal cancer significantly improves progression-free survival from inclusion. However, in both wt and mut KRAS pts, difference was not statistically significant. Unlike anti-EGFR monoclonal antibodies, the addition of erlotinib to bevacizumab does not appear to be antagonist in KRAS mutant patients. Clinical trial information: NCT00265824.
Cisplatin (C) based chemoradiation (CXRT) for locally advanced squamous cell carcinoma (SCCA) of the anal canal (AC): A 20-year perspective.
Authors: C. Eng, Y. Xing, Y. N. You, G. J. Chang, P. Das, J. Phillips, R. A. Wolff, M. A. Rodriguez-Bigas, A. Ohinata, C. H. Crane
Journal: Journal of Clinical Oncology (2011)

482 Background: The standard of care for locally advanced SCCA of the AC is 5-fluorouracil (5-FU)/mitomycin C (MMC) with concurrent XRT. C was evaluated with 5-FU in 2 large phase III studies (RTOG 98-11 and ACT II) to establish superiority over 5-FU/MMC. Neither study showed significant differences for disease-free survival (DFS) or overall survival (OS). RTOG 98-11 reported reduced colostomy-free survival (CFS) in the C-induction arm; no differences were noted in the ACT II study. We present our 20-year experience with C for locally advanced SCCA of the AC which has been adopted as the standard unless contraindicated. Methods: A retrospective, single institution analysis for locally advanced SCCA of the AC was completed in patients (pts) that received concurrent 5-FU/C/XRT from 1989-2009. Medical records were reviewed for history of STDs, chronic immunosuppression, stage, dose of XRT, toxicity, clinical response (CR), recurrence, and OS. Multidisciplinary management included surgical, radiation, and medical oncologists. OS, DFS, and CFS were calculated using the K-M method. The log-rank test was used to compare OS among these subgroups. Results: 185 pts were identified (51 M:134 F). The median age was 56 (35-83 y.o.). AJCC stage was I (n = 25); II (n = 76); IIIA (n = 36); and IIIB (n = 48). The median XRT dose was 55 Gy in 30 fractions. 181 pts were evaluable for response; 4 were lost to follow up. Complete CR (cCR) was noted in 169 pts (93%); partial response (n = 12); 6 pts received an APR. After a median follow up of 8.6 years, 14 pts (8%) developed local recurrence; 11 received salvage surgery. 16 pts (9%) developed distant metastases (DM). The 5-yr DFS = 81%, 5-yr OS = 85% and 5-yr CFS was 88%. By univariate analysis, N-stage was a poor prognostic indicator for 5-yr DFS (p = 0.02) and DM (p = 0.046) but not OS or CFS. Increased T-stage correlated with salvage surgery (p = 0.005). Conclusions: Cisplatin-based chemoradiation for locally advanced SCCA of the anal canal resulted in favorable DFS, OS, and CFS compared to historical data and phase III studies. Platinum-based therapy for anal cancer appears to be an acceptable alternative to MMC and should be considered as a standard option for locally advanced disease. No significant financial relationships to disclose.
FOXP1 controls mesenchymal stem cell commitment and senescence during skeletal aging
Authors: Hanjun Li, Pei Liu, Shuqin Xu, Yinghua Li, Joseph D. Dekker, Baojie Li, Ying Fan, Zhenlin Zhang, Yang Hong, Gong Yang, Tingting Tang, Yongxin Ren, Haley O. Tucker, Zhengju Yao, Xizhi Guo
Journal: Journal of Clinical Investigation (2017)

A hallmark of aged mesenchymal stem/progenitor cells (MSCs) in bone marrow is the pivot of differentiation potency from osteoblast to adipocyte coupled with a decrease in self-renewal capacity. However, how these cellular events are orchestrated in the aging progress is not fully understood. In this study, we have used molecular and genetic approaches to investigate the role of forkhead box P1 (FOXP1) in transcriptional control of MSC senescence. In bone marrow MSCs, FOXP1 expression levels declined with age in an inverse manner with those of the senescence marker p16INK4A. Conditional depletion of Foxp1 in bone marrow MSCs led to premature aging characteristics, including increased bone marrow adiposity, decreased bone mass, and impaired MSC self-renewal capacity in mice. At the molecular level, FOXP1 regulated cell-fate choice of MSCs through interactions with the CEBPβ/δ complex and recombination signal binding protein for immunoglobulin κ J region (RBPjκ), key modulators of adipogenesis and osteogenesis, respectively. Loss of p16INK4A in Foxp1-deficient MSCs partially rescued the defects in replication capacity and bone mass accrual. Promoter occupancy analyses revealed that FOXP1 directly represses transcription of p16INK4A. These results indicate that FOXP1 attenuates MSC senescence by orchestrating their cell-fate switch while maintaining their replicative capacity in a dose- and age-dependent manner.
Perceptions of radiation oncologists and urologists on the type of evidence that informs and changes the clinical practice of prostate cancer.
Authors: Sophia D Delpe, Nilay Shah, Jon Charles Tilburt, R. Jeffrey Karnes, Paul Linh Nguyen, Brian Shuch, Cary Gross, Peter Schulam, James B. Yu, Jeanette Ziegenfuss, Simon Kim
Journal: Journal of Clinical Oncology (2014)

167 Background: Physicians have a variety of resources available about the treatment of localized prostate cancer. Yet, it is largely unknown what resources and evidence radiation oncologists and urologists commonly use to inform patients and possibly alter clinical practice. In this national survey study, we assessed the types of resources prostate cancer specialists’ use and the level of evidence needed to change treatment recommendations in localized prostate cancer. Methods: From a random sample, 1,422 physicians were sent a mail survey assessing what type of information was used to guide prostate cancer treatment. The survey also queried what level of evidence could alter recommendations. Multivariable logistic regression models were used to identify for differences in physician characteristics for each outcome. Results: Survey response rates were similar for radiation oncologists and urologists (44% vs. 46%; p=0.46). Specialty-specific journals represented the most commonly used resource to inform the clinical practice for radiation oncologists (65%) and urologists (70%). Relative to radiation oncologists, urologists were less likely to utilize medical journals (25% vs. 38.7%, OR: 0.50; p=0.01), cancer journals (21.7% vs. 50.8%, OR: 0.50; p&lt;0.001), but more likely to rely on clinical guidelines (46.3% vs. 37.7%,OR: 1.6; p=0.006). Radiation oncologists and urologists both viewed RCT’s as the most likely source of evidence needed to change treatment recommendations (85% vs. 77%). Conclusions: Both specialties most commonly rely on their specialty-specific journals to inform their clinical practice and view RCT’s as the level of evidence needed to change treatment recommendations for localized prostate cancer. Radiation oncologists embraced greater diversity in literature, while urologists were more likely to use clinical guidelines. Utilizing this information may overcome barriers to the dissemination and adoption of new treatment paradigms for localized prostate cancer.
Stool bacteriomic profiling in patients with metastatic renal cell carcinoma suggests an etiology of VEGF TKI-related diarrhea.
Authors: Sumanta Kumar Pal, Sierra Mi Li, Xiwei Wu, Manasvi Pinnamaneni, JoAnn Hsu, Courtney Carmichael, Paul Henry Frankel
Journal: Journal of Clinical Oncology (2015)

421 Background: Vascular endothelial growth factor-tyrosine kinase inhibitors (VEGF TKIs) remain a mainstay of therapy for patients with metastatic renal cell carcinoma (mRCC). Diarrhea represents a pervasive toxicity, with all grade diarrhea affecting roughly 50% of patients receiving VEGF TKIs. The underlying cause of diarrhea in these patients is poorly understood. Methods: Patients with mRCC receiving an FDA-approved VEGF TKI therapy for mRCC were consented. Stool was collected in a standardized fashion and total genomic DNA was isolated using the PowerSoil DNA isolation kit (Mo Bio, USA). A standard PCR protocol was used to amplify bacterial 16S rRNA genes from all samples. PCR primers were used to amplify the V4 and V5 regions of the 16S rRNA. Paired-end of sequencing 2X100bp was performed by Illumina HiSeq 2000, and sequences were clustered using the CD-HIT clustering algorithm. Taxonomy was then assigned using the RDP-II classifier. Non-clustered analyses were also performed, stratifying patients by the presence or absence of diarrhea at the time of stool collection. Results: Of 26 patients consented, 23 patients submitted stool specimens and 20 had sufficient data for the current analysis. Amongst these 20 patients, the median age was 63 and the majority of patients (60%) were intermediate risk by Heng criteria. Eight patients (40%) received VEGF TKI therapy in the first-line setting. Across all lines of therapy, the most commonly used VEGF TKI was sunitinib (44%). A total of 141 bacterial species were identified. With respect to differences in patients who did and did not have diarrhea, the Mann-Whitney U-test identified 7 species with a p value of &lt;0.1. The largest difference was seen in two Bifidobacterium species, B. animalis and B. bifidum, with both bacteria more abundant in patients with no diarrhea. Conclusions: This is the first effort to use stool bacteriomic profiling to ascertain the etiology of VEGF TKI related diarrhea in patients with mRCC. Two Bifidobacterium spp identified in this analysis are commonly found in probiotics. Studies to use probiotics enriched with Bifidobacterium spp to prevent or ameliorate VEGF TKI-related diarrhea are currently in development.
Holter monitor cardiac safety evaluation of vincristine sulfate liposomes injection (VSLI) administered to humans with active cancer.
Authors: T. Sato, A. Y. Bedikian, J. A. Glaspy, R. Gonzalez, L. Prasad, G. L. Messerschmidt, J. Silverman, S. R. Deitcher
Journal: Journal of Clinical Oncology (2011)

e13005 Background: VSLI is vincristine (VCR) encapsulated in sphingomyelin and cholesterol liposome nanoparticles. VSLI is intended to enhance the dosing intensity and density, pharmacokinetic profile (PK), and cancer tissue penetration and accumulation of VCR. VSLI, up to 5.2 µM, had no inhibitory effect on the in vitro hERG channel assay and no effect on blood pressure or ECG patterns in dogs. Because standard VCR has been anecdotally reported to be associated with QT prolongation, a human cardiac safety evaluation was performed as part of VSLI development. Methods: A subset (N = 12) of subjects enrolled in a phase II multicenter, open-label, single-arm trial evaluating weekly VSLI 2.25 mg/m2 (without dose cap) for untreated metastatic uveal melanoma were monitored for cardiac safety using a 12-lead Holter monitor begun 24 hours prior to the first dose of VSLI and continued for 24 hours after the infusion start. Fridericia’s and Bazett’s correction formulae were used for QTc interval calculations. Abnormal QTcF was ≥460 msec or >60 msec change from baseline. Plasma samples for PK analysis were correlated to ECGs. Results: VSLI infusions of VCR ranged from 2.9 to 6.4 mg. Changes from baseline for key ECG values are provided in the table. No abnormal QTcF were recorded. No cases of first-degree or high-grade AV block were noted. None of the changes described in the table were considered to be clinically significant; therefore, there was no event correlation with PK. Conclusions: There is no evidence that VSLI, despite delivering VCR doses (mg/m2 or total mg) in excess to those routinely delivered with standard VCR, is associated with any potentially clinically significant changes in ECG variables in active cancer patients. The PK of VSLI is distinct from standard VCR and nearly all of the VCR in VSLI remains encapsulated (not free) during plasma circulation. To the best of our knowledge, a formal cardiac safety assessment of standard VCR remains to be reported. Maximum decrease mean ± SD Maximum increase mean ± SD Heart rate, bpm -8.0 ± 10.7 at 2 h 6.9 ± 13.0 at 24 h PR interval, msec -3.5 ± 8.6 at 10 h 10.3 ± 15.3 at 45 m QRS duration, msec -0.2 ± 4.1 at 10 h 3.2 ± 3.5 at 30 m QTcF duration, msec -2.1 ± 14.0 at 24 h 7.0 ± 16.1 at 15 m
Hedgehog inhibition and radiation therapy in non-small cell lung cancer.
Authors: J. Zeng, K. Aziz, M. Armour, B. Aftab, R. Gajula, S. Chettair, T. Salih, C. M. Rudin, P. T. Tran, R. Hales
Journal: Journal of Clinical Oncology (2011)

7065 Background: Radiation concurrent with cytotoxic chemotherapy remains the standard of care for the management of locally advanced NSCLC. Despite this treatment paradigm, local control remains a problem with local recurrence in 50-75% of patients, and may be an important contributor to metastatic spread. The hedgehog signaling pathway is aberrantly activated in adult malignancies, including NSCLC. We seek to investigate the effect of Hh pathway inhibition on radiation response in preclinical modals of NSCLC. Methods: Utilizing in vitro and in vivo models, we studied hedgehog inhibitor (HhI) cytotoxicity and radiosensitization in NSCLC. In vitro we examined the effect of HhI with and without radiation on cell death, clonogenic survival, cell cycle distribution, and GLI1 expression. Using a hind-flank xenograft model, we looked at tumor growth delay and Ki-67 staining. In a novel inducible transgenic mouse model of KrasG12D/Twist-induced autochthonous lung adenocarcinoma, tumor responses to lung radiation with or without HhI were assessed serially with weekly microCT. Results: HhI sensitized A549 cells to ionizing radiation as shown by colony formation assays (enhancement ratio 1.3). Increased cell death was a result of increased apoptosis as shown by annexin-V expression. A549 had high GLI1 expression via Western, but did not show cell cycle changes upon treatment with HhI. Hind-flank xenograft experiments demonstrate HhI and radiation delay tumor growth in vivo (one-way ANOVA p<0.001). Ki-67 immunofluorescence showed decreased cellular proliferation in tumors treated with HhI. In transgenic mice with autochthonous lung tumors, weekly micro-CT revealed improved tumor shrinkage with the addition of HhI to lung radiation. At 1-week post-radiation, HhI and radiation induced 45% tumor shrinkage, whereas radiation alone was 17% and HhI alone was 12% (p<0.01 by two-tailed t-test). Conclusions: Our data show that selectively targeting the hedgehog pathway increases the effectiveness of radiation in in-vitro and in-vivo systems of NSCLC. This data provides a framework for clinical translation of HhI with concurrent chemoradiotherapy in locally advanced NSCLC.
Biologic risk model for recurrence in resected early-stage non-small cell lung cancer (ES NSCLC).
Authors: K. A. Gold, J. J. Lee, Y. Ping, C. Behrens, D. Liu, H. Lee, J. S. Koo, R. Lotan, L. Solis, W. Rinsurongkawong, D. J. Stewart, W. L. Hofstetter, S. Swisher, S. M. Lippman, I. I. Wistuba, W. K. Hong, E. S. Kim
Journal: Journal of Clinical Oncology (2011)

7053 Background: Patients (pts) with resected ES NSCLC are at risk for recurrence of disease and mortality but we do not have tools to predict which pts are at highest risk. Risk models have been proposed but have not included predictive biomarkers for recurrence. Methods: We assembled a large comprehensive database with archival tissues and clinical follow-up from pts with resected ES NSCLC between 2002-2005. 21 biomarkers identified from our preclinical studies as related to pathogenesis of NSCLC were investigated, including pathways related to apoptosis, metabolism, DNA repair, inflammation and growth factors. Tissue microarrays were constructed from archived specimens. Cox models were fitted to estimate effects of clinical factors and biomarkers on recurrence free survival (RFS) and overall survival (OS). Predictive accuracy was quantified by C-index. Results: 370 pts are included in our analysis, 50.3% (186 pts) male, 89% (330) white. Smoking status: 44% (162) current, 46% (170) former, 10% (38) never. Stage IA 28% (103), IB 35% (131), II 20% (75), IIIA 17% (61). Adenocarcinoma 61% (227), squamous 34% (126). 45% (160) received chemotherapy or radiation as well as surgery. With median follow-up of 5.3 yrs, median OS is 6.4 yrs. 209 cases with recurrence or death were observed. The biologic risk model included relevant biomarkers, age and stage. See table for significant (p<.05) predictive markers after adjusting for age and stage. C-index is 0.66 for both models indicating adequate prediction accuracy. Conclusions: We have developed a biologic risk model predictive for recurrence in our large retrospective database. This is the first report of a risk model incorporating biomarkers and will be validated in our ongoing prospective study. DoD W81XWH-04-1-0142, NCIP01 91844. Hazard ratio RFS Hazard ratio OS Pathway Negative cytoplasmic(c-) pAMPK 1.54 1.49 Metabolism Positive membrane (m-) insulin receptor 1.44 n/a Proliferation Negative c-EpCAM 1.41 1.54 Differentiation Negative c- pmTOR 1.44 1.51 Metabolism High c-CXCR2 1.36 1.57 Inflammation High c- IGF1R (continuous variable) 1.004 n/a Proliferation Low m-CASK (continuous variable) 1.004 n/a Extracellular matrix interaction High nuclear FEN1 n/a 1.42 DNA repair
Predictors and prevalence of germ-line BRCA1 and BRCA2 mutations in high-risk patients screened at a community hospital.
Authors: S. S. Riaz, S. Ahsan, R. E. Bloom
Journal: Journal of Clinical Oncology (2011)

e11124 Background: Germline mutations in tumor suppressor genes, BRCA1 and BRCA2, confer high risks of breast and ovarian cancer in affected individuals. Genetic testing for these pathogenic mutations has potentially important health implications for judicious counseling and screening of high risk individuals. Methods: A retrospective analysis was conducted of all the patients seen at the oncology and genetics clinic from 2000 to 2010. A population of over 500 patients was identified, out of whom 310 subjects underwent risk factor assessment and genetic counseling. BRCA testing was performed on 231 of these subjects whereas 79 subjects were not tested secondary to lack of insurance/follow up, or patient/physician preference. Various ethnic groups were identified which included 138 Caucasian, 41 African American, 28 Ashkenazi Jewish, 4 Middle Eastern, 2 Asian and 2 Hispanic subjects. The race/ethnicity of 16 subjects was unknown secondary to lack of documentation. Results: BRCA mutation testing was completed on 231 subjects out of whom 34 were identified as carriers, comprising 14.72% of the population screened. Out of these, 31 were female and 3 were male individuals.25 subjects carried BRCA1 and 11 subjects carried BRCA2 mutations, whereas 2 subjects carried both mutations simultaneously. The population screened was divided into 4 main groups for which using the Maximum Likelihood Ratio Chi-Square Test, a p-value of 0.96 (p=0.9633) was obtained which indicated that the proportion of mutation did not differ for the races amongst the population screened. Conclusions: The estimated race/ethnicity prevalence of BRCA mutations was found to be the highest in African American followed by Caucasian and Ashkenazi Jewish subjects in the population screened at our facility. Overall, BRCA mutations are more common in the Jewish population on which most of the research has been focused. Our study is one of the few to indicate the possibility of high prevalence of mutations in the under-studied and less reported high risk kindred i.e the African Americans. Race Total No. Mutations Proportions Caucasian 138 20 14.49% Ashkenazi Jewish 28 4 14.29% African Americans 41 7 17.07% Others 24 3 12.07% Total 231 34 14.72%