tbuckley/cabot-search huggingface dataset:
Observational study evaluating resource utilization among metastatic renal cell carcinoma patients treated with mTOR inhibitors in the outpatient community-based setting.
Authors: C. Chen, S. K. Gruschkus, Z. Liu, N. J. Vogelzang, M. T. Forsyth, W. Lopez, T. E. Hutson
Journal: Journal of Clinical Oncology (2010)

e15027 Background: Everolimus (E), an oral mTOR inhibitor, was approved by the FDA on 3/30/2009 for the treatment of advanced renal cell carcinoma (RCC). The purpose of this retrospective study was to evaluate outpatient resource utilization associated with E relative to temsirolimus (T), an intravenous mTOR inhibitor indicated for advanced RCC. Methods: Using US Oncology's (USO) iKnowMed EMR data, we identified metastatic RCC patients (pts) who initiated a regimen of E or T from 4/1/2009 – 7/31/2009. Claims for services incurred within the USO network were used in conjunction with pharmacy data from USO's pharmacies to estimate outpatient costs and resource utilization (frequency of outpatient visits, inpatient visits, and laboratory procedures). Costs for T were based on Medicare reimbursement rates, while costs for E were based on wholesale acquisition costs. Pts were followed through 11/30/2009 to estimate outpatient costs and resource utilization as calculated using a per patient-month (PPM) metric. Results: 107 pts were identified – 40 received E and 67 received T. Median age of pts was 66 (range: 23 – 86) and 65% were male. By payer status, 54% of pts were Medicare; 38% were Private; and 8% were Medicaid/self-pay/etc. Total costs PPM were similar between pts receiving E (mean = $5,913; median=$5,660) vs. T (mean = $5,767; median=$6,156) (p=0.62). Pts receiving E had significantly fewer outpatient visits per month vs. pts receiving T (mean/median = 1.69/1.60 vs. 4.0/3.8 visits per month; p<0.001) and also underwent fewer laboratory procedures (mean/median = 2.9/2.2 vs. 5.5/5.6 procedures per month; p<0.001). No statistically significant differences in inpatient admission rates were observed between pts receiving E vs. T (27% of E pts had inpatient visits vs. 28% of T pts, p=0.94). Conclusions: It is becoming increasingly important to weigh the relative costs and benefits of oral vs. intravenous therapies from multiple perspectives. Results of this preliminary observational study suggest that direct costs were similar between E and T; however, E was associated with lower patient burden in terms of outpatient and laboratory visits relative to T. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Novartis Novartis Novartis Novartis
Use of microarray-based comparative genomic hybridization analysis to identify prognostic subgroups of ovarian clear cell carcinomas.
Authors: D. S. Tan, M. Iravani, M. B. Lambros, A. Mackay, C. Gourley, A. Williams, W. G. McCluggage, A. Ashworth, S. B. Kaye, J. S. Reis- Filho
Journal: Journal of Clinical Oncology (2010)

5020 Background: Advanced ovarian clear cell carcinomas (OCCCs) are notoriously drug resistant and aggressive tumours. We previously focused our research efforts on identifying novel therapeutic targets in these tumours (Clin Can Res. 2009;15:2269- 80). The aim of this study was to identify prognostically distinct genomic subgroups of OCCCs. Methods: 50 pure archival OCCCs were reviewed by at least two gynaecologic pathologists, and subjected to microarray-based comparative genomic hybridisation (aCGH) using a 32K tiling-path platform. Unsupervised hierarchical clustering using Ward's linkage analysis was performed to identify genomic groups of OCCCs. Survival analysis was performed using a Kaplan-Meier method and log-rank test. Cox-regression analysis was used to identify independent predictors of outcome. Differentially amplified regions between genomic subgroups of OCCCs were identified using a Multi- Fisher's exact test. Results: Patients (pts) were diagnosed between October 1988 and March 2007 with a median follow-up period of 24 mths and median age of 57.5 yrs. Unsupervised hierarchical clustering analysis revealed 2 clusters of OCCCs with distinct clinical outcomes. Cluster 1 pts had a significantly shorter median progression free survival (PFS) than Cluster 2 pts (median survival 11 vs. 65 mths, p = 0.009) following first-line treatment. A trend towards poorer median overall survival (OS) was also observed for Cluster 1 compared with Cluster 2 pts (median survival 19 vs. 66 mths, p = 0.065). In multivariate analysis, suboptimal debulking surgery (HR = 6.811, 95%CI 2.359-19.663, p = 0.014) and genomic cluster (Cluster 2 vs. 1 OCCCs HR = 0.389, 95% CI: 0.174-0.872; p = 0.022) were independently prognostic for PFS. We identified 29 genomic regions significantly differentially gained at high level/amplified between cluster 1 and 2 OCCCs, including 8q24.3, 17q21.2, and 19q13.3, which may harbour potential mediators of tumour aggressiveness and chemoresistance. These regions may also harbour novel therapeutic targets for further assessment in OCCCs. Conclusions: Our results demonstrate that genomic heterogeneity and genomic subgroups of clinical significance exist in OCCCs. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Chugai Pharma, GlaxoSmithKline, Schering-Plough Schering-Plough Schering-Plough
Work and financial disparities among adult cancer survivors in the United States.
Authors: Robin L. Whitney, Janice Bell, Sarah Reed, Andra Davis, Rebecca Salisbury Lash, Katherine Kim, David Copenhaver, Richard J. Bold, Jill G. Joseph
Journal: Journal of Clinical Oncology (2014)

238 Background: The prevalence of cancer in the US continues to increase, with 18.1 million projected survivors by 2020. Few recent population-based studies have examined cancer-related work and financial disparities in this growing population. Methods: Cancer-related work modifications (e.g., changing to a flexible schedule or less demanding job, early or delayed retirement, extended or unpaid time off) and financial difficulties (e.g., debt, worry about medical bills, bankruptcy) were examined in the 2011 Medical Expenditures Panel Survey Experiences with Cancer Survivorship Supplement (n=1,592). Survey-weighted logistic regression was used to model the odds of having any work modification or financial difficulty and negative binomial regression to model counts of these outcomes as functions of survivorship status (i.e., active treatment, &lt;5 years post-treatment, and ≥5 post-treatment=reference) and socio-demographic covariates. Results are generalizable to the civilian, non-institutionalized US population. Results: Among survivors, 27% reported at least one financial difficulty and 37% reported making work modifications due to cancer. Significant predictors of work modifications included: active treatment (OR 2.9; 95% CI 1.7-4.9), with 40% more modifications than those ≥5 years post-treatment; females (OR 1.5; 95% CI 1.1-2.2), with 30% more modifications; and race/ethnicity other than white (OR 1.7; 95% CI 1.1-2.6,), with 54% more modifications. Significant predictors of financial difficulties included: active treatment (OR 3.2; 95% CI 2.1-5.0), with 92% more difficulties; age &lt;65 years (OR 2.4; 95% CI 1.7-3.3), with 130% more difficulties; no insurance (OR 2.4; 95% CI 1.3-4.4), with 67% more difficulties; and race/ethnicity other than white (OR 1.6; 95% CI 1.1-2.3), with 41% more difficulties. Conclusions: Significant work and financial disparities exist among US cancer survivors, particularly women, younger survivors, racial/ethnic minorities, and those without insurance. Active treatment predicted these concerns, but did not fully account for observed disparities. Screening and support for work and financial concerns is needed across the survivorship trajectory, with particular attention to groups at risk.
ICD/CRT‐D患者の高い除細動閾値(DFT)を予測するための心電図,心拍同期心筋SPECT(QGS)の有用性
Authors: Yagawa Mayuko, Inoue Kanki, Yamashita Mitsumi, Tanizaki Kohei, Umemura Jun, Sumiyoshi Tetsuya, Tomoike Hitonobu
Journal: Circulation (2012)
Dose reductions and delays in patients (pts) with renal cell carcinoma (RCC) treated with sorafenib (SR) or sunitinib (SU): Retrospective analysis of two large U.S. health care claims databases.
Authors: S. M. Keefe, E. Moyneur, S. Meyers, V. Barghout, K. T. Flaherty
Journal: Journal of Clinical Oncology (2010)

6090 Background: A previously conducted retrospective analysis demonstrated that RCC pts treated with first-line SU have a higher incidence of dose reduction than pts treated with SR. The primary objective of this study was to validate these findings through the addition of a second claims database and introduction of a comparison of treatment delays. Methods: Authors pooled data from two U.S. health care claims databases to create the primary dataset used to support this retrospective cohort study. Claims originated from the care of 35 million pts per year on average from 2002 to 2009 and represented all U.S. census regions. The analysis cohort included pts with ≥ 2 RCC claims (ICD9 189.0 or 198.0) who had continuous coverage during illness, ≥ 180 days' coverage preceding diagnosis (first RCC claim) with no prior SR/SU treatment. Only pts with ≥ 2 dispensings of standard doses of SR or SU as first-line treatment were compared. Reductions in dose and treatment delays (interruption of treatment for > 30 d for SR, > 42 d for SU) were tracked across first-line therapy. Results: Most first-line pts were treated initially with standard full doses (SR 89.5%, SU 88.2%; p = 0.449). Baseline characteristics were similar between 320 SR-treated and 684 SU-treated pts, except that SR- treated pts were older (mean age 62.7 vs. 60.2; p < 0.001) and had a higher prevalence of renal disease (24.1% vs. 16.8%; p = 0.007). First-line SU- treated pts were 1.95 times more likely and had a significantly higher incidence of ≥1 dose reduction (17.5% vs. 34.1%; p < 0.001). There was no difference in treatment delays between SR (19.7%) and SU (16.0%) groups (p = 0.142). Conclusions: This study, the largest comparative retrospective US claims database analysis of its kind to date, validates prior work presented by the authors. The incidences of dose reductions in this real- world cohort are comparable to those observed in phase 3 clinical trials of these agents. There was no difference in treatment delays between groups. Differences observed between SR- and SU-treated pts suggest that SR may be chosen in practice more often for older and sicker pts. Further analyses assessing outcomes are warranted. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bayer Bayer Bayer Bayer
Sensitivity of tumor cells deficient in the fanconi anemia pathway to inhibition of ataxia telangiectasia mutated (ATM)
Authors: R. D. Kennedy, P. Stuckert, E. Archila, M. De LaVega, C. Chen, L. Moreau, A. D'Andrea
Journal: Journal of Clinical Oncology (2007)

10509 Loss of the fanconi anemia (FA) pathway function has been described in a number of sporadic tumor types including breast, ovarian, pancreatic, head and neck and hematological malignancies. Functionally, the FA pathway responds to stalled DNA replication following DNA damage. Given the importance of the FA pathway in the response to DNA damage, we hypothesized that cells deficient in this pathway may become hyper-dependent on alternative DNA damage response pathways in order to respond to endogenous genotoxic stress such as occurs during metabolism. Therefore, targeting these alternative pathways could offer therapeutic strategies in FA pathway deficient tumors. To identify new therapeutic targets we treated FA pathway competent and deficient cells with a DNA damage response siRNA library, that individually knocked out 230 genes. We identified a number of gene targets that were specifically toxic to FA pathway deficient cells, amongst which was the DNA damage response kinase Ataxia Telangiectasia Mutated (ATM). To test the requirement for ATM in FA pathway deficient cells, we interbred Fancg ± Atm± mice. Consistent with the siRNA screen result, Fancg-/- Atm-/- mice were non viable and Fancg± Atm-/- and Fancg-/- Atm ± progeny were less frequent that would have been expected. Several human cell lines with FA gene mutations were observed to have constitutive activation of ATM which was markedly reduced on correction with the appropriate wild-type FA gene. Interestingly, FA pathway deficient cells, including the FANCC mutant and FANCG mutant pancreatic cancer cell lines, were selectively sensitive to monotherapy with the ATM inhibitor KU55933, as measured by dose inhibition and colony count assays. FA pathway deficient cells also demonstrated an increased level of chromosomal breakage, cell cycle arrest and apoptosis following KU55933 treatment when compared to FA pathway corrected cells. We conclude that FA pathway deficient cells have an increased requirement for ATM activation in order to respond to sporadic DNA damage. This offers the possibility that monotherapy with ATM inhibitors could be a therapeutic strategy for tumors that are deficient for the FA pathway. No significant financial relationships to disclose.
Circulating exosomes may provide a more sensitive platform to monitor disease progression compared to circulating tumor cells.
Authors: T. L. Pawlowski, D. Spetzler, T. Tinder, J. Kimbrough, T. Deng, J. Kim, P. Ellis, A. Tyrell, P. Kennedy, C. Kuslich
Journal: Journal of Clinical Oncology (2010)

10580 Background: Circulating tumor cells (CTCs) have been used to monitor disease progression in patients with different types of metastatic cancer. However only 50% of metastatic breast, 57% of metastatic prostate, and 18% of metastatic colon cancer blood specimens have adequate levels of CTCs for clinical laboratory analysis. Levels of exosomes have recently been shown to correlate with tumor progression. Methods: Exosomes from 1 ml of plasma were isolated by ultracentrifugation. CD-81 antibodies were used to capture and measure the exosome level of breast cancer samples (n=14) and healthy controls (n=4). CTCs were measured for all samples using the Cell Search CTC test protocol. Subsequently, EpCam positive exosomes were captured from metastatic breast (n=10), prostate (n=2), and colon cancer (n=3) samples, and compared to healthy controls (n=7). RNA was extracted from these EpCam positive exosomes and microRNA-21 (miR-21) expression was quantified by a qRT-PCR. Results: The preliminary study of breast cancer samples established 11 of the 14 samples (78.6%) had CD-81 specific exosome levels significantly above the level found in the 4 healthy samples (p=0.002). Only 7 of the 14 (50%) specimens analyzed had more than 5 CTCs, the clinical threshold for metastatic breast cancer. Three cancer samples had CD-81 measured exosome levels below the average of normal samples, one of these had >5 CTCs. miR- 21 analysis of 15 additional metastatic cancer specimens, 5 of which had >5 CTCs, found miR-21 averaged 4.2 × 106, 4.82 × 106 and 5.05 × 106 copies in the breast, prostate, and colon cancer samples respectively. Conversely, the plasma specimens from healthy donors collected in EDTA tubes averaged 1.8 × 104 copies of miR21. Conclusions: This study suggests that exosome analysis from plasma samples may offer a greater opportunity to monitor and track disease than CTC analysis, while acknowledging that further study will be necessary to establish clinical definitions of exosome load. Furthermore, tumor-derived exosomes provide the ability to characterize tumor of origin miR content, which demonstrates additional opportunities for tumor-specific exosome-based biomarker analysis from a blood sample. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Caris MPI
The temozolomide O6-methylguanine-DNA methyltransferase (MGMT) study: A phase II trial to evaluate the effect of low-dose preoperative neoadjuvant temozolomide on brain tumour MGMT activity in glioma patients
Authors: R. F. Del Maestro, V. Siu, M. Seyed Sadr, J. Alshami, C. Sabau, E. Seyed Sadr, A. Samani, S. Assadian, K. Greaves, J. Pouliot
Journal: Journal of Clinical Oncology (2009)

e13027 Background: Epigenetic methylation of the O6-methylguanine-DNA methyltransferase (MGMT) DNA repair gene promoter in tumor tissue from glioblastoma multiforme patients is associated with improved survival after treatment with radiotherapy plus concomitant and adjuvant temozolomide (TMZ). We hypothesized that MGMT promoter methylation mosaicism exists in glial tumors and would affect response to TMZ. Methods: This is a nonrandomized, prospective, open-label, two cohort, single-center phase II study. Twenty-three patients with brain tumors detected by MRI scan and suspected to be gliomas were evaluated. All eligible patients were treatment naive and were self-selected into a TMZ group or a control group. The primary goal of the study was to evaluate the effect of TMZ 75 mg/m 2 daily prior to surgery on the brain tumor MGMT expression. Secondary endpoints included safety, tolerability, and MGMT promoter methylation mosaicism in glial tumors. Samples were obtained from multiple regions of each tumor intra-operatively and were analyzed by methylation specific PCR. Results: Our results on MGMT promoter methylation demonstrate that three groups of patients can be identified: Type I: all sites assessed in the tumor demonstrate no methylation of the MGMT promoter; Type II: all sites demonstrate high levels of MGMT promoter methylation; and Type III: a mixed promoter methylation pattern is observed. Conclusions: These results suggest that 1) preoperative neoadjuvant temozolomide is not associated with increased postoperative complications; 2) glial tumors can have very heterogeneous areas of MGMT promoter methylation; and 3) three patterns of MGMT promoter methylation can be discerned. This experimental paradigm may be a useful experimental platform for the assessment of the effect of new drugs at the tumor level. [Table: see text]
RTOG 0324: A phase II study of cetuximab (C225) in combination with chemoradiation (CRT) in patients with stage IIIA/B non-small cell lung cancer (NSCLC)—Association between EGFR gene copy number and patients’ outcome
Authors: C. C. Olsen, R. Paulus, R. Komaki, M. Varella-Garcia, R. Dziadziuszko, W. J. Curran, F. Robert, H. Choy, G. R. Blumenschein, F. R. Hirsch
Journal: Journal of Clinical Oncology (2008)

7607 Background: C225 in combination with chemotherapy appears promising in first-line therapy for NSCLC. EGFR gene copy number is a predictive outcome marker for treatment with EGFR tyrosine kinase inhibitors (TKIs). Here we evaluate EGFR copy number by FISH in NSCLC patients receiving C225 with concurrent chemoradiation. Methods: Patients with stage III NSCLC and PS 0–1 were treated with a loading dose C225 (400 mg/m2 IV) followed by weekly doses of C225 (250 mg/m2 IV) with concurrent chemoradiation (63 Gy/35 fractions) with weekly carboplatin (C), (AUC 2) and paclitaxel (P), (45 mg/m2) x 6 doses followed by C (AUC 6) and P (200 mg/m2) x 2 cycles. EGFR FISH analysis was performed on formalin-fixed paraffin-embedded tissue sections as described previously. Tumors with 4 or more copies of the EGFR gene in ≥ 40% of the cells (high polysomy) or tumors with EGFR gene amplification with a gene/chromosome ratio >2 or ≥ 15 gene copies in > 10% of the cells were considered FISH positive, while all others were considered FISH negative. Results: Ninety-three patients were accrued between March 2004 and June 2005, 87 of whom were evaluable for analysis. Tissue samples were collected from 51 patients and 45 were available for FISH analysis. Pretreatment characteristics for those patients with FISH data in comparison to those that did not have tissue available were similar. The 24- month survival probability for the patients with positive FISH scores was 61.9% compared to 53.8% in FISH negative samples (log-rank p=0.95). 24-month TTP was 57.1% and 45.8% (Gray’s p = 0.84), respectively. 24% of evaluable FISH positive patients underwent complete/partial response in comparison to 8% of FISH negative patients. Conclusions: Tissue testing for FISH is feasible in patients with stage III NSCLC. Despite non- mandatory collection, samples were obtained in over 50% of the patients. Patients with FISH-positive disease appeared to have a higher response rate and tendency to better outcome. The data should be verified in prospective studies. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration ImClone
The ERGO trial: A pilot study of a ketogenic diet in patients with recurrent glioblastoma.
Authors: J. Rieger, O. Baehr, E. Hattingen, G. Maurer, J. Coy, M. Weller, J. Steinbach
Journal: Journal of Clinical Oncology (2010)

e12532 Background: Increased reliance on aerobic glycolysis and suppressed mitochondrial respiration are hallmarks of cancer (Warburg Effect). Because normal tissues can satisfy energy demands largely through ketone bodies, glucose- antagonistic therapies have potential as cancer-selective interventions. Ketogenic diets, apart from their anticonvulsive activity, may reduce blood glucose levels, and case studies suggested clinical activity in glioma patients. To assess feasibility and safety of a ketogenic diet in patients with glioblastoma, we conducted a prospective trial (NCT00575146). Methods: 19 patients with glioblastoma recurrent after radiotherapy were put on a ketogenic diet restricting carbohydrate intake and containing lactate drinks and oils. Metabolic markers, ketones in the urine and body weight were monitored. MRI was performed every 6 weeks. Quality of life was regularly assessed. Results: 18 patients were evaluable. No diet-related serious adverse events occured. Adherence to the diet was good. Two patients discontinued the diet in the absence of tumor progression. Ketosis was achieved in 85% of the evaluable patients. Three patients had stable disease after 6 weeks. One patient achieved a minor response. Median PFS was 5 weeks (range 3-13 weeks). At first progression on the diet, the protocol allowed addition of a salvage therapy which consisted of bevacizumab in 7 patients. In these, objective response rate was 86%, median PFS from start of cotreatment was 19.7 weeks (range 12-55+ weeks), PFS 6 was 43%. Conclusions: This ketogenic diet is feasible and safe and has antitumor activity in glioma patients. The combination of the diet with antiangiogenic agents appears promising according to theoretical considerations and our preliminary data. Randomized trials evaluating the therapeutic potential of ketogenic diets in tumor patients are warranted. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Tavarlin Roche Tavarlin Roche