tbuckley/cabot-search huggingface dataset:
Use of telomere length in peripheral leukocytes to predict risk of recurrence in patients with early-stage non-small cell lung cancer after curative resection.
Authors: E. S. Kim, A. A. Vaporciyan, J. Xing, M. Huang, M. R. Spitz, S. M. Lippman, J. Gu, J. A. Roth, X. Wu
Journal: Journal of Clinical Oncology (2010)

7031 Background: Telomeres play a key role in maintaining chromosome stability. Shorter telomere length has been demonstrated to be a risk factor for lung cancer. A significant number of patients with non-small cell lung cancer (NSCLC) will develop recurrence after curative resection. To potentially identify this subgroup of patients, we hypothesized that telomere length in peripheral blood would have significant predictive value for risk of recurrence. Methods: Relative telomere length (RTL) of peripheral leukocytes was measured by real-time PCR in 403 patients with early stage NSCLC who underwent curative resection at M. D. Anderson Cancer Center between 1991 and 2007. The risk of recurrence was estimated as hazard ratios (HRs) and 95% confidence intervals (CIs) using a multivariable Cox proportional hazard regression model. Results: Median duration of follow- up was 29.9 months (0.1-158.8 months) and 87 patients (21.6%) had developed recurrence at time of analysis. 60 patients (14.9%) received chemotherapy (mostly adjuvant) with surgery. Our results show that the recurrence group demonstrated significantly longer mean RTL compared to the nonrecurrence group (1.19 vs. 1.07, p=0.003). Furthermore, the risk of recurrence increased as telomere length increased (p-trend=0.004). When 75th percentile value of RTL was used to dichotomize telomere length, patients with long telomeres were at higher risk of recurrence (HR=1.72; 95% CI, 1.08-2.72, p =0.021). This increased risk was most pronounced in adenocarcinoma subgroup (HR=2.28; 95% CI, 1.31-3.98, p = 0.004). When categorized into surgery only or surgery and chemotherapy group, longer telomeres increased risk of recurrence in the surgery only group (HR=1.81; 95% CI, 1.06-3.11, p=0.031). However, this association was not evident in the chemotherapy group (HR=1.13; 95% CI, 0.34-3.70, p=0.85). Conclusions: This is the first study to suggest that long telomere length is associated with increased risk of recurrence in early stage NSCLC after curative resection. Chemotherapy may be considered to overcome this increased risk. This study is supported by NCI CA 111646, CA 55769, and CA 70907. No significant financial relationships to disclose.
Neurourbanism: towards a new discipline
Authors: Mazda Adli, Maximilian Berger, Eva-Lotta Brakemeier, Ludwig Engel, Joerg Fingerhut, Ana Gomez-Carrillo, Rainer Hehl, Andreas Heinz, Juergen Mayer H, Nassim Mehran, Sissel Tolaas, Henrik Walter, Ute Weiland, Joerg Stollmann
Journal: The Lancet Psychiatry (2017)
A randomized, controlled phase III global trial comparing sipuleucel‐T plus androgen deprivation therapy versus androgen deprivation therapy alone in men with metastatic androgen dependent (hormone sensitive) prostate cancer.
Authors: K. Fizazi, T. Powles, D. J. George, C. H. Poehlein
Journal: Journal of Clinical Oncology (2011)

TPS188 Background: Prostate cancer is the most common cancer and the second leading cause of cancer deaths among men in North America and Western Europe. In Europe and North America between 10-25% and in Asia between 20-35% of all patients present and/or develop metastatic androgen dependent prostate cancer (mADPC). Androgen deprivation therapy (ADT) is the standard of care to treat men diagnosed with metastatic prostate cancer. Recently, sipuleucel-T was approved by the U.S. FDA for treatment of patients with asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer, based on a 4.1 month median survival benefit in a randomized, double blinded phase III study (IMPACT). The following proposed clinical trial is designed to evaluate the efficacy of sipuleucel-T in the mADPC patient population. Methods: Patients, diagnosed with metastatic androgen-dependent (hormone sensitive) prostate cancer (n=1684), will be enrolled in a global, randomized, open-label, multicenter trial. Patients will receive ADT to achieve castration-level testosterone and then will be randomized 1:1 to receive sipuleucel-T or continue on ADT alone. Primary endpoint of this study is overall survival. Secondary endpoints are safety, quality of life, time to castration resistance, and chemotherapy-free survival. Castration resistance will be determined by the Prostate Cancer Working Group 2 guidelines. From a subset of the study subpopulation (n=600), pharmacodynamic measures will be evaluated including serum and blood samples for cellular and humoral immune response analyses as well as circulating tumor cells (CTC). This trial will evaluate the therapeutic efficacy of sipuleucel-T in patients with mADPC while also expanding our understanding of the immunological response and clinical benefits of sipuleucel-T.
Pharmacodynamic (PD) assessment of blood pressure (BP) in a randomized dose-ranging trial of sorafenib (S).
Authors: M. L. Maitland, T. Karrison, G. L. Bakris, K. Fox, L. A. Janisch, S. Karovic, M. R. Levine, L. House, J. J. Wright, E. E. Cohen, G. F. Fleming, T. Y. Seiwert, V. M. Villaflor, W. M. Stadler, M. J. Ratain
Journal: Journal of Clinical Oncology (2011)

3016 Background: Hypertension may be a PD marker for efficacy of VEGF signaling pathway (VSP) inhibitors. The effects of S doses >800 mg/d on BP are not well characterized. To determine precisely the BP response to escalated doses of S, advanced solid tumor patients (pts; ECOG PS < 2 and screening BP < 140/90 mmHg on no antihypertensives) underwent serial 12-hour ambulatory BP measurement sessions (ABP) on different doses of S. Methods: The primary objective was to detect an increase in diastolic BP (DBP) proportional to the increased dose (based on prior data, assumed mean DBP increase for 400 mg BID = 6.0; on increased dose = 9.0 mmHg). ABP were conducted pre/post 7 d of S 400 mg BID. All pts then received no drug for 7 d, followed by another ABP. Pts with no > grade 2 toxicities during the first 2 wks were then randomized to receive escalated dose S at 400mg TID or 600mg BID. All pts repeated ABP after 7 d of additional S. Readings were collected every 10 min during daytime hrs (minimum # readings for evaluable session = 50). Results: 54 of a planned 58 pts were evaluable for data analysis by January 2011. Mean DBP elevation from baseline to Day 7 was 8.0 (SD= 6.5; 95% CI 6.3-9.8) mmHg. The variance in the change in DBP during the washout phase was unexpected, with 32/54 pts having DBP return to baseline (BL); 15/54 had DBP remain elevated and 7/54 had DBP decline below BL. After the 7 d washout, 18 were randomized to 400 mg TID, 19 to 600 mg BID, and 17 received 400 mg BID again. To detect the dose escalation effects on ABP, Day 22 DBP was fit to a regression model with main effect terms for Day 7 DBP and Day 14 DBP and interaction terms for BL DBP, age, sex, race (AA vs. other), and BSA. The final model (R2= 0.73; p < 0.00001) included terms for BL, Day 7, and Day 14 DBP. Compared to 400 mg BID, mean DBP with 400 mg TID was 4.7 mmHg greater (p=0.15, 95% CI -1.7, 11). Mean DBP for the 600 mg BID arm was 2.6 mmHg greater (p=0.41, 95% CI -3.7, 8.8). The difference between the 2 dose escalation arms was not significant (p=0.25). Conclusions: Escalating S dose in a pt population did not uniformly lead to further DBP elevations. To enhance efficacy of S, and perhaps other VSP inhibitors, will likely require a more complex PD-based scheme than dose-to-hypertension.
Spray cryotherapy for palliation of locally advanced adenocarcinoma in Barrett's esophagus.
Authors: C. Lin, D. Kerstetter, F. Habr
Journal: Journal of Clinical Oncology (2011)

152 Background: Up to 60% of patients with esophageal cancer are deemed inoperable at the time of diagnosis due to either advanced stage or significant co-morbidities. Currently, endoscopic palliative measures include stenting and photodynamic therapy. Although spray cryotherapy has been successfully used in ablating Barrett's esophagus, and different grades of dysplasia, there has been only one published case describing complete remission of squamous cell carcinoma following cryoablation. We present the first case of the use of the CryoSpray Ablation System (CSA Medical, Baltimore, MD) for palliative treatment of an esophageal T3 adenocarcinoma in an elderly woman with dysphagia and weight loss. Methods: An upper endoscopy was performed with standard monitored anesthesia. A special dual lumen Cryo decompression tube is introduced over an endoscopically placed savary guidewire in the gastric antrum and connected to suction. This tube is used to decompress the stomach when the liquid nitrogen is sprayed. Cryoablation is performed using the CryoSpray Ablation System that uses liquid nitrogen is delivered via a 7 Fr catheter at low pressures (2-3 PSI) at -196°C.The lesion was treated with four freeze cycles of 10-20 seconds each with 60 second interim thaws. Freezing and thawing techniques were monitored by direct visualization. The procedure is repeated every 4-6 weeks. The patient received a total of 7 treatments over 10 months. Results: The patient did not experience any adverse effects after treatment. After 3 treatments (week 20), complete endoscopic resolution of the lesion was noted, with regression of the Barrett's mucosa and major improvement of her dysphagia. At week 28, a recurrent mass was seen on EGD in the mid-esophagus. This was treated with 3 sessions of spray cryotherapy at 4 week intervals with improvement of dysphagia after each application. 11 months after her initial cryotherapy, the patient opted to have an esophageal stent due to tumor progression. Conclusions: Spray cryotherapy is a safe and effective endoscopic modality for the ablation of Barrett's esophagus and superficial esophageal cancer, it is a promising new modality for the palliation of advanced esophageal cancer. No significant financial relationships to disclose.
Clinical evaluation of food effects on pharmacokinetics of the novel oral taxane, tesetaxel.
Authors: H. Danesi, A. Dudek, E. Spindler, H. Alcorn
Journal: Journal of Clinical Oncology (2011)

e13059 Background: Tesetaxel is a novel, advanced-generation taxane that is orally bioavailable. The drug does not induce hypersensitivity reactions (thus avoiding premedication requirements) and is not a substrate for P-glycoprotein. Although multiple clinical trials of tesetaxel have been conducted (with positive results in breast and gastric cancer), treatment to date has required administration after an overnight fast owing to lack of information regarding food interactions. We undertook this study to determine whether co-administration of food (as a high-fat meal) would substantially alter the bioavailability and pharmacokinetics (PK) of tesetaxel. Methods: The study employed a randomized, open-label, crossover design. Patients (pts) with advanced solid tumors (age 18-75 yrs) and adequate organ function were randomized to 1 of 2 treatment sequences: tesetaxel in the fed state in period 1 and fasted state in period 2; or the reverse sequence. The second dose of tesetaxel was administered 35 days (~ 4.7 half-lives of tesetaxel) after the first dose. Serial blood sampling was performed in both periods for PK analysis. The primary comparison was determination of the ratios of fed-to-fasted state PK parameters. Results: Twelve pts completed the 2 treatment periods. Mean (standard deviation) PK values in the fed state were: Cmax 3.9 (1.0) ng/mL, Tmax 5 (2) h, t1/2 220 (103) h, AUC0-t 148 (43) ng/mL x h, Vss/F 7.2 (2.6) L/m2, and CL/F 0.025 (0.009) L/h/m2. The corresponding values for the fasted state were: Cmax 4.1 (0.9) ng/mL, Tmax 2 (3) h, t1/2 165 (84) h, AUC0-t 134 (25) ng/mL x h, Vss/F, 6.9 (2.7) L/m2, and CL/F 0.033 (0.011) L/h/m2. Thus, PK analyses in fed and fasted subjects appeared similar and displayed no clinically relevant differences. Conclusions: Tesetaxel can be orally administered in the fed state without detriment to its bioavailablity or pharmacokinetic behavior, which should facilitate its further clinical development.
Rates of central nervous system (CNS) metastases in patients with advanced non-small cell lung cancer (NSCLC) and somatic <i>EGFR</i> mutations initially treated with gefitinib or erlotinib versus chemotherapy.
Authors: S. Heon, B. Y. Yeap, N. I. Lindeman, M. S. Rabin, D. M. Jackman, B. E. Johnson
Journal: Journal of Clinical Oncology (2011)

7607 Background: The impact of tumor genotype and targeted therapies on the control and development of CNS metastases from NSCLC has not been extensively studied. We recently reported a lower than expected rate of CNS progression in patients with advanced NSCLC and somatic EGFR mutations initially treated with gefitinib or erlotinib. This retrospective study was undertaken to investigate the impact of gefitinib or erlotinib versus chemotherapy on the risk of CNS progression in EGFR mutant advanced NSCLC patients. Methods: Patients with stage IV or relapsed NSCLC with somatic EGFR mutations seen at the DFCI between 8/00 and 2/10 who were initially treated with gefitinib or erlotinib or chemotherapy without receiving gefitinib or erlotinib for at least 6 months were identified from a prospective trial. The cumulative risk of CNS progression was calculated using death as a competing risk. Results: 129 EGFR mutant patients were eligible (99 EGFR-TKI, 30 chemotherapy). 21 patients (21%) in the EGFR-TKI group and 9 patients (30%) in the chemotherapy group had brain metastases at the time of diagnosis of advanced NSCLC (P=0.331); 28 of the 30 received CNS therapy before initiating systemic treatment. 30 patients (30%) in the EGFR-TKI group and 15 patients (50%) in the chemotherapy group developed CNS progression after a median potential follow-up of 49 months (P=0.04). The 1- and 2-year cumulative risk of CNS progression was 5% (95% CI, 2–11) and 21% (95% CI, 13–30), respectively, in the EGFR-TKI group compared with corresponding rates of 24% (95% CI, 10–40) and 31% (95% CI, 15–48) in the chemotherapy group. PFS was prolonged in patients initially treated with an EGFR-TKI (median 11.5 vs. 6.9 mo; P<0.001), whereas there was no difference in OS (median 32.2 vs. 36.2 mo; P=0.366). Conclusions: Our data suggest lower rates of CNS progression in EGFR mutant advanced NSCLC patients initially treated with gefitinib or erlotinib compared with upfront chemotherapy. Additional patients with advanced NSCLC initially treated with chemotherapy are undergoing EGFR sequencing to increase the number of EGFR mutant patients treated with chemotherapy.
Economic factors as well as clinical outcomes may influence castrate-resistant prostate cancer treatment practice.
Authors: N. J. Combates, J. Beetsch, L. Nicacio
Journal: Journal of Clinical Oncology (2011)

e16557 Background: Varying treatment pathways are associated with management of castrate-resistant prostate cancer (CRPC), depending on whether disease is asymptomatic (asx) or symptomatic (sx), and may be multidisciplinary and multimodal in nature. We aimed to identify the most common pathways to determine and value resources used, and quantify reimbursements associated with alternative therapies. Methods: Common treatment pathways were identified by reviewing the CRPC literature and NCCN guidelines, and through a standardized questionnaire administered to clinicians. Financial resources associated with pathways were determined, including office visits for monitoring and PSA testing; resources were evaluated using Medicare reimbursement rates. Results: Ten alternative pathways (6 asx and 4 sx) were determined for CRPC. They include various sequences of watchful waiting (WW), hormone therapy (luteinizing hormone releasing hormone [LHRH]), antiandrogen withdrawal (AAW), ketoconazole (K), chemotherapy (docetaxel [DT], cabazitaxel [CBZ]), and immunotherapy (sipuleucel-T [ST]). Cost of regimens varied widely based on the course of therapy chosen (Table). Regimens that are mostly secondary hormonal were least expensive, at or below $25,000/patient, and resulted in a $2,500-$2,800 reimbursement/patient. Conclusions: Pursuing secondary hormonal treatment resulted in the lowest overall cost for treatment of CRPC. Although economic factors must be considered in overall health practice, clinical guidelines, patient health status, and response to therapy should be primary determinants for a therapeutic regimen chosen for CRPC. Regimen Position in range of costs Cost ($) Intermittent LHRH, AAW, WW, intermittent LHRH, WW, K Least costly asx 8,006 LHRH+ST, LHRH+DT, LHRH+CBZ Most costly asx 210,374 LHRH+DT, WW, LHRH+CBZ, WW Least costly sx 108,953 LHRH+DT, LHRH+ST, LHRH+DT Most costly sx 140,585
Correlation of anti-tumor and anti-angiogenic activity of VEGFR inhibitors with inhibition of VEGFR2 phosphorylation in mice
Authors: R. Kumar, L. E. Harrington, T. M. Hopper, C. G. Miller, J. A. Onori, M. Cheung, J. A. Stafford, A. H. Epperly, T. M. Gilmer
Journal: Journal of Clinical Oncology (2005)

9537 Background: With the development of targeted therapeutics, especially for small molecule inhibitors, it is important to understand whether the observed in vivo efficacy correlates with the modulation of the desired/intended target in vivo. We have developed a novel small molecule inhibitor of all three VEGF receptor tyrosine kinases, GW786034, which inhibits proliferation of VEGF-induced proliferation of HUVEC with an IC50 of 21 nM. It has good oral exposure and inhibits angiogenesis and tumor growth in mice. Methods: Anti-tumor and anti-angiogenic activities of a VEGFR inhibitor were measured by either bolus oral administration or continuous infusion using mini-osmotic pumps in mice. GW771806, which has similar enzyme and cellular profiles to GW786034, was used for these studies due to the higher solubility required for infusion studies. Results: Comparing the PK by two different routes of administration (bolus oral dosing and continuous infusion), we demonstrate that the anti-tumor and anti-angiogenic activities of VEGFR inhibitors are dependent on the steady-state concentration of the compound above a threshold. Furthermore, the steady-state concentration required for these effects is consistent with the concentration required for the inhibition of VEGF-induced VEGFR2 phosphorylation in mouse lungs. Conclusions: Anti-tumor and anti-angiogenic activities of VEGFR inhibitors in vivo are dependent on maintaining trough concentrations similar to those required for inhibition of VEGFR2 phosphorylation in vivo. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline
Impact of dietary habits on epidermal growth factor receptor (EGFR) mutation status of Japanese patients with lung adenocarcinomas.
Authors: Y. Yamane, M. Iwasaki, A. Kawase, K. Tsuchihara, G. Ishii, H. Ohmatsu, S. Niho, K. Yoh, K. Nagai, Y. Ohe, S. Tsugane, A. Ochiai, H. Esumi, K. Goto
Journal: Journal of Clinical Oncology (2011)

1567 Background: Epidermal growth factor receptor (EGFR) mutation plays a key role in the carcinogenesis of lung adenocarcinoma. However little is known about the environmental and life style factors, in particular dietary habits, influencing EGFR mutations. Methods: Between July 1999 and July 2004, 1995 consecutive patients with lung cancer were prospectively assessed on dietary habits using the semiquantitative Food Frequency Questionnaire (FFQ) which contains questions regarding 138 foods in National Cancer Center Hospital East. EGFR mutations (exon 19 deletion and exon 21 L858R) were examined in 298 adenocarcinomas of whom by direct sequence method. The intake of nutrients was calculated with standard tables of food composition in Japan, 5th revised and enlarged edition. The differences of consumption of 22 food groups and 45 nutrients (energy-adjusted values using the residual method) between EGFR mutations positive (156 patients) and negative (142 patients) were investigated by multivariate logistic regression model adjusted for gender, age, smoking status and body mass index, regarding patients without EGFR mutations as control cases. Results: The grain and carbohydrate consumption of patients with EGFR mutations was significantly lower than patients without EGFR mutations. The multivariate-adjusted odds ratios and 95% confidence intervals for the third tertile of grain and carbohydrate consumption of patients with EGFR mutations in comparison with the first tertile were 0.46 (0.24-0.87) (p for trend =0.021) and 0.44 (0.23-0.85) (p for trend =0.016), respectively. Conclusions: In the present study, it was suggested that the lower consumption of grain and carbohydrate correlated with EGFR mutations. Further research to investigate the influence of these dietary components and habits on carcinogenesis of lung adenocarcinoma with EGFR mutations is warranted.
Patient experience with service quality: Implications for survival outcomes in prostate cancer.
Authors: Christopher G. Lis, Maurie Markman, Mark Rodeghier, Digant Gupta
Journal: Journal of Clinical Oncology (2012)

39 Background: Prostate cancer is the second leading cause of cancer death among U.S. men. While self-reported quality of life has been shown to be prognostic of survival, there has been limited exploration of whether a patient’s assessment of the overall quality-of-care received might influence survival in prostate cancer. We evaluated the relationship between patient-reported experience with service quality and overall survival in prostate cancer. Methods: 832 returning prostate cancer patients treated at Cancer Treatment Centers of America between July 2007 and December 2010. Overall patient experience (“considering everything, how satisfied are you with your overall experience?”) was measured on a 7-point Likert scale ranging from “completely dissatisfied” to “completely satisfied”. It was dichotomized into 2 categories: top box response (7) versus all others (1-6). Cox regression was used to evaluate the association between patient experience and survival. Results: 560 patients were newly diagnosed while 272 had been previously treated. Majority of patients (n=570, 68.5%) had stage II disease at diagnosis. The mean age was 63.6 years. By the time of this analysis, 93 (11.2%) patients had expired. 710 (85.3%) patients were “completely satisfied” with the service quality they received while 122 (14.7%) patients were not. Median overall survival was 47.9 months. On univariate Cox regression analysis, “completely satisfied” patients had a significantly lower risk of mortality compared to those not “completely satisfied” (HR=0.48; 95% CI: 0.30-0.78; p=0.003). On multivariate Cox regression analysis controlling for stage at diagnosis, treatment history and age, “completely satisfied” patients demonstrated significantly lower mortality (HR=0.50; 95% CI: 0.29-0.87; p=0.01) compared to those not “completely satisfied”. Conclusions: Patient experience with service quality was an independent predictor of survival in prostate cancer. Based on this provocative observation, it is reasonable to suggest that further exploration of a possible meaningful relationship between patient perceptions of the care they have received and outcome in prostate cancer is indicated.