tbuckley/cabot-search huggingface dataset:
Clinical pharmacokinetic-pharmacodynamic (PK/PD) modeling study of the novel dual PI3K/mTOR inhibitor BEZ235.
Authors: D. Bottino, J. Tabernero, H. A. Burris, C. Britten, L. C. Chen, J. C. Bendell, O. Chiparus, V. Duval, E. Di Tomaso, C. Sarr, W. Hackl, J. Baselga, J. Rodon Ahnert
Journal: Journal of Clinical Oncology (2011)

3056 Background: BEZ235 is a novel pan-class I PI3K/mTOR inhibitor with proven apoptotic effect (Brachman et al 2009), antiangiogenic effect (Schnell et al 2009) and clinical activity especially in patients with PI3K pathway dysregulated tumors (Burris et al, 2010; Rodon et al, submitted for publication). In this study, we attempt to quantify the biologic treatment effects of BEZ235 in order to investigate relationships between exposure to drug and markers of: suppressed proliferation and increased apoptosis in tumor cells; PI3K pathway modulation in surrogate tissue (skin); suppression of angiogenesis pathway components. Methods: Exposure to drug was defined to be area under the concentration curve between dosing times (AUC0-24h) at the day of PK/PD assessment (either day +8 or day +28). PD evaluated markers are listed in the results section. Each PD marker was normalized to represent change relative to its baseline value in the same patient. Each relationship between log exposure and relative change in PD was tested for correlation. Specifically, a least-squares linear regression was performed and a relationship reported if the 95% confidence interval (CI) for the slope (relative PD change per 10-fold AUC increase) excluded zero. Results: For BEZ235, a statistically significant relationship between exposure and change in PD marker was found for FDG-PET uptake, Cpeptide, p-S6 in skin and sVEGFR2; but not for sum of longest diameters (SLD) of target lesions, M30, M65, sVEGFR1, and VEGF. Conclusions: These preliminary exploratory analysis results are consistent with the proposed mechanism of action of BEZ235. The results will be presented for an updated data set. Given the dual mechanism of BEZ235, we intend to compare its PK/PD relationship with that of a TORC1 inhibitor as well as an anti-angiogenic compound. PD marker and day Slope (95% CI) SLD d28 0.00544 (-0.00112, 0.0135) Total SUVmax d28 -0.0318 (-0.0641, -0.00418)* Fasting Cpeptide d8 0.109 (0.027, 0.191)* p-S6 skin d28 -0.0619 (-0.0975, -0.0275)* M30 d8 -0.0225 (-0.0571, 0.0114) M65 d8 -0.0291 (-0.0654, 0.00468) sVEGFR1 d28 -0.0425 (-0.0944, 0.0085) sVEGFR2 day 28 -0.0414 (-0.0574 -0.024)* VEGF day 28 -0.0144 (-0.0693, 0.0434)
Rate of hot flashes in patients with advanced prostate cancer treated with GTx-758.
Authors: Evan Y. Yu, Marc Gittelman, Thomas E. Keane, Ronald Tutrone, Laurence Belkoff, Joel Bass, Franklin Chu, Mike Gambla, Franklin Gaylis, James Bailen, Robert H. Getzenberg, Christopher Coss, Michael L. Hancock, James T. Dalton, Mitchell S. Steiner
Journal: Journal of Clinical Oncology (2013)

129 Background: When androgen deprivation therapy (ADT) for prostate cancer was first developed, life expectancy for men with advanced disease was short and the systemic effects were of limited relevance. GTx-758 is a selective ERα agonist that effects serum total testosterone (T), free T, SHBG and PSA. Herein we compare the effects of GTx-758 and leuprolide on hot flashes, one of the common side effects in men on ADT. Methods: In a Phase II study (G200705), men with advanced prostate cancer (n=159) received 1000 mg or 2000 mg of GTx-758 daily or leuprolide. Utilizing a standardized instrument to measure the frequency and severity of hot flashes, data was compiled at baseline, day 28 and day 90. The number of men experiencing hot flashes were those reporting any in the period between the respective time point and the prior patient visit. All p values describe the comparison of both GTx-758 treatment groups to the leuprolide treated men. Results: At the baseline, there were no significant differences in the number of men reporting hot flashes in any of the treatment groups (p=0.065). The percentage of men who experienced a hot flash while receiving leuprolide increased significantly to 60.4% (p&lt;0.0001) by Day 28 and increased further to 80.9% (p&lt;0.0001) by Day 90. Although some subjects experienced hot flashes while receiving GTx-758, these men were a significantly lower percentage, 18.8 and 5.6% at the 1000 mg and 2000 mg doses of GTx-758 respectively at day 90. As a result of an increased risk of venous thromboembolic events (VTEs) at these higher doses of GTx-758, the trial was stopped prior to its completion and not all of the men on the study reached the 90 day treatment date (99 evaluable). Conclusions: Men with advanced prostate cancer, receiving GTx-758 experienced a greater than 4-fold reduction in their reported hot flashes at day 90. Since hot flashes are a major side effect that impacts the quality of life in men on ADT, the ability to significantly decrease their likelihood would seem to be of great benefit. A Phase II clinical trial utilizing lower doses of GTx-758 (G200712) is currently being performed that will determine if similar effects on serum free testosterone, PSA and hot flashes can be shown with a lower rate of VTEs. Clinical trial information: NCT01326312.
Retrospective study assessing the association of single nucleotide polymorphisms in VEGFR3 and on-target toxicity in patients with advanced renal-cell carcinoma (RCC) treated with sunitinib.
Authors: Jf. Rodriguez-Moreno, Emilio Esteban, Luis Javier Leandro-García, Daniel E. Castellano, Aranzazu Gonzalez del Alba, Miguel Angel Climent, Jose Angel Arranz, Enrique Gallardo, Javier Puente, Joaquim Bellmunt, Begoña Mellado, Esther Martínez, Fernando Moreno, Albert Font, Mercedes Robledo, Susana Hernando Polo, Jesús García-Donas, Cristina Rodriguez-Antona
Journal: Journal of Clinical Oncology (2014)

537 Background: Sunitinib is a tyrosine kinase inhibitor approved as first line therapy of RCC. Some Adverse Events (AEs) of sunitinib are due to its inhibition of VEGFR and could be considered as “on-target” toxicity. They are a class-effects and have been observed even with the most selective antiangiogenic drugs. We aimed to correlate such secondary effects with germline SNPs in VEGFR3. Methods: In order to define “on target ” toxicity we considered any AEs ≥ Grade II (CTCAE 4.0) recorded in more than 10% of the patients included the pivotal studies of axitinib and tivozanib (the most selective tyrosin kinase inhibitors targeting VEGF(R). We assessed associations between polymorphisms in VEGFR3 and on-target toxicity for patients with advanced RCC treated with sunitinib prospectively included in the SUTRENT Study. Results: Polymorphisms in VEGFR3 are associated with less on-target toxicity. Probably these genetic changes confer a reduced susceptibility to the action of sunitinib. This could explain, at least partially, the worse outcome showed in this population. Conclusions: Polymorphisms in VEGFR3 are associated with less on-target toxicity. Probably these genetic changes confer a reduced susceptibility to the action of sunitinib. This could explain, at least partially, the worse outcome showed in this population.
Quality of life (QOL) as a predictor of survival in aggressive non-Hodgkin lymphoma (NHL).
Authors: C. A. Thompson, M. J. Maurer, C. Allmer, S. L. Slager, K. J. Yost, W. R. Macon, S. M. Ansell, D. J. Inwards, T. M. Habermann, B. K. Link, J. R. Cerhan
Journal: Journal of Clinical Oncology (2011)

8059 Background: QOL is predictive of survival in some malignancies. We sought to examine the relationship between QOL and survival in a cohort of newly diagnosed patients with aggressive NHL. Methods: Newly diagnosed lymphoma patients were prospectively enrolled within 9 months of diagnosis in the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource. Patients with aggressive NHL were included in this analysis. Baseline QOL was measured with the Functional Assessment of Cancer Treatment-General scale (FACT-G), which measures 4 QOL domains: physical, social/family, emotional, and functional well-being (WB); a single item Linear Analogue Self Assessment (LASA) for measuring overall QOL; and a LASA measuring spiritual WB. Clinical data were abstracted and patients were systematically followed for overall survival (OS). Cox proportional hazards models were used to evaluate the association between QOL and OS. Results: 169 patients with aggressive NHL and pre-treatment QOL questionnaire were enrolled between 9/02-2/08. Subtype was 52% diffuse large B-cell, 19% mantle cell, 13% T-cell, and 16% other NHL. Median age was 63 years and 53% were male. At a median follow-up of 40 months (range 1-75), 62 patients (37%) had an event and 39 patients (23%) died. In univariate analysis, lower scores for physical WB (HR=0.52, 95% CI 0.32-0.86), functional WB (HR=0.47, 95% CI 0.29-0.76), total FACT-G (HR=0.75, 95% CI 0.62-0.91), spiritual WB LASA (HR=0.85, 95% CI 0.73-0.99), and overall QOL LASA (HR=0.83, 95% CI 0.72-0.96) were associated with inferior OS. After adjusting for the International Prognostic Index (IPI) and subtype in multivariate analysis, only lower total FACT-G and functional WB scores still showed a trend towards an association with inferior OS (FACT-G HR=0.81, 95% CI 0.65-1.01, functional HR=0.58, 95% CI 0.33-1.01). Conclusions: We found evidence that overall and functional QOL measured pre-treatment is predictive of OS in patients with aggressive NHL, although results attenuated after adjustment for IPI. If the association is confirmed, underlying mechanisms need to be identified and whether interventions to increase QOL will also increase OS in patients with aggressive NHL.
Transbronchial biopsy with the navigation by virtual bronchoscopy for diagnosis and analysis of the target molecules of small lung cancer in the peripheral area
Authors: K. Yamazaki, N. Shinagawa, E. Kikuchi, H. Asahina, M. Nishimura, Y. Onodera, F. Asano, I. Kinoshita, H. Dosaka-Akita
Journal: Journal of Clinical Oncology (2005)

7242 Background: It is critical issues to obtain the proper and sufficient amounts of tissue samples of lung cancer when it is diagnosed, and examine the expressions and mutations of target molecules for selecting the proper strategies. However, diagnosing peripheral pulmonary lesions using a fiberoptic bronchoscope (FB) is occasionally difficult, and improvement of the yield of transbronchial biopsy (TBB) must be fully considered. We have developed a new strategy, the navigation system by virtual bronchoscopy (VB), to diagnose small lung cancer. This system can easily navigate a FB to the proper bronchus on real time. In the present study, we evaluated the safety, and efficacy of VB navigation for TBB in combination with endobronchial ultrasonography with a guide-sheath (EBUS-GS) or CT-guidance for peripheral pulmonary lesions ≤ 30 mm in diameter. Methods: VB images were reconstructed from helical CT data. TBB was then performed with VB navigation using EBUS-GS or CT-guidance. We performed TBB using VB navigation for 74 patients with 76 small peripheral pulmonary lesions between June, 2001 and October, 2004. Results: Bronchi seen on VB imaging were highly consistent with the actual structures confirmed using a FB. Diagnostic sensitivity was 65% for lesions ≤20 mm in mean diameter using VB navigation with CT-guidance, and 63% for those ≤30 mm in mean diameter using VB navigation with EBUS-GS. It was also useful for the reduction of examination time. Conclusions: TBB using VB navigation was safely performed and was effective in diagnosing and examining the expressions and mutations of target molecules of small lung cancer in the peripheral area. No significant financial relationships to disclose.
Analysis of minority-based community clinical oncology program (MBCCOP) accrual activity.
Authors: E. H. Williams, W. J. McCaskill-Stevens, T. E. Lad
Journal: Journal of Clinical Oncology (2011)

6070 Background: Minority-Based CCOPs were established in 1990 to improve access to NCI-sponsored clinical trials for minority populations. In 2009, 14 MBCCOPs and 47 CCOPs were funded. The CCOP network enrolls over 13,000 patients to clinical trials per year representing 40% of the accrual to NCI-sponsored trials. The MBCCOPs enroll over 33% of the minority patients in the CCOP network. This analysis was undertaken to discern whether the MBCCOPs differ from CCOPs in ways other than access to minority patients. Methods: The accrual activity of all CCOPs and MBCCOPs between 2005 and 2010 was compared using the CCOP and CTEP databases from the NCI. Aggregate data for total accrual, accrual to treatment and cancer control trials, research base affiliations, use of the CTSU (Clinical Trial Support Unit), phases of trials (Phase II vs III), and primary cancer sites were collected. Comparisons between CCOPs and MBCCOPs were made for these parameters. Results: A total of 64400 patients were enrolled, 55440 by CCOPs and 8960 by MBCCOPs. Annual enrollment was 231/CCOP and 128/MBCCOP. 53% of CCOP accrual was to treatment trials and 47% to control trials. Corresponding MBCCOP figures were 58 and 42% (p=NS). When compared to the CCOPs, the MBCCOPs had significantly less affiliation with CALGB, GOG, NCCTG, NSABP, RTOG, and URCC. Accrual through the CTSU represented 20% of accrual for both CCOPs and MBCCOPs. There were 303 Phase II and 208 Phase III trials with CCOP and/or MBCCOP accrual. CCOPs and MBCCOPs participated in 95% and 32% of Phase II and 98% and 64% of Phase III trials, respectively. For trials with both MBCCOP and CCOP participation, accrual per MBCCOP was higher in 59% of Phase II trials and accrual per CCOP was higher in 61% of Phase III trials. Comparison of the rank order of the top 20 tumor types enrolled in trials shows that only 12 types are present on both lists. Breast, lung, colon, and prostate cancers are underrepresented in the MBCCOP accrual, whereas GYN, head and neck, and pediatric tumors are overrepresented. Conclusions: Differences exist between MBCCOP and CCOP accrual patterns. Further research is needed to elucidate these differences.
The impact of renal cell carcinoma histopathological subtype on disease prognosis: A Canadian multi-institutional analysis.
Authors: Jennifer Bjazevic, Jasmir G. Nayak, Premal Patel, Anil Kapoor, Simon Tanguay, Antonio Finelli, Ricardo A. Rendon, Peter C. Black, Ronald Brian Moore, Rodney H. Breau, Jun Kawakami, Louis Lacombe, Laurence Klotz, Stephen E. Pautler, Darrel E Drachenberg
Journal: Journal of Clinical Oncology (2015)

480 Background: Renal cell carcinoma (RCC) is divided into several histopathological subtypes, each with significantly different clinical features. However, current data regarding the prognostic value of histological subtype is limited and conflicted. We examined the impact of RCC histology on disease prognosis in a large, multi-institutional Canadian analysis. Methods: The Canadian Kidney Cancer Information System (CKCis), a prospective database from 14 Canadian institutions, was utilized for the study. 1284 patients with non-metastatic RCC, who underwent surgical intervention with curative intent, were included in the study. Patients were stratified according to their primary histology and the Chi-squared test was used to determine associations between histopathology and clinical features. The impact of histology of disease-free survival (DFS) was determined with a multivariate analysis adjusted for age, gender, tumor size, tumor grade, and pathological stage. Results: Clear cell RCC was the most prevalent histological subtype found in 80.5% of patients. Histopathology was significantly associated with patient age, tumor grade, and pathological stage. Advanced stage disease (&gt;T3) was associated with clear cell and papillary type II RCC (p&lt;0.05). 90.7%, 86.7%, 78.5%, and 78.8% of patients with chromophobe, papillary type I, papillary type II, and clear cell RCC respectively, were free of disease after a median follow-up of 1.2 years. On multivariate analysis, histological subtype was a significant predictor of disease-free survival (DFS). When compared to clear cell histology, chromophobe RCC had a significantly higher DFS (HR=0.38, 95% CI 0.15-0.95, p&lt;0.05), and papillary type I RCC had a trend towards a lower rate of disease progression (HR=0.31, 95% CI 0.08-1.28, p=0.05). Conclusions: This study demonstrates that histological subtype impacts disease progression. Histological subtype was independently associated with DFS in surgically treated RCC, specifically chromophobe RCC was shown to have the highest DFS. This may be used to help individualize patient treatment and follow-up based on primary tumor histology.
Retinoblastoma and p53 protein expression in oral cavity leukoplakia, actinic cheilitis, and squamous cell carcinoma.
Authors: R. A. De Mello, M. G. de Oliveira, T. Piazza, L. Gaiao, L. M. P. Ramalho, D. H. Pozza
Journal: Journal of Clinical Oncology (2011)

e21089 Background: Retinoblastoma (Rb) and p53 gene play a fundamental role in cell cycle mechanisms, and their deregulation is related to many steps of oral cancer carcinogenesis. This study was conducted to evaluate the expression of p53 and Rb proteins in malignant and pre-malignant oral cavity lesions. Methods: Design: Retrospective study from 1990 to 2004. Setting: Federal University of Bahia, Salvador, Brazil, and Molecular Biology Laboratory of the Otorhinolaringology Department of the University of Heidelberg, Germany. Protocol: Forty five excisional biopsy samples of oral cavities were collected from patients with suspect oral lesions, including 15 squamous cell carcinoma, 15 leukoplakia, and 15 actinic cheilitis. The samples were processed by imunohistochemistry to be classified by a semi-quantitative score: samples < 10% positivity (-) was considered without expression; from 11 to 50% of positivity (+), moderate expression; ≥50% (++), high expression. Data was analyzed according to descriptive statistics with Statistical Package for Social Science (SPSS), Chicago, version 18.0, software. Results: Actinic cheilitis presented higher expression frequency (100%) +/++ to p53 protein; squamous cell carcinoma, 46%; and leukoplakia, 23%. However, squamous cell carcinoma showed higher frequency (93.3%) expression +/++ to Rb protein; actinic cheilitis, 80%; and leukoplakia 73.3% respectively. Conclusions: Despite the small number of samples, the expression of these cell cycle biomarkers (p53 and Rb protein) in excisional biopsies may suggest that molecular lesion assessment could determine premalignant lesions, and its use may improve clinical and surgical approach in early lesions. Thus, the p53 expression may be related with early steps of carcinogenesis in oral cavity squamous cell carcinoma. Higher Rb expression was observed in malignant lesions. Further studies with a higher number of samples are warranted to reach statistical significance.
Efficacy of rolapitant for prevention of chemotherapy-induced nausea and vomiting (CINV) in patients with gastrointestinal and colorectal cancers.
Authors: Rudolph M. Navari, Karin Jordan, Bernardo Leon Rapoport, Ian D. Schnadig, Martin Chasen, Sujata Arora, Daniel Powers, Lee Steven Schwartzberg
Journal: Journal of Clinical Oncology (2016)

222 Background: Rolapitant (VARUBI) is a selective, long-acting neurokinin-1 receptor antagonist (RA) for the prevention of CINV. Rolapitant effectively prevented CINV in phase 3 trials of patients (pts) receiving highly or moderately emetogenic chemotherapy (HEC, MEC). While MEC and HEC regimens are commonly used to treat pts with gastrointestinal and colorectal cancers (GI/CRC), very few studies have evaluated the effectiveness of a neurokinin-1 RA regimen in these pts. We assessed the incidence of CINV and efficacy of rolapitant in a subset of pts with GI/CRC. Methods: This is a post hoc analysis of 3 similarly-designed, randomized, placebo-controlled trials. Pts with cancer of the esophagus, stomach, colon/rectum, or anus received a single oral dose of 180 mg oral rolapitant or placebo prior to HEC or MEC. All pts received a 5-hydroxytryptamine type 3 (5-HT3) RA and dexamethasone (active control). The HEC studies included cisplatin, and the MEC study carboplatin, oxaliplatin, irinotecan, epirubicin, and doxorubicin. Endpoints included complete response (CR; no emesis and no use of rescue medication), no emesis, no nausea (maximum visual analogue scale [VAS] &lt; 5 mm), no significant nausea (maximum VAS &lt; 25mm) and complete protection (CP; no emesis, no use of rescue medication, and no significant nausea) in the overall (0-120 h), acute (≤ 24 h), and delayed (&gt; 24-120 h) phases. Results: Out of 188 GI/CRC pts, 101 pts received rolapitant and 87 received active control. Pts treated with rolapitant had significantly higher rates of CR, no nausea, no emesis, and CP in the overall phase (P &lt; 0.05). Rolapitant was well-tolerated and overall incidence of treatment-emergent adverse events comparable in both groups. Conclusions: Addition of rolapitant to 5-HT 3 RA and dexamethasone therapy significantly improved CR, no nausea, no emesis, and CP in pts with GI/CRC receiving emetogenic chemotherapy. Clinical trial information: NCT01500226, NCT01499849, NCT01500213. [Table: see text]
GATA-3 or T-Bet Expression In PTCL-U Identify High-Risk Patients with Poor Outcomes and Distinct Clinical Characteristics Suggesting Their Derivation From Specific Subsets of T Helper Cells
Authors: Ryan A. Wilcox, Andrew L Feldman, Kay Ristow, Thomas M. Habermann, Steven Ziesmer, Linda Wellik, Thomas E. Witzig, Stephen M. Ansell
Journal: Blood (2010)
Detection of EGFR mutations with mutation-specific antibodies in primary lesions of non-small cell lung cancer.
Authors: X. Zhang, L. Yin, X. Yang, J. Yang, Q. Zhou, J. Xu, Z. Xie, S. An, S. Chen, R. Wang, G. Zhu, Y. Gu, X. Zhang, Y. L. Wu
Journal: Journal of Clinical Oncology (2011)

7035 Background: Patients with specific mutations in EGFR likely receive more benefit from EGFR TKI therapy. Here we evaluated the utility of EGFR mutation-specific antibodies in primary tumors for screening of EGFR-mutant NSCLC patients in comparison with a sequencing method. Methods: Immunohistochemistry (IHC) were performed on formalin-fixed, paraffin-embedded samples from primary lesions of 103 NSCLC patients, using antibodies against to wild-type EGFR, dEGFR (E746-A750 del) and L858R EGFR on the serial sections. Tumors with IHC scores of 1+ to 3+ scores were interpreted as IHC positive, and tumors with 0 score were considered as negative. Each of these samples was also subjected to direct sequencing for EGFR mutation status. Results: 27 of 103 cases were detected as EGFR E746-A750 del and L858R mutation by sequencing. Among the 13 EGFR E746-A750 del samples detected by sequencing, 11 of them were also scored IHC positive, with a sensitivity of 85% for the dEGFR antibody as compared with the direct sequencing method. In the rest of 90 cases which were negative for EGFR E746-A750 del by sequencing, the anti-dEGFR antibody detected 2 positive with a specificity of 98%. The anti-L858R EGFR antibody detected 9 positive out of 14 L858R mutation cases by sequencing, with a sensitivity of 64%. In the other 89 cases which were negative for L858R mutation by sequencing, the anti-L858R EGFR antibody detected 5 positive with a specificity of 94%. In combination of the results from both antibodies, the overall sensitivity of the IHC method was 74% (20/27), and the specificity was 92% (70/76) as compared with the direct sequencing method. In addition, sequencing showed several EGFR mutations other than dEGFR or L858R in 12 cases. None of these 12 cases were detected positive by using the two IHC antibodies. Conclusions: Given over 90% specificity, our results suggested IHC using the two mutation specific antibodies could be an ancillary method for EGFR mutation screening in the NSCLC patients, especially when there is not enough tumor tissues for sequencing detection. The utility of the IHC method with mutation-specific antibodies would need further validation in clinical studies.