tbuckley/cabot-search huggingface dataset:
Effect of ketoconazole/hydrocortisone (Keto/HC) on 25 (OH) vitamin D in men with castration-resistant prostate cancer (CRPC).
Authors: D. L. Trump, M. H. AL-Hussaini, C. Silliman, A. Jarkowski, C. S. Johnson
Journal: Journal of Clinical Oncology (2011)

e13063 Background: Keto is a modestly active agent used extensively in the treatment of CRPC. Keto acts by inhibiting CYP17& disrupting androgen signaling pathways, similar to the, more specific CYP17 inhibitor, abiraterone. Keto is a non-selective inhibitor of CYP enzymes. Our group is studying the role of keto & similar agents in inhibiting CYP24A1, the dominant enzyme responsible for terminating the action of calcitriol (1,25dihydroxycholecalciferol, [1,25D3]). Keto clearly enhances 1,25D3 exposure through CYP24A1 inhibition and keto would be expected to modify circulating vitamin D levels by inhibiting vitamin D synthesizing enzymes (e.g. 25 hydroxylases, CYP2R1 and CYP27A1 & CYP27B1 [a 1-α-hydroxylase]). There is increasing indication that body stores of vitamin D are important in influencing cancer growth, bone and other health outcomes. Therefore, we examined changes in 25 (OH) cholecalciferol[25D3], the vitamin D form which reflects vitamin D sufficiency among men with CRPC treated with keto. Methods: Among 97 patients treated with K/HC at our center over the past 5 years, 25D3 serum concentrations within 6 months before & 6 months after K/HC were available in 28 patients. Results: Among these 28 patients the median age was 73 years; 25 were white and 3 were African American. 27/28 had established metastases; and in 1 progression was signaled by rising PSA only. PSA response (>50% decrease) occurred in19/28. Median PSA serum content before treatment was 35.9 ng/ml and median 25D3 was 44.3 ng/ml. After keto/HC median 25D3 content was 30.1ng/ml. 25D3 levels decreased in 21/28 patients; median decrease was 13.1 ng/ml. Prior to keto/HC 8/28 patients had 25D3 levels below normal (32ng/ml) after keto 16/28 had serum levels <32ng/ml. Conclusions: Among 28 patients with CRPC treated with keto/HC, 25D3 decreased in 75% and insufficient levels of 25D3 were seen in >50% of men. This decline may be a pharmacodynamic marker of keto activity. The clinical significance of these changes is uncertain and merits further study.
Predicting response to neoadjuvant chemotherapy (NAC) in epithelial ovarian carcinoma (EOC).
Authors: A. Montes, M. Okera, S. Ayis, S. Natas, A. Jacques, A. Winship
Journal: Journal of Clinical Oncology (2011)

e15555 Background: NAC is increasingly used in the management of EOC and is not inferior to primary surgical debulking. Methods to assess response to NAC remain poorly defined. Predictive markers would ideally allow selection of patients more likely to have a favourable outcome with NAC. This retrospective study analyses clinical, laboratory and radiologic characteristics, in order to identify predictive markers of response to NAC. Methods: Eligibility: patients with Stage III/IV EOC, received ≥3 cycles NAC, underwent primary delayed surgery. Variables included performance status, serum albumin, baseline Ca125 level and %change in Ca125 during chemotherapy, CT radiologic findings. Outcome defined as optimal debulking and pathologic response (PR). Statistical analysis performed using SPSS17. Results: 62 patients, mean age 59.5 years (30-82). Patient characteristics shown in the table. Mean albumin 38 (13-53), mean baseline CA-125 2668 (64-14549). 74% had decline in Ca125 after one cycle, mean decrease 45% (1-91%). 11% had rise in CA-125after cycle 1. Mean %decline in CA-125 after 3 cycles 85% (4-100%). Multivariate analysis: no significant association between ECOG or albumin and outcome. The %change in CA-125 between baseline and after 1 cycle was significantly associated with surgical outcome (p =0.028), as was %change in CA-125 between baseline and 3 cycles (p=0.002). Analysis of radiologic variables awaited. Conclusions: Majority of patients achieved optimal debulking after NAC but have macroscopic residual disease on histology. PR is uncommon. The most significant factor identified is the percentage decrease in CA-125. Further prospective research required to identify predictive markers, with particular focus on new imaging techniques (MRI/PET) and biomarkers. Patient characteristics (n=62). ECOG 0 1 2 3 18% 43.5% 14.5% 3% Stage II IIIc IV 3% 61% 37% Histology Serous Endometrioid Clear cell Carcinosarcoma 85.5% 3% 1.6% 5% Chemo Carboplatin-paclitaxel Carboplatin Other 82% 16% 1.6% No. of cycles pre-op ≤4 >4 (5-8) 58% 40% Surgical outcome Optimal debulked ≤1cm Suboptimal debulking >1cm residual Unresectable 76% 10% 8% Histologic outcome pCR Microscopic residual Macroscopic residual Unresectable 6% 18% 68% 8%
Targeting epidermal growth factor receptor (EGFR) in urothelial cancer (UC): A phase II randomized trial of cisplatin (C) with gemcitabine (G) with or without cetuximab.
Authors: A. S. Alva, N. Agarwal, A. O. Siefker-Radtke, B. J. Roth, D. C. Smith, S. Daignault, S. Srinivas, D. A. Bradley, M. Hussain
Journal: Journal of Clinical Oncology (2010)

TPS239 Background: Cures are rare in advanced UC. The EGF pathway is involved in proliferation, survival, angiogenesis, and metastasis of cancers including UC. EGFR is overexpressed in 50% of UC. Its expression correlates with higher tumor grade, stage, disease progression, and is an independent adverse prognostic factor for overall survival (OS) and disease-specific survival. The majority of UC metastases over-express EGFR. Resistance to chemotherapy in bladder cancer lines involves EGFR up-regulation and can be overcome by EGFR inhibition. Cetuximab (Ctx) is a humanized chimeric antibody against the extracellular domain of EGFR. In UC cell lines Ctx is cytostatic and downregulates angiogenic factors including VEGF and bFGF. In in-vivo UC tumors it results in tumor regression and growth and metastasis inhibition. Ctx is FDA approved in head and neck and colon cancer based on improvements in OS and/or progression-free survival (PFS).This study is designed to determine if Ctx + GC results in higher response rate in UC. Methods: Eligible pts have locally advanced or metastatic UC, adequate organ function, ECOG performance status 0-2, no prior chemo or anti-EGFR therapy for current stage of disease. Pts are randomized to receive C 70 mg/m2 on day (D)1 and G 1000 mg/m2 on D1,8,15 in 28 D cycles (Arm A) or same chemotherapy + Ctx 500 mg/m2 D 1 and 15 (Arm B- Recent data suggest q 2 week dosing may be equivalent with q week schedule). Response is assessed q 2 cycles. GC therapy continues till progression or completion of 6 cycles. Arm A pts progressing after 2 cycles will receive GC + Ctx. Pts on GC+Ctx who do not progress after 6 cycles will continue on Ctx. Objectives:Assess the overall response rate (ORR) of GC ± Ctx, safety, response duration, PFS, OS and if Ctx sensitizes nonresponding pts to GC. Blood and tissue samples are collected for correlative studies. Design: Phase II, with a 2:1 experimental to control randomization. Accrual target is 27 pts to Arm A (expected ORR 50%) and 54 pts to Arm B (expected ORR 65%). To date 56/81 pts are enrolled. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration ImClone Systems
Comparison of Deferasirox, Deferiprone, and Desferrioxamine Effectiveness on Myocardial Iron Concentrations and Biventricular Function by Quantitative MR in Beta-Thalassemia Major
Authors: Alessia Pepe, Brunella Favilli, Vincenzo Positano, Paolo Cianciulli, Anna Spasiano, Marcello Capra, Caterina Borgna-Pignatti, Maria Caterina Putti, Tommaso Casini, Maria Antonietta Romeo, Maria Grazia Bisconte, Aldo Filosa, Vincenzo Caruso, Antonella Quarta, Lorella Pitrolo, Vincenzo De Sanctis, Calogera Gerardi, Aurelio Maggio, Antonello Pietrangelo, Massimo Lombardi
Journal: Blood (2008)
Analyses of the peripheral immunome following multiple administrations of avelumab, a human IgG1 anti-PD-L1 monoclonal antibody
Authors: Renee N. Donahue, Lauren M. Lepone, Italia Grenga, Caroline Jochems, Massimo Fantini, Ravi A. Madan, Christopher R. Heery, James L. Gulley, Jeffrey Schlom
Journal: Journal for ImmunoTherapy of Cancer (2017)

<h3>Background</h3> Multiple anti-PD-L1/PD-1 checkpoint monoclonal antibodies (MAb) have shown clear evidence of clinical benefit. All except one have been designed or engineered to omit the possibility to mediate antibody-dependent cell-mediated cytotoxicity (ADCC) as a second potential mode of anti-tumor activity; the reason for this is the concern of lysis of PD-L1 positive immune cells. Avelumab is a fully human IgG1 MAb which has been shown in prior in vitro studies to mediate ADCC versus a range of human tumor cells, and clinical studies have demonstrated anti-tumor activity versus a range of human cancers. This study was designed to investigate the effect on immune cell subsets in the peripheral blood of cancer patients prior to and following multiple administrations of avelumab. <h3>Methods</h3> One hundred twenty-three distinct immune cell subsets in the peripheral blood of cancer patients (<i>n</i> = 28) in a phase I trial were analyzed by flow cytometry prior to and following one, three, and nine cycles of avelumab. Changes in soluble (s) CD27 and sCD40L in plasma were also evaluated. In vitro studies were also performed to determine if avelumab would mediate ADCC of PBMC. <h3>Results</h3> No statistically significant changes in any of the 123 immune cell subsets analyzed were observed at any dose level, or number of doses, of avelumab. Increases in the ratio of sCD27:sCD40L were observed, suggesting potential immune activation. Controlled in vitro studies also showed lysis of tumor cells by avelumab versus no lysis of PBMC from five donors. <h3>Conclusions</h3> These studies demonstrate the lack of any significant effect on multiple immune cell subsets, even those expressing PD-L1, following multiple cycles of avelumab. These results complement prior studies showing anti-tumor effects of avelumab and comparable levels of adverse events with avelumab versus other anti-PD-1/PD-L1 MAbs. These studies provide the rationale to further exploit the potential ADCC mechanism of action of avelumab as well as other human IgG1 checkpoint inhibitors. <h3>Trial registration</h3> ClinicalTrials.gov identifier: NCT01772004 (first received: 1/14/13; start date: January 2013) and NCT00001846 (first received date: 11/3/99; start date: August 1999).
Efficacity and safety of panitumumab in mCRC patients: A post-AMM OMIT study.
Authors: Francoise Grude, Jean François Ramée, Laurent Guivarch, Jean-Yves Douillard, Sophie Rochard, Olivier Dupuis, Chrystelle Grollier, Veronique Guerin-Meyer, Pierre Leynia, Marc Porneuf, Elodie Peguet, Jean Luc Raoul, Claude Bertrand, Philippe Deguiral, Laurent Derenne, Nacredine Achour, Bernadette Person, Jean-Philippe Metges, Marie-Annick Lebot, Christian Riche
Journal: Journal of Clinical Oncology (2012)

608 Background: Metastatic colorectal cancer (mCRC) management has been improved by targeted therapies. The evaluation of the use of panitumumab (PANI), after approval, in the real life is strategic to assess health politics. OMIT Bretagne - Pays de Loire is a network of private and public cancer centers. Methods: Data from patients treated with PANI in mCRC were collected. Previously published data are recited. Sex, age, primary tumor, Kras status, line of treatment, toxicity, reason of discontinuation, response, progression free survival (PFS) and overall survival (OS) have been studied. Results: Data of 322 patients treated between second half of 2008 and end of 2010 have been collected. PANI was used alone (85.5%) or with chemotherapy (14.5%) : mainly FOLFIRI, IRINOTECAN or FOLFOX). KRAS status was wild-type (WT 96.5%), mutated (0.5%), undetermined (2.5%) or not searched (0.5%). Only KRAS WT patients treated with monotherapy of PANI at 6 mg/kg every 2 weeks were analysed (n=263). Sexe : 177 men and 86 women. Median age : 67 years [36-90] (Van Custem JCO 2007: 62 years [27-83]). Primary tumor of patients was : colon (75%), rectum (22%) and others (3%). They received PANI mostly at line 2 (25%), 3 (46%) or 4 (19%). Discontinuation of treatment was mostly due to disease progression : 64%, death: 15% and toxicities : 7% (skin toxicities 3.7%). Clinical response was evaluated for the first 84 patients: partial response (PR): 30%, stable disease (SD): 14% and progression (P): 56%. In KRAS WT patients treated by PANI, Amado described 17% of PR, 34% of SD and 49% of P (Amado JCO 2008). Median duration of treatment was 69 days [0;360] (n=249). Median duration between end of treatment and death when death is the cause of end of treatment was 13 days [0;54] (n=35). Median of OS was 137 days [0;816] (n=143) which is lower than previously described (Van Cutsem JCO 2007 : 192 days regardless of KRAS status ; Amado JCO 2008 : 243 days in KRAS WT). Conclusions: The OMIT analysis of patients treated by PANI in Bretagne/Pays de Loire for a mCRC allows to assess the good use, according to its label, in the real life. Complete results about clinical response, PFS (cut-off 01/12/2011), OS and safety as well as previously published data will be shown at the meeting.
Phase II trial of weekly topotecan with docetaxel in recurrent small cell lung cancer (Aultman Lung 01)
Authors: R. A. Khan, B. Hahn
Journal: Journal of Clinical Oncology (2008)

19111 Background: Small cell lung cancer constitutes up to 15% of 170,000 new lung cancer cases diagnosed each year. Patients (pts) that experience recurrence after initial treatment have a very poor prognosis. The main objective of this study was to determine the overall response rate of patients treated with at least 2 cycles of topotecan and docetaxel. The secondary objectives were to determine the feasibility and toxicities of this combination. The final secondary objective is overall survival for patients that received 2 or more cycles. Methods: Eligible pts with recurrent small cell lung cancer had to be at least 3 months from initial treatment. Pts received Docetaxel 30 mg/m2 IV followed by Topotecan 3 mg/m2 IV Days 1 and 8 of a 21 day cycle. Disease assessment was done every 2 cycles. Results: Seven pts were accrued to the study, one pt died following cycle 2, of an unrelated cardiac event. The response rate was 14.2% (1pt). Three had progressive disease (PD) after 1 or 2 cycles; 2 had PD after 4 cycles; and there was 1 unrelated and unexpected death. Grade III or IV toxicities included: neutropenic fever (1), infection (1), bone pain (1), thrombocytopenia (6), neurtopenia (6). Grade I or II toxicity included: depression (2), fatigue (6), hyperglycemia (5), muscle weakness (4), nausea (4), alopecia (3pts), anxiety (1), decreased hemoglobin (1), stomatitis (1), ataxia (1), dehydration (1), hypotension (1), pain-abdominal (1), skin ulcer (1), vomiting (1), WBC (1), anorexia (3), hypocalcemia (3), dyspnea (6), arthralgia (2), leukocytes (2), diarrhea (5), anemia (4), insomnia (2), myalgia (2), confusion (1), neuropathy (4), constipation (3), weight loss (3) & pain-chest (non-cardiac) (3). The overall survival was 3.5 month (15 weeks) for the 5 patients that received at least 2 cycles of therapy. The overall survival analysis has a 95% confidence interval. Conclusion: The study was halted before the first planned interim analysis at 20 pts because of slow accrual. The toxicities were acceptable for the first seven patients. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration GlaxoSmithKline
Clinical outcomes and safety in men ≥ 75 and &lt; 75 years with metastatic castration-resistant prostate cancer (mCRPC) treated with enzalutamide in the phase 3 PREVAIL trial.
Authors: Julie Nicole Graff, Giulia Baciarello, Andrew J. Armstrong, Celestia S. Higano, Peter Iversen, David Forer, Harry H. Mansbach, De Phung, Bertrand F. Tombal, Tomasz M. Beer, Cora N. Sternberg
Journal: Journal of Clinical Oncology (2015)

200 Background: In the phase 3 PREVAIL trial, enzalutamide (ENZA), an androgen receptor inhibitor, improved overall survival (OS) and radiographic progression-free survival (rPFS) relative to placebo (PBO) in chemotherapy-naïve men with mCRPC. Methods: PREVAIL randomized 1,717 patients (pts) with asymptomatic or minimally symptomatic chemotherapy-naïve mCRPC 1:1 to ENZA 160 mg daily or PBO. Coprimary endpoints were OS and rPFS. This prespecified analysis evaluated the impact of age (≥ 75 vs &lt; 75 years) on efficacy and safety. Results: In PREVAIL, 609 (35%) pts were aged ≥ 75 years. This older subset had several poorer baseline prognostics relative to those aged &lt; 75 years: worse ECOG performance status (ECOG 1: 45.0% vs 24.7%), higher prostate-specific antigen (PSA; 73.3 vs 37.3 ng/mL) and more cardiovascular disease (26.9% vs 16.5%). In both older and younger pts, ENZA improved OS, rPFS and time to PSA progression (Table). Pts aged ≥ 75 years in both the ENZA and PBO groups combined had a higher rate of grade ≥ 3 adverse events (46% vs 37% in younger pts) and among enzalutamide-treated men more older pts reported falls (any grade; ENZA 19% and PBO 8%) than younger pts (ENZA 7% and PBO 4%). Fewer pts ≥ 75 years received subsequent antineoplastic therapies. Conclusions: In PREVAIL, efficacy outcomes in elderly (≥ 75 years) and younger (&lt; 75 years) pts with chemotherapy-naïve mCRPC were comparable and pts consistently benefited from ENZA treatment. Safety with ENZA was similar in both age groups, although older pts reported a higher incidence of falls and received fewer subsequent antineoplastic therapies. Clinical trial information: NCT01212991. [Table: see text]
Incidence and outcome of interstitial lung disease (ILD) with everolimus treatment for metastatic renal cell carcinoma.
Authors: Fumiya Hongo, Masakatsu Oishi, Takashi Ueda, Yasunori Kimura, Terukazu Nakamura, Yoshio Naya, Kazuya Mikami, Tsuneharu Miki
Journal: Journal of Clinical Oncology (2013)

427 Background: Interstitial lung disease (ILD) is known as one of the adverse events during treatment with everolimus for metastatic renal cell carcinoma (mRCC). Methods: We retrospectively assessed the incidence and outcome of ILD in mRCC patients treated with everolimus. From April 2010 to August 2012, 25 cases were treated with everolimus after failure of one or two TKIs in our institute. All adverse events were graded in accordance with NCI CTCAE, version 3.0. Results: A total of 25 patients received treatment with everolimus. They included 18 male and 7 female patients ranging in age from 21 to 84 years (median 62). According to MSKCC risk criteria, 6 cases were at favorable risk, 16 cases were at intermediate risk, and 3 cases were at poor risk. Median treatment term was 4 months (range 2-17 months). SD was in 19 cases and PD was in 6 cases. Progression free survival was 3.5 months and overall survival was 12 months. ILD was found in 7 cases (28%). 1 was G1, 5 were G2 and 1 was G3. Corticosteroid therapy was initiated in 3 cases. In 5 of 7 ILD cases, everolimus was re-challenged. In our series, patients with ILD showed significantly better progression free survival than those without ILD (PFS was 8 months vs. 3 months. Log-rank, p &lt; 0.001). There were no significant different between the 2 groups in over all survival (12 months in patients with ILD vs. 10 months in patients without ILD. Log-rank, NS). Conclusions: Everolimus appears to be effective and well-tolerated in our institute. Re-challenge of everolimus was feasible after improving of everolimus-induced ILD in cases of grade 1-2.
Metastatic non–clear cell renal cell carcinoma (nccRCC) treated with targeted therapy agents: Applying the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic model to predict outcomes.
Authors: Nils Kroeger, Wanling Xie, Jae-Lyun Lee, Georg A. Bjarnason, Jennifer J. Knox, Mary J. MacKenzie, Lori Wood, Sandy Srinivas, Ulka N. Vaishamayan, Sun Young Rha, Sumanta Kumar Pal, Frede Donskov, Neeraj Agarwal, Christian K. Kollmannsberger, Min-Han Tan, Scott A. North, Brian I. Rini, Toni K. Choueiri, Daniel Yick Chin Heng
Journal: Journal of Clinical Oncology (2013)

396 Background: The International mRCC Database Consortium (IMDC) Prognostic Model (Heng, et al. model, JCO, 2009) was defined and validated in a patient cohort that was comprised of RCC of all histological-subtypes. Clear-cell RCC (ccRCC) accounts for ~80% of RCC cases, and thus it is unknown if this model is reliable in patients with non-ccRCC (nccRCC). Therefore, we sought to evaluate the reliability of the model separately in ccRCC and nccRCC. Methods: Data on 2,215 (1,963 ccRCC/252 n-ccRCC) patients treated with 1-st line VEGF-and mTOR targeted therapies were collected from the IMDC. nccRCC included papillary, chromophobe, and other histologies. Patients were assigned to favorable, intermediate, and poor prognosis groups according to the ICDM prognostic model. The discrimination ability for overall survival (OS) was evaluated by C-index. Results: The median OS of the entire cohort was 20.9 months. nccRCC patients were of younger age (p &lt; 0.0001), more often presented with low Hb (p = 0.014) and elevated neutrophils (p = 0.0001), but displayed otherwise similar clinicopathological features compared to ccRCC. OS (22.3 vs. 12.8 months; p &lt; 0.0001), and TTF (7.8 vs. 4.2 months; p &lt; 0.0001) were worse in nccRCC compared to ccRCC. The hazard ratio for death (OS) and treatment failure (TTF) when adjusted for the prognostic factors was 1.41 (95%CI 1.19, 1.67, p &lt; 0.0001) and 1.54 (95% CI 1.33, 1.79, p &lt; 0.0001), respectively. The IMDC prognostic model reliably discriminated three risk groups to predict OS and TTF in nccRCC; the median OS and TTF of favorable, intermediate, and poor prognosis groups were 31.4, 16.1, and 5.1 months (p &lt; 0.0001) and 9.6, 4.9, and 2.1 months (p &lt; 0.0001), respectively. The C-indices for OS were 0.66 and 0.64 for the IDCM and MSKCC criteria, respectively. Conclusions: Patients with nccRCC treated with targeted therapies have a significantly worse outcome than ccRCC patients. The IMDC prognostic model reliably predicts OS and TTF in nccRCC and ccRCC.