bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mapping patterns of nodal metastases in seminoma: Rethinking radiotherapy fields.
Authors: Paly Jonathan J. , Efstathiou Jason Alexander , Hedgire Sandeep , Chung Peter W. M. , O’Malley Martin , Shah Anand , Bekelman Justin E. , Harisinghani Mukesh , Zietman Anthony L. , Shipley William U. , Beard Clair 
Published: February 2017

324 Background: Historically, radiation therapy for testicular seminoma has targeted the retroperitoneal (RPLN) and pelvic lymph nodes via standard anterior-posterior/posterior-anterior fields based upon skeletal anatomy. This study was undertaken to identify the location of involved lymph nodes and their relationship to both bony and vascular anatomy in stage II patients. Methods: Scans of 69 patients with stage II seminoma diagnosed between 1996 and 2011 were reviewed. 55% of patients had left-sided, 44% right-sided, and 1% bilateral primaries. The position of each node was recorded and then transferred to a standardized CT template scan based upon its relation to skeletal and vascular anatomy. Para-aortic fields were overlaid on the template, extending from T10/T11 to L5/S1 and bounded laterally by the contralateral transverse processes and ipsilateral renal hilum. Extended fields included ipsilateral iliac lymph node chains. The location of involved nodes within these conventional fields was assessed. Results: 113 nodes were identified as radiographically positive. 88% of involved nodes were located in the RPLN region with the remaining 12% in the pelvis. 98% of positive RPLN nodes were within a 2.2cm lateral and 1.8cm anterior expansion of the aorta between L1/L2 and L5/S1. No positive nodes were identified within the renal hilar region or superior to L1 for patients with left-sided seminomas. For right-sided seminomas, no positive nodes were superior to L2, though there was one renal hilar node. <2% of all nodes fell outside the extended treatment field. Conclusions: Nodal metastases from a contemporary cohort of stage II seminoma patients generally localized to a smaller area than is targeted using conventional fields. Notably, no positive nodes were identified superior to L1, on the contralateral side of vertebral bodies, or in the left renal hilum. Modified treatment fields based on vascular rather than bony anatomy may allow for a significant decrease in normal tissue irradiation and its associated toxicities. Validation of these results may inform guidelines for a redefined clinical target volume and allow for more targeted radiation delivery in the treatment of seminoma.
Phase II trial of docetaxel, cisplatin, 5-fluorouracil (TPF) in locally advanced and metastatic squamous cell carcinoma (SCC) of the penis (CRUK/09/001).
Authors: Bahl Amit , Nicholson Steve , Harland Stephen John , Chester John D. , Pickering Lisa M. , Barber Jim , Cruickshank Clare , Burnett Stephanie M. , Waters Rachel , Hall Emma ,   Penile TPF Trial Management Group
Published: February 2017

326 Background: Chemotherapy for penis cancer is used to palliate metastatic disease and treat locally-advanced disease. Pathologic similarities to head and neck SCC suggest that adding docetaxel (T) to platinum-based regimens may enhance efficacy. Methods: A single-stage single-arm phase II trial was conducted. Eligible patients had measurable, histologically proven penile SCC staged M1; or T4, any N, M0; or any T, N3/inoperable N2, M0; or any T, N1, M0 with Multi-Disciplinary Team agreement for chemotherapy as first-line therapy. Treatment was three 21-day cycles of TPF (day 1: T 75mg/m2, P 60mg/m2; days 1-5: F 750mg/m2/day). In 26 evaluable patients ≥14 responses were required to conclude a response rate of ≥60% (p0=0.35, p1=0.60, α=0.1, β=0.2; Fleming-A’Hern design). Primary endpoint was overall response rate at completion/discontinuation of trial treatment. Secondary endpoints included safety, tolerability, progression-free survival (PFS) and overall survival (OS). Results: 29 patients (median age 61 years) were recruited from 9 UK centres between Sept 2009 and Dec 2010. 8 patients were M1. 17 patients had performance status (PS) 0, 11 PS1, 1 PS2. 3 patients discontinued treatment early for reasons other than progression. Dose reductions/delays were reported for 13 patients. 28 patients have on-treatment toxicity data: 19 (68%) experienced grade 3/4 toxicity, with neutropenia most common (n=13, 46%). 7 patients (25%) experienced febrile neutropenia and/or neutropenic sepsis. 10/26 patients (38.5%, 95% CI: 20.2% - 59.4%) in the evaluable population responded. Twelve month PFS was 39.1% (95% CI: 20.9% - 56.8%; median PFS (all 29 patients/M1/M0): 7.1/ 3.1/ 9.6- months). Twelve month OS was 54.6% (34.9% - 70.6%; median OS (all patients/M1/M0): 13.7/ 6.9/ not reached yet-months). Conclusions: UK clinicians successfully recruited to a multi-centre trial in penis cancer, establishing a network of centres for future studies. Toxic effects of TPF were common but not unexpected. The trial did not reach its target response rate of ≥60% to justify further investigation although PFS and OS in this cohort compares favourably to reported data in literature.
Perineural versus lymphovascular invasion: Which is a better marker for unfavorable biochemical outcomes following prostatectomy? Results from the Duke Prostate Center Database.
Authors: Singh Abhay A , Banez Lionel Lloyds , Gerber Leah , Freedland Stephen J. , Robertson Cary N. , Ferrandino Michael , Polascik Thomas , Walther Philip John , Moul Judd W. 
Published: February 2017

34 Background: Despite a substantial effort to study the clinical significance of perineural invasion in prostate biopsies (PNIb) its prognostic significance remains controversial. The limited data on perineural invasion in radical prostatectomy (RP) specimens (PNIp) suggests that biopsy specimens inadequately represent whole gland pathology thus rendering investigation of PNIp even more clinically relevant. While lymphovascular invasion in pathology specimens (LVIp) has been more rigorously investigated, studies have shown conflicting results. More importantly, there has been minimal comparison of PNIp and LVIp in the same cohort to determine which marker is the superior prognostic factor. Methods: We retrospectively analyzed data from 1611 men who underwent RP from 1999 to 2010 from the Duke Prostate Center database. We evaluated PNIp and LVIp as predictors of time to BCR by comparing hazard ratios (HR) and 95% confidence intervals (CI) using crude and adjusted proportional hazards regression models that included both variables and controlled for demographic and clinico-pathological covariates. Results: A total of 1304 (81%) men had PNIp while only 82 (5%) men had LVIp. On crude regression, both PNIp (HR=3.39; 95% CI=1.94-5.84; p<0.001) and LVIp (HR=2.33; 95% CI=1.49-3.64; p<0.001) were significant predictors of adverse BCR risk. After adjusting for clinico-pathological covariates, PNIp remained significantly associated with increased BCR risk (HR=1.85; 95%CI =1.04-3.31; p=0.04). Specifically, men with PNIp were 85% more likely to experience BCR relative to PNIp (-) men. In contrast, LVIp was not independently associated with BCR risk (p=0.23). Conclusions: In a cohort of men who underwent RP, PNIp is predictive of adverse BCR outcomes independent of clinicopathological parameters that include LVIp. Consequently, LVIp is a poor predictor of BCR risk. PNIp may thus provide additional prognostic information for men treated with RP and its inclusion in predictive nomograms requires study. Further analyses to determine if PNIp is likewise associated with metastasis and cancer-specific survival are warranted.
Everolimus therapy for angiomyolipoma in patients with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis: Results from EXIST-2.
Authors: Bissler John J. , Kingswood J. Chris , Zonnenberg B. A. , Frost Michael , Belousova Elena , Radzikowska Elzbieta , Fischereder Michael , Nonomura Norio , Brakemeier Susan , de Vries Petrus , Sahmoud Tarek , Shah Gaurav , Miao Sara , Gray Diep , Budde Klemens 
Published: February 2017

356 Background: We evaluated everolimus, an oral mTOR inhibitor, for treating angiomyolipoma (AML) in patients with tuberous sclerosis complex (TSC) or sporadic lymphangioleiomyomatosis (sLAM). Methods: EXIST-2 ( NCT00790400 ) is a prospective, international, randomized, double-blind, placebo-controlled, phase III study. Patients (≥1 AML with longest diameter ≥3 cm) were stratified by (i) TSC and enzyme-inducing anti-epileptic drug (EIAED) use, (ii) TSC and EIAED non-use, (iii) sLAM and randomized 2:1 to receive everolimus 10 mg daily (n=79) or placebo (n=39). Kidney CT/MRI was performed at baseline, at 12, 24, and 48 weeks, and then annually. Primary efficacy endpoint was the proportion of patients with AML response (best overall confirmed ≥50% reduction in sum of volumes of all target AML relative to baseline). Secondary efficacy endpoints included time to AML progression and skin lesion response rate in patients with >1 skin lesion at baseline (n=114). Adverse events (AE) were monitored every visit. Core phase results (6 months from last patient randomized) are presented. Results: Patient characteristics were balanced across the 2 groups; median patient age was 31 years. Median treatment duration was 38.1 weeks (everolimus) and 34.0 weeks (placebo). Everolimus best overall response rate (41.8%) was superior to placebo (0%) for the primary efficacy endpoint (p<0.0001). Median time to AML progression was 11.4 months for placebo and was not reached for everolimus. The everolimus group had a significantly higher best overall skin lesion response rate (complete or partial response) than placebo (26% vs. 0%; p=0.0002). Everolimus was associated with an acceptable safety profile consistent with previous reports in TSC, with most AEs being grade 1 or 2. Serious AE incidence was similar in the treatment arms (everolimus 19.0% vs. placebo 17.9%). Conclusions: Everolimus treatment produced a clinically and statistically significant reduction in AML volume compared with placebo and showed a safety profile consistent with previous reports. Everolimus represents the first potential pharmacologic treatment option for patients with AML.
Incidence of benign versus malignant renal tumors in selected studies.
Authors: Russo Paul , Uzzo Robert G. , Lowrance William Thomas , Asnis-Alibozek Aviva , LaFrance Norman David , Libertino John A. , Pryma Daniel A. , Divgi Chaitanya R. 
Published: February 2017

357 Background: Use of cross-sectional imaging has increased the detection rate for small renal tumors; more patients now present with early-stage renal cell carcinoma (RCC) or benign or indolent renal masses. Histopathology after surgical resection is the definitive method for characterizing renal tumors. Stage migration of renal masses creates uncertainty about the percentage of resected masses that will be benign vs malignant. We sought to better define these proportions through a targeted review of the literature. Methods: PubMed/select congresses were searched to identify the histologic classification of renal masses in a representative sample from the contemporary literature: [search] incidence AND (renal cell carcinoma AND benign); incidence AND (renal tumor AND benign); percentage AND (renal cell carcinoma AND benign); limit: 2003–2011. Results: Most representative studies included procedures conducted in the mid-1990s to the mid-to-late 2000s. Studies origin was US (n=8), Korea (n=3), China, Japan, Germany, Austria, Australia, and multisite (Israel/France/US; all n=1). Only 8 studies had n≥500 (range, 70–10,404). The proportion of benign masses are shown (see Table); half of the studies reported values between 16% and 17%. The majority found that benign tumors were more likely to be smaller in size (<4 or <7 cm) than malignant tumors. 11 studies reported the RCC subtype (% clear cell range, 46%–83%). Conclusions: Benign renal tumors occur ~15% of the time and are more prevalent among small masses. Nearly 25% of resected lesions are benign or indolent and may not require surgery. Preoperative discrimination of more aggressive renal masses would be an important clinical advance that could improve clinicians’ diagnostic confidence and guide patient management. Funding: Wilex AG/IBA Molecular. [Table: see text]
Epithelial-mesenchymal transition: A mechanism of resistance to VEGF pathway inhibition in genitourinary cancers.
Authors: Hammers Hans , Fu Chenglai , Gerber Stephanie , Van Den Berg Susan , Steenwinkel Frans , Moriarty Whei , Keizman Daniel , Kachhap Sushant , Carducci Michael Anthony 
Published: February 2017

390 Background: There is emerging clinical data that epithelial-mesenchymal-transition (EMT), a cellular phenotype observed with aggressive disease and metastasis, is associated with resistance to angiogenesis inhibitors targeting the VEGF pathway. To better study and characterize this clinical observation we set out to generate well-defined preclinical prostate and kidney cancer models of EMT mediated resistance to the angiogenesis inhibitor sunitinib with the overarching goal to develop more effective antiangiogenic therapies in genitourinary malignancies. Methods: We screened a library of prostate and kidney cancer xenografts models for their response to the angiogenesis inhibitor sunitinib. By applying strict clinical criteria we identified models, which were refractory, resistant and also unambiguously sensitive to sunitinib. The sensitive cell lines were used to stably overexpress the EMT inducing transcription factors Twist1, Snail and ZEB1. The cell lines were then injected to form xenografts and their response to sunitinib was assessed. Correlative studies for microvascular density and cellularly mediated resistance through blood vessel maturation and myeloid cell recruitment were performed. Results: EMT mediated resistance to sunitinib was seen in both, prostate and kidney cancer models. Interestingly, EMT mediated resistance was primarily associated with an increase in blood vessel maturation. Conclusions: We present for the first time defined preclinical prostate and kidney cancer model of EMT mediated resistance to a multitargeted VEGF pathway inhibitor. These model could prove useful in our efforts to develop more effective antiangiogenic approaches in prostate cancer and kidney cancer and aid to predict response or the lack thereof to VEGF based therapies.
Safety and efficacy of everolimus in patients with non-clear cell renal cell carcinoma refractory to VEGF-targeted therapy: Subgroup analysis of REACT.
Authors: Blank Christian U. , Bono Petri , Larkin James M. G. , Gogov Svetozar , Panneerselvam Ashok , Garay Carlos A. , Grünwald Viktor ,   on behalf of the REACT Study Group
Published: February 2017

402 Background: Metastatic non-clear cell renal cell carcinoma (mncRCC), which accounts for about 25% of all RCCs, is characterized by resistance to treatment and poor overall survival. Despite recent advances in targeted therapies for patients with mRCC, effective therapies for patients with mncRCC remain limited. The REACT (RAD001 Expanded Access Clinical Trial in RCC) study was initiated to provide patients with mRCC of any histology refractory to VEGF-targeted therapy access to everolimus in advance of regulatory approval. Methods: REACT, an open-label, international, expanded-access program (Clinicaltrials.gov: NCT00655252 ) enrolled patients with measurable or nonmeasurable mRCC of any histology who were intolerant of, or progressed while on, VEGFR-TKI therapy in order to evaluate the long-term safety of everolimus 10 mg daily. Overall incidence of grade 3/4 and serious adverse events (AEs) were recorded, as was tumor response to everolimus according to RECIST criteria. A subgroup analysis of safety and efficacy in patients with mncRCC was performed. Results: Of 1367 patients enrolled, 75 patients (5.5%) had mncRCC. Median everolimus treatment duration in the mncRCC subgroup was 12.14 weeks (range, 0.9–49.0 weeks) and in the overall REACT population it was 14.0 weeks (range, 0.1–83.7 weeks). In the mncRCC subgroup, most commonly reported grade 3/4 AEs were anemia (17.3%), dyspnea (10.7%), pleural effusion (9.3%), fatigue (8.0%), and hyperglycemia (6.6%). Best overall response was similar in the mncRCC subgroup and overall population: respectively, 1.3% and 1.7% had partial response and 49.3% and 51.6% had stable disease. Conclusions: Although patients with mncRCC had a slightly lower treatment duration than the overall REACT population, approximately 50% of these patients achieved disease control on treatment. In this subgroup, everolimus was well tolerated, no new safety issues were observed, and the AE profile was consistent with that of the overall population. These encouraging results of the safety and efficacy of everolimus in patients with mncRCC support further evaluation of everolimus in these patients.
Improving outcomes through the development of quality indicators in renal cell cancer.
Authors: Wood Lori , Bjarnason Georg A. , Black Peter C. , Cagiannos Ilias , Heng Daniel Yick Chin , Kapoor Anil , Kollmannsberger Christian K. , Mohammadzadeh Forough , Moore Ronald Brian , Rendon Ricardo A. , Soulieres Denis , Tanguay Simon , Venner Peter , Finelli Antonio 
Published: February 2017

422 Background: Optimal quality of care is necessary for ideal outcomes, and quality indicators (QI) are increasingly being used to measure quality of care. In renal cell carcinoma (RCC), there is a paucity of information defining such optimal care. This is particularly important as care of RCC patients is becoming increasingly complicated with more options and requiring greater expertise. The goal of this study was to identify QI for RCC across the entire disease spectrum from presentation to palliation. Methods: A multidisciplinary expert panel (13 members) of medical and urologic oncologists from across Canada reviewed potential QI. These potential QI were identified from a systematic review of the literature. In addition, panel members were encouraged to suggest additional potential QI. A modified Delphi technique was utilized to select QI that were both relevant and practical to RCC; this technique incorporated 2 email questionnaires and 1 in-person meeting. Results: From 250 citations in the systematic review, 34 possible QI were identified; 24 additional potential QI were suggested by panel members. A final set of 23 QI were established by the expert panel. These were distributed across the RCC disease spectrum as follows (number of QI in parentheses): screening (1), diagnosis and prognosis (3), management of localized disease (7), surgical management of locally advanced or metastatic disease (3), systemic therapy (4), and follow-up (3). These 21 QI focused largely on the treatment of RCC. In addition, two QI related to survival outcomes (overall and progression-free) were selected. An example of a QI in localized disease is the proportion of patients undergoing partial nephrectomy for tumors < 4 cm. An example in advanced disease is the proportion of patients who are assessed by members of a multidisciplinary genitourinary cancer team. The final 23 QI selected will be presented in detail. Conclusions: A systematic, consensus-based approach was used to determine relevant QI in RCC care. These 23 QIs will provide a means of evaluating the quality of RCC care in an effort to improve outcomes for our patients. The next step will be to establish a means of measuring each of these QI based on defined or yet to be defined benchmarks.
Phase I/II safety and pharmacokinetic (PK) study of ARN-509 in patients with metastatic castration-resistant prostate cancer (mCRPC): Phase I results of a Prostate Cancer Clinical Trials Consortium study.
Authors: Rathkopf Dana E. , Danila Daniel Costin , Morris Michael J. , Slovin Susan F. , Steinbrecher Jill Elise , Arauz Gabrielle , Rix Peter J. , Chow Maneval Edna , Chen Isan , Fox Josef J. , Fleisher Martin , Larson Steven M. , Scher Howard I. 
Published: February 2017

43 Background: In CRPC, androgen receptor (AR) overexpression is associated with resistance to first-generation anti-androgen therapy such as bicalutamide. ARN-509 is a novel small molecule AR antagonist that impairs AR nuclear translocation and binding to DNA, inhibiting tumor growth and promoting apoptosis, with no partial agonist activity. Preclinical data shows that ARN-509 binds AR with 5-fold greater affinity than bicalutamide, and induces tumor regression in hormone-sensitive and CRPC xenograft models. Methods: In this open-label, Phase 1/2 study, mCRPC patients received ARN-509 orally on a continuous daily dosing schedule. In Phase 1 , 7 doses (30, 60, 90, 120, 180, 240, 300 mg) were tested using standard 3x3 dose escalation criteria to assess safety, PK, and determine the recommended Phase 2 dose (RP2D). Preliminary anti-tumor activity was assessed by PSA kinetics, radiographic responses, circulating tumor cells (CTCs), and FDHT-PET imaging. Results: Twenty-four patients (median age 68 yrs, Gleason Score 8; prior docetaxel 13%) were enrolled. The most common Grade 1-2 treatment-related adverse events were fatigue (38%), nausea (29%), and pain (24%). There was only 1 treatment-related Grade 3 adverse event (abdominal pain) at 300 mg, possibly related to a higher pill burden, which led to an additional 3 patients being enrolled at the highest dose with no further dose limiting toxicities. PK was shown to be linear and dose-dependent. Twelve patients (55%) had ≥ 50% PSA declines. To date, 7 patients have discontinued the study due to progression, with the longest patient still on study for more than 1 year. FDHT-PET imaging demonstrated AR blockade at 4 weeks across multiple dose levels. Based on preclinical assessment of maximum efficacious dose, PK, and promising activity across all doses, 240 mg was selected as the RP2D. Conclusions: In this Phase 1 study, ARN-509 was shown to be safe and well tolerated, with promising preliminary activity based on PSA and pharmacodynamic evidence of AR antagonism. The Phase 2 portion of the study will enroll up to 90 patients with treatment-naïve non-metastatic and mCRPC.