bluuebunny/crossref_metadata_2025 huggingface dataset:
A retrospective analysis of the effect of time from diagnosis to cystectomy on survival in patients with muscle-invasive bladder cancer receiving neoadjuvant chemotherapy.
Authors: Park Jong Chul , Gandhi Nilay M , Bivalacqua Trinity , Schoenberg Mark , Carducci Michael Anthony , Eisenberger Mario A. , Baras Alexander S , Netto George J. , Liu Jen-Jane , Drake Charles G. , Hahn Noah M.
Published: February 2017

360

Background: Retrospective population-based studies have shown that an interval longer than 12 weeks between diagnosis and cystectomy is associated with worse outcomes in patients with muscle-invasive bladder cancer (MIBC). Neoadjuvant chemotherapy (NAC) is widely used however the impact of duration from diagnosis to cystectomy is unclear in MIBC patients treated with NAC. Methods: We performed a retrospective analysis of patients with MIBC who received NAC followed by cystectomy between 1996 and 2014 at a single institution. Total therapy duration was defined as the time interval between diagnosis of MIBC on biopsy and the date of cystectomy. Cox proportional hazards regression models were used to investigate the effect of total therapy duration and other factors on overall survival (OS). Results: 201 patients who met the study criteria were analyzed.Demographics included: median age 62, 79% male, 62% cT2N0, 10% cN+, 29% w/variant histology (VHx). Cisplatin-based therapy was given to 91% of patients for a median of 3 cycles. The median time from diagnosis to the cystectomy was 28 weeks. A total therapy duration < 28 weeks did not impact OS (hazard ratio [HR], 0.68; p=0.39). Pretreatment clinical covariates associated with improved OS included age< 62 (HR 0.56; p=0.034) and absence of VHx (HR, 0.40, p=0.001). Post-treatment factors of significance included less than 3 cycles of chemotherapy received (HR 1.75, p=0.037), pT3/T4 or N+ (HR 5.18, p<0.001), and N- (HR 0.58, p=0.048). Conclusions: Total therapy duration does not significantly impact OS in patients with MIBC receiving NAC. This data adds to the evidence supporting the use of NAC in MIBC patients fit to receive cisplatin-based regimens.
Primary prevention of bladder cancer: Does the public know the risk factors?
Authors: Wood Erika L. , Golla Vishnukamal , Goswamy Rohit , Fellman Bryan , Urbauer Diana L , Canfield Steven , Shah Jay Bakul
Published: February 2017

366

Background: Smoking is the single most significant modifiable risk factor for bladder cancer, yet this is not well known outside of the medical community. Previous studies from tertiary referral centers have found that 36-58% of urology patients can identify smoking as a risk factor for bladder cancer. Since those patients may not be representative of the general population, we studied the knowledge base of bladder cancer risk factors among people encountered in the general waiting room of an urban county hospital. Methods: 215 participants over 18 years of age were recruited from the waiting room of an urban county hospital to participate in a brief survey on risk factors for various cancers. Fisher’s exact test and McNemar’s test were used to detect differences in knowledge between bladder cancer and other cancers. Results: The survey participant population was mostly female (65.6%), Hispanic (54%), and middle-aged (67% age 35-64). Most (54.8%) had an annual household income of less than $20,000, attained a high school education (49.1%) or below (24.1%), and 40.3% were current or former smokers. An overwhelming majority of participants chose smoking as a risk factor for lung cancer (92.2%), with 80.7% identifying smoking as the primary risk factor for lung cancer. In contrast, only 31.6% of participants chose smoking as a risk factor for bladder cancer with 7.4% selecting it as the primary risk factor for bladder cancer. Knowledge of smoking as a risk factor for bladder cancer was not impacted by education, income, smoking status, or personal/family history of cancer. Male gender and exposure to industrial chemicals were identified as risk factors for bladder cancer by a minority of patients (19.3% and 28.0%, respectively). Almost half of all participants surveyed (49.1%) incorrectly identified alcohol use as a risk factor for bladder cancer. Conclusions: Among participants of low socioeconomic status presenting to an urban county hospital, there is a concerning lack of knowledge about the major risk factors for bladder cancer. Given that smoking is a modifiable risk factor, future public education initiatives to prevent bladder cancer should focus on populations with low socioeconomic status as high-yield targets to affect change.
Potent suppression of proliferation of carcinoma cells by a novel non-nucleoside reverse transcriptase inhibitor.
Authors: Fisch Alexander , Schroeder William , Smart Robert , Patel Osman
Published: February 2017

367

Background: The treatment of choice for many patients with advanced carcinomas is surgery in combination with aggressive chemo- and radiotherapy. Unfortunately, even with the aggressive regime of therapy against carcinomas, there is neither guarantee of life-long remission nor of further spread to other organs including the urogenital system. However, recent advances have identified the reactivation of telomerase as a pivotal element in the development of cancer. Therefore, the objective of this study was to evaluate the efficacy of a novel anti-telomerase (GV6) developed at our Institution on MCF7 (ER+, PR+, HER2+) and MDA-MB 231 (ER-, PR-, HER2-) cell lines. Methods: Seeded flasks (T-75) were supplemented with 25μm GV6 (n=4-6) or solvent alone (control, n=3) for 14 (short-term) or 27 (long-term) days. Cell viability and replicative senescence were both assessed using the Trypan Blue (Gibco) and SA-β-Gal (Cell Signaling Tech) methods, respectively. Results: By day 27, MCF7 flasks had a greater (p<0.05) number of viable cells (35.4% vs. 29%) compared to MDA-MB 231 cells. More senescent cells were observed in GV6 supplemented MDA-MB 231 (~75%) cells than in MCF7 (~60%) by day 27. Conclusions: Our results indicate that GV6 is an equally potent inhibitor of telomerase and merits further studies.
Results of the phase I trial of cetuximab with mitomycin c and 5-fluorouracil concurrent with radiotherapy treatment in patients with muscle-invasive bladder cancer.
Authors: Hussain Syed A. , Hendron Carey , Buckley Laura , Dickinson Lynne , Syndikus Isabel , Malik Zafar , Eswar Chinnamani , James Nicholas David
Published: February 2017

368

Background: Synchronous chemo-radiotherapy is an alternative to cystectomy in patients with muscle invasive bladder cancer (MIBC). BC2001 trial reported improved local control in patients randomised to synchronous chemo-radiotherapy compared to radiotherapy alone (James, Hussain, Hall et al NEJM 2012). TUXEDO trial reports phase I trial results with additional weekly cetuximab (Cet) in combination with Mitomycin c (MMC), 5-Fluouracil (5-FU) and concurrent radiotherapy (RT). Methods: This two centre phase I trial recruited 7 patients with MIBC in Queen Elizabeth Hospital Birmingham and Clatterbridge Cancer Centre Liverpool to synchronous chemotherapy using Loading dose of Cet 400 mg/m2 followed by weekly Cet 250 mg/m2, continuous infusion 5-FU 500mg/m2/day during fractions 1-5 and 16-20 of RT and MMC12mg/m2on day 1 in combination with radical RT treatment 64 Gys in 32 fractions. The primary endpoint was to assess toxicity. Secondary end- points included 3 months pathological complete response, loco-regional disease-free survival and overall survival. Results: Median age of patients was 70 (range: 60-75) years, all were male, 6 had received prior neoadjuvant chemotherapy. Two patients had T2B, 3 T3A and 2 T3B disease, all had G3, TCC disease, 6 patients had neo-adjuvant chemotherapy. All 7 patients completed RT as planned except for 1 who withdrew from trial after 5 weeks of protocol treatment due to relocation. Median dose intensity for Cet and MMC was 97.6% and for 5-FU was 99.4%. Grade 3 toxicity to report was maculopapular rash in 3 patients. Grade 2 toxicities include UTI/ frequency/ nocturia / fatigue /constipation / hypokalemia/epistaxis/palmar-plantar reported in 3/1/1/1/1/1/1/2 cases respectively. Grade 2 maculo-papular rash was reported in 3 cases. All seven patients have achieved complete responses at 3 months cystoscopic assessment. Patients continue on surveillance as per TUXEDO trial protocol. Conclusions: Synchronous chemotherapy with Cet and 5FU/MMC concurrent with radical RT is safe to deliver. Complete response rates are encouraging and a phase II trial with added centres within UK is being launched. Clinical trial information: NOT KNOWN.
Outcomes of preoperative chemotherapy in bladder cancer patients including node-positive disease.
Authors: Faltas Bishoy , Date Pravin R. , Scherr Douglas , Nguyen Daniel P. , Al Awamlh Bashir Al Hussein , O'Malley Padraic , Christos Paul J. , Beltran Himisha , Nanus David M. , Tagawa Scott T.
Published: February 2017

370

Background: Neoadjuvant chemotherapy is associated with improved overall survival benefit and the concept of systemic therapy followed by local consolidation may also lead to favorable long-term outcomes for those with lymph node (LN) metastases at presentation. Our goal was to examine the outcome of preoperative chemotherapy in patients (pts) with and without clinical evidence of LN metastases. Methods: After informed consent, patients were enrolled in a prospective database prior to radical cystectomy with lymph node dissection for bladder cancer between December 2001 to February 2014. Data were analyzed using descriptive statistics. Results: Our cohort included 63 patients receiving pre-operative chemotherapy with a median age 68 (range 38-91), 46 (72%) were male, and 17 (27%) had gross metastatic disease to lymph nodes (LNs). 13 pts received MVAC (20%), 44 gemcitabine and cisplatin (GC) (69%), 1 gemcitabine and carboplatin, 1 received ifosfamide, paclitaxel, and cisplatin and 4 pts had unknown neoadjuvant chemo outside of the institution. Most patients with LN positive (71%) disease received GC preoperative regimens. The median and the modal number of cycles were 4 (range 1-6). 44 patients underwent robotic-assisted radical cystectomy (RARC) (69%), 19 underwent open radical cystectomy (30%), and another pt. had RARC converted to an open procedure. Overall, 20 (31%) patients achieved pathologic complete response (pCR). Four pts (24%) with initial metastatic disease achieved pCR after preoperative chemotherapy. Overall pCR rates were similar between MVAC (38%) and GC (33%). All LN positive patients who achieved pCR had received gemcitabine-cisplatin preoperatively and underwent RARC. Recurrence-free and overall-survival data will be presented at the meeting. Conclusions: Preoperative chemotherapy was associated with a significant pCR rate in all bladder cancer patients including LN positive patients.
Multi-institutional validation of the predictive value of Ki-67 in patients with high-grade urothelial carcinoma of the upper urinary tract.
Authors: Krabbe Laura-Maria , Bagrodia Aditya , Haddad Ahmed Q , Kapur Payal , Khalil Dina , Hynan Linda S. , Wood Christopher G. , Karam Jose A. , Weizer Alon Z. , Raman Jay D. , Remzi Mesut , Rioux-Leclerq Nathalie , Haitel Andrea , Roscigno Marco , Bolenz Christian , Bensalah Karim , Sagalowsky Arthur I. , Shariat Shahrokh F. , Lotan Yair , Margulis Vitaly
Published: February 2017

371

Background: To validate the independent predictive value of Ki-67 in patients with high-grade upper tract urothelial carcinoma (UTUC). Methods: 475 patients from the international UTUC collaboration who underwent extirpative surgery for high-grade UTUC were included in this study. Immunohistochemical staining for Ki-67 was performed on tissue microarray (TMA) formed from this patient cohort. Ki-67 expression was assessed in a semi-quantitative fashion and considered overexpressed at a cut-off of 20%. Multivariate analyses (MVA) were performed to assess independent predictors of oncological outcomes and Harrell’s C indices (HCI) were calculated for predictive models. Results: Median age of the cohort was 69.7 years and 55.2% of patients were male. Ki-67 was overexpressed in 25.9% of patients. Ki-67 overexpression was significantly associated with ureteral tumor location, higher pT-stage, lymphovascular invasion, sessile tumor architecture, tumor necrosis, concomitant carcinoma in situ (CIS), and regional lymph node metastases. In Kaplan-Meier analyses, overexpressed Ki-67 was associated with worse recurrence-free (RFS) (HR 12.6, p<0.001) and cancer-specific survival (CSS) (HR 15.8, p<0.001). In MVA, Ki-67 was an independent predictor of RFS (HR 1.6, 95% CI 1.07-2.30, p=0.021) and CSS (HR 1.9, 95% CI 1.29-2.90, p=0.001). Ki-67 improved HCI from 0.66 to 0.70 (p<0.0001) for both RFS and CSS in our preoperative model, and from 0.81 to 0.82 (p=0.0018) for RFS and 0.81 to 0.83 (p=0.005) for CSS in our post-operative model. Conclusions: Ki-67 was validated as an independent prognostic predictor of RFS and CSS in patients treated with extirpative surgery for high-grade UTUC in a large, multi-institutional cohort.
Clinical outcomes of intermediate risk metastatic germ cell tumors (IRGCT): Results from a single-institution series.
Authors: Raggi Daniele , Lo Vullo Salvatore , Giannatempo Patrizia , Giardiello Daniele , Nicolai Nicola , Piva Luigi , Biasoni Davide , Catanzaro Mario , Torelli Tullio , Stagni Silvia , Maffezzini Massimo , Mariani Luigi , Salvioni Roberto , Necchi Andrea
Published: February 2017

380

Background: IRGCT comprises a consistent category of metastatic patients (pts), and information on the recommended management of these pts should be updated. Usually they enter clinical trials for poor prognosis GCT. We aimed to address the heterogeneity of this category and to identify clinical prognostic factors for sub-stratification of pts. Methods: Data on consecutive pts with IRGCT and who received treatment at Fondazione INT Milano in the time-frame 02/1980-03/2014 were collected. Cox regression analyses were done evaluating potential prognostic factors for overall survival (OS, primary endpoint) to first-line therapy. Each factor was evaluated in a multivariable model. An exploratory OS comparison between outlier groups was undertaken with Kaplan Meier curves and logrank test. Results: Data on 181 pts were collected. Median age was 27 yrs (IQR 22-32), 10 pts had a retroperitoneal (RP) primary, 6 had pure seminoma. 72 (39.8%) had lung metastases and 54 (32.3%) bulky (i.e. ≥10cm) RP lymph-nodes (LN). Pts received cisplatin, bleomycin and etoposide (PEB, n=156) or vinblastine (PVB, n=23), 2 other treatments. Median follow up was 173 months (IQR: 87-237). Globally, 5-y PFS and OS were 66.8% (95%CI: 60.1-74.2) and 83.3% (77.8-89.2). However, 5-y OS for pts with AFP 5,000-10,000 IU/ml (N=19) was 61.8% (95%CI: 43.0-88.7) while it was 89.1% (95%CI: 81.2-97.7) for nonseminomas with elevated LDH only (N=57) and similar for elevated HCG only (N=22); overall p<0.001. Multivariable analysis for OS is shown in the table (c-index= 0.63). Distribution of variables over time: bulky RP LN and elevated LDH were more frequent in earlier series (p=0.003 and 0.011). Conclusions: The prognostic heterogeneity of IRGCT category is a matter of fact and should be addressed by clinical trials. Pts with highly elevated AFP have an OS similar to poor prognostic category, while those categorized by elevated HCG or LDH only are close to good risk ones. [Table: see text]
Association of age 40 and older with adverse outcome in metastatic testicular cancer (TC).
Authors: Miller Rowan , Markt Sarah C , O'Donnell Elizabeth , Bernard Brandon David , Albiges Laurence , Lago-Hernandez Carlos , Curreri Stephanie A. , Beard Clair , Wright Alexi A. , Sweeney Christopher
Published: February 2017

386

Background: We sought to determine factors associated with poorer outcome in older patients (≥ 40) with TC in a large institutional dataset. Methods: A retrospective review of a 1095 patient, IRB approved database, of men treated for TC between 1997 and 2012 at the Dana-Farber Cancer Institute was performed. Information regarding histology, stage, treatment and patient characteristics was obtained from electronic medical records. Using logistic regression analysis and Cox proportional hazard regression we investigated the association between age and outcome for (a) men with clinical stage 1 (CS1) TC and (b) men with metastatic TC, either at diagnosis or following CS1 relapse. Results: 26% of the TC patients were ≥ 40 at diagnosis. Amongst the 616 men with CS1 disease 150 (24%) were age ≥ 40, there was an association with increased likelihood of seminoma (OR 2.46, 95%CI 1.68-3.60) and larger tumour size (> 4cm, OR 1.81, 95%CI 1.23-2.66). Age ≥ 40 was not associated with an increased risk of relapse (HR 0.931, 95%CI 0.575-1.505, p=0.77). 605 men (159, 26% ≥ 40) with metastatic disease were identified. Men ≥ 40 were more likely to have seminoma (OR 3.07 95%CI 2.07-4.54). Distribution of IGCCC prognostic stage was similar in men < 40 and ≥ 40. After adjusting for stage and histology, men ≥ 40 were more likely to receive chemotherapy other than BEP as their primary treatment (OR 1.87 95%CI 1.17-3.00, p=0.009) and men ≥ 40 were also more likely to receive non-optimal chemotherapy than men < 40 (OR 2.91 95%CI 1.12-7.60, p=0.03). When adjusted for confounding variables, age ≥ 40 was associated with a non-significant increased risk of relapse (HR 1.467 95%CI 0.94-2.29, p=0.09) post primary treatment and a significant increased risk of death from TC (HR 2.41 95%CI 1.41-4.11, p=0.0013), which was greater for those with non-seminoma (HR 2.54 95%CI 1.45-4.44, p=0.0011) than seminoma (HR 1.53, 95%CI 0.33-7.2, p=0.56). Conclusions: Men ≥ 40 years diagnosed with metastatic TC were less likely to be cured with therapy for metastatic disease compared to men < 40.
Is the International Germ Cell Consensus Classification (IGCCC) sufficiently predictive in 2015?
Authors: Nichols Craig R. , Jeldres Claudio , Kollmannsberger Christian K.
Published: February 2017

387

Background: The IGCCC has been an invaluable tool to guide clinical trial development in disseminated germ cell tumors. This classification was developed in the early 1990s. The data were abstracted from records of pts treated between 1975 and 1990 and > 100 institutions submitted data. This analysis resulted in the development and validation of a simple system based on clinically derived parameters. Three risk groups were identified for disseminated nonseminoma.; “good risk” group with a predicted 5 year overall survival (OS) > 90%, ‘intermediate risk” with a 5 yr OS of 75% and “poor risk” with a predicted 48% 5 yr OS. Recently, a number of clinical trials and large institutions have reported outcomes in intermediate and poor risk disseminated germ cell tumors. Outcomes reported exceed IGCCC predictions. We hypothesize that the IGCCC substantially underestimates outcomes in the modern era. Further we speculate that a re-analysis of existing clinical trial data would be fruitful in predicting outcomes for disseminated germ cell tumors in the 21st century. Methods: Reports from large randomized clinical trials reporting outcomes in intermediate and poor risk disseminated germ cell tumors were reviewed and estimates of Progression Free and Overall survival made. Results: See Table. Conclusions: Compared to the IGCCC predictions based on data from 25-40 years ago, there appears to be improved overall survival in disseminated germ cell tumors in the modern era. Intermediate risk and poor risk disease appears to have OS exceeding 80-85% and 75% respectively. A more accurate prediction of outcomes with standard treatments should inform clinical trial design going forward. [Table: see text]
A meta-analysis of health-related quality of life after primary treatment for prostate cancer as measured by the Expanded Prostate Cancer Index Composite.
Authors: Cnossen Nicholas RIchard , Orman Amber Gail , Kwon Deukwoo , Ritch Chad , Gonzalgo Mark , Ishkanian Adrian , Reis Isildinha , Pollack Alan , Abramowitz Matthew
Published: February 2017

39

Background: Health-related quality of life (HRQoL) outcomes are important in treatment selection for prostate cancer. The Expanded Prostate Cancer Index Composite (EPIC) is a validated and widely-utilized HRQoL survey which accounts for newer radiotherapeutic, surgical, and hormonal treatment methods. We present a meta-analysis of patient reported HRQoL outcomes collected with EPIC and compare HRQoL trends with radiation therapy, surgery, or active surveillance as primary treatment. Methods: The PubMed database was systematically searched for all studies which presented data directly derived from the use of EPIC on patients with prostate cancer prior to 07/09/2014. All eligible studies were selected for either inclusion and analysis or exclusion based on pre-determined criteria. The data from included studies was compiled and a simulation-based estimation method using Approximate Bayesian Computation was performed to obtain missing standard deviation estimate. A longitudinal meta-analysis was conducted to estimate EPIC-profiles for each component using Bayesian p-spline method. Results: Over 4,000 studies were searched, 152 were deemed eligible, and 39 were included. The calculated mean summary score estimates are shown in the attached table. Conclusions: In the urinary domain, radical prostatectomy (RP) has lower acute scores than active surveillance (AS) or radiation therapy (RT) without long-term difference. In the bowel domain, RT has lower scores than AS or RP acutely and long-term. In the sexual domain, RT and RP have lower acute scores than AS. RP has lower scores than RT without long-term difference. In the hormonal domain, little difference was noted between modalities. [Table: see text]
A review of clinical stage 1 testicular cancer mortality in a high-volume center.
Authors: Kamran Sophia C. , Markt Sarah C. , Miller Rowan , O'Donnell Elizabeth , Bernard Brandon David , Curreri Stephanie A. , Albiges Laurence K. , Sweeney Christopher , Beard Clair
Published: February 2017

390

Background: Clinical stage 1 (CS1) testicular germ-cell tumors (GCT) have an overall survival of nearly 99% regardless of histology. We seek to describe the Dana-Farber/Brigham and Women’s Cancer Center (DF/BWCC) features of the clinical stage 1 testicular cancer patients who died of testis cancer. Methods: Analyses included 1,095 males treated at DF/BWCC between 1997-2012 with data entered into an IRB-approved database developed from electronic medical record abstraction. Patient, tumor, and treatment characteristics were summarized. Analyses focused on testicular-cancer death among the CS1 participants. Results: 616 CS1 testicular patients (291 seminoma-SEM and 324 non-seminoma- NS) were identified and 4 died from their disease (cause-specific survival of 99.3%). Average age at diagnosis amongst the latter patients was 26.7 years. All 4 patients had NS and 2 were embryonal predominant. Average tumor size was 6.3 cm, 2 patients did not have lymphovascular invasion, and 2 were unknown. Following treatment with orchiectomy, 2 patients received 2 cycles of adjuvant bleomycin, etoposide, cisplatin (BEP) chemotherapy. See table 1 for details. Conclusions: Four of 616 (0.6%) patients died after initial presentation with CS1 NSGCT, having relapsed at 1.25, 5.4, 6.25, and 20.7 years after orchiectomy. All patients had non-seminoma histology, 3 of these patients were late relapses (> 2 years), and 2 cases relapsed despite adjuvant BEP. [Table: see text]
Invasive penile carcinoma: Are p16, p53 and HPV ISH prognostically significant?
Authors: Dhillon Jasreman , Berglund Anders E. , Pow-Sang Julio , Spiess Philippe E. , Magliocco Anthony M.
Published: February 2017

394

Background: Penile carcinoma accounts for 0.4% to 0.6% of all malignancies in men. Due to its low incidence the prognostic role of clinicopathological characteristics, p16, p53 and HPV infection remains unclear. We report our experience with p16, p53 and HPV ISH (types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58 and 66) in determining the aggressive nature of this carcinoma. Methods: A tissue microarray (TMA) of 57 cases of invasive penile squamous cell carcinomas was immunohistochemically stained with immunohistochemical stains p16 and p53. HPV ISH was performed as well. The TMA slides were scored semi quantitatively by a specialized genitourinary surgical pathologist. The H score was calculated for p53 using a combination of staining intensity and extent according to the following formula: H score = 1 x % of tumor cells with weak staining + 2 x % of tumor cells with moderate staining + 3 x % of tumor cells with strong staining, resulting in a total score of 0 – 300. Calculations for p53 were done considering values above 0 as positive. For p16 and HPV ISH, the results were recorded as negative or positive. The overall survival curves for up to 60 months were estimated by Kaplan-Meier (KM) method. Results: HPV ISH was positive in 23 cases and p16 was positive in 23 cases as well. However, there were 9 discordant cases between the two (p16+/HPV ISH- = 5; p16-/HPV ISH+ = 4). p53 was positive in 39 cases. Tumors positive for HPV ISH had a better survival as compared to HPV ISH negative tumors (p = 0.0040; Hazard ratio 4.991). Whereas p16 (p = 0.206; Hazard ratio 1.838) and p53 (p = 0.1582; Hazard ratio 0.5198) were not significantly associated with survival at 60 months. Conclusions: Overall HPV positive penile carcinomas appear to have a distinct biology with better prognosis. There is no significant difference in survival for tumors with different p16 and p53 expression.
Need to travel for urologic care: The impact of insurance.
Authors: Mossanen Matthew , Dhartha Kenn , Holt Sarah , Wright Jonathan L. , Harper Jonathan D. , Gore John L.
Published: February 2017

396

Background: We sought to examine the impact of the Affordable Care Act on access to subspecialty services, such as urologic care, through evaluating the need to travel by insurance status for index urologic procedures. Methods: We accessed the Comprehensive Hospital Abstract Reporting System from 2011-2012. Patients were identified using billing claims and ICD-9 codes. Procedures analyzed were: radical cystectomy (RC), radical prostatectomy (RP), transurethral prostate resection, shockwave lithotripsy, nephrectomy, percutaneous nephrolithotomy (PCNL), retroperitoneal lymph node dissection (RPLND), and pyeloplasty. Patients were categorized as Medicaid, Medicare, private/Health Maintenance Organization, or other (i.e. charity care). Hospital service areas (HSAs, where the majority of local patients were hospitalized), and hospital referral regions (HRR, where most patients received tertiary care) were identified. Chi squared analysis and multivariate logistic regression were performed. Results: We identified 600 patients with Medicaid, 3,806 patients with Medicare, 4,998 patients with private insurance, and 554 with other. 13.3% of Medicaid patients undergoing RC left their HRR versus 29.9% for Medicare and 39.8% for private insurance (Chi squared p < 0.05). We found similar trends for RP (10.8% of Medicaid traveled outside of their HRR vs. 19.5% for Medicare and 24.6% for private, p < 0.05) and PCNL (21.9% of patients with private insurance traveled outside of HRR vs. 12% with Medicare and 17.2% with Medicaid, p < 0.05). On multivariate analysis, (adjusting for race, age, and comorbidity) private insurance had higher odds of leaving their HRR (OR = 1.4, CI 1.1 – 1.8, p< 0.002). Non-white patients (OR = 0.66, 0.54 – 0.81, p <0.001), those with increased comorbidities (OR = 0.95, CI 0.91 - .99, p<0.04), and older patients (p < 0.001) are less likely to travel outside of their HRR. Conclusions: Patients undergoing complex urologic procedures like RC, RP, and PCNL are more likely to travel outside of their HRR if they have private insurance, potentially reflecting increased capacity to access healthcare resources based on income. Patients of older age and with greater comorbidities may be less likely to travel outside of their HRR to obtain urologic care.
Treatment outcome of patients with intermediate- and poor-prognosis metastatic testicular cancer in the 2000s: A multicenter experience in Japan.
Authors: Kojima Takahiro , Kawai Koji , Tsuchiya Kunihiko , Abe Takashige , Shinohara Nobuo , Tanaka Toshiaki , Masumori Naoya , Yamada Shigeyuki , Arai Yoichi , Narita Shintaro , Tsuchiya Norihiko , Habuchi Tomonori , Nishiyama Hiroyuki
Published: February 2017

397

Background: As a risk classification system of metastatic germ cell tumors, the International Germ Cell Consensus (IGCC) classification was proposed in 1997 and has received broad approval. We aimed to clarify the significance of the IGCC classification in the 2000s especially in intermediate and poor-prognosis patients in Japan. Methods: We analyzed 118 patients with intermediate- and poor-prognosis metastatic non-seminomatous germ cell testicular cancer treated at five university hospitals in Japan between 2000 and 2010. Data were collected on age, levels of serum AFP, HCG and LDH, lung metastases, spread to non-pulmonary visceral metastases (NPVM) and on treatment details (first, second and third-line chemotherapy and post-chemotherapy surgery) and survival data. Results: The median age at diagnosis was 31 years (range, 2-54 years). The median follow-up period of all patients was 57 months. Sixty-eight patients were classified as poor prognosis, having LDH elevation in 14 (21%), AFP in 13 (19%), HCG in 27 (40%), presence of NPVM in 44 (65%). As first line chemotherapy, 93 (79%) were treated by BEP (bleomycin, etoposide and cisplatin)-containing regimen. Of 118 patients, 75 (64%) received second-line chemotherapy, in which the most frequently used regimen was taxane-containing regimen, including TIP (paclitaxel, ifosfamide and cisplatin), TIN (paxlitaxel, ifosfamide and nedaplatin) and DIN (docetaxel, ifosfamide and nedaplatin). Third-line chemotherapy was carried out in 33 patients (28%). Eighty-nine patients (75%) underwent post-chemotherapy surgery. The 5-year overall survivals for intermediate (n=50) and poor (n=68) prognosis was 89% and 83% (P=0.23), respectively. In poor prognosis patients, patients with more than 2 poor-prognostic factors had significantly worse survival than those with only one prognostic factor (72% vs 91%, P=0.01). Conclusions: There was a trend of increase in survival for any risk groups and, in particular, large increase in survival for patients with a poor prognosis. Further classification of poor-prognosis patients into two subgroups has a potential to identify a patient group with very poor-prognosis.
Outcomes following immediate versus delayed radical prostatectomy among men on active surveillance for prostate cancer.
Authors: Welty Christopher James , Fillipou Pauline , Cowan Janet E. , Carroll Peter
Published: February 2017

40

Background: Little is known about the risk of delaying radical prostatectomy (RP) until biopsy progression following active surveillance (AS) for prostate cancer. This study examines the pathological outcomes associated with surgery following AS compared to immediate treatment of prostate cancer with similar grades. Methods: Men who underwent RP between 1997-2013 at University of California San Francisco were included. The first comparison consisted of men who met strict AS inclusion criteria (Gleason Score ≤ 6, PSA ≤ 10, clinical stage <T3, ≤ 33% biopsy cores positive, and <= 50% of any single core positive) at diagnosis and underwent AS prior to RP (AS+RP) compared to men who met strict AS criteria and underwent RP within 6 monts (immediate RP). The second comparison consisted of men who met strict AS criteria and were upgraded on follow-up biopsy compared to a cohort of men matched on the basis pre-treatment biopsy pathology. Logistic regression was used to determine associations of RP group with adverse pathology (stage ≥pT3/N1, positive margins, and/or upgrade to Gleason >=4+3), adjusting for clinical and demographic factors. Results: We identified 241 men who underwent RP after a period of AS, 157 of whom initially met strict AS criteria. The median time to RP was 20 months (IQR 14-36). Men who met strict criteria and underwent immediate RP were less likely to have unfavorable pathology than those who underwent AS+RP (OR 0.39, 95% CI 0.24-0.62). Fifty-four of the men who underwent AS+RP did so have upgrading to Gleason 3+4 disease. These patients were matched with 154 men based on their pre-treatment biopsy features. After appropriate matching, the timing of RP was not associated with adverse pathology (OR 1.27, 9% CI 0.65-2.49). Conclusions: Men who undergo surgery following AS are a selected subset of men with low risk prostate cancer. The surgical pathology features of these patients are more similar to men undergo surgery after diagnosis with intermediate risk prostate cancer than those diagnosed with very low risk disease. Additional follow-up of this and other cohorts is needed to assess long term clinical outcomes following delayed RP.
BMI at diagnosis and adverse outcomes among men with malignant testicular germ cell tumors.
Authors: Markt Sarah C , Miller Rowan , O'Donnell Elizabeth , Albiges Laurence , Bernard Brandon David , Lago-Hernandez Carlos , Curreri Stephanie A. , Wright Alexi A. , Beard Clair , Sweeney Christopher
Published: February 2017

400

Background: Previous studies evaluating the relationship between measures of anthropometry, such as body mass index (BMI), and risk of testicular cancer have been conflicting, with most finding null or inverse associations. Methods: We conducted a retrospective review of 960 germ cell tumors among patients treated at the Dana-Farber Cancer Institute (DFCI) between 1997 and 2012 with information on BMI. BMI at diagnosis, tumor characteristics, IGCCC classification, treatment, relapse and cause of death was ascertained from electronic medical record review. We divided the men and conducted the analyses separately for two groups: 1) men who presented as clinical stage 1 (CS1), and 2) men who presented with metastases or were CS1 at diagnosis and developed metastases (lifemets). We conducted logistic regression to evaluate the association between BMI and characteristics at diagnosis, and Cox proportional hazards regression to investigate the risk of relapse and testicular cancer death. Results: 65% of men (n=628) were overweight or obese at diagnosis. We did not find an association between BMI and tumor characteristics at baseline, such as histology, lymphovascular invasion, or tumor size for either group. Among CS1 patients, men who were overweight or obese had a non-statistically significant reduced risk of relapse compared to men who were normal weight (HR: 0.83, 95% CI: 0.53-1.30). Among the lifemets group, 16% of men relapsed (n=83) and 8% died of testicular cancer (n=43). Although not statistically significant, men who were overweight or obese were less likely to present with intermediate (OR = 0.77, 95 CI: 0.39-1.52) and poor (OR = 0.66, 95% CI: 0.36-1.20) rather than good risk disease when compared to men with normal BMI. After adjusted for confounding variables, BMI was not associated with risk of relapse (HR: 0.94, 95% CI: 0.59-1.51) or risk of testicular cancer death (HR: 1.00, 95% CI: 0.54-1.84) among the lifemets group. Conclusions: We did not find an association between BMI at diagnosis and tumor characteristics at baseline, or risk of relapse or testicular cancer death among men with testicular cancer.
Change in neutrophil to lymphocyte ratio as a prognostic and predictive marker in response to targeted therapy for metastatic renal cell carcinoma.
Authors: Alimohamed Nimira S. , Templeton Arnoud J. , Knox Jennifer J. , Lin Xun , Simantov Ronit , Xie Wanling , Lawrence Nicola Jane , Broom Reuben James , Fay Andre Poisl , Rini Brian I. , Bjarnason Georg A. , Smoragiewicz Martin , Kollmannsberger Christian K. , Kanesvaran Ravindran , Wells Connor , Amir Eitan , Choueiri Toni K. , Heng Daniel Yick Chin
Published: February 2017

404

Background: The neutrophil to lymphocyte ratio (NLR) is a marker of inflammation. We evaluated whether NLR is independently prognostic when adjusted for the International mRCC Database Consortium (IMDC) model and evaluated change in NLR ("NLR conversion") as a predictive marker of response to targeted therapy. Methods: A total of 5,227 metastatic renal cell carcinoma (mRCC) patients treated with targeted therapy were included; 1,199 patients in the training cohort from the IMDC and 4028 patients as the validation cohort from pooled prospective randomized controlled trials involving targeted therapy. NLR was examined at initiation of first-line targeted therapy and at 6 weeks after. The prognostic role of NLR and NLR conversion on overall survival (OS) and progression free survival (PFS) was assessed using Cox regression models adjusting for IMDC prognostic score. Results: Median baseline NLR was 3.4 and 2.9 in the training and validation cohorts, respectively. NLR >3.0 at baseline was independently associated with OS and PFS in both the training and validation cohorts (Table). A decrease in NLR by week 6 was associated with longer OS (21.1 vs. 9.7 months; HR 0.57, p<0.001), PFS (8.8 vs. 4.6 months; HR 0.54, p<0.001), and higher objective response rates (35% vs. 13%, p<0.001) compared to patients without a decrease. A rise in NLR showed opposite effects for all three endpoints. These findings were also confirmed in the validation set. Conclusions: NLR is an independent prognostic factor after controlling for IMDC criteria. NLR conversion can be an early biomarker of benefit to targeted therapy. [Table: see text]
The impact of BMI on outcomes of patients with metastatic renal cell carcinoma treated with targeted therapy: An external validation data set and analysis of underlying biology from The Cancer Genome Atlas.
Authors: Albiges Laurence , Hakimi A. Ari , Lin Xun , Simantov Ronit , Zabor Emily C. , Jacobsen Anders , Furberg Helena , Fay Andre Poisl , Heng Daniel Yick Chin , Signoretti Sabina , McKay Rana R. , Choueiri Toni K.
Published: February 2017

405

Background: Obesity is a risk factor for renal cell carcinoma (RCC) and a poor prognostic factor across many tumor types. However, reports have suggested that RCC developing in an obesogenic environment may be more indolent. We recently reported on the favorable impact of body mass index (BMI) on survival in the International mRCC Database Consortium (IMDC). The current work aims to externally validate this finding and characterize the underlying biology. Methods: We conducted an analysis of 4,657 metastatic RCC (mRCC) patients (pts) treated on phase II-III clinical trials sponsored by Pfizer from 2003-2013. We assessed the impact of BMI on overall survival (OS), progression-free survival (PFS) and overall response rate (ORR). Additionally, we analysed metastatic pts from the clear cell RCC (ccRCC) cohort of TCGA dataset to correlate the expression of Fatty Acid Synthase (FASN) with BMI and OS. Results: At targeted therapy (TT) initiation, 1,829 (39%) pts were normal or underweight (BMI <25 kg/m2) and 2,828 (61%) were overweight or obese (BMI ≥25 kg/m2). Overall, the high BMI group had a longer median OS (23.4 months) than the low BMI group (14.5 months) (hazard ratio (HR) = 0.830, p= 0.0008, 95% CI 0.743-0.925) after adjusting for the IMDC prognostic risk group and other risks factors. In addition, pts with high BMI had improved PFS (HR=0.821, 95% CI 0.746-0.903, p<0.0001) and ORR (odds ratio =1.527, 95% CI 1.258-1.855, p<0.001). These results remain valid when stratified by line of therapy. When stratified by histological subtype, the favorable outcome associated with high BMI was only observed in ccRCC. Toxicity patterns did not differ between BMI groups. In the the Cancer Genome Atlas (TCGA) dataset (n=61), there was a trend towards improved OS in the high BMI group (p=0.07). FASN gene expression inversely correlated with both OS (p=0.002) and BMI (p=0.034). Conclusions: In an external cohort,we validate BMI as an independent prognostic factor for improved survival in mRCC. Given that this finding was observed in ccRCC only, we hypothesize that lipid metabolism may be modulated by the fat laden tumors cells. FASN staining in the IMDC cohort is ongoing to better investigate the obesity paradox in mRCC.
Proteomic stratification of clear cell renal cell carcinoma utilizing The Cancer Genome Atlas (TCGA) with external validation.
Authors: Kaffenberger Samuel D. , Ciriello Giovanni , Winer Andrew G. , Voss Martin Henner , Maranchie Jodi Kathleen , Tamboli Pheroze , Rathmell Kimryn , Choueiri Toni K. , Motzer Robert J. , Coleman Jonathan A. , Russo Paul , Hsieh James , Hakimi A. Ari
Published: February 2017

406

Background: Proteomics represents the ultimate convergence of DNA and expression alterations. We therefore sought to leverage TCGA reverse phase protein array (RPPA) data with an independent proteomic platform to identify druggable targets and pathways associated with prognosis in clear cell renal cell carcinoma (ccRCC). Methods: Unsupervised hierarchical consensus clustering was performed and differentially expressed proteins were identified for pathway analysis. Associations with clinicogenomic factors were assessed and Cox proportional hazards models were performed for disease-specific survival (DSS). Results: RPPA clustering of 324 patients from the ccRCC TCGA revealed 5 robust clusters characterized by alterations in specific pathways and divergent prognoses. Cluster 1 was characterized by poor DSS, decreased expression of receptor tyrosine kinases (RTK) and upregulation of the mTOR pathway. It was also associated with mTOR pathway genomic alterations, sarcomatoid histology and the ccb prognostic mRNA signature (all p<0.001). Cluster 2 was characterized by increased expression of RTKs and interestingly, had upregulation of the mTOR pathway with excellent DSS. After accounting for stage and grade, cluster designation remained independently associated with DSS (HR 0.23 for cluster 2, 95% CI 0.08-0.68; p=0.008). External validation was performed on a separate cohort of 189 patients with a different quantitative proteomics platform. A panel of phosphoproteins (pHER1, pHER2, pHER3, pSHC, pMEK, pAKT), highly discriminant between the most divergent RPPA clusters (1 and 2) was evaluated. Those at the highest quartile of activation in > 3 proteins were associated with improved DSS (HR 0.19, 95% CI 0.05-0.082; p=0.03). Patients with mTOR pathway activation segregated to those with coincident RTK activation (n=83) and those without (n=13). Conclusions: We have identified and validated proteomic signatures which cluster ccRCC patients into 5 prognostic groups. Furthermore, two distinct mTOR-activated clusters—one with high RTK activity and one with increased mTOR pathway genomic alterations were revealed, which may have prognostic and therapeutic implications.
Phase Ib evaluation of MPDL3280A (anti-PDL1) in combination with bevacizumab (bev) in patients (pts) with metastatic renal cell carcinoma (mRCC).
Authors: Sznol Mario , McDermott David F. , Jones Suzanne Fields , Mier James Walter , Waterkamp Daniel , Rossi Cheryl , Wallin Jeffrey , Funke Roel Peter , Bendell Johanna C.
Published: February 2017

410

Background: MPDL3280A, a human anti-PD-L1 IgG1 mAb engineered to remove Fc-effector function, prevents PD-L1 binding to the inhibitory receptors PD-1 and B7.1 on activated T cells. Single-agent MPDL3280A has demonstrated clinical activity in various cancers, including RCC. Bev was postulated to enhance the antitumor effects of MPDL3280A by blocking VEGF-related suppressive effects on immune function and lymphocyte traffic. Therefore, a multicenter Phase Ib study was conducted to determine the safety and activity of MPDL3280A + bev, including in a cohort of mRCC pts. Methods: mRCC pts with clear cell histology and available pre-treatment tumor specimens were enrolled. In addition to the safety and activity endpoints, an exploratory objective was to assess treatment effects on the tumor microenvironment and peripheral biomarkers. Bev 15 mg/kg was given alone on Cycle 1 Day 1 and concurrently with MPDL3280A 20 mg/kg q3w thereafter. On-treatment tumor biopsy was performed during Cycle 1 and 4-6 weeks after the start of Cycle 2. Objective responses were assessed by RECIST v1.1. The clinical data cutoff was July 7, 2014. Results: 12 pts were evaluable for safety. The median age was 64 y, 58% were male and 83% had no prior systemic therapy. The median duration of exposure was 232.5 days. Grade 3-4 AEs included postoperative wound infection, hypercalcemia, tumor pain, acute respiratory failure in a patient with influenza (1 pt each) and hypertension (3 pts). No Grade 3-4 AEs were assessed as related to MPDL3280A. Among first-line mRCC pts with ≥ 1 tumor assessment (n = 10), the ORR was 40% (3 of 4 responses confirmed at the time of the data cutoff). Minimum follow-up was 2.1 mo. Increases in tumor-infiltrating CD8+ T cells were observed on-treatment. Updated data, including biomarkers, will be presented. Conclusions: The combination of MPDL3280A + bev waswell tolerated in clear cell mRCC pts. Promising preliminary clinical activity and immune modulation of the tumor microenvironment were observed. A Phase II trial of MPLD3280A ± bevacizumab vs sunitinib in pts with previously untreated mRCC is currently ongoing. Clinical trial information: NCT01633970.
A phase II trial of everolimus and bevacizumab in advanced non-clear cell renal cell cancer.
Authors: Voss Martin Henner , Chen Yingbei , Chaim Joshua , Coskey Devyn Taylor , Woo Kaitlin , Patil Sujata , Molina Ana M. , Hsieh James , Motzer Robert J. , Feldman Darren Richard
Published: February 2017

411

Background: VEGF- and mTOR-directed therapies achieve inferior outcomes in patients (pts) with advanced non-clear cell renal cell cancer (ncRCC) as compared to clear cell RCC. Limited effectiveness of monotherapy supports the study of combination regimens, and a phase II trial of everolimus (E) + bevacizumab (B) was conducted in pts with metastatic ncRCC. Methods: Treatment-naïve pts received E + B at standard doses until progression or intolerance to therapy. The primary endpoint was progression free survival (PFS) with the goal to see 22 of 34 pts progression-free on treatment >6 months (mo). Correlative analyses include next generation sequencing (NGS) from tumor and germline across 341 genes of interest, as well as immunohistochemistry (IHC) for markers of mTOR activation and vessel density. Results: 34 pts were enrolled, all are evaluable (median follow up 11.2 mo). The most common histologic subtype was unclassified RCC (URCC, n=23), the majority of which had papillary growth as a major component (URCC with papillary features, n=14). Other variants included chromophobe (n=5), papillary (n=4), and medullary RCC (n=2). 19 pts achieved PFS >6 mo; 8 continue on treatment. PFS varied by histology (p<0.001), and objective response rates (ORR) were higher in pts with significant papillary (7 of 18) or chromophobe (2 of 5) elements, than for the remaining pts (1 of 11). Presence of a major papillary component was associated with treatment benefit across the entire cohort (Table), particularly in the subgroup of URCC, where this feature correlated with ORR (43 vs. 11%), median PFS (12.9 vs. 1.9mo) and OS (18.5 vs. 9.3 mo) (p<0.001). IHC markers did not correlate with treatment effect. NGS was performed on 33 cases. Conclusions: ncRCC represent a heterogeneous group of malignancies. This study did not reach its primary endpoint, yet it suggests efficacy for E+B in patients with ncRCC characterized by papillary features. Genomic tumor and germline analysis is being performed to help define the underlying biology. Clinical trial information: NCT01399918. [Table: see text]