bluuebunny/crossref_metadata_2025 huggingface dataset:
PLUTO: A randomised phase II study of pazopanib versus paclitaxel in relapsed urothelial tumours.
Authors: Powles Thomas , Hussain Syed A. , Protheroe Andrew , Birtle Alison , Chakraborti Prabir R , Huddart Robert , Jagdev Satinder , Bahl Amit , Stockdale Andrew , Sundar Santhanam , Crabb Simon J. , Dixon-Hughes Judith , Alexander Laura , Bray Caroline A , Stobo Jamie , Wimalasingham Akhila Ganeshi , Ackerman Charlotte , Paul James , Jones Rob
Published: February 2017

430

Background: Two previous single arm trials have drawn conflicting conclusions regarding pazopanib in urothelial bladder cancers (UBC) after failure of platinum-based chemotherapy. PLUTO is a randomized phase II trial to compare the efficacy of pazopanib with paclitaxel in this setting. Methods: It was planned for 140 patients with progressive, advanced UBC (with at least a component of transitional cell carcinoma) who had previously received a single prior platinum containing chemotherapy regimen for advanced UBC to be randomised(1:1). Patients in arm A received weekly paclitaxel 80mg/m2 and those in arm B received pazopanib (800mg once daily) until progression. The primary endpoint was overall survival analysis of which would occur after 110 events. The efficacy was assessed by an independent data monitoring committee during the trial. Results: Between Aug 2012- Oct 2014, 131 patients were randomised. 74.0% of patients had visceral metastases. The study was terminated early by the IDMC due to futility of pazopanib. Final analysis after 110 deaths occurred in July 2015. The median number of cycles of paclitaxel received was 4 (12 weeks). The median time on pazopanib was 11 weeks. Median overall survival was 8.0 months for paclitaxel [80% confidence interval (CI) 6.9 to 9.7 months] and 4.7 months for pazopanib [80% CI 4.2 to 6.4 months]. The hazard ratio (HR) adjusted for baseline stratification factors was 1.25 [80% CI 0.96 to 1.63; 1-sided p = 0.86] in favour of paclitaxel. Median progression free survival was 3.2 months for paclitaxel [80% CI 2.9 to 5.0 months] and 3.1 months for pazopanib [80% CI 2.7 to 3.8 months]. The adjusted HR for PFS was 1.06 [80% CI 0.83 to 1.36; 1-sided p = 0.62] (in favour of paclitaxel). Discontinuations for toxicity occurred in 6.3% and 20.0% for paclitaxel and pazopanib respectively. VHL, HIF1alpha, VEGFR2 and PD-L1 expression were measured from archived tissue and correlated with outcome. Conclusions: Pazopanib does not have greater efficacy than paclitaxel in the second line treatment of UBC. There is a trend towards superior OS with paclitaxel. Clinical trial information: NCT00949455.
Sarcopenia as a marker for prediction of long-term survival following radical cystectomy.
Authors: Kramer Mario , Hensen Bennet , Jansen Max Clemens , Hennig Martin JP , Hupe Marie C , Tezval Hossein , Wacker Frank , Kuczyk Markus A. , Merseburger Axel S.
Published: February 2017

435

Background: Patients undergoing radical cystectomy (RC) face a relevant risk of tumor relapse and mortality based on variable factors. Risk stratification may be enhanced by objective measures such as sarcopenia (loss of skeletal muscle mass) which has been described as a potential biomarker associated with survival after radical cystectomy. However, data on this highly interesting biomarker in conjunction with urothelial carcinoma of the bladder are sparse. Methods: A retrospective study including patients that were treated with RC at Hannover Medical School between 2005 and 2011 were included. The lumbar skeletal muscle index (SMI) was measured on preoperative computed tomography (CT) which was performed within 60 days prior to surgery. MeVisLab 2.7 was used to perform calculations. The fat mass index (FMI) was calculated based on the same CT slides. The body mass index (BMI) was used as a comparative value. Cut off points were developed for men and women separately. Results: Indices were measured on 103 patients (79 men, 24 women, mean age: 67.5 yrs). 72 (70%) pts. had muscle-invasive disease, 21 (20%) pts. were lymph node positive and 6 (6%) pts. had synchronous metastasis. Median follow-up time was 39 months. SMI (cm2/m2), FMI (kg/m2) and BMI (kg/m2) for men were calculated with mean scores of 51.2, 9.6 and 27.0, respectively. The corresponding calculated means for women were 38.7, 10.0 and 25.3. None of the stratification markers correlated with overall survival (OS) using Kaplan-Meier plots. However when applied on patients that survived at least 12 months, the sarcopenia index (SMI) became statistically significant (p < 0.05). Conclusions: The presence of sarcopenia may be predictor of poor overall survival later than 12 months after radical cystectomy. BMI and FMI may not be used in risk stratification models. Further research is needed to validate the current findings.
TOUCAN: A randomised phase II trial of carboplatin and gemcitabine +/- vandetanib in first line treatment of advanced urothelial cell cancer in patients who are not suitable to receive cisplatin.
Authors: Jones Robert J. , Crabb Simon J. , Chester John D. , Elliott Tony , Huddart Robert Anthony , Birtle Alison J. , Evans Linda , Lester Jason Francis , Huang Chao , Casbard Angela Claire , Madden Tracie-Ann , Griffiths Gareth
Published: February 2017

448

Background: Whilst cisplatin combination therapy remains the standard of care for patients with advanced urothelial cancers, many patients are unsuitable for cisplatin and go on to receive carboplatin combination therapy. Although responses are frequent, overall outcomes remain poor, and there is a high unmet need for more effective first line treatment. Vandetanib is a well-tolerated, oral inhibitor of vascular and epidermal growth factor receptor tyrosine kinases, both of which are implicated in the pathogenesis of urothelial cancers. Methods: Patients with metastatic or inoperable urothelial cancer who had no prior chemotherapy and were unsuitable for cisplatin were randomly allocated to receive carboplatin (AUC 4.5, day 1) plus gemcitabine (1000mg/m2, days 1 and 8) plus either vandetanib (100mg od, days 1-21) (GCV) or matching placebo (GCP) in 21-day cycles up to a total of 6 cycles. Treatment allocation was double-blind. There was a planned safety review after the first 40 patients had received at least one cycle. The primary endpoint was progression free survival (PFS). Sample size (n=82) was calculated using a one-sided alpha of 0.2 and power 80% to detect a HR of 0.65 for PFS. We present the final efficacy results. The trial was coordinated by the Wales Cancer Trials Unit at Cardiff University and funded by Cancer Research UK (CRUK/09/024) and AstraZeneca. Results: Of 82 patients, 40 received GCV. 62 (76%) had a bladder primary, and 56 (68%) had poor renal function. The arms were well balanced except for age > 75 (13 (16%) GCV, 23 (28%) GCP). Median PFS was 8.5 months (m) (95% CI 6.0, 9.7) and 8.8 m (5.8, 9.0) for GCV and GCP respectively (adjusted hazard ratio (HR) 0.93 (0.50, 1.71), P=0.89). Overall survival was 10.8 m (8.0, 13.0) and 13.8 m (11.1, 16.6) for GCV and GCP respectively (adjusted HR 1.38 (0.77, 2.46), P=0.24). Response rates were 50% (n=20) and 55% (n=23) for GCV and GCP. All-grade adverse events were similar but there were significantly more grade 3+ events in the GCV arm. Conclusion: Vandetanib did not improve efficacy of chemotherapy but increased toxicity in advanced urothelial cancer not suitable for cisplatin. Clinical trial information: 68146831.
The relationship between travel distance to cystectomy and likelihood of readmission.
Authors: Sukhu Troy , Lomboy Jason , Macey Matthew , Meyer Anne-Marie , Meng Ke , Nielsen Matthew Edward , Pruthi Raj , Wallen Eric , Woods Michael , Smith Angela
Published: February 2017

462

Background: Population-based estimates of readmissions following cystectomy range from 25-43%. Recent studies have investigated the relationship between complications and other patient- and hospital-level factors; however, the relationship between distance traveled for surgery and risk of readmission remains unclear. We hypothesized that larger distances would increase the risk of readmission following surgery. Methods: Using a linked data resource combining NC Central Cancer Registry with administrative claims data from Medicare, Medicaid, and private insurance plans, we included adult patients undergoing radical cystectomy for bladder cancer from 2003-2008. Complications were carefully coded and grouped based on previously published standards: genitourinary, gastrointestinal, wound, infection, venous thromboembolism, and others. Travel distances were calculated by using straight-line distances between zip codes of the patient and cystectomy provider. Bivariable analyses were performed, and multivariable logistic regression was used to evaluate the association of travel distance to cystectomy with likelihood of readmission within 30 and 31-90 days. Results: Of 735 patients who underwent cystectomy, 171 (23%) were readmitted within 30 days, and n = 156 (21%) were readmitted between 31-90 days. Mean age was higher among those readmitted, but was statistically non-significant. No significant differences were noted based on race, stage, comorbidity status, or complication type. However, on bivariable analysis, distance to the cystectomy provider > 30 miles was associated with a higher likelihood of readmission (p = 0.0009). On multivariable analysis, the only predictor of 30-day readmission was a longer travel distance to the cystectomy provider (OR 1.27, 95% CI: 1.05, 1.54). Results were also analyzed for 31-90 day readmissions, but no significant predictors were identified. Conclusions: Longer travel distance to a cystectomy provider is associated with higher 30-day readmission rates, suggesting that complications occurring during this time period may benefit from closer follow-up.
Molecular tumor grading of non muscle invasive bladder cancer based on whole transcriptome analysis.
Authors: Shen Jess , Noon Aidan , LIU Yu , Kuk Cynthia , Ilczynski C , Ni R , Sukhu B , Chan K , Gunaratne Adrian , Erlich Annette , Cremer Chris , Morris Quaid , Barbosa-Morais Nuno L , Fleshner Neil Eric , Kulkarni Girish S. , Blencowe Ben , Azad Azar , van der Kwast Theodorus , Zlotta Alexandre , Wrana Jeff L
Published: February 2017

467

Background: There is an unmet need for a comprehensive genomic characterization of non muscle invasive bladder cancer (NMIBC). NMIBC comprise over 70% of all bladder cancers at presentation. They have highly variable clinical behavior that is not always adequately predicted on the basis of their histological grade (2004 World Health Organization low and high grade, LG-HG). The discrepancy between phenotype and genotype is compounded further by interobserver variability in pathological grading. We have previously established methods for whole transcriptome RNAseq from formalin fixed paraffin embedded tissues (FFPE). Methods: Whole transcriptomic analysis of 110 NMI FFPE BC both LG and HG was performed incorporating messenger RNA expression, splice variants, gene fusion, and pathway perturbation. We used a discovery (n = 40) and a validation cohort (n = 70). These data were integrated and tested for correlation with both pathological grading and clinical outcomes. Grade Risk Index (GRI) score quantifying how closely a patient's transcriptome is related to a reference set of LG NMIBC samples was established. Conventional pathological grading was reviewed by 3 different expert uro-pathologists and interobserver variability calculated. Results: Unsupervised clustering of data from RNA sequencing uncovered classification of three robust - - nonoverlapping, prognostically significant subtypes of NMIBC with distinct GRIs and signatures. When applied by expert pathologists, interobserver variability in histological grading was observed in 17.5%. In the intermediate group (GRI 0.13 to 0.19), pathologists disagreed in 37.5% whether BC was LG or HG. HG NMIBC clustered with MIBC. LG NMIBC in the intermediate GRI group included either very bulky tumors or extremely rare metastatic LG BC (n = 4). HG disease was associated with a shift in BMP signaling and a germ stem cell-like phenotype. Multiple components of the centromere complex and APOBEC3B were upregulated in HG BC. FGFR3::TACC3 fusion events were observed in LG NMIBC only (11.5%). Conclusions: Whole transcriptomic sequencing data delineated three molecular classes of NMIBC.
Baseline neutrophil to lymphocyte ratio as a prognostic marker for patients with muscle-invasive bladder cancer being treated with neoadjuvant chemotherapy.
Authors: Kaiser Jeenan , Li Haocheng , Seah Jo-An , Leibowitz-Amit Raya , North Scott A. , Sridhar Srikala S. , Heng Daniel Yick Chin , Alimohamed Nimira S.
Published: February 2017

468

Background: The neutrophil-to-lymphocyte ratio (NLR), an inflammatory marker, has been associated with a poor prognosis in several solid malignancies. In muscle-invasive bladder cancer (MIBC), an elevated pre-cystectomy NLR has been shown to predict for poor survival; however, its role in prognostication for patients being treated with neoadjuvant chemotherapy (NAC) is unknown. We evaluated the baseline NLR as an independent prognostic factor in patients with MIBC treated with NAC. Methods: Patients with MIBC treated with NAC in Alberta from 2005 to 2015, and at the Princess Margaret Hospital in Ontario from 2005 to 2013 were evaluated. All 290 patients treated with NAC were included; 272 were evaluable for NLR and outcomes. Patient, disease, and treatment-related factors were evaluated. NLR was examined prior to initiation of preoperative chemotherapy. The prognostic role of NLR on overall survival (OS) and progression-free survival (PFS) was determined using Cox proportional hazard regression analysis. Results: The median age of patients was 66 years (range 36-87). The majority of patients (77%) were male. Median baseline NLR at diagnosis was 2.9. NLR > 3.0 at baseline was independently associated with PFS and OS after adjustment for age, gender and stage (Table). Patients with an NLR > 3 had a median PFS of 14.1 months compared to 25.1 months in those patients with a baseline NLR ≤ 3 (HR 0.63, p = 0.01). Similarly, OS was 19.4 months in patients with a baseline NLR > 3 compared to 33.4 months in those with a baseline NLR ≤ 3 (HR 0.65, p = 0.04). Conclusions: NLR is an independent prognostic factor for patients with MIBC undergoing NAC. [Table: see text]
Optimization of an imaging protocol for stage I seminoma surveillance based on variations in relapse location over time.
Authors: McPartlin Andrew , Hosni Ali , Bedard Philippe L. , Hansen Aaron Richard , Jewett Michael A.S. , Hamilton Robert James , O'Malley Martin , Sweet Joan , Warde Padraig Richard , Chung Peter W. M.
Published: February 2017

475

Background: Surveillance is recommended for patients with stage I seminoma post orchidectomy but CT imaging involves ionising radiation, with risk of associated secondary malignancies. We assessed site of disease relapse during surveillance to guide development of a risk adapted imaging protocol. Methods: Data was obtained from a prospectively maintained database of patients with stage I seminoma on surveillance after orchidectomy from 1981-2011. Relapse was determined by clinical and/or radiographic finding with or without pathological confirmation or tumour marker elevation. Results: 753 patients were identified. The median age at orchidectomy was 33.7 years. With a median follow up of 10.5 years, range 1.1-30.1, 115 (15.3%) patients relapsed. Relapse was detected radiologically in 114 (99.1%), with 9 (7.8%) having simultaneously elevated tumour markers. A clinical diagnosis of relapse was made in 1 case (inguinal node – 0.9%). The location and time to relapse are shown in table. Conclusions: In stage I seminoma surveillance, pelvic nodal relapse was restricted to the early period of follow up. Excluding the pelvis during CT imaging after the third year of surveillance may optimise the detection of relapse whilst minimising total radiation exposure. This has now been adopted at our centre since 2011 without any subsequent late pelvic relapses. [Table: see text]
Prognostic factors of adjuvant chemotherapy with taxane, cisplatin, and 5FU combination (TPF) in patients (pts) with nodal metastases of penile squamous cell carcinoma (PSCC).
Authors: Necchi Andrea , Lo Vullo Salvatore , Nicolai Nicola , Raggi Daniele , Giannatempo Patrizia , Colecchia Maurizio , Catanzaro Mario , Torelli Tullio , Piva Luigi , Biasoni Davide , Stagni Silvia , Mariani Luigi , Salvioni Roberto
Published: February 2017

479

Background: Little is known about the outcomes and prognostic factors of adjuvant chemotherapy for locally advanced PSCC after regional lymphadenectomy (LAD). Perioperative TPF combination regimen showed activity in PSCC in our series (Nicolai N et al, Clin Genitourin Cancer 2015). Methods: We retrospectively reviewed the clinical and histological data of 21 pts who had received 3-4 cycles TPF (q3wks) in the adjuvant setting at our center. Univariable and multivariable Cox regression analyses were done evaluating potential prognostic factors of disease-free (DFS) and overall survival (OS) of TPF: number of prior LAD, time from diagnosis of nodal disease to start TPF, time from LAD to start TPF, pN3, pelvic, and bilateral nodal disease, and p53 immunohistochemical (IHC) expression in nodal metastases. Results: Pts had received TPF from 07/04 to 07/12, after inguinal (n = 6) or inguinal + pelvic LAD (n = 15) and the median follow up was 52 months. LAD was radical in all cases and none had received radiotherapy. After surgery, 13 (61.9%) had pelvic and 5 (23.8%) bilateral inguinal nodal metastases. Median time from LAD to TPF was 5.4 wks (IQR: 4.1-7.3) and median time from diagnosis of N disease to TPF was 8.3 wks (IQR: 4.1-15.4). 11 of 19 available pts (57.9%) had p53+ve IHC. Univariably, only p53+ve IHC trended to poorer DFS (HR: 4.14, 95%CI: 0.87-19.68, p = 0.074) and OS (HR: 4.54, 95%CI: 0.95-21.56, p = 0.056). The same results were obtained multivariably for DFS (HR: 3.76, 95%CI: 0.78-17.96, p = 0.096) and OS (HR: 4.29, 95%CI: 0.89-20.57, p = 0.067). The bias-corrected c-indexes of the models were 0.64 and 0.62, respectively. Median DFS was 8.9 months (IQR: 5.9-22.7) for p53+ve pts vs not estimable (NE) for p53-ve pts (p = 0.051) and median OS was 17.2 months (IQR: 12.8-22.7) and NE, respectively (p = 0.037). Conclusions: In pts who had received adjuvant TPF for node-positive PSCC, p53 IHC positivity seemed to be associated with poorer outcome, and further study is warranted in larger datasets to confirm these findings. This information might be useful to select the optimal candidates to multimodal therapy for advanced PSCC.
Pazopanib in patients (pts) with advanced germ cell tumors (GCT): Results from an open-label, single-group, phase 2 trial (Pazotest-01).
Authors: Necchi Andrea , Raggi Daniele , Giannatempo Patrizia , Calareso Giuseppina , Togliardi Elena , Nicolai Nicola , Crippa Flavio , Mariani Luigi , Salvioni Roberto
Published: February 2017

481

Background: Therapeutic options for pts with chemoresistant GCT are limited and prognosis is poor. Pazopanib (PZP) is a potent and selective tyrosine kinase inhibitor (TKI) with distinct antiangiogenic activity. Methods: Pazotest-01 enrolled pts who were given PZP 800 mg/day orally until disease progression (PD) or unacceptable toxicity. Eligibility included failure of ≥ 2 platinum-based regimens, including high-dose chemotherapy (HDCT). Baseline serum tumor markers (STM), a computed tomography and a FDG-PET were repeated after 4 wks of PZP and q8 weeks thereafter. The primary endpoint was PFS (H0: 3-month PFS ≤ 10%, H1: ≥ 25%, α = 5%/β = 20%). PD was defined as rising STM, an increase in tumour size, or the appearance of new lesions. An enrolment of 43 pts was planned from a single center (NCT01743482). Results: From 05/2013 to 07/2015, 32 pts were enrolled (27 [84.4%] with nonseminoma, including 5 [15.6%] with malignant transformation, and 5 seminomas). 5 (15.6%) had primary mediastinal nonseminoma (PMNSGCT). 3 had failed two prior regimens, 15 (46.9%) three, and 14 (43.7%) > 3 regimens, including HDCT in 15 (46.9%). 20 (62.5%) had liver, bone, or brain metastases. 29 pts had elevated STM: 18 of them (62.1%) had a STM decline (mean: -53.5%). 1 PR, 19 SD (64.5% clinical benefit) and 12 PD were obtained according to RECIST v1.1. 8 pts (25%) had a densitometric and 10 (29%) a metabolic partial response. The kinetics of response was predictable in all pts: best response was seen within 4wks of starting PZP, neither PR nor STM decline occurred > 4wks. Median follow up was 15.7 months. Median PFS was 2.73 months, 3-month PFS was 28% (95%CI: 13.3-44.8). 4 pts (12.5%) were progression-free at > 5 months FUP (including 1 PMNSGCT). Median OS was 4.9 months. 4 cases (12.5%) of G3 AST/ALT increase, and 1 case of G3 diarrhea and vomiting each have been observed. 7 pts (21.9%) had G2 asthenia. Conclusions: PZP is endowed with potent anti-tumor activity in extensively pretreated patients with GCT. PZP was well tolerated, and the combination with paclitaxel is a rational next step to improve the response duration. The primary endpoint is pending confirmation in the full sample-size, and mature results will be presented. Clinical trial information: NCT01743482.
An update on penile cancer: Evaluating management trends and clinical outcomes using the National Cancer Data Base.
Authors: Mossanen Matthew , Holt Sarah , Gore John L. , Lin Daniel W. , Wright Jonathan L.
Published: February 2017

492

Background: Penile cancer remains a rare disease in the United States and may be associated with substantial morbidity and even mortality. Though the understanding of penile cancer is limited by the uncommon nature of the disease, the use of large volume datasets may help reveal recent management trends and clinical factors associated with treatment. We sought to describe penis cancer management over the past several years using the National Cancer Data Base. Methods: We performed a retrospective review of data obtained from the National Cancer Data Base from 1998-2012. We analyzed patient characteristics, demographic information, and therapeutic approaches within two clinical scenarios: 1) use of partial penectomy for early stage (clinical Ta-T2 disease); and 2) use of chemotherapy for metastatic disease. We performed multivariate logistic analysis to determine factors associated with these treatments. Results: A total of 2,677 patients presented with cTa-T2 penile carcinoma. Of these, the proportion receiving partial penectomy increased from 73.9% in 1998-2000, to 80.4% in 2010-2012 (p < 0.001). Compared to those aged 50-59, partial penectomy was more common in the old (age > 80, OR 1.52, 95% CI 1.05 – 2.20) and young (age < 50, OR 1.47, 95% CI 1.04 – 2.07). Treatment at academic centers and those without insurance were less likely to receive partial penectomy (both p < 0.01), as were patients with cT2 and node positive disease (both p < 0.001). Of those presenting with metastatic disease (n = 817), use of chemotherapy increased over the time period from 39% receiving chemotherapy in 1998-2000, to 49% in 2010-2012 (p <0.03). Patients least likely to receive chemotherapy were older and with higher Charlson Comorbidity score (both p < 0.05), African American (OR 0.46, 95% CI 0.29 – 0.70), and those living > 50 miles from the nearest treatment hospital (OR 0.37, 95% CI 0.25 – 0.55). Conclusions: Penile sparing surgery and use of chemotherapy are becoming more commonly utilized over the last several years. Multiple factors appear to be associated with these trends, and further work is needed to define both clinical and non-clinical factors associated with treatment.
A review of the stage, recurrence, treatment, and outcomes in penile cancer at a tertiary referral center.
Authors: Franklin Andrew , Koehne Elizabeth , Haden Tyler , Ross Gilbert , Stephen Weinstein , Wakefield Mark , Pokala Naveen , Hoyt Daniel
Published: February 2017

495

Background: This was a retrospective review analyzing the epidemiological and pathological association of penile cancer as well as the clinical results in patients managed at the University of Missouri Hospital and Clinics (UMHC) and Harry S Truman VA. Methods: Records were obtained of patients with a pathological diagnosis of penile cancer from 2001−2014 at UMHC and at the Harry S Truman VA. These charts were retrospectively reviewed. Information regarding patient demographics, pathology, treatment, and outcomes were recorded. Results: Forty-four patients with a pathologic diagnosis of penile cancer were identified. Mean age at diagnosis was 64 with 41 being White, 2 unknown, 1 Black, and 1 Hispanic. Seventy-two percent had tobacco exposure, with 66% of all patients having smoked greater than 10 years. HPV was present in 20%. Circumcision status was reviewed showing overall 61% were circumcised, with 4.5% being circumcised before the age of 18. Premalignant lesions were identified in 36% of the patients, with condyloma acuminate being the most common followed by Lichen Sclerosus and severe dysplasia. The vast majority (98%) of penile cancers were squamous cell carcinoma (SCCa), with only one patient having a Buschke−Lowenstein tumor. Invasive SCCa without nodal involvement was the most common pathologic stage (41%) followed by nodal positive disease (36%) and CIS (23%). Of those with node positive disease, 56% were dead less than 5 years after nodal involvement. Ninety-nine procedures with curative intent were performed, with a mean of 2.25 procedure per patient. However, only 79 of the procedures led to a sustainable cure. Of those patients with metastatic disease 13.6% underwent chemotherapy and 9.1% received radiation. Conclusions: Our study reflects the trends in stage, recurrence, treatment, and outcomes at two large centers for penile cancer. In this patient group the majority had exposure to tobacco and almost exclusively had SCCa. A durable cure may require multiple operative interventions. Nodal involvement carries a poor prognosis and high risk of death in less than 5 years once diagnosed.
Expression of Aldo-keto-reductase 1B1 (AKR1B1) in tubulocytic carcinoma of kidney.
Authors: Hashimoto Yasuhiro , Tanaka Toshikazu , Imai Atsushi , Hatakeyama Shingo , Yoneyama Takahiro , Koie Takuya , Ohyama Chikara
Published: February 2017

507

Background: Tubulocystic carcinoma of the kidney (TubCC) is a new entity of tumor not listed in the 2004 WHO classification. The tumor comprised tubules forming duct-like structures exhibiting hobnail change, and resembled collecting duct carcinoma (CDC) by immunostaining; thus, this tumor was named low grade CDC. Since then, similar tumors have been reportedly called tubulocystic carcinoma (TubCC)We explored the possibility whether Aldo-keto-reductase-1B1 (AKR1B1), osmoregulatory protein and abundant in collecting duct, can be used as a marker for the pathologic diagnosis of TubCC. Methods: We prepared anti-AKR1B1 monoclonal antibodies, examined expression of AKR1B1 protein in the human normal kidney. Immunohistochemical expressions of AKR1B1 was examined on normal kidney, 4 cases of TubCC, 10 cases of papillary renal cell carcinoma (pRCC), and 10 cases of invasive urothelial carcinoma (iUC). Results: AKR1B1 expression distributed preferentially in the renal medulla and not in the cortex, reflected by its high concentration in medulla (2.12 ±1.35 μg/mg) compared with cortex (0.13 ± 0.03 μg/mg). Immunohistochemically, AKR1B1 was strongly positive in 3 of 4 TubCC cases. AKR1B1 was negative in cases of either iUC or pRCC. Conclusions: Although the present study was small and preliminary, AKR1B1 may be a more specific and potentially useful marker for TubCC. [Table: see text]
Renal function in advanced renal cell carcinoma patients treated with sorafenib: Subset analyses of post-marketing surveillance in Japan with over 3,200 consecutive cases.
Authors: Oya Mototsugu , Kabu Koki , Adachi Masatoshi , Ito Yuichiro , Akaza Hideyuki
Published: February 2017

518

Background: Patients with advanced renal cell carcinoma (RCC) are predisposed to impaired renal function due to prior nephrectomy and existing renal mass. Moreover, treatment with molecular targeted agents may also affect renal function. We retrospectively analyzed post marketing all-patients surveillance to assess the effect of sorafenib on the renal function of advanced renal cell carcinoma (RCC) in real-world use. Methods: We have collected safety/efficacy data of over 3,200 consecutive Japanese patients with advanced RCC treated with sorafenib under daily medical practice (1). Using this database, the effect of sorafenib on renal function was analyzed in a post-hoc manner, by calculating estimated glomerular filtration rate (eGFR) from age, gender, and serum creatinine at each time point. Results: The eGFRs at baseline (n=2,943), 12 months after sorafenib treatment (n=636, and the time of discontinuation (n=1712) of all patients were 54 ± 21, 57 ± 24, and 59.6 ± 31.8 mL/min/1.73 mm2, respectively, and showed no significant differences. The mean eGFRs of each segment at baseline and 12 months were 110 ± 26 and 96 ± 39 in G1(eGFR ≥90), 70 ± 8 and 73 ± 23 in G2 (eGFR ≥60 and <90), 52 ± 4 and 57 ± 15 in G3a (eGFR ≥45 and <60), 39 ± 4 and 43 ± 11 in G3b (eGFR ≥30 and <45), 24 ± 4 and 30 ± 10 in G4 (eGFR ≥15 and <30), 7 ± 3 and 11 ± 12 in G5 (eGFR <15), respectively. The median daily dose were 726mg (G1), 522mg (G2), 524mg (G3a), 517mg (G3b), 483mg (G4), and 400mg (G5). The incidence of renal AEs seemed to be higher in G4 and G5 (14% and 6%, respectively) than the other groups. The objective response rate ranged from 29.2% in G3a to 18.3% in G5, and the overall survival were higher in G3a and G3b (1 year survival rate: 81.5% and 78.4%, respectively), and lower in G1 (1 year survival rate: 50.2%). Conclusions: This study demonstrated that little impact on renal function of advanced RCC patients treated with sorafenib during observational period with sufficient clinical response and safety irrespective of the baseline eGFR value.
Everolimus (E) versus axitinib (A) as second-line therapy (2L) in metastatic renal cell carcinoma (mRCC): Retrospective experience at Gustave Roussy.
Authors: Guida Annalisa , Albiges Laurence , Loriot Yohann , Massard Christophe , Fizazi Karim , Escudier Bernard J.
Published: February 2017

527

Background: Currently both E and A are standard treatments for patients (pts) with mRCC after failure of first line therapy (1L)with VEGF-targeted therapy. There is no comparative study reported so far, and this study aims to evaluate these 2 drugs in a large center. Methods: Patient characteristics, safety and outcome data from all mRCC pts who received E or A as 2L at Gustave Roussy from April 2007 to May 2015 have been compared. Progression-free Survival (PFS) and Overall Survival (OS) were assessed by the Kaplan-Meier method and compared with the log-rank test. Results: 81 pts were treated with E and 45 pts with A. The table shows patient characteristics. The 2 groups were similar. The most common 1L was sunitinib (79% in E group and 82.2% in A group). Median follow up was 29 mo (95%CI 26 – 31), 26 mo for A and 33 mo for E (p=0.046). Median OS was 21.5 mo for E and 14.9 mo for A (p = 0.23). Median PFS was 5.3 and 7.7 mo for E and A respectively (p = 0.39). Disease control rate was 69% and 73% (p=0.31) and partial response was achieved in 4% and in 24% of pts (p=0.002), respectively in E and A cohort. At time of analysis E is ongoing in 3 pts (4%) and A in 9 pts (20%) (p=0.008). Third-line therapy (3L) was administrated in 62% of pts after E and in 33% after A (p=0.003). The most common 3L after E is A (48%) and vice versa the most common after A is E (71%). Median PFS of 3L after E is 9.1 mo (12.1 mo for A and 8 mo when 3L is not A (p=0.17)). Median PFS of 3L after A is 7.8 mo (95%CI 4-12). Conclusions: No statistically significant difference for PFS and OS were observed. Nevertheless, A showed more PR than E, while more pts received 3L after E. A remains very active in 3L. [Table: see text]
Metastatic papillary renal cell carcinoma: A retrospective study from two large academic centers in Sweden.
Authors: Stenman Maria , Nearchou Andreas Demetrios , Sandström Per , Lindskog Magnus , Harmenberg Ulrika
Published: February 2017

535

Background: Non-clear cell renal cell carcinoma (nccRCC) constitute about 10-15% of all metastatic renal cell carcinoma (mRCC) and typically include papillary, chromophobe and collecting duct histologies. Despite differences in clinical behavior between subtypes they are often grouped as one due to small patient numbers. Hence, there is a lack of knowledge on type-specific prognosis and treatment options. Methods: Patients diagnosed with metastatic nncRRC (56 out of 526 patients; 10.8%) during the years 2005-2013 were retrospectively identified using data from medical records at two large academic centers in Sweden. The characteristics and outcome of those with papillary subtype (n = 44; 79% of nccRCC) was analyzed. Results: Metastatic papillary RCC patients were more often male (82%), had a median age of 69 years and 48% had M1 disease. 9% were type I, 41% type II, 4% mixed and 41% papillary NOS. 89% had a nephrectomy and 56% received at least one line of systemic therapy. The median overall survival (OS) of all papillary patients was 10.1 months. Factors associated with OS included performance status (PS; OS 25.8 months for ECOG PS 0-1 patients vs OS 3.1 months for ECOG PS > 1 patients, p = 0.00002), and systemic therapy (OS 23.4 months vs 3.8 months for patients not treated systemically, p = 0.002). Systemic therapies (ST) included VEGF targeting agents (88%), mTOR inhibitors (50%), or interferon (21%) for all lines. The most common first line ST was VEGF targeting agents (75%). 42% received one line, 33% two lines, and 25% three or more lines of ST. Characteristics of patients treated with ST included lower age at diagnosis, higher proportion of M1 disease and better PS. The reasons for not giving systemic treatment were primarily poor performance status or comorbidities. ECOG PS > 1 (p = 0.04) and poor MSKCC risk group (p = 0.02) were predictive of OS among patients treated with ST. Conclusions: Patients with metastatic papillary RCC and good performance status (ECOG PS 0-1) seem to benefit from systemic therapy using drugs primarily evaluated for clear cell RCC. However, patients not eligible for systemic therapy due to poor performance status or other reasons have a dismal prognosis.
Comprehensive genomic profiling of renal cell carcinoma with sarcomatoid dedifferentiation to pinpoint recurrent genomic alterations.
Authors: Malouf Gabriel G. , Ali Siraj Mahamed , Wang Kai , Balasubramanian Sohail , Ross Jeffrey S. , Miller Vincent A. , Stephens Philip J. , Khayat David , Mouawad Roger , Pal Sumanta K. , Su Xiaoping , Sircar Kanishka , Tamboli Pheroze , Jonasch Eric , Tannir Nizar M. , Wood Christopher G. , Karam Jose A.
Published: February 2017

537

Background: Renal cell carcinoma with sarcomatoid dedifferentiation (sRCC) is found in five percent of all renal cell carcinoma (RCC) cases, and has a significantly worse prognosis relative to matched highgrade RCC with only epithelial elements. The genomic features underpinning sRCC are not well understood, and at present, there are no specific or effective therapies for sRCC. Methods: We conducted comprehensive genomic profiling (CGP) on paired epithelial and sarcomatoid areas of 3 sRCC cases. In the course of routine clinical care, CGP was performed on another 23 sRCC harboring diverse epithelial components. CGP was conducted using a hybrid capture next generation DNA sequencing assay(NGS) of 236 cancer-related genes plus 19 genes frequently rearranged in cancer. Results were compared with 56 similarly sequenced cases of clear cell RCC devoid of sarcomatoid component, and with clear cell TCGA. Results: Two of three sRCC cases that underwent CGP of both their epithelial and the sarcomatoid components demonstrated identical mutational profiles, and a third case demonstrated commonly disrupted genes. Of the 23 sRCC, TP53(43%), CDKN2A(30%), VHL(26%) and NF2(22%) were the most frequently altered genes. NF2 mutations were mutually exclusive with TP53 but not with VHL mutations. Conclusions: Two of three sRCC cases that underwent CGP of both their epithelial and the sarcomatoid components demonstrated identical mutational profiles, and a third case demonstrated commonly disrupted genes. Of the 23 sRCC, TP53(43%), CDKN2A(30%), VHL(26%) and NF2(22%) were the most frequently altered genes. NF2 mutations were mutually exclusive with TP53 but not with VHL mutations.
Outcome of octogenarian versus (vs) young patients (pts) with metastatic renal cell carcinoma (mRCC), treated with sunitinib (su).
Authors: Kushnir Igal , Rosenbaum Eli , Sella Avishay , Sarid David , Gottfried Maya , Maimon Natalie , Peer Avivit , Neumann Avivit , Neiman Victoria , Kovel Svetlana , Gez Eliahu , Mermershtain Wilmosh , Rouvinov Keren , Carducci Michael Anthony , Eisenberger Mario A. , Hammers Hans J. , Sinibaldi Victoria J. , Berger Raanan , Keizman Daniel
Published: February 2017

538

Background: Su is a standard treatment (tx) for mRCC. Octogenarian pts (aged ≥ 80) are often considered to be unfit for su tx, and recommendations for their tx is limited by the paucity of clinical trials data in this population. We aimed to study baseline characteristics and outcome of octogenarian vs young (aged ≤45) pts with mRCC treated with su. Methods: We performed an international multicenter retrospective study of pts with mRCC, who were treated with su in 8 centers across 2 different countries. We compared baseline characteristics and outcome of octogenarian versus young pts. The effect of very old age on response rate (RR), progression free survival (PFS) and overall survival (OS), was tested with adjustment of other known confounding risk factors using a chi-square test and partial likelihood test from cox model. Furthermore, univariate and multivariate analyses of association between clinicopathologic factors and age, and outcome were performed using the entire pt cohort. Results: Between 2004-2013, 36 octogenarian (group 1; median age 83) and 37 young (group 2; median age 42) mRCC were treated with su. The groups were balanced regarding the following baseline clinicopathologic characteristics: gender, HENG risk, past nephrectomy, mRCC histology, ≥ 2 metastatic sites, lung/liver/bone metastasis, prior targeted tx, smoking status, use of angiotensin system inhibitors (ASIs), pre-tx neutrophil to lymphocyte ratio (NLR) >3, and sunitinib induced hypertension (HTN). In group 1 vs 2, 53% vs 27% (p=0.006) had dose reduction/treatment interruption d/t side effects. Clinical benefit (partial response + stable disease) in group 1 vs 2 was 76% vs 84%, while 24% vs 16% had disease progression within the first 3 months of tx (p=0.09). Median PFS was 11 vs 8 months (p=0.1). Median OS was 22 vs 20 months (p=0.7). In multivariate analyses of the entire pt cohort (n=73), age was not significantly associated with PFS or OS. Conclusions: Su is active in octogenarian mRCC pts. Vs young pts, a significantly higher proportion of octogenarian pts had dose reduction/treatment interruption d/t side effects.
Physician treatment selection in the prospective Metastatic Renal Cell Cancer (MaRCC) Registry.
Authors: Kyriakopoulos Christos , Harrison Michael Roger , Bhavsar Nrupen Anjan , Wolf Steven Paul , Costello Brian Addis , Stadler Walter Michael , Hammers Hans J. , Vaishampayan Ulka N. , Appleman Leonard Joseph , Creel Patricia A. , Samsa Greg P. , Richardson Eric M. , Johnson Kathleen A. , Borham Azah , George Daniel J.
Published: February 2017

563

Background: Clinical trials mRCC pts are different from real world pts, resulting in bias in the literature. The MaRCC Registry is designed to survey questions not asked in tri als, such as why physicians make certain management decisions. This analysis describes reasons for physician treatment (tx) selection in the first 109 real world pts enrolled in a multicenter, prospective, observational registry. Methods: MaRCC Registry will enroll 500 pts from up to 60 US academic (ACAD) and community (COMM) sites with ~2 years of recruitment and ≥ 3 years of follow-up. Key inclusion criteria are age ≥ 18 years and diagnosis of mRCC with no prior systemic therapy (STx) for mRCC at study entry. Pts currently not on STx but who are being observed are permitted. Key endpoints include descriptive characteristics of txs, tx and patient outcomes, medication adherence, and health resource utilization. Results: At data cutoff, 105 pts have been accrued with known STx status; median age 64 (Q1-3 range, 56-70); 66% male; 75% ACAD; 87% clear cell histology; and 31% stage IV at diagnosis. Initial management decision was: 40% deferred systemic therapy (DSTx), 22% pazopanib, 18% clinical trial, 10% sunitinib, and 6% other. Among STx pts (N = 61), the most common categories for therapy choice as selected by providers were likelihood of clinical benefit (41%) followed by pt characteristics (30%). Within the clinical benefit category, the most common reason was OS/PFS (31%). Within the pt characteristic category the most common reasons included performance status/frailty (12%) or prognostic factors (12%). Common reasons for DSTx pts (N = 44) were active surveillance (AS) with disease present (39%), AS without disease present following a procedure (11%), or local therapy (7%). ACAD sites had higher percentages of pts with DSTx undergoing AS with disease present and local therapy. Conclusions: This is the first report describing factors driving physician decision making in management of mRCC. Management choices are not captured in other prospective or retrospective studies. Early experience suggests that clinical benefit and pt characteristics were common reasons for initial STx. Side effect profile rarely determined initial STx selection.
Can PSA density and free-to-total PSA ratio improve our ability to predict prostate cancer on biopsy? Results from a prospective, multi-institutional, and contemporary cohort.
Authors: Rai Samarpit , Soodana-Prakash Nachiketh , Pavan Nicola , Nahar Bruno , Patel Amil , Dong Yan , Satyanarayana Ramgopal , Parekh Dipen , Punnen Sanoj
Published: February 2017

57

Background: Several studies have reported an increased value of PSA density (PSAD) and free−to−total PSA ratio (f/t PSA) over PSA alone in predicting prostate cancer (PCa). Despite this, they remain underutilized. This study analyzed a cohort of men referred for prostate biopsy (PB) to determine if PSAD and f/t PSA enhanced the prediction of any PCa and/or significant PCa (Gleason score ≥ 7) compared to PSA. Methods: 1,370 prospectively enrolled patients were referred for a PB across 26 urological centers. A phlebotomy was performed immediately prior to PB for PSA and f/t PSA measurement. PSAD was calculated using prostate volume obtained during the trans−rectal ultrasound (TRUS) guided PB. The area under the receiver operating characteristic curve (AUC) was used to assess the added discriminative value of PSAD and f/t PSA when added to a base model consisting of PSA, age, prior biopsy status, and DRE for the prediction of any and significant PCa. Results: Of the 1,290 men in the final cohort, 301 (23%) and 284 (22%) men were diagnosed with low−grade (Gleason score = 6) and significant PCa respectively. The median PSAD values in men with no PCa, low−grade PCa, and significant PCa were 0.09, 0.11, and 0.17 ng/mL/cc, respectively (P < 0.0001). The median f/t PSA in men with no PCa, low−grade PCa, and significant PCa was 0.21, 0.17, and 0.12 respectively (P < 0.0001). The AUC for a model incorporating PSAD showed superior predictive value compared to the base model for diagnosing any PCa (AUC 0.76 versus 0.70, P < 0.0001) and significant PCa (AUC 0.82 versus 0.77, P < 0.0001). Similarly, a model with f/t PSA showed superior predictive value compared to the base model for diagnosing any PCa (AUC 0.73 vs 0.70, P < 0.0001) and significant PCa (AUC 0.82 versus 0.77, P < 0.0001). While PSAD showed superior predictive value over f/t PSA for predicting any PCa (AUC 0.76 versus 0.73, P = 0.0062), there was no difference in their discrimination of significant PCa. Conclusions: PSAD and f/t PSA add substantial predictive power to the diagnostic armamentarium for any and significant PCa. Their calculation may reduce the number of unnecessary biopsies being performed for PCa detection.
Molecular profiling of renal medullary carcinoma to reveal frequent alterations in chromatin remodeling genes and to identify EZH2 as a relevant therapeutic target.
Authors: Gao Jianjun , Malouf Gabriel G. , Su Xiaoping , Yao Hui , Rao Priya , He Rong , Xiong Liangwen , Karam Jose A. , Matin Surena F. , Mouawad Roger , Comperat Eva , Khayat David , Wood Christopher G. , Tannir Nizar M.
Published: February 2017

571

Background: Renal medullary carcinoma (RMC) is a rare and highly aggressive malignancy that affects primarily young adults with sickle cell trait. The prognosis of RMC is poor with a median survival of about 12 months from diagnosis. It has been previously shown that loss of heterozygosity of SMARCB1 occurs in the majority of cases leading to protein loss. However, a comprehensive molecular profiling of this disease remains unknown. Methods: Whole-exome sequencing (WES) of 9 RMC matched tumor-normal cases and 1 unmatched case were performed. In addition, single nucleotide polymorphism (SNP) analysis was done using the Affymetrix SNP 6.0 array. To test differentially expressed genes between RMC cases and normal kidney, RNA sequencing was carried out. The effect of EZH2 inhibition on in vitro RMC tumor cell proliferation was assessed using the MTT assay. Results: WES analysis of 9 paired RMC cases identified 233 non-synonymous somatic mutations (median: 21; range: 12-44). We observed frequent mutations in chromatin remodeling genes in 7 of 10 RMC cases, including mutations in SMARCB1 (n = 2) and SMARCA5 gene (n = 1). SNP analysis demonstrated that only the case with SMARCA5 somatic mutation harbored SMARCB1 monoallelic loss. However, all RMC cases had loss of SMARCB1 protein by immunohistochemistry. Ingenuity pathway analysis using RNA sequencing data identified EZH2 as one of the top over-expressed upstream regulators (Z-score = 3.7; p-value = 1.6x10-6). RT-PCR and western blot analyses confirmed that EZH2 expression is elevated at both mRNA and protein levels corresponding to SMARCB1 loss in RMC tumors. In vitro assessment of a novel RMC tumor cell line derived from the case harboring SMARCB1 deletion showed that EZH2 inhibitor GSK343 inhibited proliferation of this cell line. Conclusions: Our data reveal that 30% of RMC cases showed inactivation of SMARCB1 through somatic mutations or monoallelic loss, suggesting that additional epigenetic mechanisms may lead to gene inactivation. In addition, our data suggest that EZH2 may be a relevant therapeutic target in RMC.