bluuebunny/crossref_metadata_2025 huggingface dataset:
Patient-derived AVATAR mouse models to predict prognosis in advanced renal cell carcinoma.
Authors: Suarez Cristina , Martinez Mar , Trilla Enrique , Jimenez-Valerio Gabriela , de Torres Ines , Morales Rafael , Jimenez Jose , Lorente David , Vivancos Ana , Nuciforo Paolo , Morote Juan , Carles Joan , Casanovas Oriol
Published: February 2017

551

Background: Anti-angiogenic (AA) drugs are the cornerstone of first-line (FL) treatment in renal cell carcinoma (RCC). While several mechanisms of resistance to AA have been described, second line (SL) therapies are disappointing with short PFS reported. A recent strategy makes use of individual patient-derived tumor models in animals for drug testing simultaneously with that patient’s FL and SL treatments (AVATARs). The predictive value of each specific AVATAR for that same original patient will be key in order to predict SL treatment response in the clinic trying to help in decision making in this setting. Methods: We generated a unique panel of patient-derived mouse models of RCC based on the orthotopic implantation of primary renal tumor biopsies or metastasis directly obtained from patients. Sunitinib FL treatment followed by different SL treatments are evaluated in each mouse model. Response to treatments in these models and molecular profiling in search of predictive factors of response/resistance will be performed. Results: In this subset of 12 advanced RCC patients, tumor take rate in mice to develop AVATARs was 75% at 5 months after implantation. Previous data demonstrated a positive association of grafting capacity with tumor stage and Fuhrman grade (p < 0.0001). AVATAR models faithfully reproduced each patient’s histological characteristics and metastatic capacity. Time to tumor growth in AVATAR models significantly correlated to clinical outcome in each patient (spearman correlation, p < 0.0001). These advanced AVATAR models are treated FL with AA drugs and, at the moment of emergence of resistance to therapy, treatment is switched to known and experimental SL treatments in different animal cohorts. Updated results on AVATAR treatment and prediction of patient’s responses will be presented. Conclusions: Thorough characterization of these AVATAR models together with their response to AA treatments we will be able to predict response/resistance to new SL treatments for our RCC patients as a personalized cancer therapy approach.
The impact of weight change during treatment with targeted therapy in patients with metastatic renal cell carcinoma (mRCC).
Authors: Albiges Laurence , McKay Rana R. , Lin Xun , de Velasco Guillermo , Simantov Ronit , Choueiri Toni K.
Published: February 2017

557

Background: A growing body of evidence suggests a relationship between baseline body mass index and outcomes in patients (pts) with mRCC. However, the role of weight loss (WL) during treatment in pts with mRCC is poorly characterized. The aim of this study was to investigate the impact of weight change in mRCC pts treated with targeted agents. Methods: We conducted an analysis of mRCC pts treated on phase II-III clinical trials sponsored by Pfizer from 2003-2013. Weight change was defined as WL (≥ 5% weight reduction from baseline), stable weight (SW) or weight gain (WG, ≥2 % weight increase). We assessed the impact of weight change on overall survival (OS) (primary endpoint), progression-free survival (PFS) and overall response rate (ORR) at week (wk) 12. Statistical analyses were performed using Cox regression and Kaplan-Meier method. Multivariate analysis was adjusted for known prognostic factors for mRCC, including IMDC criteria. Results: Among 3,311 pts, 1,916 (58 %) had SW, 936 (28 %) had WL and 459 (14%) had WG at wk 12. Overall, pts with WL demonstrated both reduced OS and PFS compared to SW (median OS: 18.68 vs. 26.94 vs. 23.03 months in WL, SW and WG respectively; median PFS: 7.17 vs. 10.12 vs. 9.93 months in WL, SW and WG), and were consistent when considering 2 other time points (table). WL at wk 12 was associated with worse ORR (23.4 vs. 32.1 vs. 35.9% in WL, SW, WG; adjusted odd ratio 0.715, 95% CI 0.590-0.867, p=0.03). Discontinuation rate due to adverse events was similar between groups. Conclusions: We demonstrated that WL during therapy for mRCC is strongly associated with worse clinical outcomes. This observation remains valid for WL at 6, 12 and 24 weeks. Weight change may be an early prognostic factor and guide physician in clinical management. Measures to avoid WL during therapy may lead to better outcomes from targeted therapy. [Table: see text]
PD-1 expression on classical monocytes (CM) as an independent predictor of cancer specific survival in clear cell renal carcinoma (ccRCC).
Authors: Haseebuddin Mohammed , Macfarlane Alexander , Ruth Karen , Uzzo Robert G. , Plimack Elizabeth R. , Jillab Mowafaq , Dulaimi Essel , Al-Saleem Tahseen I. , Campbell Kerry
Published: February 2017

562

Background: We have previously shown that PD-1 expression in peripheral blood lymphocytes is elevated in RCC patients at diagnosis and decreases subsequent to surgery. We theorize that classical monocyte (CM) inhibition through PD-1 interferes with antigen presentation necessary to stimulate adaptive immune responses, and, thus, preop CM PD-1 expression is prognostic of poor outcomes. Methods: Blood samples were obtained from RCC patients (n = 90) preop and age-matched healthy donors (n = 25). Flow cytometric (FC) data were quantified as mean fluorescence intensity (MFI) or % of cells that express a biomarker. Patients were excluded if they had comorbid CLL, had prior surgeries for RCC, had non-ccRCC histology, or if the FC data was missing. We have defined elevated CM PD-1 expression at the third quartile level of CM PD-1 expression (784 MFI) in the healthy donors. CM PD-1 level was correlated with patient clinico-pathologic data using non-parametric tests. Cancer specific survival (CSS) curves were estimated with Kaplan-Meier methods and a multivariate analysis was performed. Results: The average age of the ccRCC cohort (n = 68) was 60 (range 25-88) years. 35 patients were Fuhrman Grade III/IV high-grade (HG) histology. With median follow-up of 41 months, 10 patients died with ccRCC. No patients with low-grade disease died. Median CM (%) was lower in those who died of disease compare to censored (64% vs 52%, p = 0.029). Patients with CM PD-1 expression > 784 MFI had lower survival compared to patients with CM PD-1 < 784 MFI (p = 0.02). Among HG patients, CSS at 24 months for CM PD-1 MFI > 784 was 62.1% (95% CI 34.2-81.0) vs 93.3% (95% CI 61.3-99.0) for CM PD-1 MFI < 784. On multivariable analysis, controlling for stage related covariates, CM PD-1 MFI > 784 is associated with inferior CSS (hazard ratio = 5.1 [95% CI: 1.1-24.4], p = 0.04) among HG disease patients. Conclusions: In patients with ccRCC, an elevated preoperative CM PD-1 MFI level was associated with lower survival independent of pathological T stage and localized disease status. Preoperative CM PD-1 MFI may be an important biomarker to stratify patients at risk for poor outcome who may benefit from immunotherapy.
Isolation and analysis of circulating tumor cell samples from both spiked analytical sources and patients with renal cell cancer and prostate cancer.
Authors: Amato Robert J. , Rosenblatt Kevin P , Dehghani Mehdi , Souza Glauco R , Brobey Reynolds , Ionescu-Zanetti Cristian , Jensen Jeff , Tseng Hubert
Published: February 2017

584

Background: Tumor genotyping using fluid samples such as blood can potentially allow tracking of dynamic changes in mutational profiles over time and allow better access than biopsies. We present a method to detect somatic mutations from a blood draw, where circulating tumor cell (CTC) enrichment above 10% of total cell numbers allows the use of standard gene panels typically used to analyze tissue-based biopsies. Methods: Analytical samples were obtained from 9 prostate cancer (PC) patients and 6 renal cell cancer (RCC) patients, followed by CTC enrichment using the IsoFlux System. Cells were lysed and DNA amplified by whole genome amplification (WGA) using the NGS Kit (Fluxion Biosciences) and quantified via qPCR. Samples were enumerated to determine CTC load, with CTCs defined as CK+, CD45- nucleated cells (DAPI+). Next-generation sequencing was performed using 3 targeted cancer panels on the Ion torrent PGM platform: the Ion ampliseq cancer hotspot panel (50 genes; 6 PC samples), the Oncomine (143 genes; 3 PC samples), and a 29-gene panel of actionable mutations in RCC (6 samples). Data was analyzed using a customized variant calling/filtering pipeline based on standard alignment and variant calling tools. Variant filtering and functional interpretation was performed using VarSeq. All data was analyzed in a blinded manner. Results: Our method was able to isolate CTCs from all patient samples. Whole genome amplified DNA concentration was at a range of 25-164 ng/µL (median, 69) in PC and 29-180 ng/µL (median, 69) in RCC. CTCs were recovered in 2.9-33.7% (median, 10.5%) of PC samples and 1.9-33% (median, 14.5%) of RCC samples After WGA, we found 1 variant/sample using hotpot, 12/sample using Oncomine, and 3/sample using the RCC panel. Conclusions: Our assay consistently detected somatic variants from blood draw using standard gene panels in both PC and RCC. Obtaining repeat tumor biopsies from patients during treatment and/or at time of progression is both challenging and impractical from a clinical perspective. Our assay provides molecular characterization using standard blood draws and will be prospectively validated in clinical trials.
Impact of precise quantitative assessment of visceral obesity on outcomes of patients with metastatic renal cell carcinoma treated with systemic therapy.
Authors: Mizuno Ryuichi , Miyajima Akira , Hayakawa Nozomi , Kikuchi Eiji , Mikami Shuji , Jinzaki Masahiro , Oya Mototsugu
Published: February 2017

597

Background: With its excellent resolution of adipose tissue, CT presents precise quantitative assessment of visceral obesity. We assessed the impact of visceral obesity on progression free and overall survival in patients treated with systemic therapy for metastatic renal cell carcinoma. Methods: This retrospective cohort study included 114 patients treated with systemic therapy for metastatic renal cell carcinoma between 2007 and 2015 at Keio university hospital in Japan. The visceral fat area was measured at the level of umbilicus using CT. A visceral fat area ≥100cm2 was used as the definition of visceral obesity. Progression free and overall survival was compared according to visceral obesity. Results: In the whole cohort, the median progression free survival in first line treatment was 12.0 month. The median overall survival was 42.5 month. According to Memorial Sloan-Kettering Cancer Center classification, 31 patients were favorable risk, 61 were intermediate risk, and 22 were poor risk; median overall survival for these groups were 76.9, 40.8, and 23.7 months, respectively (P<0.0001). Visceral obesity correlated with improved progression free (P=0.0095) and overall survival (P=0.0002). On multivariate analysis, visceral obesity (HR 0.64, P=0.0393) and Memorial Sloan-Kettering Cancer Center classification (P=0.0037) were independent indices to predict progression free survival in first line treatment. In addition, visceral obesity (HR 0.42, P=0.0016) and Memorial Sloan-Kettering Cancer Center classification (P=0.0006) independently predicted overall survival. Conclusions: The precision of CT imaging for measuring visceral fat tissue provides useful clinical venue to predict prognosis for metastatic renal cell carcinoma. Visceral obesity may be a useful and independent indicator for a better prognosis in patients treated with systemic therapy for metastatic renal cell carcinoma.
Multi-institutional evaluation of multiparametric MRI and fusion-guided prostate biopsy in a biopsy-naive population.
Authors: Kadakia Meet , George Arvin Koruthu , Siddiqui Minhaj , Rais-Bahrami Soroush , Rastinehad Ardeshir , Vourganti Srinivas , Fascelli Michele , Kongnyuy Michael , Muthigi Akhil , Sidana Abhinav , Frye Thomas P , Kilchevsky Amichai , Nix Jeffrey , Yarlagadda Vidhush K. , Su Daniel , Merino Maria J , Wood Bradford J. , Choyke Peter L. , Turkbey Ismail B. , Pinto Peter A.
Published: February 2017

60

Background: Multiparametric MRI (mpMRI) and fusion biopsy (FB) has proven beneficial in men with a prior negative systematic biopsy (SB) or diagnosis of prostate cancer (CaP). The aim of the study was to evaluate mpMRI and FB in a biopsy-naive population. Methods: A multi-institutional review was performed on patients with no prior biopsy history who underwent mpMRI followed by concurrent FB and SB. Imaging protocol was standardized across institutions. Gleason score (GS) distribution/risk classifications were recorded. Univariate analysis was performed to compare FB versus SB. Results: A total of 361 biopsy-naive men were identified from 4 institutions. GS distribution/risk classification for FB and SB are presented in the table. Overall cancer detection rate (CDR) was 65.4%. In biopsy-naive men, FB detected a greater absolute number of high grade disease with 13% more high risk CaP than SB (78 vs 69). Additionally, FB detected 21% fewer cases of GS 6 CaP (57 vs 69). The CDR for FB alone was 57.3% with only 3 intermediate-risk and 1 high-risk patient not identified. The addition of SB to FB resulted in diagnosing 25 added cases of low-risk disease for each high risk CaP detected. The CDR of SB alone was 59.6%, however, 2 intermediate- and 4 high-risk CaP were missed. The addition of FB to SB alone resulted in only 4 added cases of low-risk CaP for each high-risk CaP detected. Conclusions: In biopsy-naive men, mpMRI and fusion biopsy detects a greater number of patients with high-risk disease while decreasing the detection of low-risk CaP. Additional studies with greater power will be required to validate the potential benefit of mpMRI and FB in patients with no prior biopsy history. [Table: see text]
Metastasis-associated mutations in clear cell renal cell carcinoma.
Authors: Gowrishankar Banumathy , Janakiraman Manickam , Lee Chung-Han , Thodima Venkata Jaganmohan , Molina Ana M. , Patel Premal H , Gold Theresa Margaret , Motzer Robert J. , Chaganti Raju S.K. , Kamalakaran Sitharthan , Houldsworth Jane
Published: February 2017

600

Background: Over 30% of patients with clear cell renal cell carcinoma (ccRCC) exhibit metastasis at the time of diagnosis and exhibit poor outcome. About 20-50% of patients with localized disease eventually develop metastasis after nephrectomy. The goal of the current study was to identify target gene mutations associated with ccRCC metastasis. Methods: In this IRB approved study, genomic DNA from 128 ccRCC resected specimens (128 unique patients) were profiled using a custom targeted next-generation sequencing (NGS) panel comprising 70 frequently mutated genes and prognostic SNPs in renal cancer. The specimen cohort consisted of 78 primary (29 stage I-III, 30 stage IV, 19 unknown) and 50 metastatic (10 lung, 9 bone, 25 other sites, 6 unknown) lesions. Following hybrid capture, sequencing was performed (MiSeq, Illumina) and variants identified using CLCbio (Qiagen). Chi-square test was used to test for significance. Results: The median specimen had 4 non-synonymous mutations (123/128 samples had at least one mutation). 66 genes showed a non-synonymous mutation in at least one specimen. There was no significant difference between total mutation count between primary and metastatic specimens (Mann-Whitney test). TSC1 mutation was significantly enriched in metastatic (8/50) compared with primary lesions (3/78). No TSC1 mutation was found in the 29 localized (stage I-III) primary lesions. Interestingly, TSC1 maps to 9q34 and our prior copy number studies indicated that loss of 9q is also enriched in metastatic lesions. Of the 11 specimens bearing TSC1 mutation in this cohort, 5 also had loss of 9q. In 44 specimens with known sites of resection, SETD2 and TSC1 mutations were not found in metastases to the lung but found in 30-40% of lesions at other sites, KDM5C and TSC1 mutations were not found in metastases to the bone while 25-30% of lesions at other sites exhibited these mutations. Due to the limited sample size, significance could not be determined for these associations. Conclusions: Preliminary results of this study implicated TSC1 in the metastasis of ccRCC. Since TSC1 mutation is known to confer sensitivity to mTOR inhibitors, our initial finding of absence of TSC1 mutation in lung and bone sites of metastasis may have therapeutic implications.
Effect of concomitant proton pump inhibitor (PPI) on effectiveness of tyrosine kinase inhibitor (TKI) in patients with metastatic renal cell carcinoma (mRCC).
Authors: Au Trang H. , Bailey Erin B. , Patel Shiven B. , Tantravahi Srinivas Kiran , Agarwal Neeraj , Stenehjem David D.
Published: February 2017

608

Background: PPIs may reduce TKI bioavailability resulting in reduced efficacy, shortened time on TKI treatment, and disease progression. Axitinib, sorafenib, and pazopanib exhibit pH-dependent solubility. Esomeprazole reduced the AUC and Cmax of pazopanib by 40%, but there was no significant interaction for sorafenib with omeprazole or axitinib with rabeprazole. In real world practice, the effect of PPIs as a class on the efficacy of TKIs as a class in mRCC has not been reported. Methods: This observational cohort study evaluated adult patients treated with a TKI for mRCC. Time on TKI treatment was defined as TKI initiation date to date of discontinuation, change in therapy, lost to follow-up, or death. We performed a treatment line analysis. Time on TKI treatment was compared between patients with and without concurrent PPI (Kaplan-Meier, log-rank). Results: Analysis included 128 treatment lines, including 49 TKI with PPI and 79 TKI with no PPI treatment lines. TKIs included sunitinib, pazopanib, sorafenib, and axitinib. PPIs included omeprazole, lansoprazole, esomeprazole, pantoprazole, and rabeprazole. The three most common TKI/PPI combinations involved omeprazole with sunitinib (26), pazopanib (13), and axitinib (3). No difference in time on TKI treatment with PPI (median 8.7 months) and with no PPI (median 7.0 months, p = 0.41) was observed. In pazopanib treatment lines, no difference in time on treatment was observed in those treated with omeprazole or esomeprazole (n = 14, median 4.8 months) compared to those without PPI (n = 18, median 1.7 months, p = 0.22). Conclusions: Among the TKI/PPI combinations evaluated, there was no difference in time to TKI discontinuation with or without concurrent PPI. This suggests that concurrent PPI does not affect time to discontinuation of TKI. Study limitations include the small sample size, limited number of TKI/PPI combinations, and retrospective study design. A larger study is needed to validate these findings.
Axitinib in advanced renal cell carcinoma: Outcomes following pazopanib or sunitinib.
Authors: Laskey Jennifer , Venugopal Balaji , Thomson Nicola , O'Donoghue Roisin , Jones Robert J.
Published: February 2017

609

Background: Axitinib is licensed in Europe for the treatment of adult patients with advanced renal cell carcinoma after failure of sunitinib, but not pazopanib. Efficacy is based on the AXIS trial which reported a progression free survival (PFS) of 4.8 months and an overall survival (OS) of 15.2 months in patients who had received prior sunitinib. Despite widespread use of pazopanib in the first line setting there is no randomised trial evidence to support the use of axitinib after pazopanib. The Beatson Cancer Centre (BCC) renal cancer clinic provides all systemic therapy for a population of 2.8 million. Within BCC axitinib is used post sunitinib or pazopanib. We performed an analysis of patient outcomes in patients who commenced axitinib in WOS between November 2013 and November 2014. Methods: Data were collected prospectively from the electronic clinical records. Duration of treatment was used as a surrogate for progression free survival (PFS). Data were analysed in April 2015 which served as the censor date for those still alive. Results: 46 patients were included. At the time of analysis 38 patients had stopped axitinib and 30 patients had died. 22 patients (48%) had received prior pazopanib and 21 (46%) prior sunitinib. For the patients who received axitinib in the 2nd line setting (n = 38) median duration of treatment was 4.8 months (95% CI 0.55 – 9.12). Median duration post sunitinib and pazopanib was 4.8 months (95% CI 0 – 9.7) and 5.3 months (95% CI 2.2- 8.4). Median OS was 9.2 months (95% CI 6.44 – 12.05) overall and 9.44 months (95% CI 5.36 – 13.5) and 8.36 months (95% CI 1.7 – 11.6) post sunitinib and pazopanib respectively. Conclusions: PFS appears to be comparable to reported trial data irrespective of first line treatment indicating similar efficacy and tolerability in real life. We found no evidence of a significant difference in OS regardless of first line treatment which supports the current practice of using axitinib post sunitinib or pazopanib. The inferior OS compared to AXIS trial could be multifactorial and requires further investigation.
RECORD-4 multicenter phase II trial of second-line everolimus (EVE) in patients (pts) with metastatic renal cell carcinoma (mRCC): Anti-VEGF cohort subanalysis.
Authors: Cosgriff Thomas , Yang Lin , Alyasova Anna , Ye Dingwei , Karpenko Andrey , Li Hanzhong , Alekseev Boris , Xie Li-ping , Kowalyszyn Ruben Dario , Karyakin Oleg , Neron Yeni Verónica , Collins LaTonya , Brechenmacher Thomas , Lin Chinjune , Morgan Liza , Motzer Robert J.
Published: February 2017

611

Background: RECORD-4 assessed EVE in pts with mRCC who progressed after only 1 prior therapy and enrolled pts into 3 cohorts based on first-line sunitinib (cohort 1), other anti-VEGF agents (cohort 2) or cytokines (cohort 3) (J Clin Oncol2015;abstr 4518). Median PFS in cohort 2 was 7.8 mo (95% CI, 5.7-11). This RECORD-4 subanalysis assessed EVE outcomes after individual first-line anti-VEGF agents in cohort 2. Methods: Pts received EVE 10 mg/d until progression of disease (RECIST, v1.0) or intolerance. Primary end point was PFS per investigator review. Data cutoff was Sept 1, 2014. In this analysis, efficacy and safety were analyzed for pts in cohort 2 (n=62) who received sorafenib (Sor, n=23), bevacizumab (Bev, n=16), pazopanib (Paz, n=13), tivozanib (Tiv, n=5), or axitinib (Ax, n=3); missing information for 2 pts. Results: In groups Sor/Bev/Paz/Tiv/Ax, respectively, 96/81/100/80/33% of pts had good/intermediate MSKCC prognosis, 30/94/54/100/100% were white, 70/0/38/0/0% were Asian, and 83/75/77/100/67% were <65 years of age. Median duration of exposure in groups Sor/Bev/Paz/Tiv/Ax, respectively, was 5.5/6.7/6.2/8.1/11 mo. Median PFS (95% CI) was 5.7 (3.6-11.3) mo in group Sor, 9.2 (2.2-NE) mo in group Bev, and 9.2 (1.9-18.0) mo in group Paz. Overall rate of grade 3/4 adverse events (AEs), rates of discontinuation due to AEs, and rates of dose adjustments due to AEs are presented in the table. Conclusions: Results of this RECORD-4 subanalysis demonstrated a favorable benefit-risk profile of second-line EVE in pts whose disease progressed during or after first-line anti-VEGF therapies. Results should be interpreted with caution due to small patient numbers. Clinical trial information: NCT01491672. [Table: see text]
The impact of PBRM1 and BAP1 expression on outcomes of patients with metastatic renal cell carcinoma (mRCC) treated with VEGF-targeted therapy (TT).
Authors: Fay Andre Poisl , de Velasco Guillermo , Gray Kathryn P. , Ho Thai Huu , Song Jiaxi , Kapur Payal , Albiges Laurence , McDermott David F. , Heng Daniel Yick Chin , Brugarolas James , Choueiri Toni K. , Signoretti Sabina
Published: February 2017

616

Background: Polybromo-1 (PBRM1) and BRCA1 associated protein-1 (BAP1) are genes commonly mutated in clear cell RCC (ccRCC) and have been associated with clinical outcome. This work aims to evaluate the impact of PBRM1 and BAP1 expression by IHC in mRCC patients treated with VEGF-TT. Methods: PBRM1 and BAP1 expression was evaluated by IHC in a TMA including 146 mRCC patients. PBRM1 and BAP1 IHC scores were dichotomized as a binary variable: negative (-) or positive (+) (weak positivity was excluded). The associations of PBRM1 or BAP1 expression with baseline clinico-pathological characteristics were evaluated, as well as with overall survival (OS) and time to treatment failure (TTF) usingCox proportional hazards models. Results: Out of 146 patients, 116 and 109 samples had available results for PBRM1 and BAP1 staining, respectively. Overall, 90% (n = 131) patients had ccRCC. 70/116 samples (60%) were PBRM1- and 26/109 patients (24%) were BAP1-. Only 12% (n = 13) of patients had simultaneous negative PBRM1 and BAP1. While there was no association between PBRM1 expression status and clinical factors, BAP1- samples were associated with poor IMDC prognostic risk score (p = 0.004) and higher Fuhrman grade (p = 0.012). PBRM1+ patients showed a trend towards an increased risk of death and a shorter TTF compared to PBRM1- patients (OS: HR = 1.38, 95%CI: 0.92-2.07, p = 0.1; TTF: HR = 1.39, 95%CI: 0.94-2.06, p = 0.1). BAP1 expression was not independently associated with OS or TTF. Conclusions: Loss of PBRM1, but not BAP1 expression showed a trend towards longer TTF and OS in mRCC patients treated with VEGF-TT.
Hemorrhagic complications of robot-assisted laparoscopic partial nephrectomy for renal masses.
Authors: Franklin Andrew , Campbell Jack , Pokala Naveen
Published: February 2017

621

Background: Partial nephrectomy is the current standard of care for T1a tumors. With advances in laparoscopy and robotic-assisted surgery, RPNx is increasingly being performed for complex renal tumors. However, significant hemorrhagic complications can occur. We review hemorrhagic complications following RPNx. Methods: At our institution 111 RPNx were performed on 110 patients (2011-2015). Demographic data and Nephrometry scores were determined. Total operating time, intraoperative blood loss, postoperative blood transfusion rate, gross hematuria, need for further procedures and mortality were collected. Pathology, including histologic diagnosis, and margin status was recorded. Results: Of 111 RPNx, 110 were done for renal masses and 112 masses were removed. Of these, 77% were malignant and most common commonly Renal Cell Carcinoma, Clear Cell pT1a (51%). Mean operative time was 245 minutes (SD 68), mean blood loss was 297 mL (SD 68), and average length of stay was 2.8 days. Hemorrhagic complications occurred in 21 patients (19%). Five had hematuria and 16 received a transfusion. Four patients required interventional radiology (IR) for angioembolization. Two patients died, one from hemorrhagic complications, and the other from septic shock related to a bowel injury. The most common Nephrometery score was 4a followed by 5a. Of those with hemorrhagic complications the most common Nephrometery score was 8, with 60% being 7 or higher. Among patients needing IR, 75% were 6 or higher and the one patient who died had a score of 11a in the setting of bilateral renal masses. Patients with hemorrhagic complications had a change in hemoglobin and hematocrit from per- to post-operation of 3.06 g/dL and 9.07% respectively compared to 2.34 g/dL and 6.28% for patients with no hemorrhagic complications. Conclusions: RPNx is a safe and nephron-sparing surgery for patients with appropriate renal masses. Significant hemorrhagic complications can occur, commonly managed with blood transfusions or angioembolization. However, catastrophic bleeding can occur in patients with high Nephrometry scores and monitoring in the ICU setting is recommended in high-risk patients.
Bladder and bowel symptoms with intensity-modulated radiation therapy (IMRT) for prostate cancer (PC).
Authors: Vapiwala Neha , Jacob Rojymon , Newman Diane , Markland Alayne , Kennedy Richard , Burgio Kathryn , Wilson Tracey , Bavaria Thomas , Wein Alan J. , Goode Patricia
Published: February 2017

66

Background: Perioperative behavioral therapy is effective in decreasing urinary incontinence, urgency and frequency after radical prostatectomy (RP). We conducted a pilot study to determine if these symptoms occurred with sufficient frequency and impact on quality of life (QoL) to warrant behavioral therapy prior to and during PC IMRT. Methods: Expanded Prostate Cancer Index Composite Short Form (EPIC-26) is sensitive to health-related (HR) QoL effects of PC therapies. We administered EPIC-26 immediately prior to RT (baseline), and 1, 2, 6, and 12 months (mos) from baseline to PC patients undergoing IMRT at University of Alabama and University of Pennsylvania. Paired Wilcoxon’s test was used to compare rates of bladder and bowel symptoms during IMRT. Results: Of 79 men, 48% were black, with mean: age 64.6+6.9 years; BMI 28.3+5.7; Gleason Score 7.3+1.1 and baseline PSA 11.9+23.6ng/mL; 5% had prior TURP, 30% prior RP, 64% adjuvant hormonal therapy, 8% combination brachytherapy. EPIC domain scores worsened for urinary irritative/obstructive (p<.001), UI (p=0.02), and bowel (p<0.001) symptoms during therapy (at 1 month). Conclusions: Urinary and bowel symptoms were common at baseline and increased slightly during IMRT. Studies of behavioral therapy prior to and during IMRT are warranted. [Table: see text]
Phase I/II study of hypofractionated intensity modulated radiotherapy (IMRT) for prostate cancer including simultaneously integrated boost (SIB).
Authors: Chang Michael G. , Saraiya Siddharth , Mukhopadhyay Nitai , Anscher Mitchell
Published: February 2017

67

Background: The purpose of this study is to evaluate the toxicity of hypofractionationed H- IMRT treatment including SIB IMRT when pelvic nodes were covered. Additionally, we assessed early treatment efficacy through PSA control (biochemical failure defined as PSA more than nadir + 2 ng/mL). Methods: Men with localized prostate cancer were enrolled in a phase I/II trial to receive H-IMRT to the prostate, seminal vesicles)(SV) and pelvic lymph nodes (LN) using simultaneous integrated boost (SIB) method. Low risk (LR) patients received 69.4 Gy to the prostate only in 29 fractions. The intermediate (IR) and high risk (HR) patients received 72 Gy to the prostate, 54 Gy to the proximal 1 cm SV, and 50.4 Gy to the pelvic LN when risk of LN involvement >15% by Roach formula. Treatment was given in 30 fractions using intraprostatic fiducials and daily image guidance. PTV expansion for prostate and SV was 0.3 mm posteriorly and 0.7 cm in all other directions. The IR and HR patients received androgen deprivation therapy (3 years for HR patients, and 6 months for IR patients). Acute and late genitourinary (GU) and gastrointestinal (GI) toxicity were prospectively evaluated according to CTCAE v3.0. Results: 55 men (29 African American and 26 white) were enrolled on trial with 20% LR, 41% IR and 39% HR disease (NCCN criteria). The median age was 55 with median follow-up time of 37.9 months. 26 patients received pelvic nodal SIB-IMRT. Toxicity is reported in the table. The biochemical control rate for the cohort was 91% at 3 years. Patients with pelvic LN IMRT experienced grade 2+ acute GI toxicity 38% vs 21% in the non-nodal IMRT group. (p= 0.25 by chi-square test). Conclusions: Hypofractionated SIB-IMRT can be delivered safely. Late grade III GI and GU toxicity for our cohort were 0% and 3.6% respectively. Our prospective trial shows acceptable toxicity with moderate hypofractionation in treating prostate cancer while maintaining good PSA control. Clinical trial information: NCT01117935. [Table: see text]
Trends in histology of newly diagnosed prostate cancer subsequent to USPSTF PSA screening recommendation.
Authors: Olsson Carl A. , Anderson Ann E. , Kapoor Deepak A.
Published: February 2017

68

Background: Reports on impact of the United States Preventive Services Task Force (USPSTF) Grade D recommendation against PSA screening have been short-term and contradictory. We sought to assess whether changes in prostate biopsy (PBx) pathology reporting had occurred in our large urology practices and if such changes persisted over time. Methods: We reviewed prostate histology in the 2 years prior to the USPSTF publication in 2012, and 3 years subsequent to this recommendation. All men (3,429) undergoing PBx in years 2010/11 were combined, creating a baseline against which similar reviews of 2013-August 2015 (2,773, 2,577 and 1,767 patients, respectively) were compared. Analysis of PBx results was the same in all years; we focused only on patients with a cancer diagnosis. Each PBx core was studied for both primary Gleason pattern and score and each patient was assigned a Weighted Gleason Index (WGI) wherein each positive core was multiplied by its own Gleason score, resulting in a single number representing both score and number cores positive. Results: The percent positive PBx increased over time, from the combined rate of 39% (1,338) in 2010/11 to 41.4% (1,147) in 2013, 42.6% (1,097) in 2014 and 46% (813) in 2015 (p<.001). Of 16,271 cores in 2010/11, 5,097 or 31.3% were positive; 14.8% had Gleason 8-10 scores. Of 13,960 cores in 2013, 4,415 or 31.6% were positive; 19.7% had Gleason 8-10 scores. Of 13,577 cores in 2014, 4,694 or 34.6% were positive; 26.1% had Gleason 8-10 scores. Of 10,380 cores in 2015, 3,396 or 32.7% were positive; 25.4% had Gleason 8-10 scores. Gleason 6 scores were stable over time; Gleason 7 scores "lost" 10% over time to higher scores. WGI for 2010/11 was 25.5, compared to 26.0 in 2013 (p=.60), 29.8 in 2014 (p<.001) and 29.2 in 2015 (p=.001). There was no significant difference in WGI from 2014-15. Conclusions: The combined Gleason 6 score stability and decreased biopsies suggest that fewer low risk patients are undergoing PBx- a favorable outcome. However, there has been a persisting increase in both numbers of positive cores as well as cores found with higher Gleason scores. This increases patients presenting with higher risk disease and portends a possible reversal of gains made in reducing prostate cancer mortality.
The 4Kscore to predict the grade and stage of prostate cancer in the radical prostatectomy specimen: Results from a multi-institutional prospective trial.
Authors: Nahar Bruno , Punnen Sanoj , Sjoberg Daniel , Zappala Stephen M , Parekh Dipen
Published: February 2017

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Background: A recent prospective validation study confirmed the 4Kscore accurately predicted aggressive prostate cancer on prostate biopsy. We investigated the association between the 4Kscore and pathologic grade and stage at radical prostatectomy, where the entire prostate gland is sampled. Methods: Prospective enrollment of 1,312 men who were referred for prostate biopsy for clinical suspicion of prostate cancer occurred at 26 sites throughout the United States from October 2013 to April 2014. We selected men who were found to have positive prostate cancer biopsies and elected to undergo radical prostatectomy. The 4Kscore is an algorithm that incorporates a panel of 4 Kallikreins (total PSA, free PSA, intact PSA and human kallikrein-2) in addition to age, digital rectal examination, and prior biopsy status. We assessed the concordance between the 4Kscore prior to biopsy and grade of prostate cancer at radical prostatectomy. 4Kscore test results were compared for those with and without non organ-confined tumors at surgery using the Wilcoxon rank-sum. Results: Among the 1,312 men who enrolled in this validation study, 144 were found to have prostate cancer and underwent radical prostatectomy. We saw a significant association between the 4Kscore and grade at surgery with higher scores relating to worse grade. For men with Gleason 6, 7, and 8 or higher cancers in the surgical specimen the median (IQR) 4Kscore was 7% (4, 12), 25% (12, 38), and 47% (24, 66) (p<0.0001).The median 4Kscore among men with non organ-confined cancer was significantly higher then men with cancers confined to the prostate ([36% (IQR 19,58)] vs. [19% (IQR 9, 35)], p=0.002). Conclusions: In a subset of men who underwent radical prostatectomy, the 4Kscore was significantly associated with pathological grade and extracapsular extension in the surgical specimen, with higher scores being linked to higher grade and more aggressive histology. The test can be beneficial to aid in treatment decision making for men who are contemplating observation of their cancer versus immediate treatment.
Defining the optimal PSA range for the maximal predictive efficacy of PSA density to detect prostate cancer on biopsy: Results from a multi-institutional and prospective contemporary cohort.
Authors: Rai Samarpit , Pavan Nicola , Soodana-Prakash Nachiketh , Nahar Bruno , Dong Yan , Satyanarayana Ramgopal , Parekh Dipen , Punnen Sanoj
Published: February 2017

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Background: PSA density (PSAD) is an important predictor of prostate cancer (PCa). We assessed whether the predictive accuracy of PSAD varied based on the range of PSA or whether the patient had a previous negative prostate biopsy (PB). Methods: We assessed a prospective cohort of men who were referred for a PB due to suspicion of PCa at 26 different sites across USA. The area under the receiver operating characteristic curve (AUC) was used to assess the added predictive accuracy of PSAD versus PSA across 3 different PSA ranges ( < 4, 4 – 10, > 10 ng/mL) and in men with or without a prior negative PB for the detection of any and significant (Gleason ≥ 7) PCa. Results: Of the 1,290 men, 585 (45%) and 284 (22%) had any and significant PCa, respectively. PSAD was significantly more predictive than PSA for detecting any PCa in the PSA ranges of 4 – 10 (AUC 0.70 vs 0.53, P < 0.00001) and > 10 (AUC 0.84 vs 0.65, P < 0.00001) ng/mL. Similarly, for significant PCa, PSAD was more predictive than PSA in the PSA ranges of 4 – 10 (AUC 0.72 vs 0.57, P < 0.00001) and > 10 (AUC 0.82 vs 0.68, P = 0.0001) ng/mL. Furthermore, PSAD was significantly more predictive than PSA in detecting PCa in men that had a prior negative PB (AUC 0.69 vs 0.56, P = 0.0001 for any PCa and AUC 0.81 vs 0.70, P = 0.0042 for significant PCa), and those that didn’t (AUC 0.72 vs 0.67, P = 0.0001 for any PCa and AUC 0.77 vs 0.73, P = 0.0026 for significant PCa). However the difference between the AUC of PSAD and PSA (ΔAUC) was a lot more pronounced in men that had a prior negative PB (ΔAUC = 0.13 for any PCa and ΔAUC = 0.11 for significant PCa) as opposed to those that didn’t (ΔAUC = 0.05 for any PCa and ΔAUC = 0.04 for significant PCa), suggesting that PSAD is a much better predictor than PSA alone in men who have undergone a previous PB. Conclusions: As PSA increases, the predictive accuracy of PSAD over PSA appears to improve for the detection of any PCa and significant PCa. Additionally, PSAD has a more pronounced predictive value over PSA in detecting any and significant PCa in men who have undergone a prior negativePB. We support the use of PSAD testing to avoid unnecessary biopsies in men who have elevated PSA secondary to an enlarged prostate.
Utility of prostate multiparametric MRI (mpMRI) for recurrent prostate cancer after radiation therapy and cryotherapy.
Authors: Kovac Evan , Purysko Andrei , Jones J. Stephen , Magi-Galluzzi Cristina , Klein Eric A. , Stephenson Andrew J.
Published: February 2017

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Background: We evaluated the accuracy of mpMRI for identifying locally recurrent prostate cancer after primary radiotherapy and cryotherapy. Methods: Between 2009-2015, 61 patients with evidence of rising PSA after external-beam radiotherapy (EBRT) (N = 33), brachytherapy (N = 6), and cryotherapy (N = 22) were evaluated for locally recurrent prostate cancer with mpMRI and prostate biopsy. Of these patients, 6 (10%) received androgen deprivation therapy (ADT) in combination with EBRT for a median of 24 months. Three of the cryotherapy patients received prior EBRT. Patients were identified from a prospective mpMRI database. All patients with a lesion of interest (LOI) underwent a ≥ 12-core, post-mpMRI cognitive fusion prostate biopsy. We excluded 16 patients with mpMRI who did not undergo prostate biopsy (5 positive, 11 negative). Results: Median age was 70 (IQR: 64-77). The median time from primary treatment to mpMRI was 5 years (IQR: 3-9) and the median PSA at mpMRI was 3.6 ng/mL (IQR: 2.1-5.5). Median prostate volume was 18.8 cc (IQR: 11.0-28.0 cc). mpMRI revealed lesions of interest (LOI) in 39 (64%) and 41 (67%) had biopsy-proven local recurrence. Of the 22 patients with negative mpMRI, 8 (36%) had a positive biopsy, with a median prostate volume of 19 cc, median maximum cancer length of 5 mm, median PSA of 2.5 and biopsy Gleason scores 3+3 (N = 1), 4+3 (N=2), 5+4 (N = 1), 5+5 (N = 1) and ungraded due to treatment effect (N = 3). Of the 39 patients with LOI on mpMRI, 33 (85%) had a positive biopsy. Table 1 summarizes the mpMRI and biopsy results. The sensitivity, specificity, PPV and NPV of mpMRI to predict cancer diagnosis at biopsy was 80.5%, 70.0%, 84.6% and 63.6%, respectively. On univariate analysis, gland size (p=0.367), PSA (p=0.872), biopsy Gleason score (p=0.892) and primary treatment modality (p=0.177) did not significantly predict discrepancy between mpMRI and biopsy findings. Conclusions: mpMRI reliably identifies prostate cancer recurrence after primary radiation therapy and cryoablation. [Table: see text]
Predictive parameters of symptomatic haematochezia following 5-fraction gantry-based SABR in prostate cancer.
Authors: Musunuru Hima Bindu , Davidson Melanie , Cheung Patrick , Chu William , Chung Hans T. , Vesprini Danny , Liu Stanley K. , Mamedov Alexandre , Ravi Ananth , D'Alimonte Laura , Commissso Kristina , Helou Joelle Antoine , Deabreu Andrea , Zhang Liying , Loblaw Andrew
Published: February 2017

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Background: To identify clinical and dosimetric predictors of high-grade haematochezia (HH) following 5-fraction gantry based stereotactic ablative radiotherapy (SABR). Methods: Data about haematochezia in 258 patients who received 35-40Gy SABR in 5-fractions (weekly or alternate days) as part of sequential phase II prospective trials was retrieved. Haematochezia was graded as per the Fox Chase LENT criteria, ≥ grade 2 rectal bleeding was labeled as HH. Patients needing steroid suppositories, 4% formalin or 1-2 sessions of argon plasma coagulation (APC) were graded as grade 2 haematochezia. If a patient required >2 sessions of APC, blood transfusion or a course of hyperbaric oxygen, this was grade 3 and development of visceral fistula was grade 4. Various dosimetric and clinical factors were analyzed using univariate and multivariate (MVA) analyses. Receiver-operating characteristic (ROC) curve analysis and recursive partitioning analysis (RPA) were used to determine clinically valid cut-off points and risk groups, respectively. Results: Median follow-up was 29.7 months (IQR 20.6, 61.7). HH was observed in 19.4%. Median time to develop HH was 11.7 months (IQR 9.0, 15.2). Resolution occurred a median of 6.7 months (IQR 5.7, 12.4) later; 3% was prevalent at last follow-up. At two years, cumulative HH was 4.9%, 27.2% and 42.1% in patients who received 35Gy to prostate (4mm planning target volume-PTV margin), 40Gy to prostate (5mm PTV margin) and 40Gy to prostate/seminal vesicles (5mm PTV margin), respectively ( p-value< 0.0001). In the ROC analysis, volume of rectum receiving radiation dose of 38Gy (V38) was a strong predictor of HH with an AUC of 0.65. In MVA, rectal V38 (≥2.0cc; p-value<0.0001, OR 4.9); use of anti-coagulants (p-value<0.0002, OR 14.9) and presence of hemorrhoids (p-value<0.006, OR 3.2) were the strongest predictors. In RPA, rectal V38<2.0cc and use of anticoagulants orrectal V38 ≥2.0cc plus one other risk factor resulted in a HH risk>30%. Conclusions: Rectal V38 and two clinical factors were strong predictors of high-grade haematochezia following 5-fraction SABR. Planning constraints should aim to keep the rectal V38 below 2.0cc.
Interpretation of an online surgeon scorecard by the general public and its effect on adults changing cancer surgeons even when presented with complication rates that are statistically equivalent.
Authors: Weight Christopher J. , Labine Lucas , Palma Isaac , Dixon Colby
Published: February 2017

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Background: Recently Pro-Publica, an independent, non-profit newsroom, created a surgeon scorecard. This scorecard reports calculated death and complication rates for surgeons performing elective procedures in Medicare patients, including radical prostatectomy. We wanted to understand how the general population would interpret these data and whether it would influence surgeon choice. Methods: 265 adults at the Minnesota State Fair were recruited to participate in a survey requiring interpretation of a representative output graphic from the Pro-Publica website surgeon scorecard ( https://projects.propublica.org/surgeons ). The complication point estimate and 95% confidence intervals (CI) of a hypothetical surgeon, with whom survey participants were to assume that cancer surgery was already scheduled, were presented. They were also shown a graphic with 13 other surgeons point-estimate, complication rates, all of which fell within the index surgeon’s complication rate CI. Another surgeon, with a 0.6% lower point estimate, but statistically equivalent complication rate to the first surgeon, was indicated on the graphic. Participants were asked, based on this graphic alone, would they recommend switching surgeons? Results: The surveyed population was educated with 89% having attended, or graduated from college or higher (n = 235). Median age of participants was 50 years (Range 20-74). There were 179 females (68%) and 86 males (32%). Participants were from 136 different zip codes predominantly in the upper Midwest. 124 or 46.8% (95% CI 41-53) of respondents would recommend switching surgeons based on this single graphic. Conclusions: Nearly half of adults surveyed would recommend switching cancer surgeons for genitourinary malignancies based on data graphically presented on an online website, even though the point estimates between the two surgeons are not statically significantly different. This type of data display may lead to changes in medical decision-making based on random error of measurement of true complication rates not true differences in surgeon quality.
Application of active surveillance threshold to series of samples submitted for commercial testing.
Authors: Scardino Peter T. , Cuzick Jack M. , Stone Steve , Evans Brent , Jorgensen Matthew R , Eastham James Andrew , Keane Thomas E. , Davis John W. , Lin Daniel W. , Moul Judd W. , Brawer Michael K. , Crawford E. David
Published: February 2017

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Background: Active surveillance (AS) is an increasingly popular treatment modality for men with localized prostate cancer. Recently, we developed a method to select men for AS based on a score that combines cell cycle progression (CCP) with CAPRA (combined clinical CCP risk (CCR) score). Here, we apply our validated AS threshold to a series of samples submitted for commercial testing. Methods: Formalin-fixed prostate biopsy samples from 7,881 patients were submitted by their physicians to Myriad Genetic Laboratories for CCP analysis. Patient clinicopathological data was obtained from the test request form. The CCP score was calculated based on RNA expression of 31 CCP genes normalized to 15 housekeeping genes, and combined with CAPRA to generate the CCR score. The clinicopathological data of patients with a CCR score meeting the AS threshold were analyzed focusing on their PSA, % positive cores, Gleason, stage, AUA risk classification, and CAPRA score. Results: Of the 7,881 patients included in the analysis, 4,758 (60.4%) qualified for AS based on their CCR score. A substantial number of these patients, 2,213 (46.5%), would not have qualified for AS based on their clinical characteristics alone according to the following criteria: Gleason ≤ 3+4, PSA < 10, clinical stage ≤ T2a, and < 25% positive cores. A summary of the patients’ clinicopathological characteristics is shown below. Conclusions: This analysis showed that 60.4% of commercially tested patients qualified for AS, nearly half of which would not have qualified for AS based on their clinicopathological characteristics. For patients considering deferred treatment, the CCR score provides significant prognostic information at disease diagnosis. [Table: see text]