Randomized phase II trial of MRI-guided salvage radiotherapy for prostate cancer in 4 weeks versus 2 weeks (SHORTER).

BACKGROUND: Ultra-hypofractionated image-guided stereotactic body radiotherapy (SBRT) is increasingly used for definitive treatment of localized prostate cancer. Magnetic resonance imaging-guided radiotherapy (MRgRT) facilitates improved visualization, real-time tracking of targets and/or organs-at-risk (OAR), and capacity for adaptive planning which may translate to improved targeting and reduced toxicity to surrounding tissues. Given promising results from NRG-GU003 comparing conventional and moderate hypofractionation in the post-operative setting, there is growing interest in exploring ultra-hypofractionated post-operative regimens. It remains unclear whether this can be done safely and whether MRgRT may help mitigate potential toxicity. SHORTER (NCT04422132) is a phase II randomized trial prospectively evaluating whether salvage MRgRT delivered in 5 fractions versus 20 fractions is non-inferior with respect to gastrointestinal (GI) and genitourinary (GU) toxicities at 2-years post-treatment. METHODS: A total of 136 patients will be randomized in a 1:1 ratio to salvage MRgRT in 5 fractions or 20 fractions using permuted block randomization. Patients will be stratified according to baseline Expanded Prostate Cancer Index Composite (EPIC) bowel and urinary domain scores as well as nodal treatment and androgen deprivation therapy (ADT). Patients undergoing 5 fractions will receive a total of 32.5 Gy over 2 weeks and patients undergoing 20 fractions will receive a total of 55 Gy over 4 weeks, with or without nodal coverage (25.5 Gy over 2 weeks and 42 Gy over 4 weeks) and ADT as per the investigator's discretion. The co-primary endpoints are change scores in the bowel and the urinary domains of the EPIC. The change scores will reflect the 2-year score minus the pre-treatment (baseline) score. The secondary endpoints include safety endpoints, including change in GI and GU symptoms at 3, 6, 12 and 60 months from completion of treatment, and efficacy endpoints, including time to progression, prostate cancer specific survival and overall survival. DISCUSSION: The SHORTER trial is the first randomized phase II trial comparing toxicity of ultra-hypofractionated and hypofractionated MRgRT in the salvage setting. The primary hypothesis is that salvage MRgRT delivered in 5 fractions will not significantly increase GI and GU toxicities when compared to salvage MRgRT delivered in 20 fractions. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04422132. Date of registration: June 9, 2020.

Pilot study of the diagnostic utility of 89 Zr-df-IAB2M and 68 Ga-PSMA-11 PET imaging and multiparametric MRI in localized prostate cancer.

BACKGROUND: Accurate diagnosis of localized prostate cancer (PCa) is limited by inadequacy of multiparametric (mp) MRI to fully identify and differentiate localized malignant tissue from benign pathologies. Prostate-specific membrane antigen (PSMA) represents an excellent target for molecular imaging. IAB2M, an 85-kD minibody derived from a de-immunized monoclonal antibody directed at the extracellular domain of human PSMA (huJ591), and PSMA-11, a small molecule ligand have been previously tested as probes for visualization of recurrent/metastatic PCa with PET/CT. This pilot, non-randomized trial studied their diagnostic utility in patients (pts) with localized PCa. METHODS: Pts planned for radical prostatectomy (RP) were enrolled and underwent mpMRI and PET/CT imaging with 89 Zr-df-IAB2M and/or 68 Ga-PSMA-PET/CT. Image results were read by a radiologist blinded to clinical information and pathology results, mapped and compared to corresponding histopathology findings from all lesions, both clinically significant and nonsignificant. The detection rates of all three imaging modalities were measured and correlated. RESULTS: 20 pts with median age of 64.5 (46-79) years and PSA level of 7.5 (1.6-36.56) ng/ml were enrolled. 19 pts underwent RP and were imaged pre-operatively with 89 Zr-Df-IAB2M PET/CT and mpMRI. Nine of those were imaged using 68 Ga-PSMA-11 as well. Out of 48 intraprostatic lesions verified on surgical pathology, IAB2M PET/CT was able to detect 36 (75%). A similar proportion of pathologically confirmed, clinically significant lesions (22/29, 76%) was detected. IAB2M PET/CT was also able to identify 14/19 (74%) extraprostatic lesions. The performance of mpMRI was inferior, with 24/48 detectable lesions (50%) and 18/29 clinically significant intraprostatic lesions (62%). Compared to the current standard (mpMRI), IAB2M PET/CT had a sensitivity of 88%, specificity 38%, positive predictive value 58%, and accuracy 63%. In 9 pts who underwent Ga-PSMA-11 as well, the latter yielded a detection rate of 70% (14/20), which was also seen in clinically significant lesions (10/14, 71%). Ga-PSMA-11 PET/CT also detected 4/6 (67%) extraprostatic lesions. CONCLUSIONS: In this pilot study, the performance of 89 Zr-df-IAB2M was superior to mpMRI and similar to 68 Ga-PSMA-11 PET/CT. The higher detection rate of PSMA-PET supports its use as a diagnostic tool with consequent management change implications in men with localized PCa.

Impact of prebiopsy magnetic resonance imaging on biopsy and radical prostatectomy grade concordance.

BACKGROUND: Adoption of prostate magnetic resonance imaging (MRI) before biopsy is based on evidence demonstrating superior detection of clinically significant prostate cancer on biopsy. Whether this is due to the detection of otherwise occult higher grade cancers or preferential sampling of higher grade areas within an otherwise low-grade cancer is unknown. METHODS: To distinguish these two possibilities, this study examined the effect of prebiopsy MRI on the rate of pathologic upgrading and downgrading at prostatectomy in Surveillance, Epidemiology, and End Results-Medicare linked data from 2010 to 2015. Logistic regression was performed to assess the effect of MRI use on the Gleason grade change between biopsy and prostatectomy. RESULTS: Among biopsy-naive men, those who underwent prebiopsy MRI had higher odds of downgrading at prostatectomy (odds ratio [OR], 1.32; 95% confidence interval [CI], 1.05-1.66). In contrast, the odds of upgrading were significantly lower for men who underwent prebiopsy MRI (OR, 0.78; 95% CI, 0.61-0.99). Limitations included a low overall rate of MRI-utilization prior to biopsy and an inability to distinguish between template, software-assisted and cognitive fusion biopsy. CONCLUSIONS: Prebiopsy MRI is associated with both oversampling of higher grade areas, which results in downgrading at prostatectomy, and the detection of otherwise occult higher grade lesions, which results in less upgrading at prostatectomy.

Supplemental estrogen and caloric restriction reduce obesity-induced periprostatic white adipose inflammation in mice.

Obesity is associated with an increased incidence of high-grade prostate cancer (PC) and worse prognosis for PC patients. Recently, we showed in men that obesity-related periprostatic white adipose tissue (WAT) inflammation, characterized by macrophages surrounding dead or dying adipocytes forming crown-like structures, was associated with high-grade PC. Possibly, interventions that suppress periprostatic WAT inflammation will improve outcomes for men with PC. Here, we tested the hypothesis that supplemental 17ß-estradiol (E2) could decrease periprostatic WAT inflammation in obese male mice. Mice were fed a high-fat diet to induce periprostatic WAT inflammation before being treated with supplemental E2. E2 supplementation suppressed caloric intake, induced weight loss, decreased periprostatic WAT inflammation and downregulated the expression of genes linked to inflammation including Cd68, Mcp1 and Tnf. Similar to the effects of E2 supplementation, treatment with diethylstilbestrol, a synthetic estrogen, also suppressed caloric intake and reduced periprostatic WAT inflammation. To determine whether the observed effects of supplemental estrogen could be reproduced by caloric restriction (CR) alone, obese mice were put on a 30% CR diet. Like estrogen treatment, CR was effective in reducing body weight, periprostatic WAT inflammation and the expression of pro-inflammatory genes. Transcriptomic analyses of periprostatic fat showed that obesity was associated with enrichment in inflammatory response pathways, which were normalized by both supplemental E2 and CR. Taken together, these findings strengthen the rationale for future efforts to determine whether either CR or supplemental estrogen will decrease periprostatic WAT inflammation and thereby improve outcomes for men with PC.

Association of Smoking and Death from Genitourinary Malignancies: Analysis of the National Longitudinal Mortality Study.

PURPOSE: We explored the association between tobacco use and genitourinary cancer specific survival in a contemporary, nationally representative sample of the United States civilian population. MATERIALS AND METHODS: A total of 493,282 participants in the National Longitudinal Mortality Study who provided detailed tobacco information from 1993 to 2005 were included in study. Our primary outcome was death from bladder, kidney or prostate cancer. Cause of death was determined from death certificates. Analyzed smoking parameters included smoking status at the time of the survey, age at the start of smoking and home smoking rules. Multivariable Cox regression models were used to assess associations of different smoking parameters with bladder, kidney and prostate cancer specific mortality. RESULTS: During a 5-year followup 5.6% of participants who had ever smoked died compared to 3.1% of those who had never smoked (p <0.0001). Of those who died of bladder, kidney and prostate cancer 62%, 58% and 62%, respectively, were ever smokers. On multivariable analysis ever smoking was associated with bladder and kidney cancer mortality (HR 1.92, 95% CI 1.25-2.97, and HR 1.54, 95% CI 1.01-2.34, respectively). Additionally, starting to smoke during teenage years and smoking at home were associated with bladder cancer specific mortality (HR 2.14, 95% CI 1.28-3.56 and HR 2.99, 95% CI 1.34-6.65) and kidney cancer specific mortality (HR 1.65, 95% CI 1.03-2.66 and HR 2.84, 95% CI 1.54-5.23, respectively). However, only everyday smoking was associated with an increased risk of prostate cancer mortality (HR 1.81, 95% CI 1.30-2.53). CONCLUSIONS: In a nationally representative study we confirmed the association between smoking intensity and mortality from genitourinary malignancies. Starting to smoke at a younger age and smoking at home conferred a significantly higher risk of death from bladder and kidney cancers.

Differences in trends in the use of robot-assisted and open radical cystectomy and changes over time in peri-operative outcomes among selected centres in North America and Europe: an international multicentre collaboration.

OBJECTIVES: To compare trends in the use of robot-assisted radical cystectomy (RARC) and changes over time in peri-operative outcomes in selected North American and European centres. MATERIALS AND METHODS: We conducted a retrospective evaluation of 2401 patients treated with open radical cystectomy (ORC) or RARC for bladder cancer at 12 centres in North America and Europe between 2006 and 2018. We used the Kruskal-Wallis and chi-squared test to evaluate differences between continuous and categorical variables. RESULTS: Overall, 49.5% of patients underwent RARC and 51.5% ORC. RARC became the most commonly performed procedure in contemporary patients, with an increase from 29% in 2006-2008 to 54% in 2015-2018 (P < 0.001). In the North American centres the use of RARC was higher than that of ORC from 2006, and remained stable over time, whereas in the European centres its use increased exponentially from 2% to 50%. In both groups patients who underwent RARC had less advanced T stages (P < 0.001), lower American Society of Anesthesiologists scores (P < 0.05), lower blood loss (P = 0.001) and shorter length of hospital stay (P < 0.05). No differences were found in early complications. Early readmission and re-operation rates were worse for patients treated with RARC in the European centres; however, when contemporary patients only were considered, the statistical significance was lost. CONCLUSION: The present study shows that the use of RARC has constantly increased since its introduction, overtaking ORC in the most contemporary series. While RARC was more frequently performed than ORC since its introduction in the North American centres and its use remained substantially stable over time, its use increased exponentially in the European centres. The different trends in use of RARC/ORC and changes over time in peri-operative outcomes between the North American and European centres can be attributed to the earlier introduction and spread of RARC in the former compared with the latter.

Oncogenic Addiction to ERBB2 Signaling Predicts Response to Trastuzumab in Urothelial Cancer.

Urothelial carcinoma (UC) is a common and frequently lethal cancer. Despite the presence of genomic alterations creating dependency on particular signaling pathways, the use of targeted therapies in advanced and metastatic UC has been limited. We performed an integrated analysis of whole-exome and RNA sequencing of primary and metastatic tumors in a patient with platinum-resistant UC. We found a strikingly high ERBB2 mRNA expression and enrichment of downstream oncogenic ERBB2 signaling in this patient's tumors compared with tumors from an unselected group of patients with UC (N=17). This patient had an exceptional sustained response to trastuzumab. Our findings show that oncogenic addiction to ERBB2 signaling potentially predicts response to ERBB2-directed therapy of UC.

Urinary pH and the risk of recurrence in patients with non-muscle invasive bladder cancer.

INTRODUCTION: To evaluate the effect of urine pH on tumor recurrence rates in patients undergoing surveillance after initial diagnosis of non-muscle invasive bladder cancer (NMIBC). MATERIALS AND METHODS: All patients diagnosed with NMIBC at a tertiary referral center from January 2004 to March 2015 were reviewed. Our primary outcome was time to first recurrence after transurethral resection of bladder tumor (TURBT). Patients were analyzed according to the average urine pH of all urinalysis data over the surveillance period from TURBT to first recurrence. Kaplan-Meier survival analysis was used to determine differences in median time to recurrence. Cox proportional hazards regression was used to assess independent predictors of cancer recurrence. RESULTS: A total of 252 patients were included, of which 155 patients had average pH ≤ 6 (median pH 5.5) and 97 patients had average pH > 6 (median pH 6.8), p < 0.001. There was no significant difference in median time to recurrence between low/acidic pH (≤ 6) and high/basic pH (> 6) groups (28 months versus 17 months, respectively, p = 0.3444). Similarly, urine pH did not affect the risk of recurrence in a subgroup analysis stratified by smoking status. On multivariable Cox regression analysis, there was no association between average pH and recurrence among high grade tumors (HR = 1.33, 95% CI = 0.76 to 2.34, p = 0.3186), or low grade tumors (HR = 1.013, 95% CI = 1.01 to 1.58, p = 0.96). CONCLUSIONS: There was no association between urine pH and risk of tumor recurrence, regardless of smoking status. These findings suggest that modification of urine pH is unlikely to decrease the frequency of tumor recurrence in patients with NMIBC.

Prognostic Significance of a Negative Prostate Biopsy: An Analysis of Subjects Enrolled in a Prostate Cancer Screening Trial.

PURPOSE: To our knowledge the optimal treatment of patients following a negative prostate biopsy is unknown. Consequently, resources are increasingly being directed toward risk stratification in this cohort. However, the risk of prostate cancer mortality in this group before the introduction of supplemental biomarkers and imaging techniques is unclear. MATERIALS AND METHODS: The PLCO (Prostate, Lung, Colorectal and Ovarian Cancer) Screening Trial provides survival data prior to the implementation of new diagnostic interventions. We divided men with an initial positive screen and a subsequent prostate biopsy into cohorts based on positive or negative results. Prostate cancer specific mortality was then compared to that in the trial control arm to estimate the prognostic significance of biopsy results relative to the general population. RESULTS: A total of 36,525 and 36,560 patients comprised the screening and control arms, respectively. Of 4,064 subjects with a positive first screen 1,233 underwent a linked biopsy, of which 473 were positive and 760 were negative. At a median followup of 12.9 years, 1.1% of men in the negative biopsy cohort had died of prostate cancer. The difference in mortality rates between the negative biopsy and control arms was 0.734 deaths per 1,000 person-years. The proportional subhazard ratios of prostate cancer specific mortality for negative biopsy and positive biopsy relative to the control arm were 2.93 (95% CI 1.44-5.99) and 18.77 (95% CI 12.62-27.93), respectively. CONCLUSIONS: After a negative prostate biopsy, men face a relatively low risk of death from prostate cancer when followed with traditional markers and biopsy techniques. This suggests limited potential for new diagnostic interventions to improve survival in this group.

Racial Variation in the Utility of Urinary Biomarkers PCA3 and T2ERG in a Large Multicenter Study.

PURPOSE: To our knowledge it is unknown whether urinary biomarkers for prostate cancer have added utility to clinical risk calculators in different racial groups. We examined the utility of urinary biomarkers added to clinical risk calculators for predicting prostate cancer in African American and nonAfrican American men. MATERIALS AND METHODS: Demographics, PCPT (Prostate Cancer Prevention Trial) risk scores, data on the biomarkers data PCA3 (prostate cancer antigen 3) and T2ERG (transmembrane protease serine 2 and v-ets erythroblastosis virus E26 oncogene homolog gene fusion), and biopsy pathology features were prospectively collected on 718 men as part of EDRN (Early Detection Research Network). Utility was determined by generating ROC curves and comparing AUC values for the baseline multivariable PCPT model and for models containing biomarker scores. RESULTS: PCA3 and T2ERG added utility for the prediction of prostate cancer and clinically significant prostate cancer when combined with the PCPT Risk Calculator. This utility was seen in nonAfrican American men only for PCA3 (AUC 0.64 increased to 0.75 for prostate cancer and to 0.69-0.77 for clinically significant prostate cancer, both p <0.001) and for T2ERG (AUC 0.64-0.74 for prostate cancer, p <0.001, and 0.69-0.73 for clinically significant prostate cancer, p = 0.029). African American men did not have an added benefit with the addition of biomarkers, including PCA3 (AUC 0.75-0.77, p = 0.64, and 0.65-0.66, p = 0.74) and T2ERG (AUC 0.75-0.74, p = 0.74, and 0.65-0.64, p = 0.88), for prostate cancer and clinically significant prostate cancer, respectively. Limitations include the small number of African American men (72). The post hoc subgroup analysis nature of the study limited findings to being hypothesis generating. CONCLUSIONS: As novel biomarkers are discovered, clinical utility should be established across demographically diverse cohorts.

Robot-assisted partial cystectomy: perioperative outcomes and early oncological efficacy.

OBJECTIVE: To report on patients undergoing robot-assisted partial cystectomy (RAPC), focusing on perioperative outcomes over a range of clinical, anatomical and pathological variables, as well as the overall oncological efficacy of this approach. PATIENTS AND METHODS: We retrospectively reviewed all patients who underwent RAPC by a single surgeon between 2005 and 2015. We identified 29 patients who underwent surgery for definitive management of a primary bladder tumour. Clinicopathological data and perioperative variables were recorded. Continuous variables were compared using the Student's t-test. Prediction of perioperative outcomes for those undergoing RAPC for intra-diverticular neoplasms was done using univariate logistic regression. Survival was estimated using the Kaplan-Meier method. RESULTS: The median (interquartile range) patient age was 75 (65-81) years, 18 patients (62.1%) had an American Society of Anesthesiologists classification of ≥3, and 10 patients (34.5%) had a history of prior abdominal surgery. The median estimated blood loss (EBL) was 50 mL and the median length of stay (LOS) was 1 day. Two patients (6.9%) had a perioperative complication and five (17.9%) a post-discharge complication at ≤90 days, all of which were minor. The positive surgical margin rate was 3.6% and in those with muscle-invasive disease a median of 12 lymph nodes were removed. Neither the size of diverticulum nor the need for ureteric re-implantation was predictive of LOS, EBL, or complication (P > 0.05). We did not encounter any wound, port site, or unusual recurrence patterns to suggest the technical factors of a robotic approach influenced oncological outcomes. The 5-year overall and recurrence-free survival rates were 79% and 68%, respectively. CONCLUSION: RAPC confers the ability to achieve favourable outcomes with low morbidity and reduced hospital stays. Oncological efficacy compares favourably with the published literature. For experienced surgeons, this may represent the optimal surgical approach for organ-preserving bladder surgery.

Magnetic resonance microscopy may enable distinction between normal histomorphological features and prostate cancer in the resected prostate gland.

OBJECTIVES: To determine imaging protocol parameters for characterization of prostate tissue at histological length scales. MATERIAL AND METHODS: Rapid acquisition with relaxation enhancement, spin echo and gradient echo fast low angle shot data were acquired using ex vivo 3-Tesla or 7-Tesla magnetic field strengths from fresh prostatectomy specimens (n = 15) obtained from either organ donor or patients with prostate cancer (PCa). To achieve the closest correspondence between histopathological components and magnetic resonance imaging (MRI) results, in terms of resolution and sectioning planes, multiple high-resolution imaging protocols (ranging from a few minutes to overnight) were tested. Ductograms were generated as part of image post-processing. Specimens were subsequently submitted for histopathological evaluation. RESULTS: A total of seven imaging protocols were tested. Ex vivo 7-Tesla MRI identified normal components of prostate glands, including ducts, blood vessels, concretions and stroma at a spatial resolution of 60 × 60 × 60 µm3 to 107 × 107 × 500 µm3 . Malignant glands and nests of tumour cells identified at 60 × 60 × 90 µm3 were highly similar to low-magnification (×2) histopathology. Ductograms enhanced the differentiation between benign and malignant glands. The results of the present study were encouraging, and further work is warranted with a larger sample size. CONCLUSION: We showed that critical histopathological features of the prostate gland can be identified with high-resolution ex vivo MRI examination and this offers promise that MRI microscopy of PCa will ultimately be possible in vivo.

The impact of socioeconomic status on perioperative complications and oncologic outcomes in patients undergoing radical cystectomy.

PURPOSE: To examine if patients of lower socioeconomic status (SES) are at higher risk of perioperative complications and experience different oncologic outcomes after radical cystectomy (RC). METHODS: Retrospective review was performed on 383 consecutive non-metastatic patients who underwent definitive RC at a tertiary referral center. Along with clinical and pathologic parameters traditionally utilized for risk stratification, potential social determinants of health were estimated using US Census data. Zip code-derived proxies of SES included median annual household income and percentage of residents completing high school education. Patients were grouped based on SES parameters, and potential differences were assessed. Multivariable logistic regression was then performed to identify predictors of complication within 90 days of RC. Survival outcomes were plotted using Kaplan-Meier survival curves. RESULTS: Overall, 167 (46.2%) patients suffered any complication within 90 days of RC. On multivariable analysis, length of stay (p ≤ 0.001), lower income grouping (p = 0.03), and lowest education tertile (p = 0.007) were significant predictors of any complication. Income (p = 0.04) and education (p = 0.008) groupings remained significant predictors in a subset analysis looking specifically at post-discharge complications. No significant differences in recurrence-free or overall survival estimates were observed among education (log-rank test: p > 0.9 and p = 0.6, respectively) or income (log-rank test: p = 0.2 and p = 0.09, respectively) groupings. CONCLUSION: Patients of lower socioeconomic status who undergo RC for bladder cancer are at increased risk of perioperative complications. Further studies are needed to clarify this relationship, and to explore interventions aimed to improve outcomes.

Minimally invasive vs open nephrectomy in the modern era: does approach matter?

PURPOSE: To evaluate if the widespread adoption of a minimally invasive approach to radical nephrectomy has affected short- and long-term patient outcomes in the modern era. METHODS: A retrospective cohort study of patients who underwent radical nephrectomy from 2001 to 2012 was conducted using the US National Cancer Institute Surveillance Epidemiology and End Results (SEER) Program and Medicare insurance program database. Patients who underwent open surgery were compared to those who underwent minimally invasive surgery using propensity score matching. RESULTS: 10,739 (85.9%) underwent open surgery and 1776 (14.1%) underwent minimally invasive surgery. Minimally invasive surgery increased from 18.4% from 2001-2004 to 43.5% from 2009 to 2012. After median follow-up of 57.1 months, minimally invasive radical nephrectomy conferred long-term oncologic efficacy in terms of overall (HR 0.84; 95% CI 0.75-0.95) survival and cancer-specific (HR 0.68; 95% CI 0.54-0.86) survival compared to open radical nephrectomy. Minimally invasive surgery was associated with lower risk of inpatient death [risk ratio (RR) 0.45 with 95% CI: (0.20-0.99), p = 0.04], deep vein thrombosis [RR: 0.35 (0.18-0.69), p = 0.002], respiratory complications [RR: 0.73 (0.60-0.89), p = 0.001], infectious complications [RR: 0.35 (0.14-0.90), p = 0.02], acute kidney injury [RR: 0.66 (0.52-0.84), p < 0.001], sepsis [RR: 0.55 (0.31-0.98), p = 0.04], prolonged length of stay (18.6 vs 30.0%, p < 0.001), and ICU admission (19.7 vs 26.3%, p < 0.001). Costs were similar between the two approaches (30-day costs $15,882 vs $15,564; p = 0.70). CONCLUSION: After widespread adoption of minimally invasive approaches to radical nephrectomy across the United States, oncologic standards remain preserved with improved perioperative outcomes at no additional cost burden.

Factors Impacting the Occurrence of Local, Distant and Atypical Recurrences after Robot-Assisted Radical Cystectomy: A Detailed Analysis of 310 Patients.

PURPOSE: Peritoneal carcinomatosis and extrapelvic lymph node metastases can be seen following robot-assisted radical cystectomy. In an attempt to identify predictors of these atypical metastases we report a detailed analysis of patients treated with robot-assisted radical cystectomy in whom recurrences developed. MATERIALS AND METHODS: A total of 310 patients underwent robot-assisted radical cystectomy for bladder cancer from 2001 to 2015. Descriptive statistics were used to compare baseline variables between patients without recurrence and those with local, distant or atypical recurrence. Univariate and multivariable regression models were used to assess the effect of variables on oncologic outcomes including recurrence location. RESULTS: At a median followup of 24 months (IQR 14-51) 81 patients had recurrence. On multivariable analysis tumor classification, lymphovascular invasion, estimated glomerular filtration rate less than 60 ml/minute/1.73 m2 and perioperative blood transfusion were significantly associated with any recurrence. Specific analyses showed that tumor and nodal classification, lymphovascular invasion and positive surgical margins were associated with all 3 recurrence locations (all p <0.05). Previous abdominal surgery was protective against atypical recurrences (HR 0.36, 95% CI 0.13-0.95, p = 0.04). Estimated glomerular filtration rate less than 60 ml/minute/1.73 m2 and perioperative blood transfusion conferred a higher risk of distant or atypical recurrence but not of local recurrence (all p <0.05). Operative time and previous pelvic radiotherapy were not associated with any recurrence locations. CONCLUSIONS: Predictors of distant recurrences, peritoneal carcinomatosis and extrapelvic lymph node metastases after robot-assisted radical cystectomy did not significantly differ and were mainly dictated by pathological tumor characteristics. Results suggest that the risk of atypical recurrence is chiefly influenced by tumor biology rather than surgical aspects.

Multiphoton microscopy for rapid histopathological evaluation of kidney tumours.

OBJECTIVE: To explore the potential of multiphoton microscopy (MPM) for rapid evaluation and triaging of ex vivo kidney tissue. MATERIALS AND METHODS: Fresh neoplastic and non-neoplastic tissues from nephrectomy specimens (n = 40) were imaged with MPM and later submitted for routine histopathology. RESULTS: On MPM, normal kidney architecture was evident and clearly distinguishable from tumour. Forty malignant tumours (20 clear-cell renal cell carcinomas [RCCs], 10 papillary RCCs, five chromophobe RCCs and five papillary urothelial carcinomas [UCs], as diagnosed by haematoxylin and eosin staining) were imaged and subtyped as non-papillary and papillary, based on their architecture. Non-papillary tumours were further classified based on their unique cytoplasmic signatures. Clear-cell RCCs had a predominant population of cells with fat droplets in cytoplasm. Chromophobe RCCs had cells with non-fatty/homogeneous cytoplasm and distinct intra-cytoplasmic granules. Papillary RCCs had single-cell-lined papillae with often abundant histiocytes in their core, whereas PUC had multi-layered urothelium-lined papillae. The diagnostic accuracy of tumour subtyping by two independent uropathologists was 95%. CONCLUSIONS: We showed that MPM can reliably differentiate neoplastic from non-neoplastic kidney tissue and subtype kidney tumours in fresh, unprocessed tissue, MPM might therefore be useful as a rapid real-time diagnostic tool for the evaluation of kidney biopsies, and surgical margins in partial nephrectomies, to improve overall patient management.

The safety of robot-assisted cystectomy in patients with previous history of pelvic irradiation.

OBJECTIVE: To determine the safety of robot-assisted cystectomy (RAC) in patients with an irradiated pelvis, by comparing perioperative complication outcomes after RAC in patients with and without a history of pelvic irradiation. PATIENTS AND METHODS: In all, 252 consecutive patients underwent RAC at a tertiary referral centre from 2002 to 2013. Of all patients, 46 (18%) had a history of pelvic irradiation. Complications occurring at ≤30 days and ≤90 days of RAC were graded using the modified Clavien-Dindo classification system and additionally categorised by organ system. Baseline variables and outcomes of irradiated and non-irradiated patients were compared using descriptive statistics. Multivariable logistic regression models were generated to test the effect of previous pelvic irradiation on complications. RESULTS: The indications for RAC in patients with a history of pelvic irradiation were: bladder cancer (30 patients, 65%), prostate cancer (two, 4%), fistulae (five, 11%), and intractable symptoms from radiation cystitis (nine, 20%). In all, 25 (54%) irradiated and 112 (54%) non-irradiated patients had complications at ≤90 days (P > 0.9), of which 11 (24%) and 43 (21%) respectively had major complications (P = 0.7). One (2%) patient with and two (1%) patients without a history of irradiation died from surgical complications (P = 0.5). Infectious, bleeding, and gastrointestinal complications were the most common events in both groups. In multivariable analyses, a history of pelvic irradiation was not associated with a higher risk of complications. CONCLUSION: RAC performed by an experienced surgeon is a reasonable option in selected patients with a history of pelvic irradiation, as complication rates do not significantly differ compared with non-irradiated patients.

Prognostic value of Caveolin-1 in patients treated with radical prostatectomy: a multicentric validation study.

OBJECTIVE: To validate Caveolin-1 as an independent prognostic marker of biochemical recurrence (BCR) in a large multi-institutional cohort of patients with prostate cancer treated with radical prostatectomy (RP). PATIENTS AND METHODS: Caveolin-1 expression was evaluated by immunochemistry on a tissue microarray in 3 117 patients treated with RP for prostate cancer at five institutions. Univariable and multivariable Cox proportional hazards regression models assessed the association of Caveolin-1 status with BCR. Harrell's c-index quantified prognostic accuracy. RESULTS: Caveolin-1 was overexpressed in 644 (20.6%) patients and was associated with higher pathological Gleason sum (P = 0.002) and lymph node metastases (P = 0.05). Within a median (interquartile range) follow-up of 38 (21-66) months, 617 (19.8%) patients experienced BCR. Patients with overexpression of Caveolin-1 had worse BCR-free survival than those with normal expression (log-rank test, P = 0.004). Caveolin-1 was an independent predictor of BCR in multivariable analyses that adjusted for the effects of standard clinicopathological features (hazard ratio 1.21, P = 0.037). Addition of Caveolin-1 in a model for prediction of BCR based on these standard prognosticators did not significantly improve the predictive accuracy of the model. In subgroup analyses, Caveolin-1 was associated with BCR in patients with favourable pathological features (pT2pN0 and Gleason score = 6; P = 0.021). CONCLUSIONS: We confirmed that overexpression of Caveolin-1 is associated with adverse pathological features in prostate cancer and independently predicts BCR after RP, especially in patients with favourable pathological features. However, it did not add prognostically relevant information to established predictors of BCR, limiting its use in clinical practice.

Renal cell carcinoma with inferior vena cava involvement: Prognostic effect of tumor thrombus consistency on cancer specific survival.

BACKGROUND: Renal cell carcinoma forming a venous tumor thrombus (VTT) in the inferior vena cava (IVC) has a poor prognosis. Recent investigations have been focused on prognostic markers of survival. Thrombus consistency (TC) has been proposed to be of significant value but yet there are conflicting data. The aim of this study is to test the effect of IVC VTT consistency on cancer specific survival (CSS) in a multi-institutional cohort. METHODS: The records of 413 patients collected by the International Renal Cell Carcinoma-Venous Thrombus Consortium were retrospectively analyzed. All patients underwent radical nephrectomy and tumor thrombectomy. Kaplan-Meier estimate and Cox regression analyses investigated the impact of TC on CSS in addition to established clinicopathological predictors. RESULTS: VTT was solid in 225 patients and friable in 188 patients. Median CSS was 50 months in solid and 45 months in friable VTT. TC showed no significant association with metastatic spread, pT stage, perinephric fat invasion, and higher Fuhrman grade. Survival analysis and Cox regression rejected TC as prognostic marker for CSS. CONCLUSIONS: In the largest cohort published so far, TC seems not to be independently associated with survival in RCC patients and should therefore not be included in risk stratification models. J. Surg. Oncol. 2016;114:764-768. © 2016 Wiley Periodicals, Inc.