Changes in Lean Muscle Mass Associated with Neoadjuvant Platinum-Based Chemotherapy in Patients with Muscle Invasive Bladder Cancer.

BACKGROUND: Baseline sarcopenia or severe lean muscle deficiency is independently associated with increased mortality after cystectomy for muscle-invasive urothelial carcinoma of the bladder (MIUC). The impact of chemotherapy on muscle mass in MIUC patients remains undefined. OBJECTIVES: To describe preoperative changes in body composition in MIUC patients receiving platinum-based neoadjuvant chemotherapy (NC). METHODS: Patients with cT2-4 N0-1 M0 UC of the bladder who received NC were identified. Lumbar skeletal muscle index (SMI, cm2/m2), visceral adipose index (VAI, cm2/m2), and the subcutaneous and intramuscular adipose index (SAI, cm2/m2) were calculated using validated methodology (cross sectional area of skeletal muscle/height2 at L3) from measurement of soft tissue areas on pre- (pre-NC) and post-NC (post-NC) computed tomography. Patients were classified as sarcopenic according to consensus definitions: Male: SMI <55 cm2/m2, Female: SMI <38.5 cm2/m2. Pre-NC and post-NC median body mass index (BMI kg/m2), SMI, and adipose indices were compared. RESULTS: The study cohort consisted of 26 patients, with a median age 70 years, including 7 females (27%). Chemotherapy regimens included dose-dense methotrexate, vinblastine, doxorubicin and cisplatin (31%), gemcitabine/cisplatin (62%) and gemcitabine/carboplatin (3.8%) with a median of 3.5 (range 2-6) cycles. Median pre- and post-NC BMI were 27.1 kg/m2 and 27.2 kg/m2 (p = 0.36). Median pre- and post-NC SMI were 49.1 cm2/m2 and 44.5 (p < 0.001) respectively. Median percent change in SMI was -6.4% (range -30% to 10%). Pre-NC, 18 (69%) patients were sarcopenic vs. 21 (81%, p = 0.002) post-NC. Median time between initiation of chemotherapy and cystectomy was 110 days. CONCLUSIONS: We observed a significant decrease in lean muscle mass among MIUC patients treated with platinum-based NC prior to cystectomy, with an associated increase in the prevalence of sarcopenia. Patients undergoing NC may benefit from pre-habilitative interventions to mitigate lean muscle loss prior to cystectomy.

APOBEC-mediated mutagenesis in urothelial carcinoma is associated with improved survival, mutations in DNA damage response genes, and immune response.

APOBEC enzymes are responsible for a mutation signature (TCW>T/G) implicated in a wide variety of tumors. We explore the APOBEC mutational signature in bladder cancer and the relationship with specific mutations, molecular subtype, gene expression, and survival using sequencing data from The Cancer Genome Atlas (n = 395), Beijing Genomics Institute (n = 99), and Cancer Cell Line Encyclopedia. Tumors were split into "APOBEC-high" and "APOBEC-low" based on APOBEC enrichment. Patients with APOBEC-high tumors have better overall survival compared to those with APOBEC-low tumors (38.2 vs. 18.5 months, p = 0.005). APOBEC-high tumors are more likely to have mutations in DNA damage response genes (TP53, ATR, BRCA2) and chromatin regulatory genes (ARID1A, MLL, MLL3), while APOBEC-low tumors are more likely to have mutations in FGFR3 and KRAS. APOBEC3A and APOBEC3B expression correlates with mutation burden, regardless of bladder tumor molecular subtype. APOBEC mutagenesis is associated with increased expression of immune signatures, including interferon signaling, and expression of APOBEC3B is increased after stimulation of APOBEC-high bladder cancer cell lines with IFNγ. In summary, APOBEC-high tumors are more likely to have mutations in DNA damage response and chromatin regulatory genes, potentially providing more substrate for APOBEC enzymes, leading to a hypermutational phenotype and the subsequent enhanced immune response.

A Carcinogen-induced mouse model recapitulates the molecular alterations of human muscle invasive bladder cancer.

The N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) mouse model is an attractive model system of muscle-invasive bladder cancer (MIBC) as it recapitulates the histology of human tumors in a background with intact immune system. However, it was unknown whether this carcinogen-induced model also mimicked human MIBC at the molecular and mutational level. In our study, we analyzed gene expression and mutational landscape of the BBN model by next-generation sequencing followed by a bioinformatic comparison to human MIBC using data from The Cancer Genome Atlas and other repositories. BBN tumors showed overexpression of markers of basal cancer subtype, and had a high mutation burden with frequent Trp53 (80%), Kmt2d (70%), and Kmt2c (90%) mutations by exome sequencing, similar to human MIBC. Many variants corresponded to human cancer hotspot mutations, supporting their role as driver mutations. We extracted two novel mutational signatures from the BBN mouse genomes. The integrated analysis of mutation frequencies and signatures highlighted the contribution of aberrations to chromatin regulators and genetic instability in the BBN tumors. Together, our study revealed several similarities between human MIBC and the BBN mouse model, providing a strong rationale for its use in molecular and drug discovery studies.

The emerging role of homologous recombination repair and PARP inhibitors in genitourinary malignancies.

As cells age and are exposed to genotoxic stress, preservation of the genomic code requires multiple DNA repair pathways to remove single-strand or double-strand breaks. Loss of function somatic genomic aberrations or germline deficiency in genes involved in DNA repair can result in acute cell death or, after a latency period, cellular transformation. Therapeutic exploitation of DNA repair by inhibition of poly (adenosine diphosphate [ADP]) ribose polymerases (PARP), a family of enzymes involved in the repair of single-strand and in some cases double-strand breaks, has become a novel cancer treatment. Although the application of PARP inhibitors (PARPis) initially focused on tumors with BRCA1 or BRCA2 deficiencies, synthetic susceptibilities to PARPis have been expanded due to the identification of tumors with mutations pathways involved in DNA damage repair, in particular those that repair double-strand breaks using homologous recombination (HR). There is an increasing appreciation that genitourinary (GU) malignancies, including bladder cancer and especially prostate cancer, contain subsets of patients with germline and somatic alterations in HR genes that may reflect an increased response to PARPis. In this review, the authors describe the mechanisms and rationale of the use of PARPis in patients with GU cancers, summarize previously reported preclinical and clinical trials, and identify ongoing trials to determine how PARPis and strategies targeted at HR repair can have widespread application in patients with GU cancers. Cancer 2017;123:1912-1924. © 2017 American Cancer Society.

Radiofrequency Ablation-Assisted Zero-Ischemia Robotic Laparoscopic Partial Nephrectomy: Oncologic and Functional Outcomes in 49 Patients.

Introduction and Objectives. Robotic partial nephrectomy with peritumoral radiofrequency ablation (RFA-RPN) is a novel clampless technique. We describe oncologic and functional outcomes in a prospective cohort. Methods. From May, 2007, to December, 2009, 49 consecutive patients with renal masses <7 cm underwent RFA-RPN. During this period, only the RFA-RPN technique was utilized for all cases of partial nephrectomy. Pre- and postoperative data were analyzed and compared to 36 consecutive patients who underwent LPN. Results. In total, 49 tumors were treated in the RFA-RPN group and 36 tumors in the comparison group. Mean operative time was longer in the RFA-RPN group (370 min versus 293 min, p < 0.001). There were no significant differences in mean EBL (231 cc versus 250 cc, p = 0.42), transfusion rate (8.2% versus 11.1%, p = 0.7), or hospital stay (3.9 versus 4.4 days, p = 0.2). Two patients in the RFA-RPN (4.1%) and 1 (2.7%) patient in the comparison group had a positive surgical margin (p = 0.75). 17 (34.7%) patients had a postoperative urine leak in the RFA-RPN group versus 2 (5.6%) patients in the comparison group (p = 0.001). Mean follow-up was 54 months versus 68.4 months in the comparison group. There was no significant difference between the two groups regarding change in GFR (p = 0.67). There were 3 recurrences (6.1%) in the RFA-RPN group and 0 recurrences in the RPN group (p = 0.23). There were 3 deaths (6.1%) in the RFA-RPN group (one cancer specific) and 4 deaths (11.1%) in the RPN group (non-cancer specific) over the follow-up period (p = 0.44). Conclusions. Our data suggests that this technique is associated with a similar degree of renal preservation but higher rates of postoperative urine leak and possibly higher rates of recurrence.

Predicting Patients with Inadequate 24- or 48-Hour Urine Collections at Time of Metabolic Stone Evaluation.

PURPOSE: We aimed to understand the characteristics of patients who are less likely to submit adequate urine collections at metabolic stone evaluation. METHODS: Inadequate urine collection was defined using two definitions: (1) Reference ranges for 24-hour creatinine/kilogram (Cr/24) and (2) discrepancy in total 24-hour urine Cr between 24-hour urine collections. There were 1502 patients with ≥1 kidney stone between 1998 and 2014 who performed a 24- or 48-hour urine collection at Northwestern Memorial Hospital and who were identified retrospectively. Multivariate analysis was performed to analyze predictor variables for adequate urine collection. RESULTS: A total of 2852 urine collections were analyzed. Mean age for males was 54.4 years (range 17-86), and for females was 50.2 years (range 8-90). One patient in the study was younger than 17 years old. (1) Analysis based on the Cr 24/kg definition: There were 50.7% of patients who supplied an inadequate sample. Females were nearly 50% less likely to supply an adequate sample compared with men, P<0.001. Diabetes (odds ratio [OR] 1.42 [1.04-1.94], P=0.026) and vitamin D supplementation (OR 0.64 [0.43-0.95], P=0.028) predicted receiving an adequate/inadequate sample, respectively. (2) Analysis based on differences between total urinary Cr: The model was stratified based on percentage differences between samples up to 50%. At 10%, 20%, 30%, 40%, and 50% differences, inadequate collections were achieved in 82.8%, 66.9%, 51.7%, 38.5%, and 26.4% of patients, respectively. Statistical significance was observed based on differences of ≥40%, and this was defined as the threshold for an inadequate sample. Female sex (OR 0.73 [0.54-0.98], P=0.037) predicted supplying inadequate samples. Adequate collections were more likely to be received on a Sunday (OR 1.6 [1.03-2.58], P=0.038) and by sedentary workers (OR 2.3 [1.12-4.72], P=0.023). CONCLUSION: Urine collections from patients during metabolic evaluation for nephrolithiasis may be considered inadequate based on two commonly used clinical definitions. This may have therapeutic or economic ramifications and the propensity for females to supply inadequate samples should be investigated further.

Prostate cancer diagnosis is associated with an increased risk of erectile dysfunction after prostate biopsy.

OBJECTIVE: To evaluate prospectively the characteristics, erectile function and lower urinary tract symptoms (LUTS) of men undergoing prostate needle biopsy (PNBx). PATIENTS AND METHODS: From 2008 to 2011, 134 men were prospectively administered the International Index of Erectile Function (IIEF), American Urological Association Symptom Index (AUA-SI), and quality-of-life (QoL) questionnaires before and after undergoing a single 12-core PNBx. Comparisons of IIEF and AUA-SI scores before and after PNBx, based upon baseline characteristics and prostate cancer (PCa) diagnosis, were performed. Univariable and multivariable logistic regression models were used to characterize predictors of change in IIEF scores. RESULTS: In the 85 men who fulfilled the inclusion criteria, there were no significant differences between the mean (sd) total pre-biopsy and the mean (sd) post-biopsy IIEF scores: 57.8 (12.9) vs 54.3 (17.2). Subgroup analysis showed that men who had biopsy-proven PCa had significantly greater changes in their post-biopsy IIEF scores compared with men without (-10.1 vs. 1.0; P < 0.001). After specific analyses of the IIEF domains in these groups we found significant decreases in every domain, including erectile function (P = 0.01). On multivariate analyses, only PCa diagnosis was associated with a significant change in IIEF (odds ratio 7.2; P = 0.003). There were no differences in AUA-SI or QoL scores in the overall population or in subgroups. CONCLUSIONS: Cancer diagnosis appears to have an adverse effect on the erectile function of men undergoing PNBx but no effect on LUTS. This study highlights a potential negative psychological confounder that may influence erectile function before the treatment of PCa. Additional prospective trials evaluating these relationships are warranted.

Open vs. endovascular repair of isolated iliac artery aneurysms: A 12-year experience.

OBJECTIVE: To examine contemporary operative techniques and outcomes for repair of isolated iliac artery aneurysms. METHODS: We retrospectively reviewed the charts of all patients who underwent repair of an isolated iliac artery aneurysm from February 1995 to June 2007. Mycotic aneurysms and patients with concurrent infrarenal abdominal aortic aneurysms greater than 3.5 cm in diameter were excluded from analysis. Patients with prior abdominal aortic aneurysm repair were not excluded. RESULTS: Fifty-six patients (96% male; mean age, 72 +/- 10 years) had either open (n = 24) or endovascular (n = 32) repair with median follow-up of 36 months. Seven patients were treated for rupture, six with open repair, and one with an endograft. Average aneurysm size for patients in the open and endovascular repair cohorts was 4.5 +/- 2.4 cm and 4.0 +/- 1.1 cm, respectively (P = .35). One episode of endograft limb thrombosis at five months was treated with catheter-directed thrombolytic therapy and stent placement. Thirty-day mortality for patients undergoing elective and emergent open repair was 1/18 (6%) and 1/6 (17%), respectively. There was no 30-day mortality for the endovascular group. Median length of stay was 10.5 days in the open group and one day in the endovascular elective group (P < .01). There was no mid-term aneurysm-related mortality in either group. Primary patency rates were similar between the open and endovascular groups at five years (100% vs. 96%, P = .07). Aneurysm sac diameter decreased in 67% (21/28) of patients that underwent endovascular repair. One patient with a Type III endoleak required relining of the endograft with a second endograft at 72 months. CONCLUSION: These data demonstrate that in appropriately selected patients, endovascular repair of isolated iliac artery aneurysms is a safe, effective alternative to open repair with mid-term follow-up. Endovascular repair is associated with a significantly reduced hospital length of stay and may be associated with decreased need for transfusion and mortality when compared with open repair.