Adam S. Kibel

Quality of Life and Satisfaction with Outcome among Prostate-Cancer Survivors

BACKGROUND We sought to identify determinants of health-related quality of life after primary treatment of prostate cancer and to measure the effects of such determinants on satisfaction with the outcome of treatment in patients and their spouses or partners. METHODS We prospectively measured outcomes reported by 1201 patients and 625 spouses or partners at multiple centers before and after radical prostatectomy, brachytherapy, or external-beam radiotherapy. We evaluated factors that were associated with changes in quality of life within study groups and determined the effects on satisfaction with the treatment outcome. RESULTS Adjuvant hormone therapy was associated with worse outcomes across multiple quality-of-life domains among patients receiving brachytherapy or radiotherapy. Patients in the brachytherapy group reported having long-lasting urinary irritation, bowel and sexual symptoms, and transient problems with vitality or hormonal function. Adverse effects of prostatectomy on sexual function were mitigated by nerve-sparing procedures. After prostatectomy, urinary incontinence was observed, but urinary irritation and obstruction improved, particularly in patients with large prostates. No treatment-related deaths occurred; serious adverse events were rare. Treatment-related symptoms were exacerbated by obesity, a large prostate size, a high prostate-specific antigen score, and older age. Black patients reported lower satisfaction with the degree of overall treatment outcomes. Changes in quality of life were significantly associated with the degree of outcome satisfaction among patients and their spouses or partners. CONCLUSIONS Each prostate-cancer treatment was associated with a distinct pattern of change in quality-of-life domains related to urinary, sexual, bowel, and hormonal function. These changes influenced satisfaction with treatment outcomes among patients and their spouses or partners.

Binding of the von Hippel-Lindau tumor suppressor protein to Elongin B and C

Germ-line mutations of the von Hippel-Lindau tumor suppressor gene (VHL) predispose individuals to a variety of human tumors, and somatic mutations of this gene have been identified in sporadic renal cell carcinomas and cerebellar hemangioblastomas. Two transcriptional elongation factors, Elongin B and C, were shown to bind in vitro and in vivo to a short, colinear region of the VHL protein (pVHL) that is frequently mutated in human tumors. A peptide replica of this region inhibited binding of pVHL to Elongin B and C whereas a point-mutant derivative, corresponding to a naturally occurring VHL missense mutation, had no effect. These results suggest that the tumor suppression function of pVHL may be linked to its ability to bind to Elongin B and C.

Tumour suppression by the human von Hippel-Lindau gene product.

A partial cDNA sequence for the gene linked to the von Hippel–Lindau (VHL) syndrome was reported in 1993. Mutation or loss of both VHL alleles has been documented in sporadic renal cell carcinomas and in the neoplasms that arise in von Hippel–Lindau kindreds. We have determined that the protein product of the VHL gene is an approximately 30 kilodalton cytoplasmic protein. The renal carcinoma cell line 786-O is known to harbour a VHL mutation and, as shown here, fails to produce a wild-type VHL protein. Reintroduction of wild-type, but not mutant, VHL into these cells had no demonstrable effect on their growth in vitro but inhibited their ability to form tumours in nude mice.

Prospective Study of [18F]Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography for Staging of Muscle-Invasive Bladder Carcinoma

PURPOSE Novel imaging modalities are needed to detect occult metastatic disease in bladder carcinoma. Patients with regional lymphatic spread could be targeted for neoadjuvant chemotherapy, and patients with distant metastatic disease could be spared the unnecessary morbidity of radical cystectomy. Herein, we report a prospective study of positron emission tomography/computed tomography (PET/CT) with [(18)F]fluorodeoxyglucose (FDG) in patients undergoing radical cystectomy for cT2-3N0M0 urothelial carcinoma of the bladder. METHODS Forty-three chemotherapy-naïve patients underwent FDG-PET/CT before planned cystectomy. All had negative conventional CT and bone scintigraphy before enrollment. Positive FDG-PET/CT was confirmed by percutaneous biopsy or open surgical exploration, whereas negative FDG-PET/CT was confirmed by complete lymphadenectomy. Recurrence-free survival (RFS), disease-specific survival (DSS), and overall survival (OS) were described using the Kaplan-Meier method and compared using log-rank test. RESULTS Median follow-up was 14.9 months (range, 0.4 to 46.1 months). One patient who did not undergo lymphadenectomy was excluded from the pathology data analysis (n = 42), whereas another patient who failed to return for follow-up was excluded from survival analysis (n = 42). FDG-PET/CT demonstrated a positive predictive value of 78% (seven of nine), a negative predictive value of 91% (30 of 33), sensitivity of 70% (seven of 10), and specificity of 94% (30 of 32). RFS, DSS, and OS were all significantly poorer in the patients with positive FDG-PET/CT than in those with negative FDG-PET/CT. CONCLUSION FDG-PET/CT detected occult metastatic disease in seven of 42 patients with negative conventional preoperative evaluations. PET findings were strongly correlated with survival. As such, FDG-PET/CT may help in making treatment decisions before radical cystectomy.

Contemporary Role of Systematic Prostate Biopsies: Indications, Techniques, and Implications for Patient Care

CONTEXT Prostate cancer (PCa) screening to detect early stage PCa has resulted in increased identification of small-volume, low-grade PCa, many of which meet criteria for clinically indolent disease. Nevertheless, there remains some degree of underdetection of high-risk PCa in substantial numbers of men despite current diagnostic strategies. OBJECTIVE To discuss the contemporary role of prostate biopsy (PB), focusing on the indications, techniques, and limitations of current PB techniques and evolving techniques affecting patient care. EVIDENCE ACQUISITION A comprehensive Medline search was performed using the medical subject heading search terms prostate cancer, detection, prostate biopsy, significant cancer, and diagnosis, with restriction to the English language. Emphasis was given to publications within the past 5 yr. EVIDENCE SYNTHESIS Because abnormal digital rectal examination (DRE) and prostate-specific antigen (PSA) tests alone lack specificity for cancer, there is no universal indication for PB. This lack has inspired exploration for a cancer-specific biomarker and prediction tools such as risk calculators. Indication for biopsy should involve a balance between the underdiagnosis of high-risk cancers and the potential risks for the overdetection of clinically insignificant cancers as well as biopsy-related morbidity. Evidence supports the inclusion of laterally directed cores during transrectal ultrasound (TRUS) PB in addition to the traditional sextant pattern, which significantly improves cancer detection without a demonstrable increase in morbidity. These data indicate that such PB templates, typically 12 cores, represent the optimal template in initial PB. Optimised techniques and templates for repeat PB remain controversial. However, debate continues regarding indications, sampling number, and location as well as on the potential of modern image-guided approaches or three-dimensional (3D) mapping biopsy in this unique setting. Additional limitations of repeat PB techniques include associated procedural risks if general anaesthesia is required and inherent sampling errors of template-based techniques that are not targeted to the specific tumour site. CONCLUSIONS Current data support the utility of extended PB templates for initial TRUS PB intended to detect clinically significant PCa. Repeat PB in the setting of prior negative PB on the grounds of clinical suspicion or for risk-stratified approaches to management of low risk PCa requires balancing overdetection of low-risk cancer with the potential to miss significant cancer. Several options, including modern image-guided targeting, biomarker development, transrectal saturation PB, and 3D template mapping PB, are changing the clinical paradigms for evaluation and management. Evidence to support adopting approaches other than the current established standards should be tested through appropriately designed prospective studies.

Genome-wide association study of prostate cancer in men of African ancestry identifies a susceptibility locus at 17q21

In search of common risk alleles for prostate cancer that could contribute to high rates of the disease in men of African ancestry, we conducted a genome-wide association study, with 1,047,986 SNP markers examined in 3,425 African-Americans with prostate cancer (cases) and 3,290 African-American male controls. We followed up the most significant 17 new associations from stage 1 in 1,844 cases and 3,269 controls of African ancestry. We identified a new risk variant on chromosome 17q21 (rs7210100, odds ratio per allele = 1.51, P = 3.4 × 10−13). The frequency of the risk allele is ∼5% in men of African descent, whereas it is rare in other populations (<1%). Further studies are needed to investigate the biological contribution of this allele to prostate cancer risk. These findings emphasize the importance of conducting genome-wide association studies in diverse populations.

The Learning Curve of Robot-Assisted Radical Cystectomy: Results from the International Robotic Cystectomy Consortium

BACKGROUND Robot-assisted radical cystectomy (RARC) has evolved as a minimally invasive alternative to open radical cystectomy for patients with invasive bladder cancer. OBJECTIVE We sought to define the learning curve for RARC by evaluating results from a multicenter, contemporary, consecutive series of patients who underwent this procedure. DESIGN, SETTING, AND PARTICIPANTS Utilizing the International Robotic Cystectomy Consortium database, a prospectively maintained and institutional review board-approved database, we identified 496 patients who underwent RARC by 21 surgeons at 14 institutions from 2003 to 2009. MEASUREMENTS Cut-off points for operative time, lymph node yield (LNY), estimated blood loss (EBL), and margin positivity were identified. Using specifically designed statistical mixed models, we were able to inversely predict the number of patients required for an institution to reach the predetermined cut-off points. RESULTS AND LIMITATIONS Mean operative time was 386 min, mean EBL was 408 ml, and mean LNY was 18. Overall, 34 of 482 patients (7%) had a positive surgical margin (PSM). Using statistical models, it was estimated that 21 patients were required for operative time to reach 6.5h and 8, 20, and 30 patients were required to reach an LNY of 12, 16, and 20, respectively. For all patients, PSM rates of <5% were achieved after 30 patients. For patients with pathologic stage higher than T2, PSM rates of <15% were achieved after 24 patients. CONCLUSIONS RARC is a challenging procedure but is a technique that is reproducible throughout multiple centers. This report helps to define the learning curve for RARC and demonstrates an acceptable level of proficiency by the 30th case for proxy measures of RARC quality.

Complications After Robot-assisted Radical Cystectomy: Results from the International Robotic Cystectomy Consortium

BACKGROUND Complication reporting is highly variable and nonstandardized. Therefore, it is imperative to determine the surgical outcomes of major oncologic procedures. OBJECTIVE To describe the complications after robot-assisted radical cystectomy (RARC) using a standardized and validated reporting methodology. DESIGN, SETTING, AND PARTICIPANTS Using the International Robotic Cystectomy Consortium (IRCC) database, we identified 939 patients who underwent RARC, had available complication data, and had at least 90 d of follow-up. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Complications were analyzed and graded according to the Memorial Sloan-Kettering Cancer Center (MSKCC) system and were defined and stratified by organ system. Secondary outcomes included identification of preoperative and intraoperative variables predicting complications. Logistic regression models were used to define predictors of complications and readmission. RESULTS AND LIMITATIONS Forty-one percent (n=387) and 48% (n=448) of patients experienced a complication within 30 and 90 d of surgery, respectively. The highest grade of complication was grade 0 in 52%, grade 1-2 in 29%, and grade 3-5 in 19% patients. Gastrointestinal, infectious, and genitourinary complications were most common (27%, 23%, and 17%, respectively). On multivariable analysis, increasing age group, neoadjuvant chemotherapy, and receipt of blood transfusion were independent predictors of any and high-grade complications, respectively. Thirty and 90-d mortality was 1.3% and 4.2%, respectively. As a multi-institutional database, a disparity in patient selection, operating standards, postoperative management, and reporting of complications can be considered a major limitation of the study. CONCLUSIONS Surgical morbidity after RARC is significant when reported using a standardized reporting methodology. The majority of complications are low grade. Strict reporting of complications is necessary to advocate for radical cystectomy (RC) and helps in patient counseling.

Propensity-matched comparison of morbidity and costs of open and robot-assisted radical cystectomies: a contemporary population-based analysis in the United States.

BACKGROUND Radical cystectomy (RC) is a morbid procedure associated with high costs. Limited population-based data exist on the complication profile and costs of robot-assisted RC (RARC) compared with open RC (ORC). OBJECTIVE To evaluate morbidity and cost differences between ORC and RARC. DESIGN, SETTING, AND PARTICIPANTS We conducted a population-based, retrospective cohort study of patients who underwent RC at 279 hospitals across the United States between 2004 and 2010. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Multivariable logistic and median regression was performed to evaluate 90-d mortality, postoperative complications (Clavien classification), readmission rates, length of stay (LOS), and direct costs. To reduce selection bias, we used propensity weighting with survey weighting to obtain nationally representative estimates. RESULTS AND LIMITATIONS The final weighted cohort included 34 672 ORC and 2101 RARC patients. RARC use increased from 0.6% in 2004 to 12.8% in 2010. Major complication rates (Clavien grade ≥ 3; 17.0% vs 19.8%, p = 0.2) were similar between ORC and RARC (odds ratio [OR]: 1.32; p = 0.42). RARC had 46% decreased odds of minor complications (Clavien grade 1-2; OR: 0.54; p = 0.03). RARC had

SnoRNA U50 is a candidate tumor-suppressor gene at 6q14.3 with a mutation associated with clinically significant prostate cancer.

4326 higher adjusted 90-d median direct costs (p = 0.004). Although RARC had a significantly shorter LOS (11.8 d vs 10.2 d; p = 0.008), no significant differences in room and board costs existed (p = 0.20). Supply costs for RARC were significantly higher (