Adam S. Feldman

Long-Term Oncologic Outcomes After Radiofrequency Ablation for T1 Renal Cell Carcinoma

BACKGROUND Radiofrequency ablation (RFA) of renal cell carcinoma (RCC) is used to obtain local control of small renal masses. However, available long-term oncologic outcomes for RFA of RCC are limited by small numbers, short follow-up, and lack of pathologic diagnoses. OBJECTIVE To assess the oncologic effectiveness of RFA for the treatment of biopsy-proven RCC. DESIGN, SETTING, AND PARTICIPANTS Exclusion criteria included prior RCC or metastatic RCC, familial syndromes, or T2 RCC. We retrospectively reviewed long-term oncologic outcomes for 185 patients with sporadic T1 RCC. Median follow-up was 6.43 yr (interquartile range [IQR]: 5.3-7.7). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The chi-square test and Wilcoxon rank-sum tests were used to compare proportions and medians, respectively. Disease-specific survival and overall survival (OS) were calculated using Kaplan-Meier analysis, then stratified by tumor stage, and comparisons were made using log-rank analysis. The 5-yr disease-free survival (DFS) and OS rates are reported. A p value <0.05 was considered statistically significant. RESULTS AND LIMITATIONS Median tumor size was 3 cm (IQR: 2.1-3.9 cm). Tumor stage was T1a: 143 (77.3%) or T1b: 42 (22.7%). Twenty-four patients (13%) were retreated for residual disease. There were 12 local recurrences (6.5%), 6 recurrences in T1a disease (4.2%) and 6 in T1b disease (14.3%) (p=0.0196). Median time to recurrence was 2.5 yr. Local salvage RFA was performed in six patients, of whom five remain disease free at 3.8-yr median follow-up. Tumor stage was the only significant predictor of DFS on multivariate analysis. At last follow-up, 164 patients (88.6%) were disease free (T1a: n=132 [92.3%]; T1b: n=32 [76.2%]; p=0.0038). OS was similar regardless of stage (p=0.06). Five patients developed metachronous renal tumors (2.7%). Four patients developed extrarenal metastases (2.2%), three of whom died of metastatic RCC (1.6%). CONCLUSIONS In poor surgical candidates, RFA results in durable local control and low risk of recurrence in T1a RCC. Higher stage correlates with a decreased disease-free survival. Long-term surveillance is necessary following RFA. Patient selection based on tumor characteristics, comorbid disease, and life expectancy is of paramount importance.

Adverse effect of paroxetine on sperm

OBJECTIVE To assess the effects of a selective serotonin reuptake inhibitor on semen parameters. DESIGN Prospective study. SETTING Academic medical center. PATIENT(S) Thirty-five healthy male volunteers, 18-65 years old. INTERVENTION(S) Paroxetine administration for 5 weeks. MAIN OUTCOME MEASURE(S) Serum hormone levels, semen analyses, percent sperm DNA fragmentation, and questionnaire assessment of sexual function assessed before, during, and 1 month after drug administration. RESULT(S) Mean sperm DNA fragmentation was significantly higher for men while on paroxetine (30.3%) versus baseline (13.8%). Before paroxetine, 9.7% of patients had a terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) score>or=30% compared with 50% at week 4 of treatment. The odds ratio (OR) of having abnormal DNA fragmentation while taking paroxetine was 9.33 (95% confidence interval, 2.3-37.9]. Multivariate logistic regression correcting for age and body mass index confirmed this correlation (OR, 11.12). Up to 35% of men noted significant changes in erectile function and up to 47% of men reported ejaculatory difficulties on medication. Recovery to near-normal sexual function was noted after stopping treatment. Standard semen parameters were not significantly altered during paroxetine treatment. CONCLUSION(S) In men with normal semen parameters, paroxetine induced abnormal sperm DNA fragmentation in a significant proportion of subjects, without a measurable effect on semen parameters. The fertility potential of a substantial number of men on paroxetine may be adversely affected by these changes in sperm DNA integrity.

Diagnosis and management of dysfunctional voiding.

Purpose of review This review will focus on the diagnosis and management of voiding dysfunction in neurologically and anatomically normal children. The discussion will highlight recent developments and research in the clinical approach as well as the etiology and classification of these disorders. Recent findings Voiding dysfunction in children encompasses a wide spectrum of clinical entities, recently classified collectively as dysfunctional elimination syndromes. Voiding dysfunction typically presents after toilet training and may originate from behavioral issues that arise around this time in childhood development. The spectrum of disorders includes urge syndrome, dysfunctional voiding with an uncoordination between the detrusor and urinary sphincter, and enuresis. Clinical symptoms may vary from mild incontinence to severe disorders with endpoints of irreversible bladder dysfunction with vesicoureteral reflux, urinary tract infection and resulting nephropathy. Diagnosis relies heavily on a good history and physical examination, but also includes radiologic and urodynamic evaluation. Treatment generally consists of medical therapy, primarily with anticholinergics as well as behavioral therapy to modify learned voiding patterns that contribute to the voiding dysfunction. Summary This overview of voiding dysfunction in children outlines the established approaches to its diagnosis and treatment and highlights the most recent developments in the field.

Sensitive multiplexed analysis of kinase activities and activity-based kinase identification

Constitutive activation of one or more kinase signaling pathways is a hallmark of many cancers. Here we extend the previously described mass spectrometry–based KAYAK approach by monitoring kinase activities from multiple signaling pathways simultaneously. This improved single-reaction strategy, which quantifies the phosphorylation of 90 synthetic peptides in a single mass spectrometry run, is compatible with nanogram to microgram amounts of cell lysate. Furthermore, the approach enhances kinase monospecificity through substrate competition effects, faithfully reporting the signatures of many signaling pathways after mitogen stimulation or of basal pathway activation differences across a panel of well-studied cancer cell lines. Hierarchical clustering of activities from related experiments groups peptides phosphorylated by similar kinases together and, when combined with pathway alteration using pharmacological inhibitors, distinguishes underlying differences in potency, off-target effects and genetic backgrounds. Finally, we introduce a strategy to identify the kinase, and even associated protein complex members, responsible for phosphorylation events of interest.

Renal Cell Carcinoma in Tuberous Sclerosis Complex

Renal cell carcinoma (RCC) occurs in 2% to 4% of patients with tuberous sclerosis complex (TSC). Previous reports have noted a variety of histologic appearances in these cancers, but the full spectrum of morphologic and molecular features has not been fully elucidated. We encountered 46 renal epithelial neoplasms from 19 TSC patients and analyzed their clinical, pathologic, and molecular features, enabling separation of these 46 tumors into 3 groups. The largest subset of tumors (n=24) had a distinct morphologic, immunologic, and molecular profile, including prominent papillary architecture and uniformly deficient succinate dehydrogenase subunit B (SDHB) expression prompting the novel term “TSC-associated papillary RCC (PRCC).” The second group (n=15) were morphologically similar to a hybrid oncocytic/chromophobe tumor (HOCT), whereas the last 7 renal epithelial neoplasms of group 3 remained unclassifiable. The TSC-associated PRCCs had prominent papillary architecture lined by clear cells with delicate eosinophilic cytoplasmic thread-like strands that occasionally appeared more prominent and aggregated to form eosinophilic globules. All 24 (100%) of these tumors were International Society of Urological Pathology (ISUP) nucleolar grade 2 or 3 with mostly basally located nuclei. Tumor cells from 17 of 24 TSC-associated PRCCs showed strong, diffuse labeling for carbonic anhydrase IX (100%), CK7 (94%), vimentin (88%), and CD10 (83%) and were uniformly negative for SDHB, TFE3, and AMACR. Gains of chromosomes 7 and 17 were found in 2 tumors, whereas chromosome 3p deletion and TFE3 translocations were not detected. In this study, we reported a sizable cohort of renal tumors seen in TSC and were able to identify them as different morphotypes, which may help to expand the morphologic spectrum of TSC-associated RCC.

Renal Mass Biopsy to Guide Treatment Decisions for Small Incidental Renal Tumors: A Cost-effectiveness Analysis

PURPOSE To evaluate the effectiveness, cost, and cost-effectiveness of using renal mass biopsy to guide treatment decisions for small incidentally detected renal tumors. MATERIALS AND METHODS A decision-analytic Markov model was developed to estimate life expectancy and lifetime costs for patients with small (< or = 4-cm) renal tumors. Two strategies were compared: renal mass biopsy to triage patients to surgery or imaging surveillance and empiric nephron-sparing surgery. The model incorporated biopsy performance, the probability of track seeding with malignant cells, the prevalence and growth of benign and malignant tumors, treatment effectiveness and costs, and patient outcomes. An incremental cost-effectiveness analysis was performed to identify strategy preference under a willingness-to-pay threshold of

Cystatin B As a Tissue and Urinary Biomarker of Bladder Cancer Recurrence and Disease Progression

75,000 per quality-adjusted life-year (QALY). Effects of changes in key parameters on strategy preference were evaluated in sensitivity analysis. RESULTS Under base-case assumptions, the biopsy strategy yielded a minimally greater quality-adjusted life expectancy (4 days) than did empiric surgery at a lower lifetime cost (

Long-Term Outcome of Excisional Organ Sparing Surgery for Carcinoma of the Penis

3466), dominating surgery from a cost-effectiveness perspective. Over the majority of parameter ranges tested in one-way sensitivity analysis, the biopsy strategy dominated surgery or was cost-effective relative to surgery based on a

Transperineal template-guided prostate biopsy for patients with persistently elevated PSA and multiple prior negative biopsies.

75,000-per-QALY willingness-to-pay threshold. In two-way sensitivity analysis, surgery yielded greater life expectancy when the prevalence of malignancy and propensity for biopsy-negative cancers to metastasize were both higher than expected or when the sensitivity and specificity of biopsy were both lower than expected. CONCLUSION The use of biopsy to guide treatment decisions for small incidentally detected renal tumors is cost-effective and can prevent unnecessary surgery in many cases.

Collagen XXIII Expression Is Associated with Prostate Cancer Recurrence and Distant Metastases

Purpose: Using proteomic techniques, we sought to identify novel protein biomarkers in tissue and urine from patients with transitional cell carcinoma (TCC). Experimental Design: Urinary and tissue proteomes were analyzed and differentially expressed proteins were identified by mass spectrometry. One of the proteins, cystatin B, was further analyzed in TCC tissue by immunohistochemistry and in urine by semiquantitative Western blot analysis. Results: Cystatin B tissue staining intensity significantly increased concordantly with TCC grade (P = 0.0008). Elevated urinary cystatin B levels correlated with increasing tumor grade (P = 0.062) and stage (P = 0.0047). Patients with elevated levels of cystatin B had a shorter mean ± SE time to disease recurrence (12 ± 1.82 months) compared with patients who had low levels (28.8 ± 2.26 months; P = 0.0047). Similarly, patients with elevated cystatin B levels had a shorter time to grade/stage progression compared with patients with low urinary cystatin B (P = 0.0007). By multivariate Cox regression analysis, an elevated cystatin B level was the most significant variable predicting disease recurrence (hazard ratio, 3.8; 95% confidence interval, 1.5-9.5; P = 0.0049) and grade/stage progression (hazard ratio, 10.4; 95% confidence interval, 1.6-201.5; P = 0.0104). Conclusions: Cystatin B is elevated in tissue and urine of bladder cancer patients. Cystatin B urine levels are positively correlated with tumor grade, stage, and shorter time to disease recurrence and progression. Consequently, cystatin B may be useful as a novel predictive biomarker in TCC of the bladder.