John Danella

Organ preservation for the treatment of contralateral testicular seminoma

PURPOSEnLocal excision of germ cell tumor in the remaining testicle followed by a modest dose of irradiation is an alternative to orchiectomy. This organ sparing technique provides superior quality of life and reduces the need for lifelong hormone replacement.nnnMATERIALS AND METHODSnWe treated two patients with contralateral seminomas with organ preservation. Both patients received postoperative irradiation to the remaining testicle to a dose of 20 Gy in 10 fractions and 19.8 Gy in 11 fractions.nnnRESULTSnBoth patients are alive with no evidence of disease more than 3 years since the completion of their treatments. They both have reduced but preserved androgen production and retained their virility. They both are azospermic.nnnCONCLUSIONnWe conclude that organ preservation for the treatment of contralateral testicular seminoma is a superior alternative to orchiectomy of the remaining testicle. It preserves male hormone production with equal survival outcome expectations.

Flutamide in men with prostatic intraepithelial neoplasia: A randomized, placebo-controlled chemoprevention trial

High-grade prostatic intraepithelial neoplasia (HGPIN) has been identified as a premalignant change in the prostate that indicates increased risk of the subsequent development of prostate adenocarcinoma. Prior studies have suggested that androgen deprivation therapy causes a regression of HGPIN. We therefore conducted a chemoprevention trial assessing the efficacy of flutamide in reducing the rate of prostate adenocarcinoma development in men with HGPIN. Men with biopsyproven HGPIN but no evidence of prostate adenocarcinoma were randomized in a double-blind manner to either flutamide 250u2009mg/d or a placebo. Treatment was continued for 1 year. Repeat biopsies were obtained at 12 and 24 months. Quality of life and toxicities related to treatment were also measured. Sixty patients were randomized and began therapy with either flutamide or placebo. At 1 year, 14% of men receiving flutamide and 10% of men receiving placebo had developed prostate adenocarcinoma. Flutamide-associated toxicities were mild to moderate in severity. Quality-of-life measures did not show any differences between the 2 groups. This study showed no evidence of benefit from flutamide as a chemoprevention agent in men with HGPIN.

Combined inhibition of heat shock proteins 90 and 70 leads to simultaneous degradation of the oncogenic signaling proteins involved in muscle invasive bladder cancer

Heat shock protein 90 (HSP90) plays a critical role in the survival of cancer cells including muscle invasive bladder cancer (MIBC). The addiction of tumor cells to HSP90 has promoted the development of numerous HSP90 inhibitors and their use in clinical trials. This study evaluated the role of inhibiting HSP90 using STA9090 (STA) alone or in combination with the HSP70 inhibitor VER155008 (VER) in several human MIBC cell lines. While both STA and VER inhibited MIBC cell growth and migration and promoted apoptosis, combination therapy was more effective. Therefore, the signaling pathways involved in MIBC were systematically interrogated following STA and/or VER treatments. STA and not VER reduced the expression of proteins in the p53/Rb, PI3K and SWI/SWF pathways. Interestingly, STA was not as effective as VER or combination therapy in degrading proteins involved in the histone modification pathway such as KDM6A (demethylase) and EP300 (acetyltransferase) as predicted by The Cancer Genome Atlas (TCGA) data. This data suggests that dual HSP90 and HSP70 inhibition can simultaneously disrupt the key signaling pathways in MIBC.

Utilization of Active Surveillance as Initial Management for Newly Diagnosed Prostate Cancer: Data from the Pennsylvania Urologic Regional Collaborative

Purpose: We describe contemporary active surveillance utilization and variation in a regional prostate cancer collaborative. We identified demographic and disease specific factors associated with active surveillance in men with newly diagnosed prostate cancer. Materials and Methods: We analyzed data from the PURC (Pennsylvania Urologic Regional Collaborative), a cooperative effort of urology practices in southeastern Pennsylvania and New Jersey. We determined the rates of active surveillance among men with newly diagnosed NCCN® (National Comprehensive Cancer Network®) very low, low or intermediate prostate cancer and compared the rates among participating practices and providers. Univariate and multivariable analyses were used to identify factors associated with active surveillance utilization. Results: A total of 1,880 men met inclusion criteria. Of the men with NCCN very low or low risk prostate cancer 57.4% underwent active surveillance as the initial management strategy. Increasing age was significantly associated with active surveillance (p <0.001) while adverse clinicopathological variables were associated with decreased active surveillance use. Substantial variation in active surveillance utilization was observed among practices and providers. Conclusions: More than 50% of men with low risk disease in the PURC collaborative were treated with active surveillance. However, substantial variation in active surveillance rates were observed among practices and providers in academic and community settings. Advanced age and favorable clinicopathological factors were strongly associated with active surveillance. Analysis of regional collaboratives such as the PURC may allow for the development of strategies to better standardize treatment in men with prostate cancer and offer active surveillance in a more uniform and systematic fashion.Purpose: We aimed to describe contemporary active surveillance (AS) utilization and variation in a regional prostate cancer collaborative, and to identify demographic and disease-specific factors associated with the use of AS for men with newly diagnosed prostate cancer. Materials and Methods: We analyzed data from the Pennsylvania Urologic Regional Collaborative (PURC), a cooperative effort of urology practices in Southeastern Pennsylvania and New Jersey. Among men with newly diagnosed NCCN very low, low, or intermediate prostate cancer, rates of AS were determined and compared among participating practices and providers. Univariate and multivariable analyses were used to identify factors associated with AS utilization. Results: 1880 men met inclusion criteria. Of men with NCCN very-low or low risk prostate cancer, 57.4% underwent active surveillance as initial management strategy. Increasing age was significantly associated with AS utilization (p<0.001), whereas adverse clinicopathologic variables were associated with decreased use of AS. Substantial variation in AS utilization was observed among practices and providers. Conclusions: Over 50% of men with low risk disease in the PURC collaborative were managed with AS, however substantial variation in AS rates were observed among practices and providers in both academic and community settings. Advanced age and favorable clinicopathologic factors were strongly associated with the use of AS. Analysis of regional collaboratives such as PURC may allow for the development of strategies to better standardize treatment for men with prostate cancer and to offer AS in a more uniform and systematic fashion. M AN US CR IP T AC CE PT ED ACCEPTED MANUSCRIPT Introduction In contemporary urologic practice, there is little doubt regarding the potential harms of widespread PSA screening and resultant prostate cancer overdiagnosis and overtreatment. Several decades of research now support active surveillance (AS) as a safe and effective management strategy for men with low risk prostatic malignancies 1, 2 , with the potential to decrease patient morbidity caused by overtreatment of clinically indolent tumors. As such, AS is now endorsed by most published guidelines as a preferred management strategy for men with low risk disease 3-5 , and several recent publications have shown an increase in AS utilization in recent years 6-8 . Nonetheless, the utilization of AS is known to vary widely on both a national and regional level, and even within individual urology practices. 9-11 The reasons for this variation are likely multifactorial, but likely are at least partially explained by variability in criteria used to identify men eligible for AS, physician beliefs and biases regarding AS, and patient concerns for both cancer control and preservation of quality of life. In the current study, we analyzed a regional prostate cancer collaborative encompassing multiple urology practices throughout Central and Southeastern Pennsylvania and Southern New Jersey. The participating groups comprise both academic centers and community urologists. We aimed to characterize AS utilization and to identify factors associated with the use of AS within this collaborative. Such information may offer insight into the factors M AN US CR IP T AC CE PT ED ACCEPTED MANUSCRIPT underlying the regional and practice-level variation in the practice of AS, as well as provide avenues to promote standardization of this management strategy. Material and Methods

Dual targeting of HSP70 does not induce the heat shock response and synergistically reduces cell viability in muscle invasive bladder cancer

Muscle invasive bladder cancer (MIBC) is a common malignancy and major cause of morbidity worldwide. Over the last decade mortality rates for MIBC have not decreased as compared to other cancers indicating a need for novel strategies. The molecular chaperones HSP70 and HSP90 fold and maintain the 3-dimensional structures of numerous client proteins that signal for cancer cell growth and survival. Inhibition of HSP70 or HSP90 results in client protein degradation and associated oncogenic signaling. Here we targeted HSP70 and HSP90 with small molecule inhibitors that trap or block each chaperone in a low client-affinity “open” conformation. HSP70 inhibitors, VER155008 (VER) and MAL3-101 (MAL), along with HSP90 inhibitor, STA-9090 (STA), were tested alone and in combination for their ability to reduce cell viability and alter protein levels in 4 MIBC cell lines. When combined, VER+MAL synergistically reduced cell viability in each MIBC cell line while not inducing expression of heat shock proteins (HSPs). STA+MAL also synergistically reduced cell viability in each cell line but induced expression of cytoprotective HSPs indicating the merits of targeting HSP70 with VER+MAL. Additionally, we observed that STA induced the expression of the stress-related transcription factor HSF2 while reducing levels of the co-chaperone TTI1.

Dosimetric differences between intraoperative and postoperative plans using Cs-131 in transrectal ultrasound–guided brachytherapy for prostatic carcinoma

The aim of the study was to investigate the differences between intraoperative and postoperative dosimetry for transrectal ultrasound-guided transperineal prostate implants using cesium-131 ((131)Cs). Between 2006 and 2010, 166 patients implanted with (131)Cs had both intraoperative and postoperative dosimetry studies. All cases were monotherapy and doses of 115 were prescribed to the prostate. The dosimetric properties (D90, V150, and V100 for the prostate) of the studies were compared. Two conformity indices were also calculated and compared. Finally, the prostate was automatically sectioned into 6 sectors (anterior and posterior sectors at the base, midgland, and apex) and the intraoperative and postoperative dosimetry was compared in each individual sector. Postoperative dosimetry showed statistically significant changes (p < 0.01) in every dosimetric value except V150. In each significant case, the postoperative plans showed lower dose coverage. The conformity indexes also showed a bimodal frequency distribution with the index indicating poorer dose conformity in the postoperative plans. Sector analysis revealed less dose coverage postoperatively in the base and apex sectors with an increase in dose to the posterior midgland sector. Postoperative dosimetry overall and in specific sectors of the prostate differs significantly from intraoperative planning. Care must be taken during the intraoperative planning stage to ensure complete dose coverage of the prostate with the understanding that the final postoperative dosimetry will show less dose coverage.