Faculty Bibliography

BACKGROUND:We compared the short-term oncologic and functional outcomes of salvage focal cryotherapy (SFC) with those of salvage total cryotherapy (STC) for radiotherapy (RT)-persistent/recurrent prostate cancer. MATERIALS AND METHODS:We queried the Cryo On-Line Database registry for men who had undergone SFC and STC of the prostate for RT-persistent or recurrent disease. Propensity score weighting was used to match age at treatment, presalvage therapy prostate-specific antigen level, Gleason sum, and presalvage cryotherapy androgen deprivation therapy status. The primary outcome was progression-free survival. RESULTS:A total of 385 men with biopsy-proven persistent or recurrent prostate cancer after primary RT were included in the present study. The median follow-up, age, prostate-specific antigen, and Gleason sum before salvage cryotherapy was 24.4 months (first and third quartile, 9.8 and 60.3), 70 years (first and third quartile, 66 and 74 years), 4 ng/dL (first and third quartile, 2.7 and 5.6 ng/dL), and 7 (first and third quartile, 6 and 8), respectively. After propensity score weighting, the difference in progression-free survival was not statistically significant between the patients who had undergone STC and those who had undergone SFC (79.8% vs. 76.98%; P = .11 on weighted log-rank test). SFC was associated with a lower probability of post-treatment transient urinary retention (5.6% vs. 22.4%; P < .001). No significant differences were found in the incidence of rectal fistula (1.4% vs. 3.8; P = .30), new-onset urinary incontinence within 12 months (9.3% vs. 15.1%; P = .19), or new-onset erectile dysfunction within 12 months (52.6% vs. 59.6%; P = .47) between the SFC and STC groups, respectively. CONCLUSIONS:STC resulted in similar 2-year oncologic outcomes compared with SFC in the RT-persistent/recurrent disease population. However, the patients who had undergone SFC had a lower urinary retention rate compared with those who had undergone STC.

Non-muscle-invasive bladder cancer can be a challenging disease to manage. In recent years, hyperthermia therapy in conjunction with intravesical therapy has been gaining traction as a treatment option for bladder cancer, especially if Bacillus Calmette-Guerin might not be available. Trials of intravesical chemotherapy with heat are few and there has been considerable heterogeneity between studies. However, multiple new trials have accrued and high-quality data are forthcoming. In this review, we discuss the role of combined intravesical hyperthermia and chemotherapy as a novel approach for the treatment of bladder cancer.

BACKGROUND:Hyperthermia (heating to 43 °C) activates the innate immune system and improves bladder cancer chemosensitivity. OBJECTIVE:To evaluate the tissue penetration and safety of convective hyperthermia combined with intravesical mitomycin C (MMC) pharmacokinetics in live porcine bladder models using the Combat bladder recirculation system (BRS). METHODS:Forty 60 kg-female swine were anesthetized and catheterized with a 3-way, 16 F catheter. The Combat device was used to heat the bladders to a target temperature of 43 °C with recirculating intravesical MMC at doses of 40, 80, and 120 mg. Dwell-heat time varied from 30-180 min. Rapid necropsy with immediate flash freezing of tissues, blood and urine occurred. MMC concentrations were measured by liquid chromatography tandem-mass spectrometry. RESULTS:The Combat BRS system was able to achieve target range temperature (42-44 °C) in 12 mins, and this temperature was maintained as long as the device was running. Two factors increased tissue penetration of MMC in the bladder: drug concentration, and the presence of heat. In the hyperthermia arm, MMC penetration saturated at 80 mg, suggesting that with heating, drug absorption may saturate and not require higher doses to achieve the maximal biological effect. Convective hyperthermia did not increase the MMC concentration in the liver, heart, kidney, spleen, lung, and lymph node tissue even at the 120 mg dose. CONCLUSIONS:Convective bladder hyperthermia using the Combat BRS device is safe and the temperature can be maintained at 43 °C. Hyperthermia therapy may increase MMC penetration into the bladder wall but does not result in an increase of MMC levels in other organs.

BACKGROUND:Nearly 70% of all new cases of bladder cancer are non-muscle invasive disease, the treatment for which includes transurethral resection followed by intravesical therapy. Unfortunately, recurrence rates approach 50% in part due to poor intravesical drug delivery. Hyperthermia is frequently used as an adjunct to intravesical chemotherapy to improve drug delivery and response to treatment. OBJECTIVE:To assess the solubility profile of intravesical chemotherapies under varying conditions of pH and temperature. METHODS:Using microplate laser nephelometry we measured the solubility of three intravesical chemotherapy agents (mitomycin C, gemcitabine, and cisplatin) at varying physical conditions. Drugs were assessed at room temperature (23°C), body temperature (37°C), and 43°C, the temperature used for hyperthermic intravesical treatments. To account for variations in urine pH, solubility was also investigated at pH 4.00, 6.00, and 8.00. RESULTS:Heat incrementally increased the solubility of all three drugs studied. Conversely, pH largely did not impact solubility aside for gemcitabine which showed slightly reduced solubility at pH 8.00 versus 6.00 or 4.00. Mitomycin C at the commonly used 2.0 mg/mL was insoluble at room temperature, but soluble at both 37 and 43°C. CONCLUSIONS:Hyperthermia as an adjunct to intravesical treatment would improve drug solubility, and likely drug delivery as some current regimens are insoluble without heat. Improvements in solubility also allow for testing of alternative administration regimens to improve drug delivery or tolerability. Further studies are needed to confirm that improvements in solubility result in increased drug delivery.

Background/UNASSIGNED:Immune checkpoint inhibitors (ICI) are extremely expensive and most patients with metastatic urothelial carcinoma (mUC) do not benefit significantly from their use. Objective/UNASSIGNED:We performed a systematic review and meta-analysis to determine response rates and survival outcomes on patients with mUC progressing despite prior platinum-based chemotherapy receiving ICI stratified by biomarker status. Methods/UNASSIGNED:We performed a comprehensive literature search for all articles in PubMed and Embase up to 06/15/2019 to identify all studies pertaining to programmed death-ligand 1 (PD-L1) and programmed death 1 (PD-1) receptor targeted therapies for mUC that reported biomarkers. Given that biomarkers are reported on different scales and with different metrics, we defined each biomarker as either positive or negative using the definitions implemented in each individual trial. We meta-analyzed the data, reconstructed overall (OS) and progression-free survival (PFS) curves, and analyzed response rates by biomarker status. OS and PFS were analyzed in a pooled Kaplan-Meier analysis and pseudo-individualized patient data (IPD) extracted. Results/UNASSIGNED: < 0.001) when compared to the biomarker positive group. Response data was available for 1641 patients and random effects proportion show complete response in 8% and 3% in biomarker positive and negative patients, respectively. Conclusions/UNASSIGNED:ICI therapy for metastatic UC post platinum therapy has a higher overall response rate, OS and PFS in patients who are biomarker positive compared to those who are negative. However, some patients who are biomarker negative do achieve complete responses. A better biomarker for patient selection is essential before biomarkers can be used to stratify candidates for ICI therapy.

IMPORTANCE:Fluoroquinolone (FQ)-resistant rectal vault flora is associated with infectious complications in men undergoing transrectal ultrasound-guided prostate needle biopsy (TRUS-PNB). OBJECTIVE:To determine the patient factors that predict FQ-resistant rectal cultures in men who are undergoing transrectal ultrasound-guided prostate needle biopsy. METHODS:An IRB approved retrospective review of 6183 consecutive men who had undergone a rectal swab culture in preparation for TRUS-PNB between January 2013 and December 2014 was performed. Multivariable logistic regression was used to determine the clinical and demographic factors associated with FQ-resistant Enterobacteriaceae in the rectal vault. RESULTS:Of the 6179 rectal swabs analyzed, 4842 (78%) were FQ-sensitive, and 1337 (22%) were FQ-resistant. On univariable analysis, increasing age, prior TRUS-PNB, higher number of biopsy cores obtained, diabetes mellitus, antimicrobial use within the past 6 months and non-Caucasian race were predictors of FQ-resistance (all p < 0.05). Men with FQ-resistant cultures were more likely to have benign pathology on TRUS-PNB (p = 0.004). On multivariable analysis, increasing patient age (OR = 1.01/year [1.00-1.02]), use of antimicrobials in the last 6 months (OR = 2.85[2.18-3.72]), African American (OR = 1.99 [1.66-2.37]), Asian (OR = 3.39 [2.63-4.37]), and Hispanic (OR = 2.10 [1.72-2.55]) races were independently associated with FQ-resistant rectal cultures. The overall infectious rate was 1.1% (56/5214) and the sepsis rate was 0.46% (24/5214). The infection rate in the FQ-resistant group was 3.9% (43/1107) compared to FQ-sensitive group 0.3% (13/4107), p < 0.001. CONCLUSION:In this cohort, increasing age, recent antimicrobial-use, and non-Caucasian race were independent predictors of FQ-resistance in the rectal vault. As FQ-resistance is associated with infectious complications from transrectal ultrasound-guided prostate needle biopsy, understanding risk factors may assist infection control efforts.

The original version of this article contained an error in the name of author Alfredo Mena Lora. This has now been corrected.