Faculty Bibliography

BACKGROUND:There is limited understanding about why sarcopenia is happening in bladder cancer, and which modifiable and nonmodifiable patient-level factors affect its occurrence. OBJECTIVE:The objective is to determine the extent to which nonmodifiable risk factors, modifiable lifestyle risk factors, or cancer-related factors are determining body composition changes and sarcopenia in bladder cancer survivors. DESIGN, SETTING, AND PARTICIPANTS:Patients above 18 yr of age with a histologically confirmed diagnosis of bladder cancer and a history of receiving care at Duke University Medical Center between January 1, 1996 and June 30, 2017 were included in this study. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:Bladder cancer survivors from our institution were assessed for their dietary intake patterns utilizing the Diet History Questionnaire II (DHQ-II) and physical activity utilizing the International Physical Activity Questionnaire long form (IPAQ-L) tools. Healthy Eating Index 2010 (HEI2010) scores were calculated from DHQ-II results. Body composition was evaluated using Slice-O-Matic computed tomography scan image analysis at L3 level and the skeletal muscle index (SMI) calculated by three independent raters. RESULTS AND LIMITATIONS:A total of 285 patients were evaluated in the study, and the intraclass correlation for smooth muscle area was 0.97 (95% confidence interval: 0.94-0.98) between raters. The proportions of patients who met the definition of sarcopenia were 72% for men and 55% of women. Univariate linear regression analysis demonstrated that older age, male gender, and black race were highly significant predictors of SMI, whereas tumor stage and grade, chemotherapy, and surgical procedures were not predictors of SMI. Multivariate linear regression analysis demonstrated that modifiable lifestyle factors, including total physical activity (p=0.830), strenuousness (high, moderate, and low) of physical activity (p=0.874), individual nutritional components (daily calories, p=0.739; fat, p=0.259; carbohydrates, p=0.983; and protein, p=0.341), and HEI2010 diet quality (p=0.822) were not associated with SMI. CONCLUSIONS:Lifestyle factors including diet quality and physical activity are not associated with SMI and therefore appear to have limited impact on sarcopenia. Sarcopenia may largely be affected by nonmodifiable risk factors. PATIENT SUMMARY:In this report, we aim to determine whether lifestyle factors such as diet and physical activity were the primary drivers of body composition changes and sarcopenia in bladder cancer survivors. We found that lifestyle factors including dietary habits, individual nutritional components, and physical activity do not demonstrate an association with skeletal muscle mass, and therefore may have limited impact on sarcopenia.

The nephroureterectomy (NU) is the standard of care for invasive upper tract urothelial carcinoma (UTUC) and has been around for well over one hundred years. Since then new operative techniques have emerged, new technologies have developed, and the surgery continues to evolve and grow. In this article, we review the various surgical techniques, as well as present the literature surrounding current areas of debate surrounding the NU, including the lymphatic drainage of the upper urinary tract, management of UTUC involvement with the adrenals and caval thrombi, surgical management of the distal ureter, the use of intravesical chemotherapy as well as perioperative systemic chemotherapy, as well as various outcome measures. Although much has been studied about the NU, there still is a dearth of level 1 evidence and the field would benefit from further studies.

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: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: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.