Successful Diagnosis and Treatment of Occult Prostate Cancer Despite Multiple Negative Prostate Biopsies and Negative Prostate MRIs.

Prostate-specific antigen (PSA) values above 100 ng/mL often suggest metastatic prostate cancer. We present the case of a patient with a PSA of 110 ng/mL, 4 negative prostate biopsies, and 4 negative prostate MRIs. After his fifth MRI revealed a PI-RADS 5 lesion, he underwent his fifth transrectal biopsy; this revealed Gleason 3 + 4 = 7. He was found to have organ-confined pT2 disease on subsequent radical prostatectomy pathology. This case highlights that there may be no PSA for which one can assume metastatic disease with certainty. Depending on life expectancy, patients with extremely elevated PSA may still warrant a full staging workup.

Safety and efficacy of intravesical chemotherapy and hyperthermia in the bladder: results of a porcine study.

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.

Genomic Scores are Independent of Disease Volume in Men with Favorable Risk Prostate Cancer: Implications for Choosing Men for Active Surveillance.

PURPOSE: We sought to determine whether disease volume at prostate biopsy would correlate with genomic scores among men with favorable risk prostate cancer. MATERIALS AND METHODS: We identified all men with NCCN® (National Comprehensive Cancer Network®) very low and low risk disease who underwent Oncotype DX® prostate testing at our institution from 2013 to 2016. Disease volume was characterized as the percent of positive cores, the number of cores with greater than 50% involvement, the largest involvement of any single core and prostate specific antigen density. Nonparametric testing was performed to compare the median Genomic Prostate Score™ and the likelihood of favorable pathology findings between quartiles of disease volume. RESULTS: We identified 112 (37.8%) and 184 men (62.2%) at NCCN very low and low risk, respectively. Median scores did not differ significantly between disease volume quartiles (all p >0.05). However, the median likelihood of favorable pathology findings statistically differed between volume quartiles (all <0.05). Seven of the 105 men (6.3%) with very low risk disease were reclassified at low risk and 13 of 181 (7.2%) with low risk disease were reclassified at intermediate risk. Genomic disease reclassification did not depend on biopsy tumor volume. CONCLUSIONS: In patients with NCCN very low and low risk prostate cancer genomic scores did not demonstrate meaningfully significant differences by volume based on clinically established cutoff points. Moreover, genomic scores identified and reclassified men with higher risk disease despite generally acceptable surveillance characteristics in this group according to grade and volume. This suggests that in patients at low risk the tumor biological potential measured by genomics rather than by volume should inform decisions on active surveillance candidacy.

Early MRI Detection and Closed Bone Graft Epiphysiodesis May Alter the Course of Avascular Necrosis Following Unstable Slipped Capital Femoral Epiphysis.

BACKGROUND: Unstable slipped capital femoral epiphysis (SCFE) has an increased incidence of avascular necrosis (AVN). Early identification and surgical intervention for AVN may help preserve the femoral head. METHODS: We retrospectively reviewed 48 patients (50 hips) with unstable SCFE managed between 2000 and 2014. AVN was diagnosed based on 2 different postoperative protocols. Seventeen patients (17 hips) had a scheduled magnetic resonance imaging (MRI) between 1 and 6 months from initial surgery, and the remaining 31 patients (33 hips) were evaluated by plain radiographs alone. If AVN was diagnosed, we offered core decompression and closed bone graft epiphysiodesis (CBGE) to mitigate its affects. At final follow-up, we assessed progression of AVN using the Steinberg classification. RESULTS: Overall 13 hips (26%) with unstable SCFEs developed AVN. MRI revealed AVN in 7 of 17 hips (41%) at a mean of 2.5 months postoperatively (range, 1.0 to 5.2 mo). Six hips diagnosed by MRI received surgical intervention (4 CBGE, 1 free vascularized fibula graft, and 1 repinning due to screw cutout) at a mean of 4.1 months (range, 1.3 to 7.2 mo) postoperatively. None of the 4 patients treated with CBGE within 2 months postoperatively progressed to stage IVC AVN. The 2 patients treated after 4 months postoperatively both progressed to stage VC AVN.Plain radiographs demonstrated AVN in 6 of 33 hips (18%) at a mean of 6.8 months postoperatively (range, 2.1 to 21.1 mo). One patient diagnosed with stage IVB AVN at 2.4 months had screw cutout and received CBGE at 2.5 months from initial pinning. The remaining 5 were not offered surgical intervention. Five of the 6 radiographically diagnosed AVN, including the 1 treated with CBGE, progressed to stage IVC AVN or greater. CONCLUSIONS: Although all patients with positive MRI scans developed radiographic AVN, none of the 4 patients treated with CBGE within 2 months after pinning developed grade IVC or greater AVN. Early MRI detection and CBGE may mitigate the effects of AVN after SCFE. LEVEL OF EVIDENCE: Level III-retrospective comparative study.

Update on Intraoperative Cultures, Biofilms, and Modifiable Factors During Revision of Clinically Non-Infected Penile Implants.

INTRODUCTION: Penile implants have a limited lifespan, and as the population using inflatable penile prostheses ages, revision surgery has become increasingly common. Devices are frequently cultured during non-infectious revision surgeries, providing a burgeoning of evidence of positive cultures without clinical infection. However, the clinical significance of these cultures remains unclear. OBJECTIVES: We aim to review the current literature on culture results from revision surgery for clinically non-infected devices and summarize the available data to formulate a synopsis of clinically significant organisms and their significance and modifiable approaches to prosthesis surgery. METHODS: A literature review was performed on 1 March, 2020 in PubMed and Google Scholar. Search terms centered on penile prosthesis revision surgery, cultures, and infection. Titles and abstracts were reviewed for topical relevance with emphasis placed on literature from the last 20 years. Most publications comprised small case series aside from a single meta-analysis. RESULTS: Since 1995, seven series have been published examining culture positivity at the time of revision surgery for clinically non-infected devices. Isolated organisms are most commonly from the Staphylococcus genus with Staphylococcus epidermidis being the most frequently isolated organism on clinically non-infected devices. Reported culture positivity rates at the time of revision range between 9.8% and 80%. CONCLUSION: Current literature pertaining to the clinical significance of culture positivity at the time of revision surgery for clinically non-infected penile prostheses is lacking; however, multiple series do report high rates of culture positivity. This does appear to confer a higher rate of subsequent infection and a lower revision-free survival. Staphylococcus epidermidis is the most commonly isolated organism followed by other members of the Staphylococcus genus. Further studies are needed to determine the impact of modifiable variables or techniques on asymptomatic culture positivity and the ideal technologies for biofilm prevention. Nosé BD, Grimberg DCD, Lentz AC. Update on Intraoperative Cultures, Biofilms, and Modifiable Factors During Revision of Clinically Non-Infected Penile Implants. Sex Med Rev 2021;9:160-168.

Clinical trial of high dose hyperthermic intravesical mitomycin C for intermediate and high-risk non-muscle invasive bladder cancer during BCG shortage.

PURPOSE: Intravesical Bacillus Calmette-Guérin (BCG) is the gold standard for intermediate and high-risk non-muscle invasive bladder cancer (NMIBC), but availability is limited by global shortages. We present the first North American clinical experience using intravesical hyperthermia (HIVEC) with high-dose mitomycin C (MMC) during BCG shortage. MATERIALS AND METHODS: Single arm intermediate size expanded access protocol for high dose HIVEC MMC in patients with intermediate and high-risk NMIBC during BCG shortage. Patients received 120 mg intravesical MMC using the Combat BRS to achieve 43°C HIVEC. Primary outcome was a safety assessment of adverse events, with recurrence-free survival and a descriptive analysis of hematologic impacts as secondary outcomes. RESULTS: Fourteen patients were treated from May 2019 to June 2020, 4 (29%) intermediate and 10 (71%) high risk. The cohort is heavily pretreated, only 2 (14%) BCG naïve and median 6 BCG instillations (IQR 5.25, 8.25), with median 3.5 recurrences per patient (IQR 1.00, 5.25) 67% with >1 per year. Patients underwent a median 6 instillations (IQR 3.25, 9.25) which were well tolerated in 11/14 (79%). Seven patients (50%) experienced 10 adverse events, all grades 1 or 2. Most common was MMC allergy (4/14, 29%), followed by bladder spasm (3/14, 21%). Two had recurrences at median 11 months follow up, but both discontinued HIVEC after only 2 treatments. CONCLUSIONS: High dose MMC HIVEC is a safe and well-tolerated substitute for BCG during global shortages. The higher rate of systemic effects implies increased drug delivery, which may improve efficacy.

Overview of Taris GemRIS, a Novel Drug Delivery System for Bladder Cancer.

GemRIS, an implantable drug delivery system from Taris Biomedical that delivers continuous intravesical gemcitabine, shows potential for use in multiple bladder cancer settings. Ongoing and recently completed phase 1 trials in non-muscle-invasive as well as muscle-invasive bladder cancer are yielding promising preliminary results.

Assessments of frailty in bladder cancer.

BACKGROUND AND AIMS: The incidence of frailty is increasing as the population ages, which has important clinical implications given the associations between frailty and poor outcomes in the bladder cancer population. Due to a multi-organ system decline and decreased physiologic reserve, frail patients are vulnerable to stressors of disease and have poorer mortality and morbidity rates than their nonfrail peers. The association between frailty and poor outcomes has been documented across multiple populations, including radical cystectomy, creating a need for frailty assessments to be used preoperatively for risk stratification. We aim to provide a review of the common frailty assessments and their relevance to radical cystectomy patients. FINDINGS: A variety of assessments for frailty exist, from short screening items to comprehensive geriatric assessments. The syndrome spans multiple organ systems, as do the potential diagnostic instruments. Some instruments are less practical for use in clinical practice by urologists, such as the Canadian Study of Health and Aging Frailty Index and Comprehensive Geriatric Assessment. The tool most studied in radical cystectomy is the modified Frailty Index, associated with high grade complications and 30-days mortality. Frailty often coexists with malnutrition and sarcopenia, stressing the importance of screening for and addressing these syndromes to improve patient's perioperative outcomes. CONCLUSIONS: There is no universally agreed upon frailty assessment, but the most studied in radical cystectomy is the modified Frailty Index, providing valuable data with which to counsel patients preoperatively. Alterations in immune phenotypes provide potential future diagnostic biomarkers for frailty.

Hyperthermia Improves Solubility of Intravesical Chemotherapeutic Agents.

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.

Results and Outcomes After Midshaft Clavicle Fracture: Matched Pair Analysis of Operative Versus Nonoperative Management.

This study evaluated patients with displaced clavicle fractures treated surgically vs nonoperatively. The authors hypothesized that functional outcomes would be no different. A retrospective comparative study was performed of 138 patients with closed midshaft clavicle fractures. Sixty-nine patients were treated operatively and matched for sex, age, and fracture pattern to 69 patients treated nonoperatively. Charts and radiographs were reviewed, and the American Shoulder and Elbow Surgeons survey was administered. A poor outcome was defined as a treatment complication or an American Shoulder and Elbow Surgeons score less than 60. There were 116 men and 22 women with a mean age of 37.7 years and fracture patterns of 15B-1 (n=78), 15B-2 (n=48), and 15B-3 (n=12). Thirty-seven percent were tobacco smokers, with 23 treated operatively and 28 nonoperatively. Ten (14.5%) initially nonoperative patients underwent plate fixation at a mean of 25.9 weeks (range, 7-48 weeks) because of persistent pain and motion at the fracture site. Fifteen (21.7%) of the 69 patients treated acutely with surgery had 16 complications, which resulted in secondary procedures in 11 patients (15.9%). Overall, poor outcomes occurred in 21 (30.4%) of 69 after fixation and in 19 (27.5%) of 69 in the nonoperative group. Unemployment (P=.05) and tobacco use (P=.03) were associated with poor outcome, irrespective of type of treatment. Initial nonoperative treatment presents a reasonable option for many patients. No differences in complications or poor outcomes were noted for surgical vs nonoperative treatment. Social factors proved to be greater predictors of outcome than other patient or injury features. Management of clavicle fractures should be individualized with assessment of patient expectations and activity level. Social factors should also be considered. [Orthopedics. 2018; 41(5):e689-e694.].

Factors Associated With Narcotic Use After Clavicle Fractures.

Clavicle fractures are common in adults. Recent studies have shown that operative treatment of clavicle fractures has benefits in many situations. However, there is controversy about the indications. Data on social outcomes are limited. A total of 434 patients with 436 clavicle fractures treated both operatively and nonoperatively at a level 1 trauma center were identified. Narcotic use was recorded 2, 4, 6, 8, 10, 12, 14, and 16 weeks after injury for both treatment groups. Other descriptive data included age, sex, laterality, hand dominance, rib fractures, smoking, alcohol use, employment, long bone or spine fracture, open clavicle fracture, and mechanism of injury. Logistic regression analysis was performed to determine the independent predictors of narcotic use after clavicle fracture. Open reduction and internal fixation was performed in 105 fractures (24%), and 329 fractures were managed nonoperatively. A total of 154 patients (35%) reported some narcotic use 2 weeks after injury, and 15% were still using narcotics 16 weeks after injury. Narcotic use decreased over time in patients treated with open reduction and internal fixation (10% vs 15% after nonoperative management). Patients treated with open reduction and internal fixation reported reduced narcotic use at 16 weeks (odds ratio [OR], 0.454; P=.070). Concurrent rib fracture (OR, 5.668; P<.001), smoking (OR, 3.095; P=.013), unemployment (OR, 5.429; P<.0005), and long bone or spine fracture (OR, 6.761; P<.001) were predictors of narcotic use. Further studies of the social, economic, and financial outcomes of clavicle fracture and osteosynthesis are warranted. [Orthopedics. 2016; 39(5):e917-e923.].