Clinical Upstaging After Neoadjuvant Chemotherapy Impacting Eligibility for Vaginal-sparing Cystectomy: Identifying Bladder Cancer Patients Who May Benefit From Interim Imaging.

OBJECTIVE: Limited data exist on the frequency with which clinical progression during neoadjuvant chemotherapy (NAC) for muscle-invasive bladder cancer (MIBC) impacts eligibility for a vaginal-sparing surgical approach or on the utility of interim imaging assessment. We sought to evaluate the incidence of clinical upstaging following NAC that would render a patient ineligible for a vaginal-sparing cystectomy. METHODS: Eighty-nine female patients with non-metastatic MIBC treated with NAC and radical cystectomy (RC) (2012-2023) were retrospectively reviewed. Tumor location(s) was determined from transurethral resection of bladder tumor operative reports. Pre- and post-NAC clinical staging was determined from imaging. Outcomes of interest included clinical upstaging and upstaging to vaginal invasion after NAC. RESULTS: 75/89 patients had pre- and post-NAC imaging. Fifty-five had no change in clinical staging, 6 patients were upstaged (4 cT2→cT3, 2 cT3→cT4), and 14 patients were downstaged (13 cT3→cT2, 1 cT4→cT2). Of the 75 patients with pre- and post-NAC imaging, 39 had trigone tumors. Of these, 28 had no change in clinical staging, 2 were upstaged (1 cT2→cT3, 1 cT3→cT4) and 9 were downstaged (8 cT3→cT2, 1 cT4→cT2). Overall, 6/75 (8%) of patients demonstrated clinical upstaging after NAC. 2/39 (5%) of patients with trigone tumors clinically progressed after NAC and both had vaginal invasion (pT4) on final pathology. CONCLUSION: Although clinical upstaging after NAC was infrequent, 5% of patients with trigonal MIBC were rendered ineligible for vaginal-sparing cystectomy following NAC due to progression. Interim imaging assessment may identify non-responders and preserve eligibility for vaginal-sparing RC.

Impact of pathologic re-review on grade, clinical stage, and risk stratification for patients with nonmuscle invasive bladder cancer.

OBJECTIVES: Pathologic re-review of transurethral resection of bladder tumor (TURBT) specimen is a common practice at our tertiary care center, but its impact on disease risk stratification remains unknown. We sought to determine how pathologic re-review of specimen initially read at an outside institution changed grade, clinical T (cT) stage, and AUA non-muscle-invasive bladder cancer (NMIBC) risk stratification. METHODS AND MATERIALS: The laboratory information system was searched for patients who underwent TURBT from 2021 to 2022, yielding 561 records. 173 patients met inclusion criteria: 113 with

Body morphometry may predict parastomal hernia following radical cystectomy with ileal conduit.

OBJECTIVE: To investigate whether preoperative body morphometry analysis can identify patients at risk of parastomal hernia (PH), which is a common complication after radical cystectomy (RC). PATIENTS AND METHODS: All patients who underwent RC between 2010 and 2020 with available cross-sectional imaging preoperatively and at 1 and 2 years postoperatively were included. Skeletal muscle mass and total fat mass (FM) were determined from preoperative axial computed tomography images obtained at the level of the L3 vertebral body using Aquarius Intuition software. Sarcopenia and obesity were assigned based on consensus definitions of skeletal muscle index (SMI) and FM index (FMI). PH were graded using both the Moreno-Matias and European Hernia Society criteria. Binary logistic regression and recursive partitioning were used to identify patients at risk of PH. The Kaplan-Meier method with log-rank and Cox proportional hazards models included clinical and image-based parameters to identify predictors of PH-free survival. RESULTS: A total of 367 patients were included in the final analysis, with 159 (43%) developing a PH. When utilising binary logistic regression, high FMI (odds ratio [OR] 1.63, P < 0.001) and low SMI (OR 0.96, P = 0.039) were primary drivers of risk of PH. A simplified model that only relied upon FMI, SMI, and preoperative albumin improved the classification of patients at risk of PH. On Kaplan-Meier analysis, patients who were obese or obese and sarcopenic had significantly worse PH-free survival (P < 0.001). CONCLUSION: Body morphometry analysis identified FMI and SMI to be the most consistent predictors of PH after RC.

Oncologic outcomes of intravesical therapy in the management of nonmuscle invasive bladder cancer with variant histology.

PURPOSE: There is limited data on oncologic outcomes in nonmuscle invasive bladder cancer (NMIBC) with variant histology (VH) managed with intravesical therapy. We sought to evaluate oncologic outcomes for this cohort at a high-volume center. MATERIALS AND METHODS: A retrospective review of an IRB-approved bladder cancer database was performed. Patients with a history of NMIBC with VH present on transurethral resection of bladder tumor (TURBT) treated with intravesical therapy (BCG or chemotherapy) were identified. Outcomes of interest included recurrence within the bladder, progression to muscle-invasive bladder cancer (MIBC), metastatic progression, cancer-specific, and overall survival. Survival time was computed from the date of initiation of intravesical therapy to the date of event or censoring. For patients who underwent radical cystectomy, recurrence-free, cancer-specific, and overall survival were also computed. The Kaplan-Meier method with log rank was utilized to compare survival time between VH sub-groups. RESULTS: Ninety patients were included in the final cohort with a median follow-up of 38 months. The majority of patients had T1 disease (72%) and received intravesical BCG (83%) as their only form of intravesical therapy. The most commonly represented VH in this series were glandular and squamous differentiation (26%). Forty-eight patients (53%) experienced recurrence within the bladder with a median recurrence-free survival of 24 months (95% Confidence Interval [CI]: 2-46 months). Five-year rates of progression to MIBC and distant metastasis were both 14% respectively. Twenty-six patients (28%) eventually required cystectomy. When stratifying by VH, patients with sarcomatoid, plasmacytoid, and micropapillary had significantly worse oncologic outcomes. CONCLUSION: In this series of highly-selected patients with NMIBC and VH, bladder-sparing treatment with intravesical therapy demonstrated acceptable oncologic outcomes for most VHs. This may be an acceptable treatment option for patients without plasmacytoid, sarcomatoid, or micropapillary features who are not suitable cystectomy candidates or who prioritize bladder-sparing treatment.

Functional recovery after partial nephrectomy: next generation analysis.

OBJECTIVES: To provide a more rigorous assessment of factors affecting functional recovery after partial nephrectomy (PN) using novel tools that allow for analysis of more patients and improved accuracy for assessment of parenchymal volume loss, thereby revealing the potential impact of secondary factors such as ischaemia. PATIENTS AND METHODS: Of 1140 patients managed with PN (2012-2014), 670 (59%) had imaging and serum creatinine levels measured before and after PN necessary for inclusion. Recovery from ischaemia was defined as the ipsilateral glomerular filtration rate (GFR) saved normalised by parenchymal volume saved. Acute kidney injury was assessed through Spectrum Score, which quantifies the degree of acute ipsilateral renal dysfunction due to exposure to ischaemia that would otherwise be masked by the contralateral kidney. Multivariable regression was used to identify predictors of Spectrum Score and Recovery from Ischaemia. RESULTS: In all, 409/189/72 patients had warm/cold/zero ischaemia, respectively, with median (interquartile range [IQR]) ischaemia times for cold and warm ischaemia of 30 (25-42) and 22 (18-28) min, respectively. The median (IQR) global preoperative GFR and new baseline GFR (NBGFR) were 78 (63-92) and 69 (54-81) mL/min/1.73 m2 , respectively. The median (IQR) ipsilateral preoperative GFR and NBGFR were 40 (33-47) and 31 (24-38) mL/min/1.73 m2 , respectively. Functional recovery correlated strongly with parenchymal volume preserved (r = 0.83, P < 0.01). The median (IQR) decline in ipsilateral GFR associated with PN was 7.8 (4.5-12) mL/min/1.73 m2 with loss of parenchyma accounting for 81% of this loss. The median (IQR) recovery from ischaemia was similar across the cold/warm/zero ischaemia groups at 96% (90%-102%), 95% (89%-101%), and 97% (91%-102%), respectively. Independent predictors of Spectrum Score were ischaemia time, tumour complexity, and preoperative global GFR. Independent predictors of recovery from ischaemia were insulin-dependent diabetes mellitus, refractory hypertension, warm ischaemia, and Spectrum Score. CONCLUSIONS: The main determinant of functional recovery after PN is parenchymal volume preservation. A more robust and rigorous evaluation allowed us to identify secondary factors including comorbidities, increased tumour complexity, and ischaemia-related factors that are also independently associated with impaired recovery, although altogether these were much less impactful.

PAM50 and Beyond: When Will Tissue Transcriptomics Guide Clinical Decision-making?

Emerging transcriptomics-based classifiers show promise as biomarkers to guide clinical decision-making in prostate cancer, but require further research, optimization, and validation.

The association between modifiable perioperative parameters and renal function after nephrectomy.

OBJECTIVE: To evaluate the association between intraoperative anaesthetic parameters, primarily intraoperative hypotension, and postoperative renal function in patients undergoing nephrectomy. PATIENTS AND METHODS: We reviewed data from 3240 consecutive patients who underwent nephrectomy between 2010 and 2018. Anaesthetic parameters evaluated included duration of hypotension, tachycardia, hypothermia, volatile anaesthetic use and mean arterial pressure in the post-anaesthesia care unit. Outcomes included acute kidney injury (AKI) and estimated glomerular filtration rate (eGFR) within the first year after nephrectomy. Associations between anaesthetic parameters and outcomes were evaluated with multivariable logistic regression and generalised estimating equation, respectively, adjusted for predictors of renal function after nephrectomy. RESULTS: Before nephrectomy, 677 (21%) patients had moderate-severe chronic kidney disease. A quarter of patients (n = 809) had postoperative AKI and 35% (n = 746) had Stage ≥3 chronic kidney disease 12-months after surgery. Only 12% of patients (n = 386) had >5 min of intraoperative hypotension. While not statistically significant, longer duration of intraoperative hypotension was associated with slightly higher rates of AKI (odds ratio [OR] per 10-min 1.14, 95% confidence interval [CI] 0.98, 1.32). Prolonged hypothermia was associated with increased rate of AKI (OR per 10-min 1.02, 95% CI 1.00, 1.04), and decreased eGFR (change in eGFR per 10-min -0.19, 95% CI -0.27, -0.12); however, these results have limited clinical significance. CONCLUSIONS: Under current practice, intraoperative anaesthetic parameters are tightly maintained, restricting the significance of their effect on postoperative renal function. Future studies should evaluate whether haemodynamic parameters during the early postoperative period, when they are monitored less frequently, are associated with renal functional outcome.

Contemporary management of advanced prostate cancer: an evolving landscape.

Recent population-based studies suggest that the incidence of advanced and metastatic prostate cancer may be increasing. Concurrently with this apparent stage migration toward advanced disease, several major developments have occurred in the treatment paradigm for men with advanced prostate cancer. These include the US Food and Drug Administration approval of 8 novel agents over the last decade. In addition to novel pharmaceuticals, rapidly evolving diagnostic tools have emerged. This review provides a primer for clinicians who treat men with advanced prostate cancer, including medical oncologists, radiation oncologists, and urologists.

Impact of 5α-Reductase Inhibitors on Disease Reclassification among Men on Active Surveillance for Localized Prostate Cancer with Favorable Features.

PURPOSE: We determined the effect of 5α-reductase inhibitors on disease reclassification in men with prostate cancer optimally selected for active surveillance. MATERIALS AND METHODS: In this retrospective review we identified 635 patients on active surveillance between 2002 and 2015. Patients with favorable cancer features on repeat biopsy, defined as absent Gleason upgrading, were included in the cohort. Patients were stratified by those who did or did not receive finasteride or dutasteride within 1 year of diagnosis. The primary end point was grade reclassification, defined as any increase in Gleason score or predominant Gleason pattern on subsequent biopsy. This was assessed by multivariable Cox proportional hazards regression analysis. RESULTS: At diagnosis 371 patients met study inclusion criteria, of whom 70 (19%) were started on 5α-reductase inhibitors within 12 months. Median time on active surveillance was 53 vs 35 months in men on vs not on 5α-reductase inhibitors (p <0.01). Men on 5α-reductase inhibitors received them for a median of 23 months (IQR 6-37). On actuarial analysis there was no significant difference in grade reclassification for 5α-reductase inhibitor use in patients overall or in the very low/low risk subset. The overall percent of patients who experienced grade reclassification was similar at 13% vs 14% (p = 0.75). After adjusting for baseline clinicopathological features 5α-reductase inhibitors were not significantly associated with grade reclassification (HR 0.80, 95% CI 0.31-1.80, p = 0.62). Furthermore, no difference in adverse features on radical prostatectomy specimens was observed in treated patients (p = 0.36). CONCLUSIONS: Among our cohort of men on active surveillance 5α-reductase inhibitor use was not associated with a significant difference in grade reclassification with time.

Intermediate-Term Outcomes for Men with Very Low/Low and Intermediate/High Risk Prostate Cancer Managed by Active Surveillance.

PURPOSE: We compare intermediate term clinical outcomes among men with favorable risk and intermediate/high risk prostate cancer managed by active surveillance. MATERIALS AND METHODS: A total of 635 men with localized prostate cancer have been on active surveillance since 2002 at a high volume academic hospital in the United States. Median followup is 50.5 months (IQR 31.1-80.3). Time to event analysis was performed for our clinical end points. RESULTS: Of the cohort 117 men (18.4%) had intermediate/high risk disease. Overall 5 and 10-year all cause survival was 98% and 94%, respectively. Cumulative metastasis-free survival at 5 and 10 years was 99% and 98%, respectively. To date no cancer specific deaths had been observed. Overall freedom from intervention was 61% and 49% at 5 and 10 years, respectively. Overall cumulative freedom from failure of active surveillance, defined as metastasis or biochemical failure after local therapy with curative intent, was 97% and 91% at 5 and 10 years, respectively. Of the men 21 (9.9%) experienced biochemical failure after deferred treatment and the 5-year progression-free probability was 92%. Compared to men with favorable risk disease those with intermediate/high risk cancer experienced no difference in metastases, surveillance failure or curative intervention. However, patients at higher risk were at significantly increased risk for all cause mortality, likely reflecting patient selection factors. These conclusions may be limited by the small number of events and the duration of our study. CONCLUSIONS: Patients with localized prostate cancer who are on active surveillance demonstrated a low rate of active surveillance failure, prostate cancer specific mortality and metastases regardless of baseline risk.

Central but not systemic lipid infusion augments the counterregulatory response to hypoglycemia.

This study tests the hypothesis that lipids could act as an alternative fuel source in the brain during insulin-induced hypoglycemia. Male Sprague-Dawley rats were subjected to hyperinsulinemic (5 mU.kg(-1).min(-1)) hypoglycemic (approximately 50 mg/dl) clamps. In protocol 1, intralipid (IL), a fat emulsion, was infused intravenously to prevent the fall in free fatty acid levels that occurs in response to hyperinsulinemic hypoglycemia. Intravenous lipid infusion did not alter the counterregulatory responses to hypoglycemia. To test whether IL could have central effects in mediating the counterregulatory response to hypoglycemia, in protocol 2 the brains of precannulated rats were intracerebroventricularly (icv) infused with IL or artificial cerebrospinal fluid (aCSF) as control. Unexpectedly, the epinephrine and glucagon response to hypoglycemia was significantly augmented with icv IL infusion. To determine whether central IL infusion could restore defective counterregulation, in protocol 3 rats were made recurrently hypoglycemic (RH) for 3 days and on the 4th day underwent hyperinsulinemic hypoglycemic clamps with icv IL or aCSF infusion. RH rats had the expected impaired epinephrine response to hypoglycemia, and icv IL infusion again significantly augmented the epinephrine response in RH rats to normal. With regard to our experimental model of hypoglycemic counterregulation, we conclude that 1) systemic lipid infusion did not alter the counterregulatory response to hypoglycemia, 2) the icv infusion of lipids markedly increased CSF FFA levels and paradoxically augmented the epinephrine and glucagon responses, and 3) the blunted sympathoadrenal response in recurrently hypoglycemic rats was completely normalized with the icv lipid infusion. It is concluded that, in the setting of insulin-induced hypoglycemia, increased brain lipids can enhance the sympathoadrenal response.

Brain insulin infusion does not augment the counterregulatory response to hypoglycemia or glucoprivation.

Although high dosages of insulin can cause hypoglycemia, several studies suggest that increased insulin action in the head may paradoxically protect against severe hypoglycemia by augmenting the sympathoadrenal response to hypoglycemia. We hypothesized that a direct infusion of insulin into the third ventricle and/or the mediobasal hypothalamus (MBH) would amplify the sympathoadrenal response to hypoglycemia. Nine-week-old male rats had insulin (15 mU) or artificial cerebrospinal fluid (aCSF, control) infused bilaterally into the MBH or directly into the third ventricle. During the final 2 hours of the brain insulin or aCSF infusions, the counterregulatory response to either a hyperinsulinemic hypoglycemic (approximately 50 mg/dL) clamp or a 600-mg/kg intravenous bolus of 2-deoxyglucose (2DG) was measured. 2-Deoxyglucose was used to induce a glucoprivic response without peripheral insulin infusion. In response to insulin-induced hypoglycemia, epinephrine rose more than 60-fold, norepinephrine rose more than 4-fold, glucagon rose 8-fold, and corticosterone rose almost 2-fold; but these increments were not different in aCSF vs insulin treatment groups with either intracerebroventricular or bilateral MBH insulin protocols. Intracerebroventricular insulin infusion stimulated insulin signaling as noted by a 5-fold increase in AKT phosphorylation. In the absence of systemic insulin infusion, 2DG-induced glucopenia resulted in an equal counterregulatory response with brain aCSF and insulin infusions. Under the conditions studied, although insulin infusion acted to stimulate hypothalamic insulin signaling, neither intrahypothalamic nor intracerebroventricular insulin infusion augmented the counterregulatory response to hypoglycemia or to 2DG-induced glucoprivation. Therefore, it is proposed that the previously noted acute actions of insulin to augment the sympathoadrenal response to hypoglycemia are likely mediated via mechanisms exterior to the central nervous system.