Integrating Prostate-specific Antigen Kinetics into Contemporary Predictive Nomograms of Salvage Radiotherapy After Radical Prostatectomy.

BACKGROUND: Salvage radiotherapy (SRT) is an established treatment for men with biochemical recurrence following radical prostatectomy (RP). There are several risk factors associated with adverse outcomes; however, the value of postoperative prostate-specific antigen (PSA) kinetics is less clear in the ultrasensitive PSA era. OBJECTIVE: To characterize the impact of PSA kinetics on outcomes following SRT and generate nomograms to aid in identifying patients with an increased risk of adverse clinical outcomes. DESIGN, SETTING, AND PARTICIPANTS: A multi-institutional analysis was conducted of 1005 patients with prostate cancer treated with SRT after RP, with a median follow-up of 5 years. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Variables examined include immediate postoperative PSA, postoperative PSA doubling time (DT), and pre-SRT PSA, in addition to previously identified predictive factors. Multivariable survival analyses were completed using Fine-Gray competing risk regression. Rates of biochemical failure (BF), distant metastasis (DM), and prostate cancer-specific mortality (PCSM) were estimated by the cumulative incidence method. Nomograms were generated from multivariable competing risk regression with bootstrap cross-validation. RESULTS AND LIMITATIONS: Factors associated with BF after SRT include PSA DT <6 mo, initial postoperative PSA ≥0.2 ng/ml, higher pre-SRT PSA, lack of androgen deprivation therapy, a higher Gleason score (GS), negative margins, seminal vesicle invasion, lack of pelvic nodal radiation, radiation total dose <66 Gy, a longer RP to SRT interval, and older age (p < 0.05 for each). Factors associated with DM include PSA DT <6 mo, pre-SRT PSA, a higher GS, and negative margins. Factors associated with PCSM include PSA DT not calculable or <6 mo and a higher GS. Nomograms were generated to estimate the risks of BF (concordance index [CI] 0.74), DM (CI 0.77), and PCSM (CI 0.77). Limitations include retrospective nature, broad treatment eras, institutional variations, and multiple methods available for the estimation of PSA DT. CONCLUSIONS: Postoperative PSA kinetics, particularly pre-SRT PSA and PSA DT, are strongly associated with adverse oncologic outcomes following SRT and should be considered in management decisions. PATIENT SUMMARY: In this report of men with prostate cancer who developed a prostate-specific antigen (PSA) recurrence after prostatectomy, we found that PSA levels after surgery and how quickly a PSA level doubles significantly impact the chance of prostate cancer recurrence after salvage radiation therapy. Based on this information, we created a tool to calculate a man's chance of cancer recurrence after salvage radiation therapy, and these estimations can be used to discuss whether additional treatment with radiation should be considered.

Erythrocytosis is associated with intradialytic hypotension: a case series.

BACKGROUND: For patients with end stage renal disease undergoing hemodialysis, erythrocytosis occurs rarely. Erythrocytosis increases the risk of thrombosis, which is a common complication in hemodialysis patients. The risk of thrombosis may also be increased by hypotension. The purpose of our report is to examine the relationship between intradialytic hypotension and erythrocytosis. CASE PRESENTATION: We present a series of five patients with end stage renal disease and erythrocytosis (peak hemoglobin range 15.2-18.5 g/dL). All were erythropoiesis-stimulating agent naïve and non-smokers. Prior to developing erythrocytosis, each patient developed recurring episodes of intradialytic hypotension over several months. A statistically significant inverse correlation was observed between nadir intradialytic systolic blood pressure and hemoglobin concentration. In the index case, midodrine treatment resulted in resolution of the hypotension and erythrocytosis. Most of the patients had multiple acquired renal cysts, which is a potential source of erythropoietin. Four of the five cases developed arteriovenous dialysis access or deep venous thrombosis. CONCLUSIONS: An association between intradialytic hypotension and erythrocytosis was observed in five cases. We postulate that chronic intermittent hypotension and renal ischemia may lead to erythropoietin secretion, and this cascade could represent a newly recognized cause of secondary erythrocytosis.

Urologic provider experiences in transitioning spina bifida patients from pediatric to adult care.

PURPOSE: The lack of precedent in transitioning from pediatric to adult care poses a challenge to providers for patients with spina bifida (SB). The purpose of this study was to summarize perceptions about best practices for the care of adult spina bifida patients. MATERIALS AND METHODS: A national survey was electronically distributed to 174 urologists who are current members of the Spina Bifida Association Network and AUA Working Group on Urologic Congenitalism. De-identified voluntary responses were assessed for implementation of and barriers to interdisciplinary adult SB clinics, continuity of care, and practices for transitioning from pediatric to adult care. RESULTS: The response rate was 40% with urologists practicing pediatrics, genitourinary reconstruction, female pelvic medicine and general urology. Patients undergoing transition or who have transitioned were seen in a multidisciplinary clinic (14%), regular adult clinic (34%), combined adult-pediatric multidisciplinary care (20%), or pediatric multidisciplinary clinic (28%). A majority believed transitioning to adult care should occur at 18 (24%) or 21 years (22%). In the absence of acute changes, providers followed adult SB patients annually with upper tract imaging (typically renal ultrasound) and serum creatinine. Acute urologic changes were preferentially managed with urodynamic testing and cystoscopy. Providers identified a need for multidisciplinary care in adult life, with neurosurgery/neurology (87%), social work (84%), and orthopedics (73%). CONCLUSIONS: Potential solutions to improve the urologic care of this population suggest additional national provider resources, standardized guidelines, multidisciplinary collaboration, access to care, and an advanced-training pathway to improve care of adult patients with spina bifida.

Improved surgical outcomes following radical cystectomy at high-volume centers influence overall survival.

OBJECTIVES: Positive surgical margins (PSM) and lymph node yield (LNY) following radical cystectomy (RC) for urothelial carcinoma of the bladder affect survival. Variations in PSM or LNY at different care facilities are poorly described. We evaluated the relationship between hospital surgical volume and academic hospital status with these surgical outcomes and overall survival (OS). METHODS AND MATERIALS: Patients with nonmetastatic urothelial carcinoma of the bladder who underwent RC were identified from the National Cancer Database (2004-2013). Treatment centers were categorized as academic (ACC) and community cancer centers (CCC). Logistic regression was used to identify factors associated with PSM status and LNY, and a multivariate Cox proportional hazards model was used to determine factors associated with OS. RESULTS: In our cohort, 39,274 patients underwent RC. A lower proportion of PSMs (10% vs.12%; P<0.001) and higher median LNY (14 vs. 8, P<0.001) was observed at ACCs compared to CCCs. On logistic regression, there were lower odds of PSM (OR = 0.89, 95% CI: 0.81-0.97) and higher odds of LNY ≥ 10 nodes (OR = 1.84, 95% CI: 1.74-1.96) among patients at ACCs compared to CCCs. Cox proportional hazards analysis demonstrated benefit to OS at high-volume centers (HR = 0.91, 95% CI: 0.87-0.95) but not based on ACC designation. The OS advantage at high-volume centers is attenuated (HR = 0.95, 95% CI: 0.91-0.99) by PSM status and LNY. CONCLUSIONS: ACCs demonstrate improved surgical outcomes following RC, and a survival advantage attributable to high surgical volume is identified. Centralization of care may lead to improved outcomes in this lethal malignancy.

Comparison Between Adjuvant and Early-Salvage Postprostatectomy Radiotherapy for Prostate Cancer With Adverse Pathological Features.

Importance: Prostate cancer with adverse pathological features (ie, pT3 and/or positive margins) after prostatectomy may be managed with adjuvant radiotherapy (ART) or surveillance followed by early-salvage radiotherapy (ESRT) for biochemical recurrence. The optimal timing of postoperative radiotherapy is unclear. Objective: To compare the clinical outcomes of postoperative ART and ESRT administered to patients with prostate cancer with adverse pathological features. Design, Setting, and Participants: This multi-institutional, propensity score-matched cohort study involved 1566 consecutive patients who underwent postprostatectomy ART or ESRT at 10 US academic medical centers between January 1, 1987, and December 31, 2013. Propensity score 1-to-1 matching was used to account for covariates potentially associated with treatment selection. Data were collected from January 1 to September 30, 2016. Data analysis was conducted from October 1, 2016, to October 21, 2017. Main Outcomes and Measures: Freedom from postirradiation biochemical failure, freedom from distant metastases, and overall survival. All outcomes were measured from date of surgery to address lead-time bias. Results: Of 1566 patients, 1195 with prostate-specific antigen levels of 0.1 to 0.5 ng/mL received ESRT and 371 patients with prostate-specific antigen levels lower than 0.1 ng/mL received ART. The median age (interquartile range) was 60 (55-65) years. After propensity score matching, the median (interquartile range) follow-up after surgery was similar between the ESRT and ART groups (73.3 [44.9-106.6] months vs 65.8 [40-107] months; P = .22). Adjuvant RT, compared with ESRT, was associated with higher freedom from biochemical failure (12-year actuarial rates: 69% [95% CI, 60%-76%] vs 43% [95% CI, 35%-51%]; effect size, 26%), freedom from distant metastases (95% [95% CI, 90%-97%] vs 85% [95% CI, 76%-90%]; effect size, 10%), and overall survival (91% [95% CI, 84%-95%] vs 79% [95% CI, 69%-86%]; effect size, 12%). Adjuvant RT, lower Gleason score and T stage, nodal irradiation, and postoperative androgen deprivation therapy were favorable prognostic features on multivariate analysis for biochemical failure. Sensitivity analysis demonstrated that the decreased risk of biochemical failure associated with ART remained significant unless more than 56% of patients in the ART group were cured by surgery alone. This threshold is greater than the estimated 12-year freedom from biochemical failure rate of 33% to 52% after radical prostatectomy alone, as determined by a contemporary dynamic nomogram. Conclusions and Relevance: Adjuvant RT, compared with ESRT, was associated with reduced biochemical recurrence, distant metastases, and death for high-risk patients, pending prospective validation. These findings suggest that a greater proportion of patients with prostate cancer who have adverse pathological features may benefit from postprostatectomy ART rather than surveillance followed by ESRT.

Multi-institutional Evaluation of Elective Nodal Irradiation and/or Androgen Deprivation Therapy with Postprostatectomy Salvage Radiotherapy for Prostate Cancer.

BACKGROUND: Outcomes with postprostatectomy salvage radiation therapy (SRT) are not ideal. Little evidence exists regarding potential benefits of adding whole pelvic radiation therapy (WPRT) alone or in combination with androgen deprivation therapy (ADT). OBJECTIVE: To explore whether WPRT and/or ADT added to prostate bed radiation therapy (PBRT) improves freedom from biochemical failure (FFBF) or distant metastases (DM). DESIGN, SETTING, AND PARTICIPANTS: A database was compiled from 10 academic institutions of patients with postprostatectomy prostate-specific antigen (PSA) >0.01 ng/ml; pT1-4, Nx/0, cM0; and Gleason score (GS) ≥7 treated between 1987 and 2013. Median follow-up was 51 mo. INTERVENTIONS: WPRT and/or ADT in addition to PBRT. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSES: FFBF and DM were calculated using cumulative incidence estimation. Multivariable analysis (MVA) utilized cumulative incidence regression. RESULTS AND LIMITATION: Median pre-SRT PSA was 0.5 ng/ml for 1861 patients. Median follow-up for patients not experiencing biochemical failure (BF) was 55 mo. MVA showed increased BF for PBRT versus WPRT (hazard ratio [HR] 1.82, p<0.001) and no ADT versus ADT (HR 1.70, p<0.001). WPRT was associated with a 5-yr FFBF of 62% versus 49% (p<0.001) for PBRT. ADT use was associated with improved 5-yr FFBF (55% vs 50%, p=0.012). No significant differences in DM cumulative incidence were found. CONCLUSIONS: For patients with GS ≥7 receiving SRT, clinicians should weigh FFBF benefits of WPRT and ADT against toxicities. Future studies should explore the impact of WPRT on quality of life, clinical progression, and overall survival. PATIENT SUMMARY: We evaluated patients with prostate cancer treated with radiation after surgery to remove the prostate. Both radiation to the pelvic lymph nodes and suppression of testosterone lowered the chance of increasing prostate-specific antigen (a marker for cancer returning).

Secondary Urethral Malignancies Following Prostate Brachytherapy.

OBJECTIVE: To understand urethral secondary malignancies among patients treated with brachytherapy (BRT) for primary prostate cancer. PATIENTS AND METHODS: Institutional retrospective review identified 13 patients evaluated from 2003 to 2014 with urethral cancer and history of BRT monotherapy for prostate cancer. All patients were biochemically free of their primary disease and radiation-associated secondary malignancies (RASMs) were confirmed pathologically to be histologically distinct from primary tumor. BRT characteristics, patient age, presentation, staging workup, and clinical course were evaluated. RESULTS: The mean time from BRT to presenting symptoms of hematuria, urinary retention, and/or renal failure was 71 months. Symptom onset to RASM diagnosis interval was 24 months. Mean time from BRT to RASM diagnosis was 95 months. Eighty-five percent of patients had an undetectable prostate-specific antigen level (<0.2 ng/mL) at last follow-up. Types of RASM included sarcomatoid carcinoma (6), small cell carcinoma (2), urothelial carcinoma with squamous differentiation (2), squamous cell carcinoma (1), rhabdomyosarcoma (1), and urothelial carcinoma (1). A majority of patients were diagnosed with advanced disease with either distant metastases (54%) or local progression (23%). Ten patients died during this study period with median time to death after RASM diagnosis of 6 months. CONCLUSION: RASMs localized to the posterior urethra displayed advanced disease and high mortality rates. Refractory lower urinary tract symptoms, hematuria, and history of prostate BRT should raise suspicion for urethral RASMs. Further studies are warranted to determine patient and disease characteristics that correlate with disease-specific mortality of secondary urethral malignancies.

Predictive factors on outcomes in metaplastic breast cancer.

PURPOSE: Metaplastic breast cancer (MBC) is a rare, aggressive variant of breast cancer, with limited data available regarding treatment and outcomes. This study aims to review patients with MBC treated at our tertiary care institution with an emphasis on the role of treatment modality and histologic classification. METHODS: With IRB-approval, we queried our pathology database for patients with MBC diagnosis. All cases were re-evaluated by dedicated breast pathologists and confirmed as MBC breast cancer. Patient demographics, clinical/pathologic histology, and treatment were analyzed with respect to outcomes including local-regional recurrence (LRR), distant metastasis (DM), and overall survival (OS). Univariate and multivariate Cox proportional hazards models were performed to evaluate the impact on outcomes. Kaplan-Meier methods estimated survival. RESULTS: We evaluated 113 patients with MBC diagnosed between 2002 and 2013. Median age was 61 years and median pathologic tumor size 2.5 cm; 76 (67%) were ER/PR/Her2 negative, 83 (74%) grade 3. Median follow-up was 38 months. 47 (42%) underwent breast conservation therapy (BCT), 66 (58%) had mastectomy, 61 (54%) underwent adjuvant radiation (RT), and 85 (75%) had chemotherapy. At 2 and 5 years, the LRR/DM/OS rates were 12%/15%/90% and 21%/35%/69%, respectively. On Cox regression analysis, only adjuvant RT correlated with reduced LRR [RR 3.1 (1.13-9.88), p = 0.027], while chemotherapy, type of surgery, and T-N stage did not. Only T-stage (p = 0.008) correlated with DM, however chemotherapy, RT, surgery type, and N-stage were not. Univariate analysis demonstrated histologic subtype did not significantly correlate with local (p = 0.54) or distant (p = 0.83) disease control. CONCLUSIONS: This study represents among the largest institutional experiences in the outcomes of MBC. At this time, there does not appear to be a clear histologic subset of MBC which has significantly different clinical outcomes from the other subtypes. Although limited in its sample size, this study shows RT remains important in local-regional control.

Establishing a Multidisciplinary Approach to the Management of Neurologic Disease Affecting the Urinary Tract.

Neurologic diseases often affect the urinary tract and may be congential or acquired. The progressive nature of many neurologic diseases necessitates routine surveillance and treatment with a multidisciplinary approach. Urologic treatments may interact with pharmacologic or procedural interventions planned by other specialists, mandating close coordination of care and communication among providers. Primary care and nursing often can serve as the quarterbacks of the multidisciplinary team by identifying when a slowly progressive condition warrants further investigation and management by specialists.

Comparative Effectiveness of Surgical Treatments for Small Renal Masses.

In the management of small renal masses (SRMs), treatment options include partial nephrectomy (PN), radical nephrectomy (RN), ablation, renal biopsy, and active surveillance. Large series retrospective and meta-analyses demonstrate PN may confer greater preservation of renal function, overall survival, and equivalent cancer control when compared with RN. As newer therapies emerge, we should critically evaluate the risks and benefits associated with the surgical management of SRMs among patients with competing comorbidities, complex tumors, and high-risk disease. Among younger patients with SRMs amenable to resection, optimization of postoperative patient health should be prioritized.

Salvage Radiation Therapy Dose Response for Biochemical Failure of Prostate Cancer After Prostatectomy-A Multi-Institutional Observational Study.

PURPOSE: To determine whether a dose-response relationship exists for salvage radiation therapy (RT) of biochemical failure after prostatectomy for prostate cancer. METHODS AND MATERIALS: Individual data from 1108 patients who underwent salvage RT at 10 academic centers were pooled. The cohort was enriched for selection criteria more likely associated with tumor recurrence in the prostate bed (margin positive and pre-RT prostate-specific antigen [PSA] level of ≤2.0 ng/mL) and without the confounding of planned androgen suppression. The cumulative incidence of biochemical failure and distant metastasis over time was computed, and competing risks hazard regression models were used to investigate the association between potential predictors and these outcomes. The association of radiation dose with outcomes was the primary focus. RESULTS: With a 65.2-month follow-up duration, the 5- and 10-year estimates of freedom from post-RT biochemical failure (PSA level >0.2 ng/mL and rising) was 63.5% and 49.8%, respectively, and the cumulative incidence of distant metastasis was 12.4% by 10 years. A Gleason score of ≥7, higher pre-RT PSA level, extraprostatic tumor extension, and seminal vesicle invasion were associated with worse biochemical failure and distant metastasis outcomes. A salvage radiation dose of ≥66.0 Gy was associated with a reduced cumulative incidence of biochemical failure, but not of distant metastasis. CONCLUSIONS: The use of salvage radiation doses of ≥66.0 Gy are supported by evidence presented in the present multicenter pooled analysis of individual patient data. The observational reporting method, limited sample size, few distant metastasis events, modest follow-up duration, and elective use of salvage therapy might have diminished the opportunity to identify an association between the radiation dose and this endpoint.

Contemporary Update of a Multi-Institutional Predictive Nomogram for Salvage Radiotherapy After Radical Prostatectomy.

PURPOSE: We aimed to update a previously published, multi-institutional nomogram of outcomes for salvage radiotherapy (SRT) following radical prostatectomy (RP) for prostate cancer, including patients treated in the contemporary era. METHODS: Individual data from node-negative patients with a detectable post-RP prostate-specific antigen (PSA) treated with SRT with or without concurrent androgen-deprivation therapy (ADT) were obtained from 10 academic institutions. Freedom from biochemical failure (FFBF) and distant metastases (DM) rates were estimated, and predictive nomograms were generated. RESULTS: Overall, 2,460 patients with a median follow-up of 5 years were included; 599 patients (24%) had a Gleason score (GS) ≤ 6, 1,387 (56%) had a GS of 7, 244 (10%) had a GS of 8, and 230 (9%) had a GS of 9 to 10. There were 1,370 patients (56%) with extraprostatic extension (EPE), 452 (18%) with seminal vesicle invasion (SVI), 1,434 (58%) with positive surgical margins, and 390 (16%) who received ADT (median, 6 months). The median pre-SRT PSA was 0.5 ng/mL (interquartile range, 0.3 to 1.1). The 5-yr FFBF rate was 56% overall, 71% for those with a pre-SRT PSA level of 0.01 to 0.2 ng/mL (n = 441), 63% for those with a PSA of 0.21 to 0.50 ng/mL (n = 822), 54% for those with a PSA of 0.51 to 1.0 ng/mL (n = 533), 43% for those with a PSA of 1.01 to 2.0 ng/mL (n = 341), and 37% for those with a PSA > 2.0 ng/mL (n = 323); P < .001. On multivariable analysis, pre-SRT PSA, GS, EPE, SVI, surgical margins, ADT use, and SRT dose were associated with FFBF. Pre-SRT PSA, GS, SVI, surgical margins, and ADT use were associated with DM, whereas EPE and SRT dose were not. The nomogram concordance indices were 0.68 (FFBF) and 0.74 (DM). CONCLUSION: Early SRT at low PSA levels after RP is associated with improved FFBF and DM rates. Contemporary nomograms can estimate individual patient outcomes after SRT in the modern era.

Utilizing Low-Volume Aqueous Acoustic Transfer with the Echo 525 to Enable Miniaturization of qRT-PCR Assay.

Quantitative reverse transcription PCR (qRT-PCR) is a valuable tool for characterizing the effects of inhibitors on viral replication. The amplification of target viral genes through the use of specifically designed fluorescent probes and primers provides a reliable method for quantifying RNA. Due to reagent costs, use of these assays for compound evaluation is limited. Until recently, the inability to accurately dispense low volumes of qRT-PCR assay reagents precluded the routine use of this PCR assay for compound evaluation in drug discovery. Acoustic dispensing has become an integral part of drug discovery during the past decade; however, acoustic transfer of microliter volumes of aqueous reagents was time consuming. The Labcyte Echo 525 liquid handler was designed to enable rapid aqueous transfers. We compared the accuracy and precision of a qPCR assay using the Labcyte Echo 525 to those of the BioMek FX, a traditional liquid handler, with the goal of reducing the volume and cost of the assay. The data show that the Echo 525 provides higher accuracy and precision compared to the current process using a traditional liquid handler. Comparable data for assay volumes from 500 nL to 12 µL allowed the miniaturization of the assay, resulting in significant cost savings of drug discovery and process streamlining.