Active Surveillance for Taiwanese Men with Localized Prostate Cancer: Intermediate-Term Outcomes and Predictive Factors.

PURPOSE: Active surveillance (AS) is one of the management options for patients with low-risk and select intermediate-risk prostate cancer (PC). However, factors predicting disease reclassification and conversion to active treatment from a large population of pure Asian cohorts regarding AS are less evaluated. This study investigated the intermediate-term outcomes of patients with localized PC undergoing AS. MATERIALS AND METHODS: This cohort study enrolled consecutive men with localized non-high-risk PC diagnosed in Taiwan between June 2012 and Jan 2023. The study endpoints were disease reclassification (either pathological or radiographic progression) and conversion to active treatment. The factors predicting endpoints were evaluated using the Cox proportional hazards model. RESULTS: A total of 405 patients (median age: 67.2 years) were consecutively enrolled and followed up with a median of 64.6 months. Based on the National Comprehensive Cancer Network (NCCN) risk grouping, 70 (17.3%), 164 (40.5%), 140 (34.6%), and 31 (7.7%) patients were classified as very low-risk, low-risk, favorable-intermediate risk, and unfavorable intermediate-risk PC, respectively. The 5-year reclassification rates were 24.8%, 27.0%, 18.6%, and 25.3%, respectively. The 5-year conversion rates were 20.4%, 28.8%, 43.6%, and 37.8%, respectively. A prostate-specific antigen density (PSAD) of ≥0.15 ng/mL² predicted reclassification (hazard ratio [HR] 1.84, 95% confidence interval [CI] 1.17-2.88) and conversion (HR 1.56, 95% CI 1.05-2.31). A maximal percentage of cancer in positive cores (MPCPC) of ≥15% predicted conversion (15% to <50%: HR 1.41, 95% CI 0.91-2.18; ≥50%: HR 1.97, 95% CI 1.1453-3.40) compared with that of <15%. A Gleason grade group (GGG) of 3 tumor also predicted conversion (HR 2.69, 95% CI 1.06-6.79; GGG 3 vs 1). One patient developed metastasis, but none died of PC during the study period (2,141 person-years). CONCLUSIONS: AS is a viable option for Taiwanese men with non-high-risk PC, in terms of reclassification and conversion. High PSAD predicted reclassification, whereas high PSAD, MPCPC, and GGG predicted conversion.

Unilateral adrenalectomy in bilateral adrenal hyperplasia with primary aldosteronism.

PURPOSE: Mineralocorticoid receptor antagonists are the first-line treatment for bilateral adrenal hyperplasia (BAH) with primary aldosteronism (PA), while unilateral adrenalectomy is the standard treatment for aldosterone-producing adenoma (APA). In this study, we investigated the outcomes of patients with BAH after unilateral adrenalectomy and compared them with those of patients with APA. METHODS: From January 2010 to November 2018, 102 patients with a diagnosis of PA confirmed by adrenal vein sampling (AVS) and available NP-59 scans were enrolled. All patients underwent unilateral adrenalectomy based on the lateralization test results. We prospectively collected the clinical parameters over 12 months and compared the outcomes of BAH and APA. RESULTS: A total of 102 patients were enrolled in this study: 20 (19.6%) had BAH and 82 (80.4%) had APA. Significant improvements in serum aldosterone-renin ratio (ARR), potassium level, and reduction of antihypertensive drugs were observed in both groups at 12 months after surgery (all p < 0.05). Patients with APA showed a significant decrease in blood pressure after surgery (p < 0.001) than those with BAH. Additionally, multivariate logistic regression analysis indicated that APA was associated with biochemical success (odds ratio: 4.32, p = 0.024) compared to BAH. CONCLUSION: Patients with BAH had a higher failure rate in clinical outcomes, and APA was associated with biochemical success after unilateral adrenalectomy. However, significant improvements in ARR, hypokalemia, and a decreased use of antihypertensive drugs were noted in patients with BAH after surgery. Unilateral adrenalectomy is feasible and beneficial in selected patients, and could potentially serve as a treatment option.

A case report of right cardiac ventricle perforation by uncontrolled embolization coil inserted for treating penile veno-occlusive dysfunction.

Coil embolization (CE) is believed effective-safe for treating penile veno-occlusive dysfunction (VOD). From 2012 to 2016, refractory impotence prompted four men to seek further treatment, although they underwent six CEs elsewhere. Uncontrolled coils scattered along penile drainage veins including the deep dorsal veins (n = 3), periprostatic plexus (n = 1), iliac vein (n = 1), right pulmonary artery (n = 2), left pulmonary artery (n = 1), and right ventricle (n = 1). The last one occurred in a 40-year-old house builder, and the coil perforated the right ventricle wall and diaphragm 18 months later. Given no sustainable improvement, CE's safety and efficacy are unreliable for treating patients with VOD.

Factors associated with renal function change after unilateral adrenalectomy in patients with primary aldosteronism.

OBJECTIVES: Decreased glomerular filtration rate has been reported in patients with primary aldosteronism after unilateral adrenalectomy. Glomerular hyperfiltration has been assumed to mask the preoperative subtle renal impairment. In this study, we investigated predictors for decreased estimated glomerular filtration rate after adrenalectomy in patients with primary aldosteronism. METHODS: From January 2006 through September 2018, 328 patients with confirmatory diagnoses of primary aldosteronism received unilateral laparoscopic adrenalectomy and subsequent follow-up for 12 months. We prospectively collected related parameters of the clinical outcomes and renal function to identify predictors of renal function impairment at 12 months after surgery. RESULTS: Patients were stratified into three groups by preoperative estimated glomerular filtration rate level: 144 (43.9%) with estimated glomerular filtration rate ≥90, 130 (39.6%) with estimated glomerular filtration rate within 60-89.9, and 54 (16.5%) with estimated glomerular filtration rate <60 mL/min/1.73 m2 . The estimated glomerular filtration rate decreased significantly at the 6th month and remained stable at the 12th month, postoperatively. Patients with estimated glomerular filtration rate ≥90 had better clinical outcome with 59.6% success rate (P = 0.006) among three groups. Multivariate logistic regression analysis indicated that preoperative estimated glomerular filtration rate (odds ratio 1.012, P = 0.02) and hypokalemia (odds ratio 2.018, P = 0.024) were associated with renal impairment at 12th month after adrenalectomy. Multivariate linear regression analysis revealed high preoperative estimated glomerular filtration rate (ß = 0.261, P < 0.001), high preoperative systolic blood pressure (ß = 0.168, P = 0.003), high level of microalbuminuria (ß = 0.024, P = 0.001), and low level of serum potassium (ß = -4.883, P = 0.007) were associated with estimated glomerular filtration rate percentage decline at 12th month after adrenalectomy. CONCLUSIONS: Estimated glomerular filtration rate declined significantly after adrenalectomy in patients with estimated glomerular filtration rate ≥90. The study provided important information to identify primary aldosteronism patients with higher risk of estimated glomerular filtration rate decline after adrenalectomy and might help to adopt early interventions to improve the outcomes.

Acute Kidney Injury and Septic Shock-Defined by Updated Sepsis-3 Criteria in Critically Ill Patients.

Sepsis is commonly associated with acute kidney injury (AKI), particularly in those requiring dialysis (AKI-D). To date, Sepsis-3 criteria have not been applied to AKI-D patients. We investigated sepsis prevalence defined by Sepsis-3 criteria and evaluated the outcomes of septic-associated AKI-D among critically ill patients. Using the data collected from a prospective multi-center observational study, we applied the Sepsis-3 criteria to critically ill AKI-D patients treated in intensive care units (ICUs) in 30 hospitals between September 2014 and December 2015. We described the prevalence, outcomes, and characteristics of sepsis as defined by the screening Sepsis-3 criteria among AKI-D patients, and compared the outcomes of AKI-D patients with or without sepsis using the Sepsis-3 criteria. A total of 1078 patients (median 70 years; 673 (62.4%) men) with AKI-D were analyzed. The main etiology of AKI was sepsis (71.43%) and the most frequent indication for acute dialysis was oliguria (64.4%). A total of 577 (53.3% of 1078 patients) met the Sepsis-3 criteria, and 206 among the 577 patients (19.1%) had septic shock. Having sepsis and septic shock were independently associated with 90-day mortality among these ICU AKI-D patients (hazard ratio (HR) 1.23 (p = 0.027) and 1.39 (p = 0.004), respectively). Taking mortality as a competing risk factor, AKI-D patients with septic shock had a significantly reduced chance of weaning from dialysis at 90 days than those without sepsis (HR 0.65, p = 0.026). The combination of the Sepsis-3 criteria with the AKI risk score led to better performance in forecasting 90-day mortality. Sepsis affects more than 50% of ICU AKI patients requiring dialysis, and one-fifth of these patients had septic shock. In AKI-D patients, coexistent with or induced by sepsis (as screened by the Sepsis-3 criteria), there is a significantly higher mortality and reduced chance of recovering sufficient renal function, when compared to those without sepsis.

Plasma Aldosterone Concentration as a Determinant for Statin Use among Middle-Aged Hypertensive Patients for Atherosclerotic Cardiovascular Disease.

The use of statin therapy on the prevention of atherosclerotic cardiovascular disease (ASCVD) is recommended by the American College of Cardiology (ACC) and the American Heart Association (AHA); nevertheless, its validation on primary aldosteronism (PA) patients has not been reported. We investigated the risk of incident ASCVD in middle-aged patients with PA compared with essential hypertension (EH) based on ACC/AHA recommendations. We enrolled 461 PA patients and 553 EH patients. Even though the ratio of metabolic syndrome in each group was similar, the PA group had higher systolic blood pressures, higher low-density lipoprotein levels, higher plasma aldosterone concentration (PAC), lower high-density lipoprotein levels, and higher 10-year ASCVD compared to the EH group. The discriminative power for predicting ASCVD by the recommended statin use from the ACC/AHA guidelines was proper in the PA group (i.e., under the receiver operating characteristic curve (95% confidence interval; 0.94 (0.91⁻0.96)). The generalized additive model showed patients with PAC higher than 60 ng/dL accompanying the standard timing of the statin use suggested by the ACC/AHA. The ACC/AHA guidelines have good discriminative power in the prediction of middle-aged high-risk hypertensive patients, while PAC identifies those high-risk individuals who may benefit from early statin therapy.

Effects of Statin Use in Advanced Chronic Kidney Disease Patients.

Although statin treatment is recommended for patients with chronic kidney disease (CKD) stages I⁻IV, its potential benefits have not been reported in advanced CKD patients. Non-diabetic patients with advanced CKD (pre-dialysis patients, estimated glomerular filtration rate <15 mL/min/1.73 m²) were enrolled from a National Health Insurance Research Database with a population of 23 million. Statin users and non-users were matched using propensity scoring and analyzed using Cox proportional hazards models, taking mortality as a competing risk with subsequent end-stage renal disease (ESRD) and statin doses as time-dependent variables. A total of 2551 statin users and 7653 matched statin non-users were identified from a total 14,452 patients with advanced CKD. Taking mortality as a competing risk, statin use did not increase the risk of new-onset diabetes mellitus (NODM) or decrease the risk of de novo major adverse cardiovascular events (MACE), but reduced all-cause mortality (hazard ratio (HR) = 0.59 [95% CI 0.42⁻0.84], p = 0.004) and sepsis-related mortality (HR = 0.53 [95% CI 0.32⁻0.87], p = 0.012). For advanced CKD patients, statin was neither associated with increased risks of developing NODM, nor with decreased risk of de novo MACE occurrence, but with a reduced risk of all-cause mortality, mainly septic deaths.

miRNA-203 Modulates Aldosterone Levels and Cell Proliferation by Targeting Wnt5a in Aldosterone-Producing Adenomas.

Context: The aberrant expression or alternation of miRNA in the pathogenesis of aldosterone-producing adenomas (APAs) is still largely unknown. Objective: We investigated the role of miRNA-203 (screened from miRNA microarrays) and elucidated its effects on the Wnt/ß-catenin pathway regarding aldosterone production and cell proliferation in APAs. Methods: miR-203 expression was upregulated or downregulated by transfecting miR-203 mimics or inhibitors into primary APA cells, the human adrenocortical cell line HAC15, and C57BL/6 mice. In vitro and biochemical data were correlated with the respective clinical parameters of APAs to evaluate their clinical importance. Results: The expression of miR-203 in human APA samples was significantly lower than that of peritumor adrenal samples. Tumoral miR-203 abundance correlated negatively with both plasma aldosterone level and tumor size in patients with APAs. miR-203 inhibitors increased aldosterone production and cell proliferation in HAC15 cells, and restoration of expression via miR-203 mimics showed decreased cell proliferation and aldosterone hypersecretion in APA cell cultures. In vivo selective inhibition of miR-203 via intra-adrenal injection of miR-203 inhibitors in mice led to a substantial increase in systolic blood pressure and plasma aldosterone levels. Additionally, the dual-luciferase reporter assay demonstrated that WNT5A is a direct target of miR-203. Furthermore, plasma Wnt5a levels in adrenal vein sampling were helpful in differentiating tumor localization, and preoperative plasma Wnt5a levels predicted the cure of hypertension after adrenalectomy. Conclusion: We have demonstrated that attenuated miR-203 expression in APAs increases aldosterone production and the tumorigenesis of adrenal cells by activating the Wnt5a/ß-catenin pathway.

Outcome Prediction of Acute Kidney Injury Biomarkers at Initiation of Dialysis in Critical Units.

: The ideal circumstances for whether and when to start RRT remain unclear. The outcome predictive ability of acute kidney injury (AKI) biomarkers measuring at dialysis initializing need more validation. This prospective, multi-center observational cohort study enrolled 257 patients with AKI undergoing renal replacement therapy (RRT) shortly after admission. At the start of RRT, blood and urine samples were collected for relevant biomarker measurement. RRT dependence and all-cause mortality were recorded up to 90 days after discharge. Areas under the receiver operator characteristic (AUROC) curves and a multivariate generalized additive model were applied to predict outcomes. One hundred and thirty-five (52.5%) patients died within 90 days of hospital discharge. Plasma c-terminal FGF-23 (cFGF-23) had the best discriminative ability (AUROC, 0.687) as compared with intact FGF-23 (iFGF-23) (AUROC, 0.504), creatinine-adjusted urine neutrophil gelatinase-associated lipocalin (AUROC, 0.599), and adjusted urine cFGF-23 (AUROC, 0.653) regardless whether patients were alive or not on day 90. Plasma cFGF-23 levels above 2050 RU/mL were independently associated with higher 90-day mortality (HR 1.76, p = 0.020). Higher cFGF-23 levels predicted less weaning from dialysis in survivors (HR, 0.62, p = 0.032), taking mortality as a competing risk. Adding cFGF-23 measurement to the AKI risk predicting score significantly improved risk stratification and 90-day mortality prediction (total net reclassification improvement = 0.148; p = 0.002). In patients with AKI who required RRT, increased plasma cFGF-23 levels correlated with higher 90-day overall mortality after discharge and predicted worse kidney recovery in survivors. When coupled to the AKI risk predicting score, cFGF-23 significantly improved mortality risk prediction. This observation adds evidence that cFGF-23 could be used as an optimal timing biomarker to initiate RRT.

Urinary biomarkers predict advanced acute kidney injury after cardiovascular surgery.

BACKGROUND: Acute kidney injury (AKI) after cardiovascular surgery is a serious complication. Little is known about the ability of novel biomarkers in combination with clinical risk scores for prediction of advanced AKI. METHODS: In this prospectively conducted multicenter study, urine samples were collected from 149 adults at 0, 3, 6, 12 and 24 h after cardiovascular surgery. We measured urinary hemojuvelin (uHJV), kidney injury molecule-1 (uKIM-1), neutrophil gelatinase-associated lipocalin (uNGAL), α-glutathione S-transferase (uα-GST) and π-glutathione S-transferase (uπ-GST). The primary outcome was advanced AKI, under the definition of Kidney Disease: Improving Global Outcomes (KDIGO) stage 2, 3 and composite outcomes were KDIGO stage 2, 3 or 90-day mortality after hospital discharge. RESULTS: Patients with advanced AKI had significantly higher levels of uHJV and uKIM-1 at 3, 6 and 12 h after surgery. When normalized by urinary creatinine level, uKIM-1 in combination with uHJV at 3 h post-surgery had a high predictive ability for advanced AKI and composite outcome (AUC = 0.898 and 0.905, respectively). The combination of this biomarker panel (normalized uKIM-1, uHJV at 3 h post-operation) and Liano's score was superior in predicting advanced AKI (AUC = 0.931, category-free net reclassification improvement of 1.149, and p <  0.001). CONCLUSIONS: When added to Liano's score, normalized uHJV and uKIM-1 levels at 3 h after cardiovascular surgery enhanced the identification of patients at higher risk of progression to advanced AKI and composite outcomes.

Hemojuvelin Predicts Acute Kidney Injury and Poor Outcomes Following Cardiac Surgery.

Acute kidney injury (AKI) is detrimental after cardiac surgery. In this multicenter study, the novel biomarker hemojuvelin (HJV) was evaluated for AKI prediction following cardiac surgery. Urinary HJV, neutrophil gelatinase-associated lipocalin (NGAL), and urinary creatinine were measured in 151 patients after surgery. The outcomes of advanced AKI (KDIGO stages 2 and 3) and all causes of in-hospital mortality as the composite outcome were recorded. Areas under the receiver operator characteristic curves (AUC) and a multivariate generalized additive model (GAM) were applied to predict these outcomes of interest. Urinary HJV differentiated patients with/without AKI, advanced AKI or composite outcome after surgery (p < 0.001, by a generalized estimating equation) in this study. At three hours post-surgery, urinary HJV predicted advanced AKI (p < 0.001) and composite outcome (p < 0.001) with corresponding AUC values of 0.768 and 0.828, respectively. The performance of creatinine-adjusted HJV was also superior to NGAL in predicting advanced AKI (AUC = 0.784 and 0.694; p = 0.037) and composite outcome (AUC = 0.842 and 0.676; p = 0.002). The integration of HJV into the Cleveland Clinic score for advanced AKI led to a significant increase in risk stratification (net reclassification improvement [NRI] = 0.598; p < 0.001).

Earlier versus later initiation of renal replacement therapy among critically ill patients with acute kidney injury: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Although the optimal timing of initiation of renal replacement therapy (RRT) in critically ill patients with acute kidney injury has been extensively studied in the past, it is still unclear. METHODS: In this systematic review, we searched all related randomized controlled trials (RCTs) that directly compared earlier and later RRT published prior to June 25, 2016, from PubMed, MEDLINE, and EMBASE. We extracted the study characteristics and outcomes of all-cause mortality, RRT dependence, and intensive care unit (ICU) and hospital length of stay (LOS). RESULTS: We identified 51 published relevant studies from 13,468 screened abstracts. Nine RCTs with 1627 participants were included in this meta-analysis. Earlier RRT was not associated with benefits in terms of mortality [relative risk (RR) 0.88, 95% confidence interval (CI) 0.68-1.14, p = 0.33] and RRT dependence (RR 0.81, 95% CI 0.46-1.42, p = 0.46). There were also no significant differences in the ICU and hospital LOS between patients who underwent earlier versus later RRT [standard means difference -0.08 (95% CI -0.26 to 0.09) and -0.11 (95% CI -0.37 to 0.16) day, respectively]. In subgroup analysis, earlier RRT was associated with a reduction in the in-hospital mortality among surgical patients (RR 0.78, 95% CI 0.64-0.96) and patients who underwent continuous renal replacement therapy (CRRT) (RR 0.80, 95% CI 0.67-0.96). CONCLUSIONS: Compared with later RRT, earlier initiation of RRT did not show beneficial impacts on patient outcomes. However, a lower rate of death was observed among surgical patients and in those who underwent CRRT. The included literature is highly heterogeneous and, therefore, potentially subject to bias. Further high-quality RCT studies are warranted.

Multiple Uric Acid Bladder Stones: Clinical Presentation and Endoscopic Management.

Background: Bladder urinary calculi occur in 3%-8% of men with bladder outlet obstruction, and although most of them are composed of calcium, in a few cases uric acid bladder stones are diagnosed. Case Presentation: We present clinical images and therapeutic management of a 65-year-old diabetic man with significant prostate enlargement and >30 bladder stones, the largest being 17 mm. Despite the large stone burden, the patient was managed by cystolithotripsy. Remarkably, stone composition analysis revealed 100% uric acid stone. Intraoperative and postoperative course were uneventfully. Conclusion: Uric acid bladder stone pathogenesis seems to be multifactorial with local and systemic factors contributing in different manners and even large stone burdens may be cystoscopically managed.

The prevalence of CTNNB1 mutations in primary aldosteronism and consequences for clinical outcomes.

Constitutive activation of the Wnt pathway/ß-catenin signaling may be important in aldosterone-producing adenoma (APA). However, significant gaps remain in our understanding of the prevalence and clinical outcomes after adrenalectomy in APA patients harboring CTNNB1 mutations. The molecular expression of CYP11B2 and gonadal receptors in adenomas were also explored. Adenomas from 219 APA patients (95 men; 44.2%; aged 50.5 ± 11.9 years) showed a high rate of somatic mutations (n = 128, 58.4%). The majority of them harbored KCNJ5 mutations (n = 116, 52.9%); 8 patients (3.7%, 6 women) had CTNNB1 mutations. Patients with APAs harboring CTNNB1 mutations were older and had shorter duration of hypertension. After adrenalectomy, CTNNB1 mutation carriers had a higher possibility (87.5%) of residual hypertension than other APA patients. APAs harboring CTNNB1 mutations have heterogeneous staining of ß-catenin and variable expression of gonadal receptors and both CYP11B1 and CYP11B2. This suggests that CTNNB1 mutations may be more related to tumorigenesis rather than excessive aldosterone production.

Risk of Fracture in Primary Aldosteronism: A Population-Based Cohort Study.

Primary aldosteronism (PA) is associated with increased urinary calcium excretion and osteoporosis prevalence. We studied the long-term effect of hyperaldosterone on fracture risk and possible risk mitigation via treatments, by comparing PA patients and their essential hypertension (EH) counterparts extracted by propensity score match. We used a longitudinal population database from the Taiwan National Health Insurance, and used a validated algorithm to identify PA patients diagnosed in 1997-2010. Our sample included 2533 PA patients, including 921 patients with aldosterone-producing adenoma (APA). Our methods for assessing excessive fracture risk included multivariable Cox regression and the competing risk regression. The incidence rate of fracture at any site was 14.4 per 1000 person-years for PA, and 11.2 per 1000 person-years for APA. In contrast, the incidence rate of fracture at any site was 8.3 per 1000 person-years in EH controls for PA, and 6.5 per 1000 person-years in EH controls for APA. Mineralocorticoid receptor antagonist (MRA) treatment might be associated with higher risk of osteoporotic fracture in the whole female PA cohort (subdistribution hazard ratio [SHR] = 2.12, p = 0.008) as well as female APA patients (SHR = 1.15, p = 0.049). As to fracture at any site, MRA treatment was also associated with higher risk; the SHR was 1.88 (p < 0.001) in the whole female PA cohort, and 2.17 (p = 0.019) in female APA patients. PA is tightly associated with higher risk of bone fracture, even in the case where the competing risk of death was controlled. Particularly, female PA patients treated with MRA were confronted with significantly higher risk in bone fracture than their EH controls. © 2017 American Society for Bone and Mineral Research.

Long term outcome of Aldosteronism after target treatments.

There exists a great knowledge gap in terms of long-term effects of various surgical and pharmacological treatments on outcomes among primary aldosteronism (PA) patients. Using a validated algorithm, we extracted longitudinal data for all PA patients diagnosed in 1997-2010 and treated in the Taiwan National Health Insurance. We identified 3362 PA patients for whom the mean length of follow-up was 5.75 years. PA has higher major cardiovascular events (MACE) than essential hypertension (23.3% vs 19.3%, p = 0.015). Results from the Cox model suggest a strong effect of adrenalectomy on lowering mortality (HR = 0.23 with residual hypertension and 0.21 with resolved hypertension). While the need for mineralocorticoid receptor antagonist (MRA) after diagnosis suggests that a defined daily dose (DDD) of MRA between 12.5 and 50 mg may alleviate risk of death in a U-shape pattern. A specificity test identified patients who has aldosterone producing adenoma (HR = 0.50, p = 0.005) also confirmed adrenalectomy attenuated all-cause mortality. Adrenalectomy decreases long-term all-cause mortality independently from PA cure from hypertension. Prescription corresponding to a DDD between 12.5 and 50 mg may decrease mortality for patients needing MRA. It calls for more attention on early diagnosis, early treatment and prescription of appropriate dosage of MRA for PA patients.