Publications by authors named "Kuo-How Huang"

174 Publications

Cortisol-producing-adenoma Related Somatic Mutations in Unilateral Primary Aldosteronism with Concurrent Autonomous Cortisol Secretion - Their Prevalence and Clinical Characteristics.

Eur J Endocrinol 2022 Jul 1. Epub 2022 Jul 1.

V Wu, Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.

Objective: Concurrent autonomous cortisol secretion(ACS) in patients with primary aldosteronism(PA) was reported more frequently. Several somatic mutations including PRKACA, GNAS, and CTNNB1 were identified in cortisol-producing adenomas(CPAs). The presence of these mutations in unilateral PA(uPA) patients concurrent with ACS(uPA/ACS) is not well known. This study aimed to investigate the prevalence of these mutations and their clinical versus pathological characteristics in uPA/ACS.

Design: Retrospective cohort study.

Methods: 98 uPA patients among the TAIPAI registry having overnight 1-mg dexamethasone suppression test(DST) and adrenalectomy from 2016-2018 were enrolled. Their adrenal tumors were tested for PRKACA, GNAS, and CTNNB1 mutations.

Results: 11 patients had CPA-related mutations (7 PRKACA and 4 GNAS). The patients carrying these mutations had higher post-DST cortisol (5.6 versus. 2.6 μg/dL, p=0.003) and larger adenoma (2.2±0.3 vs. 1.9±0.7 cm, p=0.025). Adenomas with these mutations had a higher prevalence of non-classical uPA (72.7% vs. 26.3%, p=0.014). Numerically, slightly more complete clinical success of uPA patients with these mutations was noticed after adrenalectomy, although it was statistically non-significant. Post-DST cortisol levels, adenoma size >1.9cm, and the interaction of adenoma size >1.9cm with potassium level were found to be associated with the presence of these mutations.

Conclusion: Our study showed that CPA-related mutations were detected in 36.7% of uPA/ACS adenomas. The presence of these mutations was associated with higher post-DST cortisol levels, larger adenoma sizes, and a high percentage of non-classical uPA. However, these mutations did not significantly affect clinical and biochemical outcomes after adrenalectomy of uPA/ACS patients but they showed a better trend.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1530/EJE-22-0286DOI Listing
July 2022

Propensity score matching analysis comparing radical prostatectomy and radiotherapy with androgen deprivation therapy in locally advanced prostate cancer.

Sci Rep 2022 Jul 21;12(1):12480. Epub 2022 Jul 21.

Institute of Biomedical Engineering, National Taiwan University, No. 1, Changde St., Zhongzheng Dist., Taipei City, 10048, Taiwan.

To compare clinical outcomes between the use of robotic-assisted laparoscopic radical prostatectomy (RP) and radiotherapy (RT) with long-term androgen deprivation therapy (ADT) in locally advanced prostate cancer (PC), 315 patients with locally advanced PC (clinical T-stage 3/4) were considered for analysis retrospectively. Propensity score-matching at a 1:1 ratio was performed. The median follow-up period was 59.2 months (IQR 39.8-87.4). There were 117 (37.1%) patients in the RP group and 198 (62.9%) patients in the RT group. RT patients were older and had higher PSA at diagnosis, higher Gleason score grade group and more advanced T-stage (all p < 0.001). After propensity score-matching, there were 68 patients in each group. Among locally advanced PC patients, treatment with RP had a higher risk of biochemical recurrence compared to the RT group. In multivariate Cox regression analysis, treatment with RT plus ADT significantly decreased the risk of biochemical failure (HR 0.162, p < 0.001), but there was no significant difference in local recurrence, distant metastasis and overall survival (p = 0.470, p = 0.268 and p = 0.509, respectively). This information supported a clinical benefit in BCR control for patients undergoing RT plus long-term ADT compared to RP.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-022-16700-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9304348PMC
July 2022

Yttrium-90 Selective Internal Radiation Therapy Plus Cryoablation for Recurrent Adrenocortical Carcinoma With Liver Metastases.

J Endocr Soc 2022 Aug 13;6(8):bvac091. Epub 2022 Jun 13.

Department of Medical Imaging, National Taiwan University Hospital Hsin-Chu Branch, Taiwan.

Advanced adrenocortical carcinoma (ACC) has a poor prognosis and is often resistant to the conventional regimens of mitotane administration and systemic chemotherapy. In addition to surgery, local therapeutic measures can be valuable. Here, we present the case of a 33-year-old woman who developed left retroperitoneal local recurrent ACC with hepatic and pulmonary metastases 1 year after radical adrenalectomy. The tumors progressed under chemotherapy and mitotane treatments. She was treated with yttrium-90 selective internal radiation therapy (Y SIRT) for hepatic metastases and cryoablation of the local recurrent tumor, after which significant tumor shrinkage was observed. She then received radiofrequency ablation for the residual hepatic metastases and radiotherapy to the residual local recurrent tumor. Complete remission was achieved and maintained at least until the data cutoff day (15.8 months after the last treatment). This is the first published report of cryoablation in a patient with ACC and the third report of Y SIRT use for hepatic metastasis of ACC. Cryoablation and Y SIRT are local treatment choices for ACC that are worthy of further study.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/jendso/bvac091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9249972PMC
August 2022

A Novel Somatic Mutation of p.V1937M in Unilateral Primary Hyperaldosteronism.

Front Endocrinol (Lausanne) 2022 9;13:816476. Epub 2022 Jun 9.

Department of Urology, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan.

Background: Somatic mutations for excess aldosterone production have been frequently identified as important roles in the pathogenesis of unilateral primary hyperaldosteronism (uPA). Although mutation represents a minor etiology in primary aldosteronism, it plays a significant role in causing uPAs in sporadic cases.

Objective: To identify novel somatic mutation in patients with uPA and investigate the pathophysiological, immunohistological, and clinical characteristics of the variant.

Methods: We applied a customized and targeted gene panel next-generation sequencing approach to detect mutations from the uPA cohort in Taiwan Primary Aldosteronism Investigation study group. Information from pre-diagnostic to postoperative data was collected, including past history, medications, blood pressure readings, biochemical data, and image studies. The functional role of the variant was confirmed by studies, demonstrating aldosterone production in variant-transfected human adrenal cell lines.

Results: We identified a novel somatic mutation c.5809G>A (p.Val1937Met) in a uPA case. The gene encodes the pore-forming alpha-1H subunit of the voltage-dependent T-type calcium channel Cav3.2. This somatic p.V1937M variant showed excellent clinical and biochemical outcomes after ipsilateral adrenalectomy. The functional effect of somatic p.V1937M variant results in increased CYP11B2 expression and aldosterone biosynthesis in HAC15 cells. A distinct heterogeneous foamy pattern of CYP11B2 and CYP17A1 expression was identified in immunohistological staining, supporting the pathological evidence of aldosterone synthesis.

Conclusions: The somatic mutation of p.V1937M might be a pathogenic driver in aldosterone overproduction. This study provides new insight into the molecular mechanism and disease outcomes of uPA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fendo.2022.816476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9218183PMC
June 2022

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

Int J Urol 2022 Aug 26;29(8):831-837. Epub 2022 Apr 26.

Department of Urology, National Taiwan University Hospital, Taipei, Taiwan.

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 m . 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 (β = 0.261, P < 0.001), high preoperative systolic blood pressure (β = 0.168, P = 0.003), high level of microalbuminuria (β = 0.024, P = 0.001), and low level of serum potassium (β = -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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/iju.14905DOI Listing
August 2022

The Detection Performance of 18 F-Prostate-Specific Membrane Antigen-1007 PET/CT in Primary Prostate Cancer : A Systemic Review and Meta-analysis.

Clin Nucl Med 2022 Sep 22;47(9):755-762. Epub 2022 Apr 22.

Departments of Urology.

Background: Multiple tools are now available to determine the requirement for a biopsy to diagnose prostate cancer, and PET/CT with radiolabeled prostate-specific membrane antigen (PSMA)-targeting radiotracers has been recommended for detecting primary prostate cancer. Particularly, the radiotracer 18 F-PSMA-1007 was found to be more favorable for primary tumors compared with other PSMA-targeting radiotracers because of its low clearance via the urinary tract and better image resolution. Thus, we performed a systematic review and meta-analysis to more accurately evaluate the detection performance of 18 F-PSMA-1007 PET/CT in primary prostate cancer patients.

Methods: An update on the databases of PubMed/MEDLINE, EMBASE, and Cochrane Library for comprehensive literature search was performed on September 30, 2021. The pooling detection rate was calculated on a per-patient basis. The pooling median of the SUV max was analyzed from the included studies. Furthermore, the positive predictive value of 18 F-PSMA-1007 PET/CT with pathologic lesions was analyzed using the criterion standard.

Results: Twelve studies (540 patients total) were included in the meta-analysis. The overall pooling detection rate of 18 F-PSMA-1007 per patient was 94%, and the pooling median of SUV max located at the intraprostate tumor was 16 (range, 3.7-77.7). The positive predictive value of 18 F-PSMA-1007 per lesion with histopathological validation was 0.90, detecting regional lymph node metastasis was 0.94, and detecting localized prostatic tumors was 0.84.

Conclusions: In the current meta-analysis, we revealed the excellent performance of 18 F-PSMA-1007 to detect localized prostatic tumor lesions and regional lymph node metastasis. Moreover, the uptake of localized tumors in primary prostate cancer was nearly liver uptake and may be considered a suspicious malignancy if it was equal to or greater than the liver uptake.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/RLU.0000000000004228DOI Listing
September 2022

Delivery of sorafenib by myofibroblast-targeted nanoparticles for the treatment of renal fibrosis.

J Control Release 2022 06 23;346:169-179. Epub 2022 Apr 23.

Institute of Biomedical Engineering and Frontier Research Center on Fundamental and Applied Sciences of Matters, National Tsing Hua University, Hsinchu 30013, Taiwan. Electronic address:

Fibrosis is an excessive accumulation of the extracellular matrix within solid organs in response to injury and a common pathway that leads functional failure. No clinically approved agent is available to reverse or even prevent this process. Herein, we report a nanotechnology-based approach that utilizes a drug carrier to deliver a therapeutic cargo specifically to fibrotic kidneys, thereby improving the antifibrotic effect of the drug and reducing systemic toxicity. We first adopted in vitro-in vivo combinatorial phage display technology to identify peptide ligands that target myofibroblasts in mouse unilateral ureteral obstruction (UUO)-induced fibrotic kidneys. We then engineered lipid-coated poly(lactic-co-glycolic acid) nanoparticles (NPs) with fibrotic kidney-homing peptides on the surface and sorafenib, a potent antineoplastic multikinase inhibitor, encapsulated in the core. Sorafenib loaded in the myofibroblast-targeted NPs significantly reduced the infiltration of α-smooth muscle actin-expressing myofibroblasts and deposition of collagen I in UUO-treated kidneys and enhanced renal plasma flow measured by Technetium-99m mercaptoacetyltriglycine scintigraphy. This study demonstrates the therapeutic potential of the newly identified peptide fragments as anchors to target myofibroblasts and represents a strategic advance for selective delivery of sorafenib to treat renal fibrosis. SIGNIFICANCE STATEMENT: Renal fibrosis is a pathological feature accounting for the majority of issues in chronic kidney disease (CKD), which may progress to end-stage renal disease (ESRD). This manuscript describes a myofibroblast-targeting drug delivery system modified with phage-displayed fibrotic kidney-homing peptides. By loading the myofibroblast-targeting nanoparticles (NPs) with sorafenib, a multikinase inhibitor, the NPs could suppress collagen synthesis in cultured human myofibroblasts. When given intravenously to mice with UUO-induced renal fibrosis, sorafenib loaded in myofibroblast-targeting NPs significantly ameliorated renal fibrosis. This approach provides an efficient therapeutic option to renal fibrosis. The myofibroblast-targeting peptide ligands and nanoscale drug carriers may be translated into clinical application in the future.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jconrel.2022.04.004DOI Listing
June 2022

Long-term mortality and cardiovascular events in patients with unilateral primary aldosteronism after targeted treatments.

Eur J Endocrinol 2021 Dec 20;186(2):195-205. Epub 2021 Dec 20.

Department of Urology, National Taiwan University Hospital, Taipei, Taiwan.

Objective: Long-term outcomes (especially mortality and/or major cardiovascular events (MACE)) of the unilateral primary aldosteronism (uPA) patients who underwent medical or surgery-targeted treatment, relative to those with essential hypertension (EH), have been scarcely reported.

Design And Settings: Using the prospectively designed observational Taiwan Primary Aldosteronism Investigation cohort, we identified 858 uPA cases among 1220 primary aldosteronism patients and another 1210 EH controls.

Exposures: Operated uPA patients were grouped via their 1-year post-therapy statuses.

Results: Primary Aldosteronism Surgical Outcome clinical complete success (hypertension remission) was achieved in 272 (49.9%) of 545 surgically treated uPA patients. After follow-up for 6.3 ± 4.0 years, both hypertension-remissive (hazard ratio (HR): 0.54; P < 0.001) and not-cured (HR: 0.61; P < 0.001) uPA patients showed a lower risk of all-cause mortality than that of EH controls; whereas the not-cured group had a higher risk of incident MACE (sub-hazard ratio (sHR), 1.41; P = 0.037) but similar atrial fibrillation (Af) and congestive heart failure (CHF). Mineralocorticoid receptor antagonist (MRA)-treated uPA patients had higher risks of MACE (sHR: 1.38; P = 0.033), Af (sHR:1.62, P = 0.049), and CHF (sHR: 1.44; P = 0.048) than those of EH controls, with mortality as a competing risk. Using inverse probability of treatment-weighted matching and counting adrenalectomy as a time-varying factor, treatment with adrenalectomy was associated with lower risks of all-cause mortality (HR: 0.57; P = 0.035), MACE (HR: 0.67; P = 0.037), and CHF (HR: 0.49; P = 0.005) compared to those of MRA therapy.

Conclusions: Adrenalectomy, independent of post-surgical hypertension remission, was associated with lower all-cause mortality of uPA patients, compared to that of EH patients. We further documented a more beneficial effect of adrenalectomy over MRA treatment on long-term mortality, MACE, and CHF in uPA patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1530/EJE-21-0836DOI Listing
December 2021

PR-619, a General Inhibitor of Deubiquitylating Enzymes, Diminishes Cisplatin Resistance in Urothelial Carcinoma Cells through the Suppression of c-Myc: An In Vitro and In Vivo Study.

Int J Mol Sci 2021 Oct 28;22(21). Epub 2021 Oct 28.

Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei 100, Taiwan.

Cisplatin-based chemotherapy is the standard treatment for bladder urothelial carcinoma (UC). Most patients experience chemoresistance, the primary cause of treatment failure, which leads to disease relapse. The underlying mechanism of chemoresistance involves reduced apoptosis. In this study, we investigated the antitumor effect of the deubiquitylating enzyme inhibitor PR-619 in cisplatin-resistant bladder UC. Deubiquitinase (ubiquitin-specific protease 14 (USP14) and USP21) immunohistochemical staining demonstrated that deubiquitination is related to chemoresistance in patients with metastatic UC and may be a target for overcoming chemoresistance. Cytotoxicity and apoptosis were assessed using fluorescence-activated flow cytometry and a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium assay, and PR-619 was found to enhance the cytotoxic and apoptotic effects of cisplatin in cisplatin-resistant T24/R cells. Mitigated cisplatin chemoresistance was associated with the concurrent suppression of c-Myc expression in T24/R cells. Moreover, the expression of c-Myc was upregulated in human bladder UC specimens from patients with chemoresistance. Experiments in a xenograft nude mouse model confirmed that PR-619 enhanced the antitumor effects of cisplatin. These results are promising for the development of therapeutic strategies to prevent UC chemoresistance through the combined use of chemotherapeutic agents/deubiquitination inhibitors (PR-619) by targeting the c-Myc pathway.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms222111706DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8584183PMC
October 2021

Outcomes and Prediction Models for Exclusive Prostate Bed Salvage Radiotherapy among Patients with Biochemical Recurrence after Radical Prostatectomy.

Cancers (Basel) 2021 May 28;13(11). Epub 2021 May 28.

Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei 100233, Taiwan.

Background: The addition of androgen-deprivation therapy (ADT) or pelvic radiation to prostate bed salvage radiotherapy (SRT) has been debated for prostate cancer patients with biochemical recurrence (BCR) after radical prostatectomy. This study aimed to assess the outcomes and propose prediction models for exclusive prostate bed SRT.

Methods: This is a prospective observational cohort study with patients who underwent SRT with a pre-SRT PSA < 1.5 ng/mL after radical prostatectomy. Patients were treated with 70-Gy SRT to the prostate bed exclusively. Kaplan-Meier survival analyses and Cox regression analyses were applied for depicting and predicting BCR-free survival, ADT-free survival, and metastasis-free survival (MFS). Regression-based coefficients were used to develop nomograms.

Results: A total of 105 patients were included and 91 patients were eligible. The median follow-up period was 39 months. The 5-year BCR-free survival, ADT-free survival, and MFS were 37%, 50%, and 66%, respectively. Multivariable analysis showed that a pre-SRT PSA < 0.45 ng/mL was the only independent factor associated with longer BCR-free survival ( = 0.034), while a PSA-DT > 8 months had better ADT-free survival ( = 0.008). Patients with a PSA-DT > 8 months showed a 100% MFS and a 43% 5-year absolute benefit in MFS than a PSA-DT ≤ 8 months. All patients with a pre-SRT PSA < 0.45 ng/mL and PSA-DT > 8 months were free from subsequent ADT and any metastasis.

Conclusions: In patients with a PSA < 0.45 ng/mL and PSA-DT > 8 months for post-prostatectomy BCR, prostate bed SRT provided excellent outcomes without the need for concomitant ADT or pelvic radiotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers13112672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8199341PMC
May 2021

CDK7 inhibition by THZ1 suppresses cancer stemness in both chemonaïve and chemoresistant urothelial carcinoma via the hedgehog signaling pathway.

Cancer Lett 2021 06 16;507:70-79. Epub 2021 Mar 16.

Department of Urology, National Taiwan University Hospital, Taipei, 100, Taiwan; Department of Urology, College of Medicine, National Taiwan University, Taipei, 100, Taiwan. Electronic address:

Urothelial carcinoma (UC) is the most common type of bladder cancer, with a 5-year survival rate of only 4.6% in metastatic UC. Despite the advances related to immune-checkpoint inhibitor therapy, chemotherapy remains the standard of care for metastatic diseases, with a 50% response rate. The covalent cyclin-dependent kinase 7 (CDK7) inhibitor THZ1 interferes with transcription machinery and is reported to be effective in cancers without targetable mutations. Therefore, we investigated the therapeutic effect of THZ1 on UC and examined possible mechanisms underlying its effects in both chemonaïve and chemosensitive cancers. CDK7 expression is increased in bladder cancer tissues, especially in patients with chemoresistance. THZ1 induced apoptosis and decreased viability in RT4, BFTC905, HT1376, T24, and T24/R UC cell lines. RNA-sequencing, immunoblotting, and sphere-formation assays confirmed that THZ1 suppressed cancer stemness. In the mouse xenograft model, THZ1 suppressed both chemonaïve and chemoresistant tumors. These results indicate that CDK7 inhibition-related cancer stemness suppression is a potential therapeutic strategy for both chemonaïve and chemoresistant UC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.canlet.2021.03.012DOI Listing
June 2021

Outcomes of stratified transurethral resection of bladder tumor: A propensity score-matched analysis.

J Formos Med Assoc 2022 Jan 5;121(1 Pt 1):73-80. Epub 2021 Feb 5.

Department of Urology, National Taiwan University Hospital, National Taiwan University, College of Medicine, Taipei, Taiwan. Electronic address:

Background/purpose: Several strategies have been reported for improving the integrity of transurethral resection of bladder tumor (TURBT). However, no standard has been established. Stratified TURBT (SR) is one of protocols for TURBT, wherein exophytic tumors are first resected and retrieved, and tumor bases are then resected. In this study, we aimed to evaluate the outcomes of SR in patients with nonmuscle invasive bladder cancer (NMIBC).

Methods: From January 2012 to December 2017, patients newly diagnosed as having NMIBC with a follow-up period of more than 2 years were enrolled and categorized into SR and conventional TURBT (CR) groups. Propensity score matching at a 2:1 ratio was performed. Outcomes were the detrusor muscle sampling rate, recurrence-free survival (RFS), and progression-free survival (PFS).

Results: In total, 205 patients were included in our study. The detrusor muscle sampling rate was higher in the SR group (P = 0.043). After propensity score matching, 162 patients were selected for outcome analysis, with 108 and 54 patients undergoing SR and CR, respectively. Compared with the CR group, the SR group showed a lower recurrence rate (P = 0.015) and better RFS in univariate (P = 0.010) and multivariate (P = 0.006) Cox proportional hazards regression. Progression rate and PFS were not significantly different between the two groups.

Conclusion: SR results in a higher detrusor muscle sampling rate and better disease outcomes. Our findings suggest that SR is a promising strategy for TURBT in patients with NMIBC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jfma.2021.01.012DOI Listing
January 2022

THZ1, a covalent CDK7 inhibitor, enhances gemcitabine-induced cytotoxicity via suppression of Bcl-2 in urothelial carcinoma.

Am J Cancer Res 2021 1;11(1):171-180. Epub 2021 Jan 1.

Department of Urology, College of Medicine, National Taiwan University and National Taiwan University Hospital Taipei, Taiwan.

Chemotherapy with gemcitabine plus cisplatin remains the mainstay of treatment for metastatic urothelial carcinoma (UC); however, drug resistance occurs in most patients and eventually leads to treatment failure. In this study, we investigated the role of cyclin-dependent kinase 7 (CDK7) regulation in the treatment of human UCs. Moreover, we studied the effect of THZ1, a CDK7 inhibitor, alone and in combination with gemcitabine, on UCs and explored the underlying mechanism. Immunohistochemical staining showed that CDK7 expression was significantly higher in UC tumors than in counterpart urothelium. THZ1 elicited dose-dependent cytotoxicity and apoptosis in two high-grade UC cells (BFTC905 and T24). THZ1 co-treatment potentiated gemcitabine-induced cytotoxicity with suppression of B-cell lymphoma 2 (Bcl-2). Studies with a xenograft nude mouse model also confirmed that THZ1 enhanced the antitumor effect of gemcitabine on UC. These findings provide important pilot data to target CDK7 or Bcl-2 for the treatment of UCs and for overcoming chemoresistance in UCs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7840706PMC
January 2021

Presence of Subclinical Hypercortisolism in Clinical Aldosterone-Producing Adenomas Predicts Lower Clinical Success.

Hypertension 2020 11 14;76(5):1537-1544. Epub 2020 Sep 14.

From the Departments of Internal Medicine (K.-Y.P., S.-Y.Y., Y.-H.L., V.-C.W.), National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei.

The clinical characteristics and outcomes in patients with clinical aldosterone-producing adenomas harboring mutations with or without subclinical hypercortisolism remain unclear. This prospective study is aimed at determining factors associated with subclinical hypercortisolism in patients with clinical aldosterone-producing adenomas. Totally, 82 patients were recruited from November 2016 to March 2018 and underwent unilateral laparoscopic adrenalectomy with at least a 12-month follow-up postoperatively. Standard subclinical hypercortisolism (defined as cortisol >1.8 μg/dL after 1 mg dexamethasone suppression test [DST]) was detected in 22 (26.8%) of the 82 patients. Intriguingly, a generalized additive model identified the clinical aldosterone-producing adenoma patients with 1 mg DST>1.5 μg/dL had significantly larger tumors (=0.02) than those with 1 mg DST<1.5 μg/dL. Multivariable logistic regression showed that the presence of mutations (odds ratio, 0.22, =0.010) and body mass index (odds ratio, 0.87, =0.046) were negatively associated with 1 mg DST>1.5 μg/dL, whereas tumor size was positively associated with it (odds ratio, 2.85, =0.014). Immunohistochemistry revealed a higher degree of immunoreactivity for CYP11B1 in adenomas with wild-type (=0.018), whereas CYP11B2 was more commonly detected in adenomas with mutation (=0.007). Patients with wild-type and 1 mg DST>1.5 μg/dL exhibited the lowest complete clinical success rate (36.8%) after adrenalectomy. In conclusion, subclinical hypercortisolism is common in clinical aldosterone-producing adenoma patients without mutation or with a relatively larger adrenal tumor. The presence of serum cortisol levels >1.5 μg/dL after 1 mg DST may be linked to a lower clinical complete success rate.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.15328DOI Listing
November 2020

Arterial Stiffness Is Associated with Clinical Outcome and Cardiorenal Injury in Lateralized Primary Aldosteronism.

J Clin Endocrinol Metab 2020 11;105(11)

Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.

Context: The association between arterial stiffness and clinical outcome in lateralized primary aldosteronism (PA) patients after adrenalectomy has not been clearly identified.

Objective: We hypothesized that arterial stiffness estimated by brachial-ankle pulse wave velocity (baPWV) before adrenalectomy was associated with the clinical outcomes and cardiorenal injury in lateralized PA patients after adrenalectomy.

Design And Patients: We designed a retrospective observational cohort study. We collected lateralized PA patients who had undergone adrenalectomy between 2013 and 2016 from the Taiwan Primary Aldosteronism Investigation database. The primary outcome was achieving complete clinical success at 1 year after adrenalectomy. The secondary outcome was estimated glomerular filtration rate declining over 20% and improved left ventricular mass index.

Results: We enrolled 221 patients with lateralized PA (50.7% men; mean age, 51.9 years), of whom 101 patients (45.7%) achieved complete clinical success at the 1-year follow-up assessment after adrenalectomy. Lower baPWV before adrenalectomy (odds ratio = 0.998; 95% confidence interval, 0.996-0.999; P = 0.003) correlated with higher likelihood of complete clinical success by multivariate logistic regression analysis. Multifactorial adjusted generalized additive model demonstrated that preoperative baPWV<1600 cm/sec was significantly associated with complete cure of hypertension. In addition, higher preoperative baPWV was associated with renal function decline and less left ventricular mass regression after adrenalectomy in lateralized PA patients during the follow-up period.

Conclusions: Our study demonstrated that the preoperative severe arterial stiffness was associated with absent complete clinical success in lateralized PA patients after adrenalectomy, and this effect may contribute to cardiorenal injury, which at least partially explains kidney function deterioration and lessened regression of heart mass.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/clinem/dgaa566DOI Listing
November 2020

Effect of diabetes mellitus and glycemic control on the prognosis of non-muscle invasive bladder cancer: a retrospective study.

BMC Urol 2020 Aug 5;20(1):117. Epub 2020 Aug 5.

Department of Urology, National Taiwan University Hospital, National Taiwan University, College of Medicine, No.7, Chung-Shan South Road, Zhongzheng District, Taipei, 100, Taiwan.

Background: Hyperglycemia is associated with series of process leading to oncogenesis. Evidence has shown that diabetes mellitus (DM) seems to be associated with poor prognosis in patients with bladder cancer. However, evidence on the effect of glycemic control on the outcomes of bladder cancer is still limited. In the current study, we aimed to investigate the effect of DM and glycemic control on the prognosis of bladder cancer.

Methods: We conducted a retrospective chart review of a prospective database from January 2012 to December 2017. Patients with newly diagnosed non-muscle invasive bladder cancer (NMIBC) were included. They were classified into the DM and non-DM groups. Prognosis including recurrence rate, progression rate, recurrence-free survival (RFS), and progression-free survival was compared between the two groups. Subgroup analysis of the DM subgroup, in which patients were classified by HbA1C level, was conducted to investigate the effect of glycemic control.

Results: A total of 287 patients were included in our study, with 61 patients in the DM group and 226 patients in the non-DM group. No statistically significant difference was found in the prognosis between the DM and non-DM groups. Subgroup analysis revealed higher recurrence rate (P = 0.037) and worse RFS (log-rank P = 0.019) in patients with HbA1C ≥ 7.

Conclusions: DM is not a risk factor for recurrence and progression in patients with NMIBC. However, poor glycemic control is associated with poor prognosis in patients with both DM and NMIBC. Further prospective studies are needed to confirm current results.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12894-020-00684-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409398PMC
August 2020

Author Correction: Simvastatin reduces the carcinogenic effect of 3-methylcholanthrene in renal epithelial cells through histone deacetylase 1 inhibition and RhoA reactivation.

Sci Rep 2020 Jul 22;10(1):12526. Epub 2020 Jul 22.

Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-69592-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7374539PMC
July 2020

Association between low prostate-specific antigen levels and greater disease progression in high-grade locally-advanced prostate cancer.

J Formos Med Assoc 2021 Jan 23;120(1 Pt 2):483-491. Epub 2020 Jun 23.

Institute of Biomedical Engineering, National Taiwan University, Taipei, Taiwan; Department of Urology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan. Electronic address:

Purpose: In advanced or high-grade prostate cancer (PCa), prostate-specific antigen (PSA) is usually elevated, however, some patients may present with low initial PSA (iPSA) levels. The objective of this study was to evaluate whether different iPSA levels were associated with dissimilar clinical outcomes among men with high-grade PCa and advanced disease after robot-assisted laparoscopic radical prostatectomy (RaLRP).

Methods: This study enrolled 69 PCa patients with initial Gleason score ≥8 and pathologic T-stage ≥3a from April 2012 to December 2018. Patients were stratified into 3 groups based on iPSA levels at diagnosis: <5.0, 5.0-9.9, and ≥10.0. The patients' related parameters were compared among these groups.

Results: The median follow-up period was 33.1 months (IQR: 12.1-48.1). There was no difference in biochemical recurrence (BCR) between the 3 groups (Log-rank test, p = 0.484). We found a higher risk of biochemical recurrence in patients with positive surgical margins (HR: 5.04, 95% CI: 1.64-15.50, p = 0.005). In addition, patients with low iPSA levels (<5.0 ng/mL) had poor radiographic progression-free survival (Log-rank test, p = 0.001) and a higher risk of disease progression (HR: 12.2, 95% CI: 1.18-1260.99, p = 0.036) compared with patients with higher iPSA levels (≥10 ng/mL).

Conclusion: In patients with high-grade locally-advanced PCa, a low iPSA level was associated with a higher risk of disease progression, but not with biochemical recurrence. In this unique population, serum PSA may not be a reliable marker to detect disease progression. Monitoring of these patients may warrant other biomarkers or imaging.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jfma.2020.06.021DOI Listing
January 2021

Neddylation inhibitor, MLN4924 suppresses angiogenesis in huvecs and solid cancers: and study.

Am J Cancer Res 2020 1;10(3):953-964. Epub 2020 Mar 1.

Department of Urology, National Taiwan University Hospital, College of Medicine, National Taiwan University Taipei 100, Taiwan.

Cullin-RING E3 ligases are involved in the ubiquitination of substrates that regulate important biological processes and are a potential therapeutic target in many types of cancer. MLN4924, a small molecule of NEDD8-activating enzyme inhibitor, inactivates CRL by blocking cullin neddylation and has been reported to elicit anti-tumor effect. In this study, In this study, we aimed to investigate the effects of MLN4924 on angiogenesis in human umbilical vascular endothelial cells (HUVECs) and four types of cancer cells. Our results showed that MLN4924 inhibits cell viability and induced apoptosis in HUVECs in a dose-dependent manner. MLN4924 inhibits proliferation and interferes with the cell cycle checkpoint regulators, p21, p27, and phospho-histone H3. Vascular endothelial growth factor (VEGF) treatment increased the level of UBC12 in HUVECs, indicating that neddylation pathway is involved in VEGF-activated angiogenesis. MLN4924 decreased VEGF-activated cell proliferation via neddylation inhibition. MLN4924 inhibited VEGF-activated cell migration, capillary tube formation and VEGF-mediated Erk1/2 activation in HUVECs. We also examined antitumor effect of MLN4924 using xenograft SCID mouse models of four different types of cancer cells. The in vivo results showed MLN4924 inhibited tumor growth in all four types of cancers with decreasing CD31 expression in xenograft tumor. In conclusion, MLN4924 inhibited viability, migration, and VEGF-promoted angiogenic activity in HUVECs; consistently, MLN4924 inhibited tumor growth in four types of cancers with suppression of angiogenesis. These findings provide evidence to develop therapeutic strategy for cancer treatment through anti-angiogenesis through neddylation inhibition.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136913PMC
March 2020

Familial Aggregation and Heritability of Aldosteronism with Cardiovascular Events.

J Clin Endocrinol Metab 2020 06;105(6)

Division of Rheumatology, Allergy and Immunology, Chang Gung Memorial Hospital, Taoyuan, Taiwan.

Context: To date, the effect of positive family history as a risk factor of primary aldosteronism (PA) is largely unknown. Studies have failed to distinguish the heritability of PA as well as the associations between positive family history of PA and clinical outcomes.

Objectives: We quantified the prevalence, the extent of familial aggregation, the heritability of PA among family members of patients with PA, and the association between positive PA family history and major cardiovascular events (MACE).

Design And Settings: Using the Taiwan National Health Insurance Database, 30 245 077 National Health Insurance beneficiaries (both alive and those deceased between January 1, 1999, and December 31, 2015) were identified.

Results: We identified 7902 PA patients. Forty-four had PA (0.3%) among 10 234 individuals with affected parents, 2298 with affected offspring, 1924 with affected siblings, and 22 with affected twins. A positive family history was associated with the adjusted relative risk (RR) (95% confidence interval [CI]) of 11.60 (7.63-17.63) for PA in people with an affected first-degree relative. In subgroup analysis, the risk for PA across all relationships (parent, siblings, offspring, and spouse) showed highly significant differences to PA without family history. The accountability for phenotypic variance of PA was 51.0% for genetic factors, 24.9% for shared environmental factors, and 24.1% for nonshared environmental factors. PA patients with an affected first-degree relative were associated with an increased risk for composite major cardiovascular events (RR 1.31; 95% CI 1.24-1.40, P < .001) compared with PA patients without family history.

Conclusion: Familial clustering of PA exists among a population-based study, supporting a genetic susceptibility leading to PA. There is increased coaggregation of MACE in first-degree relatives of PA patients. Our findings suggest a strong genetic component in the susceptibility of PA, involving different kinships.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/clinem/dgz257DOI Listing
June 2020

Preoperative %p2PSA and Prostate Health Index Predict Pathological Outcomes in Patients with Prostate Cancer Undergoing Radical Prostatectomy.

Sci Rep 2020 01 21;10(1):776. Epub 2020 Jan 21.

Department of Urology, National Taiwan University Hospital, Taipei, Taiwan.

To evaluate the predictive accuracy of the %p2PSA and prostate health index (PHI) in predicting aggressive pathological outcomes in patients with prostate cancer (PCa) undergoing radical prostatectomy (RP), we enrolled 91 patients with organ-confined PCa who were treated with robot-assisted RP. p2PSA levels and the PHI were investigated for their ability to predict pathological results. The %p2PSA and PHI were both significantly higher in patients with ≥pT3 disease, high-risk disease, positive surgical margin, or seminal vesical invasion (SVI). In univariable analysis, p2PSA derivatives were significant predictors of the presence of ≥pT3 disease, high-risk disease, positive surgical margin, and SVI. To predict adverse pathological outcomes at a sensitivity of 90%, p2PSA derivatives had higher specificity than standard PSA derivatives. In multivariable analysis, additional increases in the area under the receiver operating characteristic curve (AUC) were observed with the %p2PSA and PHI for ≥pT3 disease, high-risk disease, and positive surgical margin (8.2% and 2.7%, 6.2% and 4.1%, and 8.6% and 5.4%, respectively). A PHI ≥61.26 enhanced the predictive accuracy of the model for SVI by increasing the AUC from 0.624 to 0.819 (p = 0.009). The preoperative %p2PSA and PHI accurately predict adverse pathological results and are useful for decision-making.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-57618-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6972898PMC
January 2020

Nasogastric tube decompression is unnecessary in patients undergoing laparoscopic nephroureterectomy for localized upper tract urothelial carcinoma.

J Formos Med Assoc 2020 Sep 5;119(9):1353-1359. Epub 2019 Dec 5.

Department of Urology, National Taiwan University Hospital, Taipei, Taiwan; Department of Urology, College of Medicine, National Taiwan University, Taipei, Taiwan. Electronic address:

Background/purpose: This study investigates the safety and feasibility to perform laparoscopic nephroureterectomy (LNU) for upper tract urothelial carcinoma (UTUC) without routine nasogastric tube (NGT) decompression.

Methods: The hospital-based samples comprised of 100 consecutive UTUC patients receiving elective LNU performed by two experienced surgeons. The nationwide data was based on LHID2005 composed of one million beneficiaries randomly selected from the Taiwan National Health Insurance Research Database to identify patients with the diagnoses of UTUCs receiving LNUs. We then compared baseline characteristics, peri-operative data, convalescence parameters and complications between two groups stratified by use of NGT tube.

Results: The hospital-based samples composed of 50 subjects with NGT and 50 without. There were no significant differences in baseline characteristics between two groups. Peri-operative and convalescence parameters were similar when comparing no NGT versus NGT: blood loss of 206 vs. 165 mL; operative time of 180.5 vs.181.1 min; days to intake was 2.1 vs.1.7 days; and hospital stay of 7.8 vs. 7.5 days (all p > 0.05). The nationwide study samples comprised 140 subjects, of which 72 were with NGT and 68 were with no NGT. The baseline data, complications and length of hospital stay were similar between two groups.

Conclusion: Surgery-naïve patients with localized UTUC received LNU without peri-operative NGT is safe and feasible.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jfma.2019.11.011DOI Listing
September 2020

The covalent CDK7 inhibitor THZ1 enhances temsirolimus-induced cytotoxicity via autophagy suppression in human renal cell carcinoma.

Cancer Lett 2020 02 6;471:27-37. Epub 2019 Dec 6.

Department of Urology, National Taiwan University Hospital, Taipei, 100, Taiwan; Department of Urology, College of Medicine, National Taiwan University, Taipe, 100, Taiwan. Electronic address:

Renal cell carcinoma (RCC) is a major cancer of the kidney. The 5-year survival rate is overall 74% and only 8% for Stage 4 cancers. Several agents including tyrosine kinase inhibitors, mTOR inhibitors, and immune checkpoint inhibitors are available as first- or second-line therapy for metastatic RCC. However, the survival benefits are limited. Recently, THZ1 has been identified as a cyclin-dependent kinase 7 (CDK7) inhibitor that interferes with the transcriptional machinery. Although it is apparently effective in various cancer models, the data for RCC has never been reported. In this study, we demonstrated the impact of CDK7 expression on tumor progression and patient survival in a clinical cohort. We found that THZ1 induced apoptosis and cell cycle arrest in RCC cells, thereby reducing cell viability. Furthermore, THZ1 acted synergistically with temsirolimus in vitro, probably by inhibiting autophagy. Moreover, compared to either THZ1 or temsirolimus used individually, the combination treatment further suppressed tumor growth in vivo. These results indicate that CDK7 is associated with the progression and prognosis of RCC, and is a potential therapeutic target for overcoming drug resistance in this cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.canlet.2019.12.005DOI Listing
February 2020

Author Correction: Comparison of Multipulse Laser Vaporesection versus Plasmakinetic Resection for Treatment of Benign Prostate Obstruction.

Sci Rep 2019 Nov 25;9(1):17872. Epub 2019 Nov 25.

Department of Urology, National Taiwan University Hospital, Taipei, Taiwan.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-019-54254-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6877521PMC
November 2019

Risk of new-onset autoimmune diseases in primary aldosteronism: a nation-wide population-based study.

J Hypertens 2020 04;38(4):745-754

Department of Internal Medicine, National Taiwan University Hospital.

Objective: The association between hyperaldosteronism and autoimmune disorders has been postulated. However, long-term incidence of a variety of new-onset autoimmune diseases (NOAD) among patients with primary aldosteronism has not been well investigated.

Methods: From Taiwan's National Health Insurance Research Database with a 23-million population insurance registry, the identification of primary aldosteronism, essential hypertension and NOAD as well as all-cause mortality were ascertained by a validated algorithm.

Results: From 1997 to 2009, 2319 primary aldosteronism patients without previously autoimmune disease were identified and propensity score-matched with 9276 patients with essential hypertension. Among those primary aldosteronism patients, 806 patients with aldosterone-producing adenomas (APA) were identified and matched with 3224 essential hypertension controls. NOAD incidence is augmented in primary aldosteronism patients compared with its matched essential hypertension (hazard ratio 3.82, P < 0.001, versus essential hypertension). Furthermore, NOAD incidence is also higher in APA patients compared with its matched essential hypertension (hazard ratio = 2.96, P < 0.001, versus essential hypertension). However, after a mean 8.9 years of follow-up, primary aldosteronism patients who underwent adrenalectomy (hazard ratio = 3.10, P < 0.001, versus essential hypertension) and took mineralocorticoid receptor antagonist (MRA) still had increased NOAD incidence (hazard ratio = 4.04, P < 0.001, versus essential hypertension).

Conclusion: Primary aldosteronism patients had an augmented risk for a variety of incident NOAD and all-cause of mortality, compared with matched essential hypertension controls. Notably, the risk of incident NOAD remained increased in patients treated by adrenalectomy or MRA compared with matched essential hypertension controls. This observation supports the theory of primary aldosteronism being associated with a higher risk of multiple autoimmune diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/HJH.0000000000002300DOI Listing
April 2020

Suppression of Angiogenesis by Targeting Cyclin-Dependent Kinase 7 in Human Umbilical Vein Endothelial Cells and Renal Cell Carcinoma: An In Vitro and In Vivo Study.

Cells 2019 11 19;8(11). Epub 2019 Nov 19.

Department of Urology, College of Medicine, National Taiwan University, and National Taiwan University Hospital, Taipei 100, Taiwan.

Cancer cells rely on aberrant transcription for growth and survival. Cyclin-dependent kinases (CDKs) play critical roles in regulating gene transcription by modulating the activity of RNA polymerase II (RNAPII). THZ1, a selective covalent inhibitor of CDK7, has antitumor effects in several human cancers. In this study, we investigated the role and therapeutic potential of CDK7 in regulating the angiogenic activity of endothelial cells and human renal cell carcinoma (RCC). Our results revealed that vascular endothelial growth factor (VEGF), a critical activator of angiogenesis, upregulated the expression of CDK7 and RNAPII, and the phosphorylation of RNAPII at serine 5 and 7 in human umbilical vein endothelial cells (HUVECs), indicating the transcriptional activity of CDK7 may be involved in VEGF-activated angiogenic activity of endothelium. Furthermore, through suppressing CDK7 activity, THZ1 suppressed VEGF-activated proliferation and migration, as well as enhanced apoptosis of HUVECs. Moreover, THZ1 inhibited VEGF-activated capillary tube formation and CDK7 knockdown consistently diminished tube formation in HUVECs. Additionally, THZ1 reduced VEGF expression in human RCC cells (786-O and Caki-2), and THZ1 treatment inhibited tumor growth, vascularity, and angiogenic marker (CD31) expression in RCC xenografts. Our results demonstrated that CDK7-mediated transcription was involved in the angiogenic activity of endothelium and human RCC. THZ1 suppressed VEGF-mediated VEGFR2 downstream activation of angiogenesis, providing a new perspective for antitumor therapy in RCC patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cells8111469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6912535PMC
November 2019

Surgery decreases the long-term incident stroke risk in patients with primary aldosteronism.

Surgery 2020 02 29;167(2):367-377. Epub 2019 Oct 29.

Taiwan Primary Aldosteronism Investigation (TAIPAI) Study Group, Taipei, Taiwan.

Background: Hypertension with hyperaldosteronism could be associated with stroke attributable to endothelial injury. Whether the detrimental effect of aldosterone on stroke among primary aldosteronism patients could be mitigated by administration of mineralocorticoid receptor antagonist or by reduction of aldosterone level via adrenalectomy is still inconclusive.

Methods: Primary aldosteronism and essential hypertensive patients were enrolled in the Taiwan National Health Insurance from 1997 to 2009. We used a validated algorithm to enroll primary aldosteronism patients. We conducted a competing risk analysis, using a time-varying Cox proportional hazard model.

Results: We enrolled 3,167 primary aldosteronism patients with a subgroup of 1,047 aldosterone-producing adenoma patients, and matched these with essential hypertensive controls in a 1:4 ratio. The risk of incident stroke, both ischemic and hemorrhagic, was statistically higher in primary aldosteronism patients than in their essential hypertensive control. The differences in stroke incidences between primary aldosteronism and essential hypertensive patients significantly increased as the hypertensive period lengthened. Primary aldosteronism patients who received mineralocorticoid receptor antagonist treatment had higher risk of all stroke (competing hazard ratio = 1.83, P < .001) compared with their essential hypertensive controls. In light of this, aldosterone-producing adenoma patients had a lower risk of incident stroke after adrenalectomy (competing for hazard ratio = 0.75), but a higher cumulative risk of incident stroke after mineralocorticoid receptor antagonist only (competing for hazard ratio = 1.76) than their matched essential hypertensive patients.

Conclusion: We observed an increased stroke risk among primary aldosteronism patients than among their matched essential hypertensive controls. A prolonged duration of hypertension was proportionate to the raised risk of stroke. Our findings emphasize the importance of aldosterone-producing adenoma benefitting from adrenalectomy in attenuating the cerebrovascular event.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.surg.2019.08.017DOI Listing
February 2020

The Deubiquitinating Enzyme Inhibitor PR-619 Enhances the Cytotoxicity of Cisplatin via the Suppression of Anti-Apoptotic Bcl-2 Protein: In Vitro and In Vivo Study.

Cells 2019 10 17;8(10). Epub 2019 Oct 17.

Department of Urology, College of Medicine, National Taiwan University, and National Taiwan University Hospital, Taipei 100, Taiwan.

After chemotherapy for the treatment of metastatic bladder urothelial carcinoma (UC), most patients inevitably encounter drug resistance and resultant treatment failure. Deubiquitinating enzymes (DUBs) remove ubiquitin from target proteins and play a critical role in maintaining protein homeostasis. This study investigated the antitumor effect of PR-619, a DUBs inhibitor, in combination with cisplatin, for bladder UC treatment. Our results showed that PR-619 effectively induced dose- and time-dependent cytotoxicity, apoptosis, and ER-stress related apoptosis in human UC (T24 and BFTC-905) cells. Additionally, co-treatment of PR-619 with cisplatin potentiated cisplatin-induced cytotoxicity in UC cells and was accompanied by the concurrent suppression of Bcl-2. We also proved that Bcl-2 overexpression is related to the chemo-resistant status in patients with metastatic UC by immunohistochemistry (IHC) staining. In a xenograft mice model, we confirmed that PR-619 enhanced the antitumor effect of cisplatin on cisplatin-naïve and cisplatin-resistant UCs. Our results demonstrated that PR-619 effectively enhanced the cisplatin-induced antitumor effect via concurrent suppression of the Bcl-2 level. These findings provide promising insight for developing a therapeutic strategy for UC treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cells8101268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6830310PMC
October 2019

Trends in the use of antimuscarinics and alpha-adrenergic blockers in women with lower urinary tract symptoms in Taiwan: A nationwide, population-based study, 2007-2012.

PLoS One 2019 7;14(10):e0220615. Epub 2019 Oct 7.

Department of Urology, National Taiwan University Hospital, Taipei, Taiwan.

Background: We aim to examine the trend in the use of antimuscarinics and off-label alpha-adrenergic blockers for treatment of lower urinary tract symptoms (LUTS) in a Taiwanese Women Cohort between 2007 and 2012.

Methods: This population-based National Health Insurance Research Database (NHIRD) was used to examine the trends in the use of antimuscarinics or off-label alpha-adrenergic blockers in Taiwan. A sample of 1,000,000 individuals randomly drawn from the whole population of 23 million individuals who were registered in the NHI in 2005. From 2007 through 2012, women aged over 18 years whose claim record contained prescriptions of either of the two drugs for treatment of any of the LUTS-related diagnoses were identified and analyzed. The annual usage of the two drug classes were calculated by defined daily dose (DDD).

Results: From 2007-2012, there was a 0.80 fold (69676.8 to 125104.3) increase in DDD of antimuscarinics in our cohort. The overall healthcare seeking prevalence of LUTS was 7.33% in 2007 and 12.38% in 2012, in a rising trend. The prevalence of antimuscarinics-treated LUTS in our cohort increased from 2.53 in 2007 to 3.41 per 1000 women in 2012. The prevalence of LUTS treated by antimuscarinics increased especially for those older than 60 years during the study period.

Conclusions: This 6-year observational study provided the epidemiologic information of clinically significant LUTS of Asian female population. Moreover, there was a rising trend in the use of antimuscarinics and off-label alpha-adrenergic blockers in the population-based cohort.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0220615PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6779229PMC
March 2020

The impact of primary location and age at orchiopexy on testicular atrophy for congenital undescended testis.

Sci Rep 2019 07 1;9(1):9489. Epub 2019 Jul 1.

Department of Urology, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan.

In this study, we investigated post-orchiopexy testicular growth of undescended testes (UDTs) at different primary locations and determined the risk factors for testicular atrophy (TA). We conducted a retrospective chart review of boys who had undergone orchiopexy for UDTs during January 2001-December 2013. Patient profile, age at operation, primary UDT location, and testicular volume were noted. TA was defined as ≥50% loss of volume after orchiopexy. The primary endpoints were testicular growth and TA after orchiopexy. The secondary endpoint was risk factors for TA. In total, 182 boys had undergone regular ultrasonography; the median follow-up period was 34 months. Among 230 UDTs, 18 (7.8%) atrophic testicles were identified within a median interval of 13 months after orchiopexy. TA rates were 3.3% (1/30), 6.9% (12/173), and 18.5% (5/27) in primary suprascrotal, canalicular, and above-inguinal UDTs, respectively. The survival probability of UDT was 91%, 92% and 100% when orchiopexy was performed in age ≤1 year, 1 < age ≤2 years, and 100% in age >2 years, respectively. Multivariate analysis revealed that inguinal and above-inguinal UDTs (hazard ratio [HR] 11.76, 95% confidence interval [CI] 1.55-89.33, p = 0.017) and genetic or endocrine disorders (HR 3.19, 95% CI 1.19-8.56, p = 0.021) were the risk factors for TA, but not age at operation, premature birth, and laterality. Thus, TA incidence was higher when patients had high primary testicular locations. Early orchiopexy before two years of age may be associated with higher TA risk, while most testicles have promising growth after orchiopexy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-019-45921-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6602959PMC
July 2019
-->