Treatment of primary aldosteronism: Clinical practice guidelines of the Taiwan Society of Aldosteronism.

Primary aldosteronism (PA) is the most common cause of secondary hypertension and one of the few medical diseases that can be cured by surgery. Excessive aldosterone secretion is highly associated with cardiovascular complications. Many studies have shown that patients with unilateral PA treated with surgery have better survival, cardiovascular, clinical, and biochemical outcomes than those who receive medical treatment. Consequently, laparoscopic adrenalectomy is the gold standard for treating unilateral PA. Surgical methods should be individualized according to the patient's tumor size, body shape, surgical history, wound considerations, and surgeon's experience. Surgery can be performed through a transperitoneal or retroperitoneal approach, and via a single-port or multi-port laparoscopic approach. However, total or partial adrenalectomy remains controversial in treating unilateral PA. Partial excision will not completely eradicate the disease and is prone to recurrence. Mineralocorticoid receptor antagonists should be considered for patients with bilateral PA or patients who cannot undergo surgery. There are also emerging alternative interventions, including radiofrequency ablation and transarterial adrenal ablation, for which data on long-term outcomes are currently lacking. The Task Force of Taiwan Society of Aldosteronism developed these clinical practice guidelines with the aim of providing medical professionals with more updated information on the treatment of PA and improving the quality of care.

Estimated glomerular filtration rate-dip after medical target therapy associated with increased mortality and cardiovascular events in patients with primary aldosteronism.

OBJECTIVES: The correlation of the changes of estimated glomerular filtration rate (eGFR) with long-term cardiovascular complications in patients with primary aldosteronism (PA) following mineralocorticoid receptor antagonists (MRA) treatment remains ambiguous. This prospective study aims to determine factors associated with all-cause mortality and de novo cardiovascular events of PA patients against the eGFR-dip. METHODS: A total of 208 newly diagnosed PA patients were enrolled from January 2017 to January 2019. MRA was administered with at least a 6-month follow-up. The 'eGFR-dip' was defined as the difference between eGFR at 6 months after MRA treatment and respective baseline eGFR divided by the baseline eGFR. RESULTS: After a mean 5.7 years follow-up, an eGFR-dip more than 12%, which was detected in 99 (47.6%) of the 208 patients, was a significant independent risk factor predicting composite outcomes (all-cause mortality, de-novo three-point major adverse cardiovascular events, and/or congestive heart failure). Multivariable logistic regression showed that age [odds ratio (OR), 0.94; P = 0.003], pretreatment plasma aldosterone concentration (PAC; OR, 0.98; P  = 0.004), and initial eGFR (OR, 0.97; P  < 0.001) had a positive linkage with the eGFR-dip more than 12%. CONCLUSIONS: Nearly half of PA patients had an eGFR-dip more than 12% after 6 months of MRA treatment. They had a higher incidence of all-cause mortality and de novo cardiovascular events. Elder age, higher pretreatment PAC, or higher initial eGFR could be associated with an elevated risk of an eGFR-dip more than 12%.

Tumor budding in gastric cancer.

The tumor, nodes, metastasis (TNM) staging system has long been the gold standard for the classification and prognosis of solid tumors. However, the TNM staging system is not without limitations. Prognostic heterogeneity exists within patients at the same stage. Therefore, the pursuit of other biomarkers with the potential to classify patients with cancer has never stopped. One of them, tumor budding (TB), has gained much success in colorectal cancer. In recent years, TB in gastric cancer has attracted much attention from researchers, beginning to reveal the molecular and biological aspects of this phenomenon in gastric cancer, and has emerged as a promising prognostic biomarker in gastric cancer, predicting disease progression and unfavorable survival. Therefore, it is time and essential to provide a holistic overview of TB in gastric cancer, which has not been achieved and is the aim of this review.

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.

Diabetes mellitus is associated with more adverse non-hemodynamic left ventricular remodeling and less recovery in patients with primary aldosteronism.

The elevated aldosterone in primary aldosteronism (PA) is associated with increased insulin resistance and prevalence of diabetes mellitus (DM). Both aldosterone excess and DM lead to left ventricular (LV) pathological remodeling. In this study, we investigated the impact of DM on LV non-hemodynamic remodeling in patients with PA. We enrolled 665 PA patients, of whom 112 had DM and 553 did not. Clinical, biochemical, and echocardiographic data were analyzed at baseline and 1 year after adrenalectomy. LV non-hemodynamic remodeling was represented by inappropriate excess left ventricular mass index (ieLVMI), which was defined as the difference between left ventricular mass index (LVMI) and predicted left ventricular mass index (pLVMI). Propensity score matching (PSM) was used with age, sex, systolic, and diastolic blood pressure to adjust for baseline variables. After PSM, the patient characteristics were balanced between the DM and non-DM groups, except for fasting glucose, HbA1c, and lipid profile. A total of 111 DM and 419 non-DM patients were selected for further analysis. Compared to the non-DM group, the DM group had significantly higher ieLVMI and LVMI. After multivariable linear regression analysis, the presence of DM remained a significant predictor of increased ieLVMI. After adrenalectomy, ieLVMI decreased significantly in the non-DM group but not in DM group. The presence of DM in PA patients was associated with more prominent non-hemodynamic LV remodeling and less recovery after adrenalectomy.

New-onset diabetes mellitus risk associated with concurrent autonomous cortisol secretion in patients with primary aldosteronism.

Concurrent autonomous cortisol secretion (ACS) in patients with primary aldosteronism (PA patients) is not uncommon. This work aimed to determine the effect of cortisol levels on incident new-onset type 2 diabetes mellitus (NODM) in PA patients. Using the prospectively designed observational TAIPAI cohort, the PA patients were grouped by cortisol level after an overnight low-dose dexamethasone suppression test (1-mg DST). Of the 476 PA patients, 387 (43.7% men; mean age 52.8 years) did not have baseline DM. After a mean follow-up of 4.3 ± 2.9 years, 32 patients (8.3%) developed NODM. The cutoff value obtained via a generalized additive model showed that a serum cortisol level ≥ 2.65 µg/dL after 1-mg DST was a risk factor for developing NODM (HR, 3.5, p = 0.031) by Cox proportional- hazards model.. In PA patients with a higher body mass index (>25 kg/m2; HR, 3.16), lower estimated glomerular filtration rate (<90 ml/min/1.73 m2; HR, 3.18), longer hypertension duration (>7 years; HR, 3.34), and higher waist-to-hip ratio (>0.9; HR, 3.07), a concomitant cortisol level ≥ 2.65 µg/dL after 1-mg DST were more likely to develop NODM. The high-cortisol group of patients with aldosterone-producing adenoma (APA) using mineralocorticoid receptor antagonist (MRA) was associated with an increased risk of NODM (HR, 5.72). Our results showed that PA patients with a concomitant cortisol level ≥ 2.65 µg/dL after 1-mg DST, independent of the aldosterone level, had a higher incidence of NODM. Such PA patients should be carefully evaluated and managed to achieve better glucose control and prevent metabolic syndrome.

Implication of MR Activity in Posttreatment Arterial Stiffness Reversal in Patients With Primary Aldosteronism.

CONTEXT: Primary aldosteronism (PA) patients have a higher degree of arterial stiffness, which can be reversed after adrenalectomy. OBJECTIVE: We aimed to compare the reversal of arterial stiffness between surgically and medically treated PA patients and to identify the predictors of effective medical treatment. METHODS: We prospectively enrolled 445 PA patients and collected data on baseline clinical characteristics, biochemistry, blood pressure, and pulse wave velocity (PWV) before treatment and 12 months after treatment. In the mineralocorticoid receptor antagonist (MRA)-treated patients, the relationship between the change in PWV after 1 year (ΔPWV) and posttreatment renin activity was explored using the restricted cubic spline (RCS) method. RESULTS: Of the 445 enrolled PA patients, 255 received adrenalectomy (group 1) and 190 received MRAs. In the RCS model, posttreatment plasma renin activity (PRA) 1.5 ng/mL/h was the best cutoff value. Therefore, we divided the MRA-treated patients into 2 groups: those with suppressed PRA (< 1.5 ng/mL/h, group 2), and those with unsuppressed PRA (≥ 1.5 ng/mL/h, group 3). Only group 1 and group 3 patients had a statistically significant improvement in PWV after treatment (both P < .001), whereas no significant improvement was noted in group 2 after treatment (P = .151). In analysis of variance and post hoc analysis, group 2 had a significantly lower ΔPWV than group 1 (P = .007) and group 3 (P = .031). Multivariable regression analysis of the MRA-treated PA patients identified log-transformed posttreatment PRA, age, and baseline PWV as independent factors correlated with ΔPWV. CONCLUSION: The reversal of arterial stiffness was found in PA patients receiving adrenalectomy and in medically treated PA patients with unsuppressed PRA.

Efficacy and Safety of Jianpi Jieyu Decoction for Patients with Mild-to-Moderate Depression of Xin (Heart)-Pi (Spleen) Deficiency Syndrome: A Multi-centre Randomized Controlled Study / 中国结合医学杂志

OBJECTIVE@#To evaluate the efficacy and safety of Jianpi Jieyu Decoction (JJD) for treating patients with mild-to-moderate depression of Xin (Heart)-Pi (Spleen) deficiency (XPD) syndrome.@*METHODS@#In this multi-center, randomized, controlled study, 140 patients with mild-to-moderate depression of XPD syndrome were included from Xiyuan Hospital of China Academy of Chinese Medical Sciences and Botou Hospital of Traditional Chinese Medicine from December 2017 to December 2019. They were randomly divided into JJD group and paroxetine group by using a random number table, with 70 cases in each group. The patients in the JJD group were given JJD one dose per day (twice daily at morning and evening, 100 mL each time), and the patients in the paroxetine group were given paroxetine (10 mg/d in week 1; 20 mg/d in weeks 2-6), both orally administration for a total of 6 weeks. The primary outcome was the change of 17-item Hamilton Depression Rating Scale (HAMD-17) score at week 6 from baseline. The secondary outcomes included the Hamilton Anxiety Scale (HAMA) score, Traditional Chinese Medicine Symptom Scale (TCMSS), and Clinlcal Global Impression (CGI) scores at the 2nd, 4th, and 6th weekends of treatment, HAMD-17 response (defined as a reduction in score of >50%) and HAMD-17 remission (defined as a score of ⩽7) at the end of the 6th week of treatment. Adverse events (AEs) were also recorded.@*RESULTS@#From baseline to week 6, the HAMD-17 scores decreased 10.2 ± 4.0 and 9.1 ± 4.9 points in the JJD and paroxetine groups, respectively (P=0.689). The HAMD-17 response occurred in 60% of patients in the JJD group and in 50% of those in the paroxetine group (P=0.292); HAMD-17 remission occurred in 45.7% and 30% of patients, respectively (P=0.128). The differences of CGI scores at the 6th week were not statistically significant (P>0.05). There were significant differences in HAMD-17 scores between the two groups at 2nd and 4th week (P=0.001 and P=0.014). The HAMA scores declined 8.1 ± 3.0 and 6.9 ± 4.3 points from baseline to week 6 in the JJD and paroxetine groups, respectively (P=0.905 between groups). At 4th week of treatment, there was a significant difference in HAMA between the two groups (P=0.037). TCMSS decreased 11.4 ± 5.1, and 10.1 ± 6.8 points in the JJD and paroxetine groups, respectively (P=0.080 between groups). At the 6th week, the incidence of AEs in the JJD group was significantly lower than that in the paroxetine group (7.14% vs. 22.86%, P<0.05).@*CONCLUSION@#Compared with paroxetine, JJD was associated with a significantly lower incidence of AEs in patients with mild-to-moderate depression of XPD syndrome, with no difference in efficacy at 6 weeks. (Trial registration No. ChiCTR2000040922).

Optimization of extraction process of Chuanxiong Rhizoma-Gastrodiae Rhizoma based on network pharmacology and multi-index orthogonal test / 中国中药杂志

To optimize the extraction process of Chuanxiong Rhizoma-Gastrodiae Rhizoma herb pair by network pharmacology combined with analytic hierarchy process(AHP)-entropy weight method and multi-index orthogonal test. The potential active components and targets of Chuanxiong Rhizoma-Gastrodiae Rhizoma were screened by network pharmacology and molecular docking, and the process evaluation indexes were determined with reference to the Chinese Pharmacopoeia(2020 edition). The core components of Chuanxiong Rhizoma-Gastrodiae Rhizoma were determined as gastrodin, parishin B, parishin C, parishin E, ferulic acid, and 3-butylphthalide. With the extraction volume of each indicator and yield of dry extract as comprehensive evaluation indicators, the extraction conditions were optimized by the AHP-entropy weight method and orthogonal test as the ethanol volume of 50%, the solid-liquid ratio of 1∶8(g·mL~(-1)), extraction for three times, and 1.5 h each time. Through network pharmacology and molecular docking, the process evaluation index was determined, and the optimized process was stable and reproducible for the extraction of Chuanxiong Rhizoma-Gastrodiae Rhizoma herb pair, which could provide reference for in-depth research.

Circulating Plasma Concentrations of ACE2 in Primary Aldosteronism and Cardiovascular Outcomes.

CONTEXT: The plasma concentrations of angiotensin-converting enzyme 2 (pACE2) has been independently associated with cardiovascular diseases. OBJECTIVE: Higher pACE2 concentrations may be found in patients with primary aldosteronism (PA) and might lead to increased cardiovascular events. METHODS: Using an inception observational cohort, we examined pACE2 among 168 incident patients with PA. The expression of ACE2, serine protease 2 (TMPRSS2), and metalloprotease 17 (ADAM17) were assessed in peripheral blood mononuclear cells. RESULTS: Incident PA and essential hypertension (EH) patients had similarly elevated pACE2 (47.04 ± 22.06 vs 46.73 ± 21.06 ng/mL; P = .937). Age was negatively (ß = -2.15; P = .033) and higher serum potassium level (ß = 2.29; P = .024) was positively correlated with higher pACE2 in PA patients. Clinical complete hypertension remission after adrenalectomy (Primary Aldosteronism Surgery Outcome criteria) was achieved in 36 (50%) of 72 surgically treated unilateral PA (uPA) patients. At follow-up, pACE2 decreased in surgically treated patients who had (P < .001) or had no (P = .006) hypertension remission, but the pACE2 attenuation was not statistically significant in uPA (P = .085) and bilateral PA (P = .409) administered with mineralocorticoid receptor antagonist (MRA). Persistently elevated pACE2 (> 23 ng/mL) after targeted treatments was related to all-cause mortality and cardiovascular events among PA patients (hazard ratio = 8.8; P = .04); with a mean follow-up of 3.29 years. TMPRSS2 messenger RNA (mRNA) expression was higher in uPA (P = .018) and EH (P = .038) patients than in normotensive controls; it was also decreased after adrenalectomy (P < .001). CONCLUSION: PA and EH patients had elevated pACE2 and higher expression of TMPRSS2 mRNA compared to those of normotensive population. Persistently elevated pACE2 (> 23 ng/mL) after targeted treatments was associated risk of mortality and incident cardiovascular events.

A Novel Somatic Mutation of CACNA1H p.V1937M in Unilateral Primary Hyperaldosteronism.

Background: Somatic mutations for excess aldosterone production have been frequently identified as important roles in the pathogenesis of unilateral primary hyperaldosteronism (uPA). Although CACNA1H mutation represents a minor etiology in primary aldosteronism, it plays a significant role in causing uPAs in sporadic cases. Objective: To identify novel somatic CACNA1H 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 in vitro studies, demonstrating aldosterone production in variant-transfected human adrenal cell lines. Results: We identified a novel somatic CACNA1H mutation c.5809G>A (p.Val1937Met) in a uPA case. The CACNA1H gene encodes the pore-forming alpha-1H subunit of the voltage-dependent T-type calcium channel Cav3.2. This somatic CACNA1H p.V1937M variant showed excellent clinical and biochemical outcomes after ipsilateral adrenalectomy. The functional effect of somatic CACNA1H 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 CACNA1H p.V1937M might be a pathogenic driver in aldosterone overproduction. This study provides new insight into the molecular mechanism and disease outcomes of uPA.

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.

Case Report: Primary Aldosteronism Due to Bilateral Aldosterone-Producing Micronodules With HISTALDO Classical and Contralateral Non-Classical Pathology.

Background: Non-classical multiple aldosterone-producing micronodules/nodules (mAPM/mAPN) could be the pathogenesis of primary aldosteronism (PA). The co-existence of mAPM with adenomas harboring somatic mutations has not previously been reported. Methods: We presented a PA patient with bilateral mAPM and concomitant autonomous cortisol secretion (ACS). Results: A 46-year-old Taiwanese woman presented with hypertension, hypokalemia, and bilateral adrenal adenomas. A 1 mg low-dose dexamethasone suppression test showed elevated morning serum cortisol. An adrenal vein sampling (AVS) suggested a left-sided lateralization of hyperaldosteronism. A right partial adrenalectomy and a left total adrenalectomy were performed. The patient showed biochemical and hypertension remission after the operation. This patient had bilateral mAPM with concomitant ACS, a right histopathologically classical PA adenoma, and a left non-classical PA adenoma. The right adrenal adenoma showed CYP11B1-negative and CYP11B2-positive staining and harbored the KCNJ5-L168R mutation. The left adrenal adenoma showed CYP11B1-positive and CYP11B2-negative staining and harbored the PRKACA-L206R mutation. Conclusion: In a PA patient with concomitant ACS, bilateral APM could coexist with both histopathologically classical and non-classical PA adenomas, each with different somatic mutations. The presence of ACS could lead to the misinterpretation of AVS results.

Ceiling effect of clomiphene citrate on the testosterone to estradiol ratio in eugonadal infertile men.

INTRODUCTION: The testosterone to estradiol ratio (T/E2 ratio) reportedly exerts a stronger effect on semen quality and sexual desire than does testosterone alone. Clomiphene citrate is a selective estrogen receptor modulator that has long been used as an empirical treatment option in the management of idiopathic oligozoospermia. Clomiphene may change the hypothalamus-pituitary-gonad axis and result in the alteration of the T/E2 ratio. No reliable data are available regarding the change in the T/E2 ratio after clomiphene use in eugonadism. METHODS: This study included 24 male patients who were diagnosed with idiopathic infertility with eugonadism. They all received clomiphene citrate (25 mg/day) as empirical treatment. Blood tests for serum testosterone, estradiol, prolactin, luteinizing hormone, and follicle stimulating hormone were performed before and after 4 weeks of clomiphene use. Paired t-tests were used to evaluate the significance of the hormone level change. RESULTS: Overall, the patients' T/E2 ratio did not increase significantly after clomiphene use. In the subgroup analysis, the T/E2 ratio of patients with a baseline ratio of <200 increased significantly after clomiphene use. CONCLUSIONS: Clomiphene citrate may significantly increase the T/E2 ratio in eugonadal men under the premise of its ceiling effect (T/E2 ratio < 200), providing practitioners with guidance on the use of clomiphene in this demographic.

Enhanced Recovery After Surgery protocol for elderly gastric cancer patients: A prospective study for safety and efficacy.

BACKGROUND: Enhanced Recovery After Surgery (ERAS) has been used to improve surgical outcomes in recent years. However, its safety and efficacy in elderly patients with gastric cancer remain unclear. The aim of this study was to reveal the safety and efficacy of the ERAS protocol in elderly patients with gastric cancer. METHODS: Elderly gastric cancer patients (age≥70 years) who underwent gastrectomy were divided into the ERAS group and the conventional group. Postoperative complications, postoperative hospital stay, hospitalization expenses, and readmission rates were compared between the two groups. RESULTS: From December 2019 to January 2021, 100 eligible patients were enrolled in our study. All baseline data were balanced between the ERAS group and the conventional group. There was no significant difference in terms of complications (18% vs. 16%, P = 0.14) between the two groups. The most common complication was pneumonia. Four patients were observed in the conventional group and three patients in the ERAS group. The postoperative hospital stay was shorter in the ERAS group (8.2 vs. 10.4, P = 0.001). CONCLUSIONS: The ERAS protocol could be safely used in elderly gastric cancer patients undergoing gastrectomy and shorten postoperative hospital stay.

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

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.

Characterization of a mutated KCNJ5 gene, G387R, in unilateral primary aldosteronism.

Somatic mutation in the KCNJ5 gene is a common driver of autonomous aldosterone overproduction in aldosterone-producing adenomas (APA). KCNJ5 mutations contribute to a loss of potassium selectivity, and an inward Na+ current could be detected in cells transfected with mutated KCNJ5. Among 223 unilateral primary aldosteronism (uPA) individuals with a KCNJ5 mutation, we identified 6 adenomas with a KCNJ5 p.Gly387Arg (G387R) mutation, previously unreported in uPA patients. The six uPA patients harboring mutant KCNJ5-G387R were older, had a longer hypertensive history, and had milder elevated preoperative plasma aldosterone levels than those APA patients with more frequently detected KCNJ5 mutations. CYP11B2 immunohistochemical staining was only positive in three adenomas, while the other three had co-existing multiple aldosterone-producing micronodules. The bioinformatics analysis predicted that function of the KCNJ5-G387R mutant channel could be pathological. However, the electrophysiological experiment demonstrated that transfected G387R mutant cells did not have an aberrantly stimulated ion current, with lower CYP11B2 synthesis and aldosterone production, when compared to that of the more frequently detected mutant KCNJ5-L168R transfected cells. In conclusion, mutant KCNJ5-G387R is not a functional KCNJ5 mutation in unilateral PA. Compared with other KCNJ5 mutations, the observed mildly elevated aldosterone expression actually hindered the clinical identification of clinical unilateral PA. The KCNJ5-G387R mutation needs to be distinguished from functional KCNJ5 mutations during genomic analysis in APA evaluation because of its functional silence.

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

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 (p = 0.034), while a PSA-DT > 8 months had better ADT-free survival (p = 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.

Laparoscopic proximal gastrectomy with double-tract reconstruction for upper third gastric cancer.

BACKGROUND: Proximal gastrectomy with double-tract reconstruction (DTR) has been used for upper third gastric cancer as a function-preserving procedure. However, the safety and feasibility of laparoscopic proximal gastrectomy (LPG) with DTR remain uncertain. This study compared open proximal gastrectomy (OPG) with DTR and LPG with DTR for proximal gastric cancer. METHODS: Sixty-four patients who had undergone OPG with DTR and forty-six patients who had undergone LPG with DTR were enrolled in this case-control study. The clinical characteristics, surgical outcomes and postoperative nutrition index were analysed retrospectively. RESULTS: The operation time was significantly longer in the LGP group than in the OPG group (258.3 min vs 205.8 min; p = 0.00). However, the time to first flatus and postoperative hospital stay were shorter in the LPG group [4.0 days vs 3.5 days (p = 0.00) and 10.6 days vs 9.2 days (p = 0.001), respectively]. No significant difference was found between the two groups in the number of retrieved lymph nodes, complications or reflux oesophagitis. The nutrition status was assessed using the haemoglobin, albumin, prealbumin and weight levels from pre-operation to six months after surgery. No significant difference was found between the groups. CONCLUSION: LPG with DTR can be safely performed for proximal gastric cancer patients by experienced surgeons.

Transtubular potassium gradient predicts kidney function impairment after adrenalectomy in primary aldosteronism.

BACKGROUND: In primary aldosteronism (PA), kidney function impairment could be concealed by relative hyperfiltration and emerge after adrenalectomy. We hypothesized transtubular gradient potassium gradient (TTKG), a kidney aldosterone bioactivity indicator, could correlate to end organ damage and forecast kidney function impairment after adrenalectomy. METHODS: In the present prospective study, we enrolled lateralized PA patients who underwent adrenalectomy and were followed up 12 months after operation in the Taiwan Primary Aldosteronism Investigation (TAIPAI) registry from 2010 to 2018. The clinical outcome was kidney function impairment, defined as estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2 at 12 months after adrenalectomy. End organ damage is determined by microalbuminuria and left ventricular mass. RESULTS: In total, 323 patients [mean, 50.8 ± 10.9 years old; female 178 (55.1%)] were enrolled. Comparing pre-operation and post-operation data, systolic blood pressure, serum aldosterone, urinary albumin to creatinine ratio and eGFR decreased. TTKG ⩾ 4.9 correlated with pre-operative urinary albumin to creatinine ratio >50 mg/g [odds ratio (OR) = 2.42; p = 0.034] and left ventricular mass (B = 20.10; p = 0.018). Multivariate logistic regression analysis demonstrated that TTKG ⩾ 4.9 could predict concealed chronic kidney disease (OR = 5.42; p = 0.011) and clinical success (OR = 2.90, p = 0.017) at 12 months after adrenalectomy. CONCLUSIONS: TTKG could predict concealed kidney function impairment and cure of hypertension in PA patients after adrenalectomy. TTKG more than 4.9 as an adverse surrogate of aldosterone and hypokalaemia correlated with pre-operative end organ damage in terms of high proteinuria and cardiac hypertrophy.