Immune checkpoint inhibitors (ICPis) induce various immune-related adverse events (irAEs), despite their beneficial effects in treating various advanced cancers. ICPi-induced secondary adrenal ...insufficiency is described as a prevalent and serious ‘pituitary irAE.’ However, its precise mechanism remains unclear, and no definitive predictive markers have been reported.
We enrolled and studied 11 patients with advanced cancer (aged 39–70 years; 6 male patients) receiving nivolumab, pembrolizumab or ipilimumab who developed pituitary irAEs. Their clinical data, including endocrine functions, were retrospectively assessed and human leucocyte antigen (HLA) genotypes were determined to compare the HLA allele frequencies in these patients and healthy controls.
Among 11 patients, 7, 3 and 1 patients exhibited malignant melanoma, non–small-cell lung cancer and gastric cancer, respectively. HLA type screening results revealed that HLA-DR15, B52 and Cw12 were observed in 9, 7, and 7 patients with pituitary irAE, respectively. DR15, B52 and Cw12 were significantly more prevalent in our group than in the healthy control group from the Japanese HLA-haplotype database (this study vs healthy control group); DR15: 81.8% vs 33.5% (n = 11, P = 0.0014), B52: 63.6% vs 21.0% (n = 11, P = 0.0026) and Cw12: 70% vs 21.3% (n = 10, P = 0.0013).
HLA-DR15, B52 and Cw12 are possible predisposing factors for pituitary irAEs. HLA-DR15 is reportedly associated with autoimmune disease via interleukin-17 regulation, suggesting its involvement in pituitary irAE development. Using HLA haplotypes as pituitary irAE predictive markers, we could provide safe ICPi treatment and understand irAE pathogenesis.
•Specific human leucocyte antigen types were correlated with pituitary immune-related adverse events (irAEs).•This was seen especially in patients with secondary adrenal insufficiency.•This information may enable effective prediction of irAEs.•These data could enable safer treatment with immune checkpoint inhibitors.•This study provides clues regarding the aetiology of these adverse events.
Primary aldosteronism (PA) is associated with an increased risk of cardiometabolic diseases, especially in unilateral subtype. Despite its high prevalence, the case detection rate of PA is limited, ...partly because of no clinical models available in general practice to identify patients highly suspicious of unilateral subtype of PA, who should be referred to specialized centers. The aim of this retrospective cross-sectional study was to develop a predictive model for subtype diagnosis of PA based on machine learning methods using clinical data available in general practice. Overall, 91 patients with unilateral and 138 patients with bilateral PA were randomly assigned to the training and test cohorts. Four supervised machine learning classifiers; logistic regression, support vector machines, random forests (RF), and gradient boosting decision trees, were used to develop predictive models from 21 clinical variables. The accuracy and the area under the receiver operating characteristic curve (AUC) for predicting of subtype diagnosis of PA in the test cohort were compared among the optimized classifiers. Of the four classifiers, the accuracy and AUC were highest in RF, with 95.7% and 0.990, respectively. Serum potassium, plasma aldosterone, and serum sodium levels were highlighted as important variables in this model. For feature-selected RF with the three variables, the accuracy and AUC were 89.1% and 0.950, respectively. With an independent external PA cohort, we confirmed a similar accuracy for feature-selected RF (accuracy: 85.1%). Machine learning models developed using blood test can help predict subtype diagnosis of PA in general practice.
Abstract
Context
The current clinical guidelines suggest that confirmatory tests for primary aldosteronism (PA) may be excluded in some of patients who have elevated plasma aldosterone concentration ...(PAC) under plasma renin suppression. However, this has low-priority evidence and is under debate in use of serum potassium.
Objective
This study aimed to investigate an appropriate setting for sparing confirmatory tests in PA.
Design and Setting
A retrospective cross-sectional study in a single referral center.
Participants
This study included 327 patients who had hypertension under plasma renin suppression and underwent the captopril challenge test (CCT) between January 2007 and April 2019. CCT results were used to diagnose PA.
Main Outcome Measure
Diagnostic value of PAC and serum potassium in confirmation of PA.
Results
Of the studied patients, 252 of 327 (77%) were diagnosed with PA. All 61 patients with PAC > 30 ng/dL were diagnosed with PA. In patients with PAC between 20 and 30 ng/dL, 44 of 55 (80%) were diagnosed with PA, while all 26 with PAC between 20 to 30 ng/dL who had spontaneous hypokalemia were diagnosed with PA. The proportion of unilateral PA determined by adrenal vein sampling (AVS) was higher in patients who had PAC > 30 ng/dL or those with spontaneous hypokalemia who had PAC between 20 and 30 ng/dL than those who did not meet the criteria (76% vs. 17%, P < .001).
Conclusion
Confirmatory tests in PA could be spared in patients who have typical features of PA and these patients had a high probability of unilateral PA on AVS.
Unilateral subtype of primary aldosteronism (PA) is a common surgically curable form of endocrine hypertension. However, more than half of the patients with PA who undergo unilateral adrenalectomy ...suffer from persistent hypertension, which may discourage those with PA from undergoing adrenalectomy even when appropriate. The aim of this retrospective cross-sectional study was to develop machine learning-based models for predicting postoperative hypertensive remission using preoperative predictors that are readily available in routine clinical practice. A total of 107 patients with PA who achieved complete biochemical success after adrenalectomy were included and randomly assigned to the training and test datasets. Predictive models of complete clinical success were developed using supervised machine learning algorithms. Of 107 patients, 40 achieved complete clinical success after adrenalectomy in both datasets. Six clinical features associated with complete clinical success (duration of hypertension, defined daily dose (DDD) of antihypertensive medication, plasma aldosterone concentration (PAC), sex, body mass index (BMI), and age) were selected based on predictive performance in the machine learning-based model. The predictive accuracy and area under the curve (AUC) for the developed model in the test dataset were 77.3% and 0.884 (95% confidence interval: 0.737-1.000), respectively. In an independent external cohort, the performance of the predictive model was found to be comparable with an accuracy of 80.4% and AUC of 0.867 (95% confidence interval: 0.763-0.971). The duration of hypertension, DDD of antihypertensive medication, PAC, and BMI were non-linearly related to the prediction of complete clinical success. The developed predictive model may be useful in assessing the benefit of unilateral adrenalectomy and in selecting surgical treatment and antihypertensive medication for patients with PA in clinical practice.
Prolonged exposure to pathological cortisol, as in Cushing's syndrome causes various age-related disorders, including sarcopenia. However, it is unclear whether mild cortisol excess, for example, ...accelerates sarcopenia due to aging or chronic stress.
We used Mendelian randomization (MR) analysis to assess whether cortisol was causally associated with muscle strength and mass.
Three single-nucleotide polymorphisms associated with plasma cortisol concentrations in the CORtisol NETwork consortium (n = 12 597) were used as instrumental variables. Summary statistics with traits of interest were obtained from relevant genome-wide association studies. For the primary analysis, we used the fixed-effects inverse-variance weighted analysis accounting for genetic correlations between variants.
One SD increase in cortisol was associated with SD reduction in grip strength (estimate, -0.032; 95% CI -0.044 to -0.020; P = 3e-04), whole-body lean mass (estimate, -0.032; 95% CI, -0.046 to -0.017; P = 0.004), and appendicular lean mass (estimate, -0.031; 95% CI, -0.049 to -0.012; P = 0.001). The results were supported by the weighted-median analysis, with no evidence of pleiotropy in the MR-Egger analysis. The association of cortisol with grip strength and lean mass was observed in women but not in men. The association was attenuated after adjusting for fasting glucose in the multivariable MR analysis, which was the top mediator for the association in the MR Bayesian model averaging analysis.
This MR study provides evidence for the association of cortisol with reduced muscle strength and mass, suggesting the impact of cortisol on the development of sarcopenia.
Aim
Non‐alcoholic fatty liver disease (NAFLD), a hepatic manifestation of metabolic syndrome, is associated with an increased risk of developing lifestyle‐related diseases including type 2 diabetes, ...cardiovascular disease and cerebral vessel disease. No current drug therapy provides the ideal effects of decreasing hepatic inflammation while simultaneously improving liver fibrosis. Liraglutide is a glucagon‐like peptide‐1 receptor agonist that affects the histological findings in patients with non‐alcoholic steatohepatitis (NASH). This study was conducted to evaluate the effect and action of liraglutide for biopsy‐proven NASH.
Methods
After lifestyle modification intervention for 24 weeks, subjects whose hemoglobin A1c levels failed to improve to less than 6.0% and/or whose alanine aminotransferase levels were not lower than baseline, received liraglutide at 0.9 mg/body per day for 24 weeks.
Results
Of 27 subjects, 26 completed the lifestyle modification intervention. Nineteen subjects received liraglutide therapy for 24 weeks. Body mass index, visceral fat accumulation, aminotransferases and glucose abnormalities improved significantly. Repeated liver biopsy was performed in 10 subjects who continued liraglutide therapy for 96 weeks. Six subjects showed decreased histological inflammation as determined by NASH activity score and stage determined by Brunt classification. We saw no significant adverse events during therapy with liraglutide.
Conclusion
Our pilot study demonstrated that treatment with liraglutide had a good safety profile and significantly improved liver function and histological features in NASH patients with glucose intolerance.
Dehydroepiandrosterone sulfate (DHEAS) from the adrenal cortex substantially decreases with age, which may accelerate osteoporosis. However, the association of DHEAS with bone mineral density (BMD) ...and fracture is inconclusive. We conducted a Mendelian randomization (MR) analysis to investigate the role of DHEAS in age-related changes in BMD and fracture risk.
Single nucleotide polymorphisms (SNPs) associated with serum DHEAS concentrations were used as instrumental variables (4 SNPs for main analysis; 4 SNPs for men and 5 SNPs for women in sex-related analysis). Summary statistics were obtained from relevant genome-wide association studies.
A log-transformed unit (µmol/L) increase in serum DHEAS concentrations was associated with an SD increase in estimated BMD at the heel (estimate, 0.120; 95% CI, 0.081-0.158; P = 9 × 10-10), and decreased fracture (odds ratio, 0.989; 95% CI, 0.981-0.996; P = 0.005), consistent with dual-energy X-ray absorptiometry-derived BMD at the femoral neck and lumbar spine. Their associations remained even after adjusting for height, body mass index, testosterone, estradiol, sex hormone-binding globulin, and insulin-like growth factor 1. The association of DHEAS with fracture remained after adjusting for falls, grip strength, and physical activity but was attenuated after adjusting for BMD. The MR-Bayesian model averaging analysis showed BMD was the top mediating factor for association of DHEAS with fracture. The association between DHEAS and BMD was observed in men but not in women.
DHEAS was associated with increased BMD and decreased fracture. DHEAS may play a protective role in decreasing fracture risk, mainly by increasing bone mass.
Glucagon-like peptide-1 (GLP-1) receptor agonists are used to treat diabetes, but their effects on nonalcoholic steatohepatitis (NASH) and the development of hepatocellular carcinoma (HCC) remain ...unclear. In this study, mice with streptozotocin- and high-fat diet-induced diabetes and NASH were subcutaneously treated with liraglutide or saline (control) for 14 weeks. Glycemic control, hepatocarcinogenesis, and liver histology were compared between the groups. Fasting blood glucose levels were significantly lower in the liraglutide group than in the control group (210.0 ± 17.3 mg/dL vs. 601.8 ± 123.6 mg/dL), and fasting insulin levels were significantly increased by liraglutide (0.18 ± 0.06 ng/mL vs. 0.09 ± 0.03 ng/mL). Liraglutide completely suppressed hepatocarcinogenesis, whereas HCC was observed in all control mice (average tumor count, 5.5 ± 3.87; average tumor size, 8.1 ± 5.0 mm). Liraglutide significantly ameliorated steatosis, inflammation, and hepatocyte ballooning of non-tumorous lesions in the liver compared with the control findings, and insulin-positive β-cells were observed in the pancreas in liraglutide-treated mice but not in control mice. In conclusion, liraglutide ameliorated NASH and suppressed hepatocarcinogenesis in diabetic mice. GLP-1 receptor agonists can be used to improve the hepatic outcome of diabetes.
Abstract
Context
Current clinical guidelines recommend confirmation of a positive result in at least one confirmatory test in the diagnosis of primary aldosteronism (PA). Clinical implication of ...multiple confirmatory tests has not been established, especially when patients show discordant results.
Objective
The aim of the present study was to explore the role of 2 confirmatory tests in subtype diagnosis of PA.
Design and Setting
A retrospective cross-sectional study was conducted at two referral centers.
Participants and Methods
We identified 360 hypertensive patients who underwent both a captopril challenge test (CCT) and a saline infusion test (SIT) and exhibited at least one positive result. Among them, we studied 193 patients with PA whose data were available for subtype diagnosis based on adrenal vein sampling (AVS).
Main Outcome Measure
The prevalence of bilateral subtype on AVS according to the results of the confirmatory tests was measured.
Results
Of patients studied, 127 were positive for both CCT and SIT (double-positive), whereas 66 were positive for either CCT or SIT (single-positive) (n = 34 and n = 32, respectively). Altogether, 135 were diagnosed with bilateral subtype on AVS. The single-positive patients had milder clinical features of PA than the double-positive patients. The prevalence of bilateral subtype on AVS was significantly higher in the single-positive patients than in the double-positive patients. (63/66 95.5% vs 72/127 56.7%, P < .01). Several clinical parameters were different between CCT single-positive and SIT single-positive patients.
Conclusion
Patients with discordant results between CCT and SIT have a high probability of bilateral subtype of PA on AVS.
Context
Primary aldosteronism (PA) is known to increase vertebral fracture (VF), although the detailed mechanism remains to be elucidated. We hypothesized that the PA subtype is associated with VF.
...Objective
To evaluate whether unilateral PA is associated with the prevalence of VF.
Design
This was a retrospective cross‐sectional study in a single referral centre.
Patients
We identified 210 hypertensive patients whose clinical data were available for case‐detection results. One hundred and fifty‐two patients were diagnosed with PA using captopril challenge tests.
Measurements
We measured the prevalence of VF, according to PA subtype.
Results
One hundred thirteen patients with PA were subtype classified by adrenal vein sampling. Of these, 37 patients had unilateral PA, 76 patients had bilateral PA, 58 patients had non‐PA; 39 patients with PA were not subtype‐classified. Patients with PA had a higher prevalence of VF (29%, 44/152) than those with non‐PA (12%, 7/58; P = .011). Moreover, unilateral PA had a higher prevalence of VF (46%, 17/37) than bilateral PA (20%, 15/76; P = .021). There was no significant difference in the prevalence of VF between bilateral PA and non‐PA. Unilateral PA was an independent risk factor for VF after adjusting for age and sex (OR: 3.16, 95% confidence interval: 1.12‐8.92; P = .017). Among patients with unilateral PA, serum cortisol concentrations after 1‐mg dexamethasone suppression test were higher in those with VF (1.32 ± 0.67 g/dL) than those without (0.96 ± 0.33 g/dL; P = .048).
Conclusions
Unilateral PA is an independent risk factor for VF.
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