Home Blood Pressure-based Guidance Did Not Increase Anti-albuminuric Effects on Diagnostic Provision of Microalbuminuria in School Workers: A Miyagi Karoshi Prevention Study.

Objective We examined whether home blood pressure (BP)-based behavioural guidance had an additional anti-albuminuric effect on school workers with the simple diagnostic provision of microalbuminuria. Methods Of 169 school staff diagnosed with microalbuminuria (30-299.9 mg/gCr) in the annual 2019 health check-up, 91 agreed to receive home-BP-based guidance. Guidance comprised, for subjects with ≥135/85 mmHg, 5 days mean of home BP measurements, or encouraging medical consultation and lifestyle guidance; lifestyle guidance for subjects with BP 125-134/80-84 mmHg; and adequate lifestyle guidance for subjects BP <125/80 mmHg, if necessary. The main outcome was a change in the frequency of microalbuminuria the following year. Subjects with menstruation were excluded from analysis. Finally, there were 48 and 43 participants in guided and the non-guided groups, respectively. Results The guided and non-guided groups demonstrated similar baseline clinical data. Their prescription rates for hypertension (39.6 vs. 41.9 %) and diabetes (18.8 vs. 30.2 %) were similar. One year later, microalbuminuria was present in 31.2% and 30.2% of the guided and non-guided groups (n.s.), respectively, suggesting a ~70% risk reduction of microalbuminuria in both groups. Sensitivity analysis, excluding patients treated for hypertension or diabetes at baseline, demonstrated essentially similar results. In conclusion, the risk reduction of microalbuminuria was nearly 70% for both the home-BP-based guidance and non-guidance groups. Conclusion These data suggest that home BP-based guidance did not increase anti-albuminuric effects on simple diagnostic provision of microalbuminuria in school workers.

Tumor microenvironment in functional adrenocortical adenomas: immune cell infiltration in cortisol-producing adrenocortical adenoma.

The tumor microenvironment plays pivotal roles in various human neoplasms. However, that of benign tumor, particularly hormone-secreting endocrine tumors, has remained virtually unknown. Therefore, we firstly attempted to analyze the tumor microenvironment of autonomous hormone-secreting adrenocortical adenomas. We first histologically evaluated 21 cortisol-producing adrenocortical adenoma (CPA) and 13 aldosterone-producing adrenocortical adenoma (APA) cases. Quantitative histologic analysis revealed that intratumoral immune cell infiltration (ICI) was more pronounced in CPAs than in APAs. We then evaluated the cytokine and chemokine profiles using polymerase chain reaction arrays in APAs and CPAs. Angiogenic chemokines, C-X-C motif chemokine ligand (CXCL) 1 and CXCL2, were significantly more abundant in CPAs than in APAs using subsequent quantitative polymerase chain reaction and immunohistochemical analyses. We then examined the vascular density between these 2 adenomas, and the density was significantly higher in overt CPAs than in APAs. Of particular interest, CXCL12-positive vessels were detected predominantly in CPAs, and their infiltrating immune cells were C-X-C motif chemokine receptor 4 (CXCR4) positive. These results above indicated that CXCL12-CXCR4 signaling could partly account for ICI detected predominantly in CPAs. We then further explored the etiology of ICI in CPAs by evaluating the senescence of tumor cells possibly caused by excessive cortisol in CPAs. The status of senescence markers, p16 and p21, was significantly more abundant in CPAs than in APAs. In addition, all CPA cases examined were positive for senescence-associated ß-galactosidase. These results all indicated that exposure to local excessive cortisol could result in senescence of tumors cells and play essential roles in constituting the characteristic tissue microenvironment of CPAs.

Expression of steroidogenic enzymes and their transcription factors in cortisol-producing adrenocortical adenomas: immunohistochemical analysis and quantitative real-time polymerase chain reaction studies.

Adrenal Cushing syndrome (CS) is caused by the overproduction of cortisol in adrenocortical tumors including adrenal cortisol-producing adenoma (CPA). In CS, steroidogenic enzymes such as 17α-hydroxylase/17, 20-lase (CYP17A1), 3ß-hydroxysteroid dehydrogenase (HSD3B), and 11ß-hydroxylase (CYP11B1) are abundantly expressed in tumor cells. In addition, several transcriptional factors have been reported to play pivotal roles in the regulation of these enzymes in CPA, but their correlations with those enzymes above have still remained largely unknown. Therefore, in this study, we examined the status of steroidogenic enzymes and their transcriptional factors in 78 and 15 CPA cases by using immunohistochemistry and quantitative real-time polymerase chain reaction (qPCR), respectively. Immunoreactivity of HSD3B2, CYP11B1, CYP17A1, steroidogenic factor-1 (SF1[NR5A1]), GATA6, and nerve growth factor induced-B (NGFIB[NR4A1]) was detected in tumor cells. Results of qPCR analysis revealed that expression of HSD3B2 mRNA was significantly higher than that of HSD3B1, and CYP11B1 mRNA was significantly higher than CYP11B2. In addition, the expression of CYP11B1 mRNA was positively correlated with those of NR5A1, GATA6, and NR4A1. These results all indicated that HSD3B2 but not HSD3B1 was mainly involved in cortisol overproduction in CPA. In addition, NR5A1, GATA6, and NR4A1 were all considered to play important roles in cortisol overproduction through regulating CYP11B1 gene transcription.

Comparison of the methods for measuring the Ki-67 labeling index in adrenocortical carcinoma: manual versus digital image analysis.

Adrenocortical carcinoma (ACC) is a rare, highly malignant neoplasm harboring marked histologic heterogeneity. The Ki-67 labeling index (LI) is one of the most effective diagnostic and prognostic markers in ACC. However, its assessment has by no means been standardized. Therefore, in this study, we analyzed the Ki-67 LI in 18 ACC cases both by seven pathologists using microscopes (MA; manual analysis) and with digital image analysis (DIA) and also compared the Ki-67 LI obtained by selecting "hot spots" and formulating the "average" reading of the whole tumor specimen. In addition, we performed statistical analysis of the association between Ki-67 LI and the clinical and pathologic features of individual cases. The DIA was significantly correlated with MA in hot spots but not in the average fields. The Ki-67 LI in hot spots was significantly and consistently higher than that in average areas by both MA and DIA, indicating intratumoral heterogeneity. The Ki-67 LI was significantly correlated with the Weiss criteria (eosinophilic cytoplasm, nuclear atypia, atypical mitoses, and sinusoidal invasion) by any mode of evaluation. The clinical outcome was significantly better in the patients with a Ki-67 < 10% than in those with a Ki-67 > 10% by MA in hot spots. The Ki-67 LI in hot spots measured by MA best reflected the clinical and pathologic features of ACC. Employment of DIA to obtain the Ki-67 LI in ACC requires further improvement, including correction of its overestimation of the value by counting non-tumorous cells and nuclear segmentation in areas of high cell density.