Challenges in the diagnosis of the enigmatic primary adrenal leiomyosarcoma: two case reports and review of the literature.

BACKGROUND: Primary adrenal leiomyosarcoma is a rare and aggressive mesenchymal tumor derived from the smooth muscle wall of a central adrenal vein or its tributaries; therefore, tumors tend to invade the inferior vena cava and cause thrombosis. The great majority of tumors grow rapidly, which makes the disease difficult to diagnose in its early clinical stages and needs differentiation from adrenocortical carcinomas for the selection of chemotherapy including mitotane which causes adrenal insufficiency. CASE PRESENTATION: We presented two patients with adrenal leiomyosarcoma who were referred to our hospital with abdominal pain and harboring large adrenal tumors and inferior vena cava thrombosis. The endocrine findings, including serum catecholamine levels, were unremarkable. These two patients were considered clinically inoperable, and CT-guided core needle biopsy was performed to obtain the definitive histopathological diagnosis and determine the modes of therapy. The masses were subsequently diagnosed as primary adrenal leiomyosarcoma based on the histological features and positive immunoreactivity for SMA (smooth muscle actin), desmin, and vimentin. CONCLUSIONS: Adrenal leiomyosarcoma derived from the smooth muscle wall of a central adrenal vein or its tributaries is rare but should be considered a differential diagnosis in the case of nonfunctioning adrenal tumors extending directly to the inferior vena cava. CT-guided biopsy is considered useful for histopathological diagnosis and clinical management of patients with inoperable advanced adrenal tumors without any hormone excess.

Antihypertensive Effects of Esaxerenone in Older Patients with Primary Aldosteronism.

Design: Retrospective cohort study. Patients. The data was obtained from a total of 87 PA patients treated with esaxerenone. The treatment group comprised 33 patients who received esaxerenone as first-line therapy and 54 patients that switched from another MRA to esaxerenone. Measurements. Blood pressure (BP), plasma aldosterone concentration (PAC), plasma renin activity (PRA), serum potassium level, estimated glomerular filtration rate (eGFR), urinary albumin-creatinine ratio (UACR), and brain natriuretic peptide (BNP) were assessed before and after treatment with esaxerenone. Patients with overall reductions in their systolic or diastolic BP by 10 mmHg, or more, were considered responders. Unpaired t-tests of the biochemical and personal parameters between responders and nonresponders were run to find the most influencing characteristic for treatment success. Results: BP overall decreased after treatment with esaxerenone (systolic BP: P=0.025, diastolic BP: P=0.096). Serum potassium levels increased, while eGFR decreased (P=0.047 and 0.043, respectively). No patients needed a dose reduction or treatment discontinuation of esaxerenone based on the serum potassium and eGFR criteria. UACR and BNP decreased insignificantly. The responders were significantly older than the nonresponders of the esaxerenone treatment (P=0.0035). Conclusions: Esaxerenone was effective in older patients with primary aldosteronism.

Clinical Usefulness of the Growth Hormone-Releasing Peptide-2 Test for Hypothalamic-Pituitary Disorder.

Context: Growth hormone deficiency (GHD) develops early in patients with hypothalamic-pituitary disorder and is frequently accompanied by other anterior pituitary hormone deficiencies, including secondary adrenal insufficiency (AI). A growth hormone-releasing peptide-2 (GHRP2) test, which is widely used for the diagnosis of patients with GHD, is thought to induce release of not only growth hormone (GH) but also ACTH. However, its clinical usefulness in hypothalamic-pituitary disorder is unclear. Objective: We aimed to determine the clinical utility of the GHRP2 test in patients with hypothalamic-pituitary disorders, particularly for AI concomitant with GHD. Methods: The GHRP2 test, a cosyntropin stimulation test, corticotropin-releasing hormone (CRH) tests, and/or insulin tolerance tests (ITTs) were performed on 36 patients with hypothalamic-pituitary disorder. Results: Twenty-two (61%) had severe GHD, and 3 (8%) had moderate GHD by GHRP2. There was no difference in baseline ACTH and cortisol between non-GHD, moderate GHD, and severe GHD participants. However, a cosyntropin stimulation test and subsequent CRH tests and/or ITTs revealed that 17 (47%) had secondary AI and 16/17 (94%) cases of secondary AI were concomitant with severe GHD. ROC curve analysis demonstrated that the ACTH response in the GHRP2 test was useful for screening pituitary-AI, with a cutoff value of 1.55-fold (83% sensitivity and 88% specificity). Notably, the combination of ACTH response and the peak cortisol level in the GHRP2 test using each cutoff value (1.55-fold and 10 µg/dL, respectively) showed high specificity (100%) with high accuracy (0.94) for diagnosis of pituitary-AI. Conclusion: We recommend measuring ACTH as well as GH during the GHRP2 test to avoid overlooking or delaying diagnosis of secondary AI that frequently accompanies GHD.

ICAM1-Negative Intravascular Large B-Cell Lymphoma of the Pituitary Gland: A Case Report and Literature Review.

OBJECTIVE: Intravascular large B-cell lymphoma (IVLBCL) is a rare and aggressive type of B-cell lymphoma with large cells growing within the lumen of blood vessels. Although previous reports revealed highly variable symptoms resulting from small-vessel occlusion by neoplastic cells in a variety of organs, there are few reports of IVLBCL with pituitary involvement. METHOD: We present a case of IVLBCL with pituitary infiltration from our institution together with a literature review of similar cases to better understand this rare case of IVLBCL involving the pituitary gland. RESULTS: Our case and the pertinent literature demonstrated that IVLBCL with pituitary involvement predominantly occurred in women at a mean age of 64 years, and most of them showed panhypopituitarism that was reversible after standard therapy of rituximab-containing chemotherapy with intrathecal methotrexate. Notably, the pituitary biopsy in our case revealed that atypical large B-cells found within blood vessels and the pituitary gland were negative for intercellular adhesion molecule 1. Intercellular adhesion molecule 1-negative lymphoid cells may have contributed to panhypopituitarism by extravasation into the pituitary tissues, which do not have a blood-brain barrier and receive abundant blood flow. CONCLUSION: IVLBCL of the pituitary gland is a rare lymphoma with nonspecific manifestations and a dismal prognosis. Recognition of the clinicopathological features is necessary for early clinical diagnosis and appropriate treatment.

Characteristics of benign adrenocortical adenomas with 18F-FDG PET accumulation.

INTRODUCTION: Although 18F-FDG PET was originally developed to evaluate benign and malignant tumors, the frequency of detection of benign adrenocortical adenomas showing FDG-PET accumulation has increased. However, the details of FDG-PET-accumulated benign adrenocortical adenomas have not been elucidated. METHODS: To elucidate the pathophysiology of FDG-PET-positive cortisol-producing adrenal tumors, we performed clinicopathological and genetic analyses of adrenocortical adenomas examing FDG-PET in 30 operated patients with unilateral cortisol-producing adrenal tumors (26 adrenal adenomas and 4 adrenal cancers). RESULTS: All adrenocortical carcinomas and 17/26 (65%) benign adrenocortical adenomas showed high FDG accumulation (SUVmax ≥ 3). In adrenocortical adenomas with high FDG accumulation (SUVmax ≥ 3), SUVmax showed a positive correlation with the CT Hounsfield units. A higher SUVmax showed a clear black adenoma appearance with predominantly compact cells, which exhibited high T1 and T2 signals, a lack of signal drop on out-of-phase imaging on MRI, and less accumulation on 131-I adsterol scintigraphy. Furthermore, RNA-sequencing analysis revealed significant increases in the lysosomal and autophagy pathways and metabolic pathways, including glycolysis through glucose transporter (GLUT) 1 and 3, in black adenomas with high-level FDG accumulation. DISCUSSION: A black adenoma is blackish due to lipofuscin, which accumulates as a result of damaged mitochondria or proteins that escape lysosomal degradation or autophagy. Since FDG in PET is taken up via GLUTs, alteration of the intracellular metabolic dynamics associated with mitochondrial damage in black adenomas may increase PET accumulation. CONCLUSION: Black adrenal adenomas should be considered with adrenal tumors showing PET accumulation and low lipid contents.

Association of urinary free cortisol with bone formation in patients with mild autonomous cortisol secretion.

CONTEXT: Mild autonomous cortisol secretion (ACS) is associated with an increased risk of vertebral fractures (VFx). However, the influence of this condition on bone turnover or its association with mild ACS is still controversial. OBJECTIVE: This study aimed to evaluate the impact of mild ACS on bone quality among patients living with the disease. DESIGN AND SETTING: A retrospective study was conducted using data from 55 mild ACS and 12 nonfunctioning adrenal tumour (NFT) patients who visited Chiba University Hospital, Japan, from 2006 to 2018. PATIENTS AND MAIN OUTCOME MEASURES: We analysed clinical features and bone-related factors, including bone mineral density (BMD) and VFx, performed blood tests to assess bone metabolism markers in patients with mild ACS and NFT, and assessed the associations between bone-related markers and endocrinological parameters in patients with mild ACS. RESULTS: No significant differences between mild ACS and NFT patients were observed with respect to the presence or absence of VFx and BMD. Urinary free cortisol (UFC) was higher in mild ACS patients with VFx than those without (p = .037). The T-score and young adult mean (YAM) of the BMD of the femoral neck in mild ACS patients with a body mass index <25 were positively correlated with dehydroepiandrosterone sulphate levels (ρ: 0.42, p = .017; ρ: 0.40, p = .024, respectively). Pearson's correlation analysis showed that bone-specific alkaline phosphatase was negatively correlated with UFC in the patients with mild ACS (ρ: -0.37, p = .026). CONCLUSIONS: These results suggest that urinary free cortisol may be useful for predicting bone formation in mild ACS patients.

Steroid metabolites for diagnosing and predicting clinicopathological features in cortisol-producing adrenocortical carcinoma.

BACKGROUND: Approximately 60% of adrenocortical carcinomas (ACC) are functional, and Cushing's syndrome is the most frequent diagnosis that has been revealed to have a particularly poor prognosis. Since 30% of ACC present steroid hormone-producing disorganization, measurement of steroid metabolites in suspected ACC is recommended. Previous reports demonstrated that steroid hormone precursors or their urine metabolites, which can be assessed using liquid chromatography tandem mass spectrometry (LC-MS/MS) or gas chromatography mass spectrometry (GC-MS) respectively, are useful for distinguishing ACC from cortisol-producing adenomas (CPA); however, despite high precision, LC-MS/MS and GC-MS require a highly trained team, are expensive and have limited capacity. METHODS: Here, we examined 12 serum steroid metabolites using an immunoassay, which is a more rapid and less costly method than LC-MS/MS, in cortisol-producing ACC and CPA. Further, the correlation of each steroid metabolite to the classification stage and pathological status in ACC was analyzed. RESULTS: Reflecting disorganized steroidogenesis, the immunoassay revealed that all basal levels of steroid precursors were significantly increased in cortisol-producing ACC compared to CPA; in particular, 17-hydroxypregnenolone (glucocorticoid and androgen precursor) and 11-deoxycorticosterone (mineralocorticoid precursor) showed a large area under the ROC curve with high sensitivity and specificity when setting the cut-off at 1.78 ng/ml and 0.4 mg/ml, respectively. Additionally, a combination of androstenedione and DHEAS also showed high specificity with high accuracy. In cortisol-producing ACC, 11-deoxycortisol (glucocorticoid precursor) showed significant positive correlations with predictive prognostic factors used in ENSAT classification, while testosterone showed significant positive correlations to the Ki67-index in both men and women. CONCLUSION: Less expensive and more widely available RIA and ECLIA may also biochemically distinguish ACC from CPA and may predict the clinicopathological features of ACC.

Investigation of the optimal b-value to detect breast tumors with diffusion weighted imaging by 1.5-T MRI.

BACKGROUND: Previous studies have reported that the signal attenuation of diffusion-weighted magnetic resonance imaging (DWI) for normal breast tissue and tumor were well fitted by a monoexponential and a biexponential function, respectively. The aim of this study was to investigate the optimal b-value to detect breast tumors from DWI signal attenuations. METHODS: Sixty-four subjects with breast cancer underwent DWI using six b-values up to 3500 s/mm2. The signal attenuations of normal breast and tumor were fitted by mono- and biexponential functions, respectively. The maximum contrast b-values were estimated and compared in terms of frequency. RESULTS: In almost all cases, the contrast increased with a b-value from 0 to approximately 1500 s/mm2. For b > 1500 s/mm2, the contrast decreased. The highest contrast b-value in the range of 0 to 2500 s/mm2 most frequently was b = 1500 and the next most frequent was 1400 s/mm2. Comparing sensitivity and specificity between b = 700 and b = 1400 s/mm2, b =1400 s/mm2 was slightly superior. CONCLUSION: Based on these results, DWI with a b-value of approximately 1400-1500 s/mm2 is recommended for optimizing breast tumor detectability.

Comparisons of multi b-value DWI signal analysis with pathological specimen of breast cancer.

Previous studies have reported that the signal attenuation of diffusion weighted magnetic resonance imaging for tumor tissues displays a non-monoexponential biexponential decay, and the apparent diffusion coefficients (ADCs) can be divided into a fast and slow diffusion component by using a simple biexponential decay model. The purpose of this study is to examine the non-monoexponential character of the diffusion weighted magnetic resonance imaging signal attenuations of breast cancers, estimate the fast and slow diffusion components, and compare them with the extra- and intracellular component information obtained from the pathological specimens. Twenty-two subjects having breast cancers underwent diffusion weighted magnetic resonance imaging using six b-values up to 3500 s/mm(2) and the signal attenuations were analyzed using the biexponential function. The derived slow component fraction correlated with the cellular fraction and the ADCs converged to 0.2-0.3 × 10(-3) mm(2) /s for the higher cellular fractions. The ADCs of the fast component ranged from 1.3 to 3.9 × 10(-3) mm(2) /s and showed no correlation with the extracellular components. This result suggests that the main reason for the decreasing ADC of a breast tumor is the decreasing fraction of the fast component and the increasing fraction of the slow component having a low ADC rather than the decreasing ADC of the fast component by the restricted water diffusion in the reduced extracellular spaces.

Biexponential Signal Attenuation Analysis of Diffusion-weighted Imaging of Breast.

PURPOSE: in vivo, the attenuation of diffusion-weighted imaging (DWI) signal at high b-values is sometimes nonlinear when plotted with semilogarithmic function and is fit well by a biexponential function. Previous reports have indicated that the fast and slow component fractions of the apparent diffusion coefficient (ADC) can be derived by biexponential fitting and that these fractions correspond to the actual diffusion components in the extra- and intracellular space. In this study, we investigated the clinical utility of DWI for the breast by performing DWI using multiple b-factors on healthy volunteers and clinical subjects, analyzing the signal by fitting it with a biexponential equation, and comparing the fitting parameters of breast lesions. PATIENTS AND METHODS: we investigated 8 healthy women as normal cases and 80 female patients with a total of 100 breast tumors (42 benign, 58 malignant tumors) as clinical cases. We performed DWI using 12 b-values for the healthy cases and 6 b-values for the clinical cases, up to a maximum b-value of 3500 s/mm(2). RESULTS: decay of DWI signal of normal mammary glands, most cysts, and some fibroadenomas showed a monoexponential relationship, and conversely, that of intraductal papilloma (IDP) and malignant tumors was well fitted by a biexponential function. Comparison of parameters derived from biexponential fitting demonstrated no significant difference between benign and malignant lesions. For malignant tumor subtype, the fast component fraction of noninvasive ductal carcinoma was statistically greater than that of invasive ductal carcinoma. CONCLUSIONS: although the parameters from biexponential fitting may reflect the character of tumor cellularity, because pathological diagnosis was performed with an emphasis on cell configuration or shape rather than cellularity, it was difficult to distinguish malignant from benign tumors, including many IDPs, or to distinguish tissue types using DWI signal attenuation alone.

Accuracy of sonographic elastography in the differential diagnosis of enlarged cervical lymph nodes: comparison with conventional B-mode sonography.

OBJECTIVE: The purpose of our study was to evaluate the diagnostic performance of sonographic elastography and B-mode sonography individually and combined in the differentiation of reactively and metastatically enlarged cervical lymph nodes. SUBJECTS AND METHODS: Eighty-five lymph nodes (metastatic, n = 53; reactive, n = 32) from 37 patients were examined by both elastography and B-mode sonography in this prospective study. Elastographic patterns were determined on the distribution and percentage of the lymph node area with high elasticity (hard), with pattern 1 being an absent or very small hard area to pattern 5, a hard area occupying the entire lymph node. The cutoff line for reactive versus metastatic was set between patterns 2 and 3; patterns 3-5 were considered metastatic. B-mode sonographic diagnosis was based on the sum of scores for five criteria: short-axis diameter, shape, border (regular or irregular), echogenicity (homogeneous or inhomogeneous), and hilum (present or absent). The cutoff line for reactive versus metastatic was set between scores 6 and 7; scores 5 and 6 were considered reactive, and scores 7-10, metastatic. RESULTS: Sensitivity, specificity, and accuracy of B-mode sonography were 98%, 59%, and 84%, respectively; 83%, 100%, and 89% for elastography; and 92%, 94%, and 93% for the combined evaluation. CONCLUSION: The combination of highly specific elastography with highly sensitive conventional B-mode sonography has the potential to further improve the diagnosis of metastatic enlarged cervical lymph nodes.

Crucial roles of D-type cyclins in the early stage of adipocyte differentiation.

Cyclin D2 was isolated as one of the genes expressed early in adipogenesis. The expression of cyclin D2 increased temporarily early on and then again late in the differentiation process. The expression of cyclin D1 and cyclin D3, the other D-type cyclins, was also transiently induced early during adipocyte differentiation. RNAi (RNA interference)-mediated knockdown of cyclin D1, D2, or D3 inhibited the differentiation of 3T3-L1 cells into lipid-laden adipocytes. Moreover, the knockdown of cyclin D1 or D3 significantly inhibited mitotic clonal expansion (MCE), while silencing of the cyclin D2 gene had a milder effect on MCE. Each of the D-type cyclins seems to play a crucial role in adipocyte differentiation by regulating MCE.

peg10, an imprinted gene, plays a crucial role in adipocyte differentiation.

An imprinted gene, paternally expressed gene (peg) 10, was isolated as one of the genes expressed early in adipogenesis. The expression of peg10 was elevated after the addition of inducers, and was detected in adipocyte differentiable 3T3-L1 cells, but not observed in the non-adipogenic cell line NIH-3T3. Moreover, the knockdown of peg10 by RNA interference (RNAi) inhibited the differentiation of 3T3-L1 cells into lipid-laden adipocytes. Interestingly, peg10 RNAi-treatment reduced the expressions of C/EBPbeta and C/EBPdelta, and inhibited mitotic clonal expansion. These findings strongly indicate that peg10 plays a crucial role at the immediate early stage of adipocyte differentiation.

A cyanobacterial non-coding RNA, Yfr1, is required for growth under multiple stress conditions.

Small, regulatory, non-coding RNA (ncRNA) is involved in various cell functions in both prokaryotes and eukaryotes. However, information on ncRNA in cyanobacteria is still scarce. We studied ncRNA genes by computational screening to compare the intergenic regions of the Synechococcus elongatus PCC 6301 genome with the genomes of three freshwater cyanobacteria. We identified an ncRNA gene in S. elongatus, which has been previously described as yfr1 in marine cyanobacteria. The S. elongatus yfr1 gene is 65 nucleotides long and is positioned between guaB and trxA. We found a high conservation of the yfr1 gene in most cyanobacterial lineages. A yfr1-deficient mutant showed reduced growth under various stress conditions, e.g. oxidative stress and high salt stress conditions, and showed unusual accumulation of sbtA mRNA. A gel shift assay demonstrated interaction of the Yfr1 RNA with sbtA mRNA in vitro. This suggests that the sbtA transcript is a target RNA for the Yfr1 RNA.

Prevalence of atherosclerosis in relation to atomic bomb radiation exposure: an RERF Adult Health Study.

PURPOSE: To determine whether exposure to atomic bomb radiation altered the prevalence of asymptomatic atherosclerosis. MATERIAL AND METHODS: In a cross-sectional analysis, we examined aortic arch calcification by plain chest radiography and common carotid artery intima-media thickness (IMT) by ultrasonography among 1804 survivors of the atomic bombing in Hiroshima. We evaluated the association between atherosclerotic changes and radiation exposure, while adjusting for potentially confounding factors. RESULTS: Multivariate logistic regression analysis showed that aortic arch calcification was significantly associated with radiation exposure (p < 0.05). The odds ratio at 1 Gy was 1.30 (95% confidence interval [CI]: 1.05 - 1.53) for men and 1.31 (95% CI: 1.13 - 1.51) for women. Carotid artery IMT did not vary significantly with radiation dose (p = 0.18). CONCLUSION: Radiation dose contributed to the prevalence of aortic atherosclerosis but not carotid artery atherosclerosis in atomic bomb survivors.

Fracture prediction from bone mineral density in Japanese men and women.

UNLABELLED: In a cohort of 2356 Japanese elderly, after adjusting for age and prevalent vertebral fracture, baseline BMD predicted the risk of spine and hip fracture with similar RR to that obtained from previous reports in whites. The RR per SD decrease in BMD for fracture declined with age. INTRODUCTION: Low bone mineral density (BMD) is one of the most important predictors of a future fracture. However, we are not aware of any reports among Japanese in Japan. MATERIALS AND METHODS: We examined the association of BMD with risk of fracture of the spine or hip among a cohort of 2356 men and women aged 47-95 years, who were followed up by biennial health examinations. Follow-up averaged 4 years after baseline measurements of BMD that were taken with the use of DXA. Vertebral fracture was assessed using semiquantitative methods, and the diagnosis of hip fracture was based on medical records. Poisson and Cox regression analysis were used. RESULTS: The incidence was twice as high in women as in men, after adjusting for age. After adjusting for baseline BMD and prevalent vertebral fracture, however, the gender difference was no longer significant. Age, baseline BMD of spine and femoral neck, and prior vertebral fracture predicted vertebral fracture and hip fracture. Loss of absolute BMD of the femoral neck predicted spine fracture, after adjusting for baseline BMD; rates of change in percent BMD, weight, height, body mass index, and age at menopause did not. The predictive value of baseline BMD for vertebral fracture risk was similar in men and women. The relative risk (RR) for vertebral fracture and hip fracture per SD decrease in BMD declined with age, after adjustment for prevalent vertebral fractures. CONCLUSIONS: Baseline BMD, loss of femoral neck BMD, and prior vertebral fracture predict the risk of spine and hip fracture in Japanese with similar RR to that obtained from previous reports in whites. The RR per SD decrease in BMD for fracture declined with age, suggesting that factors other than BMD might play a greater role in the elderly.