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The rapid progression of chronic kidney disease and higher incidence of cardiovascular complications are well known in patients with hyperaldosteronism. However, detailed renal histopathologic characteristics of this disease have remained unknown. Therefore, renal biopsy specimens of 19 cases with unilateral hyperaldosteronism were compared with 22 autopsy renal cases of estimated glomerular filtration rate-matched essential hypertension without nephropathy or endocrine disorders to explore the hyperaldosteronism-specific histopathologic renal changes in this study. Global and segmental glomerulosclerosis, interstitial fibrosis, infiltration of inflammatory cells, arteriosclerosis, hyalinization of arterioles and immunoreactivity of mineralocorticoid receptor, 11β-hydroxysteroid dehydrogenase type 1 and 2, and renin were all quantitatively evaluated. The ultrastructural analysis was added in 3 hyperaldosteronism cases. Both mineralocorticoid receptor ( P P P P P =0.08). Glomerular size was significantly larger in hyperaldosteronism ( P P =0.08), and intima-to-media ratio was significantly lower ( P =0.02) in hyperaldosteronism. Arteriolar hyalinization was significantly more pronounced ( P P

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.

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

Objectives To investigate whether the result of the 1-mg dexamethasone suppression test can predict the improvement of comorbidities after adrenalectomy in patients with subclinical Cushing syndrome. Methods This retrospective study included 117 subclinical Cushing syndrome patients who underwent adrenalectomy. The numbers of prescribed drugs for metabolic comorbidities and the clinical variables at diagnosis were compared with those at the follow up. Patients were classified into subgroups according to the result of the 1-mg dexamethasone suppression test. Results Significant improvements in blood pressure, serum cholesterol and body mass index were observed. Furthermore, a significant improvement in glycated hemoglobin was observed in patients with diabetes mellitus. These improvements led to a discontinuation or reduction of prescribed drugs after surgery. In addition, the greatest reduction of prescribed drugs was observed in patients whose serum cortisol levels were between 1.8 and 3.0 µg/dL after the 1-mg dexamethasone suppression test. Conclusions The result of the 1-mg dexamethasone suppression test can be a useful factor predicting the improvement of comorbidities after adrenalectomy. Current data might give us a new insight into the decision-making for the treatment of subclinical Cushing syndrome.

Background Diabetes carries a known risk of bone fracture despite high bone mineral density (BMD). The fracture risk assessment tool (FRAX) predicts the 10-year major osteoporotic fracture risk and hip fracture risk. We investigated the effects of clinical parameters on the FRAX score and evaluated the validity of FRAX for evaluating current bone fragility in diabetes subjects. Materials and Methods Forty-seven thousand, three hundred eighty-nine Japanese women participated in the Chiba bone survey, a population-based, multicenter, cross-sectional study of postmenopausal osteoporosis; we estimated FRAX scores without BMD and compared scores between subjects with and without type 2 diabetes. Results Mean FRAX major osteoporotic fracture risk was significantly higher in the diabetes group. A multiple regression model demonstrated some clinical parameters that affected the FRAX score and, after adjusting for such parameters, the FRAX score was not significantly different between the diabetes and nondiabetes groups, although the type 2 diabetes rate was significantly higher in subjects with a fracture in the past 5 years, which reflected current bone fragility. After adjusting for clinical parameters, the diabetes rate remained significantly higher in subjects with a fracture in the past 5 years, confirming that type 2 diabetes influences current bone fragility. Our study demonstrated that type 2 diabetes truly carries a risk of bone fracture, but adjusted FRAX major osteoporotic fracture risk is not significantly different between subjects with and without type 2 diabetes. Conclusions The FRAX major osteoporotic fracture risk without BMD does not correctly indicate current bone fragility in Japanese middle-aged women with type 2 diabetes.

Purpose To compare post-implant dosimetrics between intraoperatively built custom-linked (IBCL) seeds and loose seeds (LS) at 24 hours and 1 month by sector analysis, and to evaluate the effect of IBCL seeds with regard to change in dosimetric parameters, in patients with prostate cancer treated with brachytherapy. Material and methods Consecutive patients treated for localized prostate cancer who received definitive brachytherapy between March 2013 and October 2017 were retrospectively analyzed. Prostate V100 (PV100), prostate D90 (PD90), prostate V150 (PV150), urethral D30 (UD30), urethral V150 (UV150), and rectal V100 (RV100) were assessed. Results Thirty-two patients were treated with LS and 32 patients were treated with IBCL seeds. The median follow-up time was 49.9 months in the LS group and 27.1 months in the IBCL group. PV150, UV150, and UD30 at 24 hours and UD30 at 1 month showed significant difference (F-test), and standard deviation (SD) tended to be lower in the IBCL group. Analysis of change in the variables revealed significance for ΔPV100 and ΔPD90 (F-test, p = 0.014 and < 0.001, respectively), and ΔPV150 and ΔUD30 showed marginal significance (p = 0.084 and 0.097, respectively). PV150, UV150, and UD30 at 24 hours and 1 month were significantly lower in the IBCL group, and there was no significant difference in PV100, PD90, and RV100 compared with the LS group (t-test). The homogeneity index (HI) was significantly higher in the IBCL group (p < 0.001). Conclusions In this retrospective single institutional study, there was a decrease in the SD of the dosimetric parameters in the IBCL group, and it was statistically significant in change in the variables between 24 hours and 1 month (F-test). The use of IBCL seeds significantly decreased PV150, UV150, and UD30, and significantly improved HI, without lowering PD90 or PD100.

This phase 2, single-arm, open-label, dose-titration, multicenter study evaluated osilodrostat (11β-hydroxylase inhibitor) in Japanese patients with endogenous Cushing's syndrome (CS) caused by adrenal tumor/hyperplasia or ectopic adrenocorticotropic hormone syndrome. The primary endpoint was percent change from baseline to week 12 in mean urinary free cortisol (mUFC) at the individual patient level. Of the nine patients enrolled in the study, seven completed the 12-week core treatment period and two discontinued at or prior to week 12 due to adverse events (AEs). Of the seven patients who completed 12 weeks of study treatment, two completed 48 weeks of study treatment. Median osilodrostat exposure was 12 weeks. Median (range) average dose including dose interruption (0 mg/day) was 2.143 (1.16-7.54) mg/day. Median (range, population) percentage change in mUFC was -94.47% (-99.0% to -52.6%, n = 7) at week 12. At week 12, 6/9 patients were complete responders (mUFC ≤ upper limit of normal [ULN]) and 1/9 was a partial responder (mUFC > ULN but decreased by ≥50% from baseline). Most frequent AEs were adrenal insufficiency (n = 7), gamma-glutamyl transferase increase, malaise, and nasopharyngitis (n = 3 each). Serious AEs were seen in four patients. No deaths occurred in this study. In conclusion, osilodrostat treatment led to a reduction in mUFC in all nine patients with endogenous CS other than Cushing's disease (CD), regardless of disease type, with >80% reduction seen in 6/7 patients at week 12. The safety profile was consistent with previous reports in CD patients, and the reported AEs were manageable.

Taq1A polymorphism is a DRD2 gene variant located in an exon of the ANKK1 gene and has an important role in the brain’s dopaminergic functions. Some studies have indicated that A1 carriers have an increased risk of developing Parkinson’s disease (PD) and show poorer clinical performance than A2 homo carriers. Previous studies have suggested that A1 carriers had fewer dopamine D2 receptors in the caudate and increased cortical activity as a compensatory mechanism. However, there is little information about morphological changes associated with this polymorphism in patients with PD. The study aim was to investigate the relationship between brain volume and Taq1A polymorphism in PD using voxel-based morphometry (VBM). Based on Taq1A polymorphism, 103 patients with PD were divided into two groups: A1 carriers (A1/A1, A1/A2) and A2 homo carriers (A2/A2). The volume of the left prefrontal cortex (PFC) was significantly decreased in A2 homo carriers compared to A1 carriers. This finding supports the association between Taq1A polymorphism and brain volume in PD and may explain the compensation of cortical function in A1 carriers with PD.

Background: α-cyclodextrin (α-CD) is one of the dietary fibers that may have a beneficial effect on cholesterol and/or glucose metabolism, but its efficacy and mode of action remain unclear. Methods: In the present study, we examined the anti-hyperglycemic effect of α-CD after oral loading of glucose and liquid meal in mice. Results: Administration of 2 g/kg α-CD suppressed hyperglycemia after glucose loading, which was associated with increased glucagon-like peptide 1 (GLP-1) secretion and enhanced hepatic glucose sequestration. By contrast, 1 g/kg α-CD similarly suppressed hyperglycemia, but without increasing secretions of GLP-1 and insulin. Furthermore, oral α-CD administration disrupts lipid micelle formation through its inclusion of lecithin in the gut luminal fluid. Importantly, prior inclusion of α-CD with lecithin in vitro nullified the anti-hyperglycemic effect of α-CD in vivo, which was associated with increased intestinal mRNA expressions of SREBP2-target genes (Ldlr, Hmgcr, Pcsk9, and Srebp2). Conclusions: α-CD elicits its anti-hyperglycemic effect after glucose loading by inducing lecithin inclusion in the gut lumen and activating SREBP2, which is known to induce cholecystokinin secretion to suppress hepatic glucose production via a gut/brain/liver axis.

Context Hashimoto’s thyroiditis is the most common cause of hypothyroidism. Patients usually respond well to oral synthetic thyroxine (levothyroxine); however, for unknown reasons some individuals present with treatment-resistant Hashimoto thyroiditis. In cases of cancer and certain infectious diseases, the ATP binding cassette (ABC) transporters have been implicated in multidrug resistance, and we hypothesized and investigated a role of ABC transporters in drug-resistant Hashimoto’s thyroiditis. Case Description The patient whose case we report had a history of Hashimoto’s thyroiditis, immune thrombocytopenia, and refractory hypertension, with varying treatment resistance to the oral medications prescribed for each condition. In order to establish or exclude a genetic basis for her illness, we examined the patient’s gene expression profiles using peripheral blood leukocytes, and found that ABCG2/BCRPexpression was significantly high compared with healthy volunteers. Also, the increased daunomycin efflux capacity of our patient’s lymphocytes was successfully inhibited by fumitremorgin C, a specific ABCG2/BCRP inhibitor, and the patient’s level of thyroid-stimulating hormone increased by 248.6% after administration of intact levothyroxine tablets but decreased by 45.1% when tablets were crushed. Her average blood pressure decreased from 166.3/108.5 mmHg to 125.9/78.8 mmHg when switching from intact to crushed losartan tablets. Conclusions High expression and accelerated efflux transporter activity of ABCG2/BCRP in the small intestine are expected to contribute to the ineffectiveness of orally administered intact tablets in cases with treatment-resistant Hashimoto’s thyroiditis, and crushed tablets can be more effective for some of these patients.

Objective Accurate assessment and localization of aldosterone-producing adenomas (APAs) are essential for the treatment of primary aldosteronism (PA). Although adrenal venous sampling (AVS) is the standard method of reference for subtype diagnosis in PA, controversy exists concerning the criteria for its interpretation. This study aims to determine better indicators that can reliably predict subtypes of PA. Method Retrospective, single-cohort analysis including 209 patients with PA who were subjected to AVS. Eighty-two patients whose plasma aldosterone concentrations (PAC) were normalized after surgery were histopathologically or genetically diagnosed with APA. The accuracy of image findings was compared to AVS results. Receiver operating characteristic (ROC) curve analysis between the operated and the no-apparent laterality groups was performed using AVS parameters and loading test for diagnosis of PA. Result Agreement between image findings and AVS results was 56.3%. ROC curve analysis revealed that the lateralization index (LI) after adrenocorticotropin stimulation cutoff was 2.40, with 98.8% sensitivity and 97.1% specificity. The contralateral suppression index (CSI) cutoff value was 1.19, with 98.0% sensitivity and 93.9% specificity. All patients over the LI and CSI cutoff values exhibited unilateral subtypes. Among the loading test, the best classification accuracy was achieved using the PAC reduction rate after a saline infusion test (SIT) >33.8%, which yielded 87.2% sensitivity or a PAC after a SIT Conclusion The combined criteria of the PAC reduction rate and PAC after the SIT can determine which subset of patients with APA who should be performed AVS for validation.

Adipose-derived stem cells and ceiling culture-derived preadipocytes can be harvested from subcutaneous adipose tissue. Little is known about the epigenetic differences, which may contribute to differences in osteogenic potential, between these cell types. The purpose of this study was to address the osteogenic potential and underlying epigenetic status of adipose-derived stem cells and ceiling culture-derived preadipocytes.Adipose-derived stem cells and ceiling culture-derived preadipocytes were cultured from abdominal subcutaneous fat tissues of four metabolically healthy, lean female patients. After 7 weeks of culture, cellular responses to osteogenic differentiation media were examined. To evaluate the osteogenic potentials of undifferentiated adipose-derived stem cells and ceiling culture-derived preadipocytes, two types of epigenetic assessment were performed using next-generation sequencing: DNA methylation assays with the Human Methylation 450K BeadChip, and chromatin immunoprecipitation assays for trimethylation of histone H3 at lysine 4.Human ceiling culture-derived preadipocytes showed greater osteogenic differentiation ability than did adipose-derived stem cells. In an epigenetic survey of the promoters of four osteogenic regulator genes (RUNX2, SP7, ATF4, and BGLAP), the authors found a general trend toward decreased CpG methylation and increased trimethylation of histone H3 at lysine 4 levels in ceiling culture-derived preadipocytes as compared to adipose-derived stem cells, indicating that these genes were more likely to be highly expressed in ceiling culture-derived preadipocytes.The surveyed epigenetic differences between adipose-derived stem cells and ceiling culture-derived preadipocytes were consistent with the observed differences in osteogenic potential. These results enhance the authors' understanding of these cells and will facilitate their further application in regenerative medicine.

We recently conducted an open-label phase I/II study to evaluate the efficacy and safety of preoperative and chronic treatment with metyrosine (an inhibitor of catecholamine synthesis) in pheochromocytoma/paraganglioma (PPGL) in Japan. We compared creatinine-corrected metanephrine fractions in spot urine and 24-hour urine samples (the current standard for the screening and diagnosis of PPGLs) from 16 patients to assess the therapeutic effect of metyrosine. Percent changes from baseline in urinary metanephrine (uMN) or normetanephrine (uNMN) were compared between spot and 24-hour urine samples. Mean percent changes in uMN or uNMN in spot and 24-hour urine were -26.36% and -29.27%, respectively. The difference in the percent change from baseline between uMN or uNMN in spot and 24-hour urine was small (-2.90%). The correlation coefficient was 0.87 for percent changes from baseline between uMN or uNMN measured in spot and 24-hour urine. The area under the receiver operator characteristic (ROC) curve of uMN or uNMN measured in spot urine vs. 24-hour urine (reference standard) to assess the efficacy of metyrosine treatment was 0.93. Correlations and ROCs between 24-hour urinary vanillylmandelic acid, adrenaline, and noradrenaline and 24-hour uMN or uNMN were similar to those between spot uMN or uNMN and 24-hour uMN or uNMN. No large difference was observed between spot and 24-hour urine for the assessment of metyrosine treatment by quantifying uMN or uNMN in Japanese patients with PPGLs. These results suggest that spot urine samples may be useful in assessing the therapeutic effect of metyrosine.

Aim To investigate whether hyperbaric oxygen (HBO) is effective for the pathophysiological findings in an IC/PBS-like mouse model induced by intravesical hydrogen peroxide (H2 O2 ). Methods Six-week-old ICR female mice (N = 16) were divided into four experimental groups: (1) sham control with intravesical vehicle instillation twice, and without subsequent treatment (N = 4); (2) H2 O2 instillation twice, followed by HBO (100% O2 , 2 ATA, 30 min per session) (N = 4); (3) H2 O2 instillation twice, followed by dummy hyperbaric treatment (air, 2ATA, 30 min per session) (N = 4); and (4) H2 O2 instillation twice, followed by no treatment (N = 4). Body weight, voiding frequency, tidal voiding volume, and individual bladder pain threshold using the von-Frey test were measured. Whole body uptake of an inflammation-specific fluorescent pan-cathepsin was assessed by an in vivo imaging. Immunohistochemical staining and the mRNA expression of several biomarkers associated with chronic inflammation in resected bladders were evaluated. Results The HBO-treated group showed significant improvement in voiding frequency, tidal voiding volume, and the individual bladder pain threshold. Moreover, HBO markedly suppressed H2 O2 -induced inflammation, edema, and fibrosis in bladder wall, concomitant with a significant decrease in mRNA expressions of inflammation biomarkers and a significant increase in endothelial nitric oxide synthase expression. HBO also inhibited the expression of transient receptor potential channels induced by H2 O2 instillation. Conclusion These results suggest that HBO contributes to elimination of H2 O2 -induced long-lasting cystitis through the repair of chronically inflamed bladder tissue and inhibition of the bladder sensory system.

Rathke's cleft cyst (RCC) is a common incidental tumor in the hypothalamic-pituitary region. Some reports have shown that the clinical symptoms and endocrine functions of symptomatic RCCs are temporarily improved by glucocorticoid administration. However, it is still unknown whether glucocorticoid treatment is effective for symptomatic RCCs according to long-term observations. In this study, we describe the long-term clinical outcomes of two cases of glucocorticoid-treated biopsy-proven secondary hypophysitis caused by RCCs. We summarize the symptoms, imaging findings, and endocrine evaluations of two symptomatic RCC patients with concomitant hypophysitis before and after prednisolone treatment. In both evaluated cases, visual impairments and altered endocrine parameters were present due to chiasm and stalk compression; these outcomes improved after shrinkage of RCCs in response to prednisolone administration, and partial recovery of anterior pituitary hormone secretion was observed. However, in both cases, the deficits in anterior pituitary hormone secretion recurred, possibly due to persistent inflammatory infiltration in the RCCs and pituitary glands. After relapse of hypophysitis, anterior hormone secretion did not fully recover. In our cases of secondary hypophysitis caused by RCCs, prednisolone administration had an early effect of cyst shrinkage, followed by partial improvements in clinical symptoms and pituitary functions. However, long-term observation showed that prednisolone treatment did not contribute to complete improvement in anterior pituitary hormone dysfunction.

Background Pressure sores are sometimes refractory to treatment, often due to malnutrition. Small intestinal bacterial overgrowth (SIBO) obstructs absorption in the digestive tract and causes malnutrition. However, little is known about the association between pressure sore wound healing and SIBO. Here, we report a case of a patient with a refractory sacral pressure sore and SIBO. Case presentation A 66-year-old woman who was spinal cord injured 14 years before visiting our hospital presented with the chief complaint of a sacral pressure sore, 10.0 × 6.5 cm in size, which was refractory to treatment. Physical examination showed abdominal distension and emaciation, with a body mass index of 15. Further examination revealed elevated serum alkaline phosphatase (1260 U/L), bilateral tibial fracture, multiple rib fracture, and osteoporosis. We diagnosed the patient with osteomalacia with vitamin D deficiency. Despite oral supplementation, serum levels of calcium, phosphorous, and vitamin D remained low. Also, despite concentrative wound therapy for the sacral pressure sore by plastic surgeons, no wound healing was achieved. Due to a suspicion of disturbances in nutrient absorption, we performed bacterial examination of collected gastric and duodenal fluid, which showed high numbers of bacteria in gastric content (104E. coli, 105Streptococcus species, and 105Neisseria species) and duodenal content (106E. coli, 104Candida glabrata). Therefore, we diagnosed the patient with SIBO and started selective decontamination of the digestive tract using polymyxin B sulfate and amphotericin B. After starting treatment for SIBO, the sacral pressure sore began to heal and was nearly healed after 285 days. The patient’s serum levels of calcium, phosphorous, vitamin D, and other fat-soluble vitamins also gradually increased after starting treatment for SIBO. Conclusion We report a case of a patient with a refractory sacral pressure sore that healed after starting treatment for SIBO. We conclude that SIBO may be an overlooked cause of malnutrition and poor wound healing in patients with chronic pressure sores.

OBJECTIVES To identify pre-treatment factors affecting the duration of post-surgical steroid replacement in patients undergoing adrenalectomy for subclinical Cushing syndrome. METHODS The present retrospective analysis included 64 patients who underwent unilateral laparoscopic adrenalectomy for subclinical Cushing syndrome. Adrenal tumor and contralateral adrenal sizes together with various clinical factors were studied in association with the duration of post-surgical steroid replacement. Adrenal tumor and contralateral adrenal size were measured at the level of the maximum transverse plane of the adrenal glands using computed tomography scan or magnetic resonance imaging. Cox's proportional hazards model was used for the statistical analysis. RESULTS All 64 patients were treated with post-surgical steroid replacement after adrenalectomy. The median duration of the steroid treatment was 6 months. When assessing the duration of post-surgical steroid replacement, contralateral adrenal volume 2.65 μg/dL were significant predictors of prolonged post-surgical steroid treatment on univariate analysis. On multivariate analysis, contralateral adrenal width

Objective: To review a case of congestive heart failure (CHF) due to a thyroid-stimulating hormone (TSH)-secreting pituitary adenoma (TSH-oma) concomitant with Takotsubo cardiomyopathy in an elderly patient.Methods: We describe the clinical course, laboratory data, imaging studies, and management of the patient and provide a brief literature review regarding Takotsubo cardiomyopathy associated with hyperthyroidism.Results: A 76-year-old woman was admitted to our hospital for CHF treatment. Chest X-ray and electrocardiogram (ECG) showed cardiomegaly and broad T-wave inversion, respectively. Furthermore, left ventricular angiogram and subsequent coronary angiogram showed mild hypokinesis of the apex, without signs of obstructive coronary disease. Pulmonary hypertension was determined through right-heart catheterization. Accordingly, we clinically diagnosed this patient with Takotsubo cardiomyopathy complicated with pulmonary hypertension. Administration of β-blockers and angiotensin-receptor blockers markedly improved the abnormal ECG findings and wall motion due to Takotsubo cardiomyopathy. However, the cardiomegaly and pulmonary hypertension remained. We then detected hyperthyroidism with inappropriate TSH secretion. Brain magnetic resonance imaging revealed a pituitary macroadenoma, suggesting hyperthyroidism due to TSH-oma. Octreotide administration immediately led to the normalization of thyroid hormone secretion, which in turn improved the hyperthyroidism, cardiac enlargement, and pulmonary hypertension. Transsphenoidal surgery was safely performed. Pathologic investigation confirmed the diagnosis of TSH-oma.Conclusion: We report a rare case of Takotsubo cardiomyopathy complicated with hyperthyroidism due to TSH-oma in an elderly patient. Clinically, CHF is an important sign of hyperthyroidism in the elderly. Octreotide administration could be useful for the peri-operative management of elderly patients with TSH-omas and cardiovascular complications.Abbreviations: CHF congestive heart failure ECG electrocardiogram LAR long-acting release SITSH syndrome of inappropriate thyroid-stimulating hormone secretion TRH thyrotropin-releasing hormone TSH thyroid-stimulating hormone TSH-oma thyroid-stimulating hormone–secreting pituitary adenoma TR-PG tricuspid regurgitation pressure gradient

We herein report the case of a 25-year-old woman who presented with severe headache and visual field defects after childbirth. Magnetic resonance imaging revealed marked swelling of the pituitary gland, and an endocrinological examination revealed panhypopituitarism and diabetes insipidus. An immunohistological analysis of a transsphenoidal biopsy sample of the pituitary gland showed the significant accumulation of an immunogloblin G4 (IgG4)-positive population, leading to the diagnosis of IgG4-related hypophysitis. The patient was treated with prednisolone, which markedly reduced the swelling of the pituitary gland, in association with recovery of the pituitary function. This is a rare case of biopsy-proven IgG4-related hypophysitis with a postpartum onset.

Purpose : To evaluate the correlations of post-implant regional dosimetrics at 24 hours (24 h) and 1 month after implant procedures, with clinical outcomes of low-dose-rate (LDR) brachytherapy for localized prostate cancer. Material and methods : Between January 2008 and December 2014, 130 consecutive patients treated for localized prostate cancer, receiving definitive iodine-125 ( 125 I) brachytherapy treatment were retrospectively analyzed. All patients underwent post-implant CT imaging for dosimetric analysis at 24 h and 1 month after implantation procedure. Prostate contours were divided into quadrants: anterior-superior (ASQ), posterior-superior (PSQ), anterior-inferior (AIQ), and posterior-inferior (PIQ). Predictive factors and cut-off values of biochemical failure-free survival (BFFS) and toxicities of LDR brachytherapy were analyzed. Results : The median follow-up time was 69.5 months. Seven patients (5.4%) had biochemical failure. The 3-year and 5-year BFFS rates were 96.7% and 93.1%, respectively. On multivariate analysis, prostate-specific antigen and Gleason score were significant prognostic factors for biochemical failure. D 90 (the minimal dose received by 90% of the volume) of PSQ and PIQ at 24 h, and D 90 of PSQ at 1 month were also significant factors. The cut-off values of PSQ D 90 were 145 Gy at 24 h and 160 Gy at 1 month. D 90 of the whole prostate was not significant at 24 h and at 1 month. D 90 of PSQ at 1 month was a significant factor for rectal hemorrhage. Conclusions : Post-implant D 90 of PSQ is significantly associated with BFFS for localized prostate cancer not only at 1 month, but also at 24 hours. D 90 of PSQ at 1 month is also a significant factor for rectal hemorrhage.

Nonclassic congenital adrenal hyperplasia (NCAH) is an autosomal-recessive disorder caused by 21-hydroxylase deficiency and manifests as hirsutism and oligomenorrhea due to excess adrenal androgen and progesterone. We report a case of a woman with NCAH who showed continuous high serum progesterone levels in the follicular phase associated with impaired folliculogenesis. NCAH was diagnosed based on high 17-hydroxyprogesterone levels after rapid adrenocorticotropic hormone loading, and three heterozygous missense mutations in CYP21A2, encoding 21-hydroxylase, were identified. Recurrent failure of in vitro fertilization programs occurred because of empty follicles and preterm rupture of leading follicles, and vaginal stenosis with a hypoplastic cervix. Glucocorticoid administration normalized serum progesterone levels, restored folliculogenesis, and stretched the vaginal wall, which contributed to the success of the in vitro fertilization program. The patient delivered at term following blastocyst transfer. Correction of hyperandrogenism and high progesterone levels using glucocorticoids may improve fertility in women with NCAH.

Laparoscopic adrenalectomy has been established as a standard surgical method for unilateral primary aldosteronism. Meanwhile, the background characteristics of the patients undergoing adrenalectomy have changed over the last 20 years. The aim of this study was to investigate the changes in hypertension cure rates after laparoscopic adrenalectomy during the last two decades. This retrospective clinical study included 176 patients who underwent unilateral laparoscopic adrenalectomy for primary aldosteronism from 1995 to 2015. The patients were divided into two groups by decade. The patients’ baseline characteristics and the hypertension cure rates were compared between the two groups. Additionally, the values were re-examined based on predictive model predicting postoperative hypertension cure. The hypertension cure rate decreased significantly from 51.8 to 31.1%. The following variables were significantly different between the two groups: age, sex, body mass index, history of diabetes mellitus, preoperative systolic and diastolic blood pressures, potassium level, and plasma renin activity. This study showed that the number of patients with unfavorable conditions for hypertension cure after adrenalectomy has recently increased. The treatment goal for primary aldosteronism is not only to cure the hypertension but also to prevent organ disorders due to inappropriate aldosterone levels. Therefore, we recommend laparoscopic adrenalectomy for unilateral primary aldosteronism, even if hypertension is not always cured postoperatively. However, clinicians need to fully explain the postoperative hypertension outcomes to primary aldosteronism patients.

To investigate the relationship between urodynamic study (UDS) data and recovery of urinary incontinence (UI) in elderly patients who underwent robot-assisted radical prostatectomy (RARP).Seventy-five prostate cancer (PCa) patients received UDS before and at 3 months after RARP. They were divided into two groups; a younger group (70 years old,In the older group, preoperative maximum urethral closure pressure (MUCP) in the UI group was significantly lower than that in the UC group. Detrusor overactivity (DO) rate was significantly higher in the older UI group than in the older UC group at both pre- and 3 months post-RARP. Persistent DO rate pre- and post-RARP was significantly higher in the older group than in the younger group. Regardless of age, postoperative DO was an independent predictor of UI 6 months post-RARP.In elderly patients, low preoperative MUCP and both pre- and postoperative DO are associated with postoperative UI.

This review summarizes the latest insights on ABO‐incompatible living‐donor renal transplantation. Desensitization protocols and clinical outcomes were investigated, and a comparison was made with kidney‐paired donation, which is not permitted in Japan for ethical reasons. Although renal transplantation is greatly beneficial for most patients with end‐stage kidney disease, many of these patients must remain on dialysis therapy for extended periods due to the scarcity of organs from deceased donors. ABO blood type incompatibility was once believed to be a contraindication to renal transplantation due to the increased risk for antibody‐mediated rejection and early graft loss attributable to isoagglutinins. Recently, pretransplant desensitization strategies, such as removal of isoagglutinins and antibody‐producing cells, have achieved successful outcomes, although it remains unclear whether graft survival and patient morbidity are equivalent to those for ABO‐compatible renal transplantation. The present review suggested that ABO‐incompatible living‐donor renal transplantation might be a favorable radical renal replacement therapy for patients with end‐stage kidney disease.

Type 2 innate lymphoid cells (ILC2s) were recently identified as essential components of innate immunity. Besides, beneficial roles of ILC2s in metabolic diseases are attracting attentions. Although the liver contains various immune cells including T cells and ILC2s, little is known about ILC2s in hepatic gluconeogenesis. We therefore investigated the role of ILC2s and the effect of IL-33, a potent ILC2 activator, on hepatic gluconeogenesis in mice. We found that recombinant IL-33 injection decreased fasting blood glucose levels in wild type mice. This effect was not observed in NOD/SCID Il2rg null (NSG) mice lacking certain immune cells including ILC2s, whereas the similar response was seen in another immune deficient mice Foxnnu/nu (nude mice), which have normal development in ILC2s. IL-33 treatment also suppressed hepatic gluconeogenesis assessed by pyruvate tolerance test in wt mice, while there was no response in NSG. Moreover, ILC2 transplantation was able to rescue the absence of glucose response by IL-33 in NSG. We observed a marked increase of IL-13+ ILC2 population in liver after IL-33 treatment, and Il13-/- mice did not show the decrease of blood glucose or the suppression of gluconeogenesis by IL-33 treatment. Additionally, the transfer of Il13-/- ILC2 failed to gain IL-33 induced glucose response in NSG, suggesting that the hypoglycemic effect of IL-33/ILC2s depends on IL-13. In consistent with these results, the differentially expressed gene analysis revealed that IL-13 treatment mostly altered the gene expressions of glucose metabolic process in primary hepatocytes. Notably, we identified GATA3 as a direct regulator of the effecter molecules such as Il5, Il13 and I1rl1 in hepatic ILC2s. These phenomena were also reproducible in human ILC2s and primary hepatocyte. In conclusion, these findings indicate that hepatic ILC2s suppress hepatic gluconeogenesis via the IL-33/GATA3/IL-13 axis, thus reducing blood glucose levels. Disclosure M. Fujimoto: None. K. Yokote: None. T. Tanaka: None.

In Japan, diagnostic criteria of subclinical Cushing’s syndrome (SCS) were formulated in 1996, using cutoff value for serum cortisol of 3.0 μg/dL after an overnight 1-mg dexamethasone suppression test (DST). It has made considerable contributions to the understanding and pathology of SCS. However, it has elicited two main problems: (i) the relatively low reliability of a low range of serum cortisol essential for the diagnosis by DST; (ii) different cutoff values for serum cortisol after a 1-mg DST compared with those of other countries. For the proposal of new diagnostic criteria, we conducted a retrospective cross-sectional study. 530 cases (270 men and 260 women, mean age: 60.1 ± 11.1 years) with an adrenal tumor were assessed. In the present study, the assay kits adopted for measurement of serum cortisol differed among facilities. A calibration formula was previously developed by Kuwa et al. for standardization of different kits. Using this formula, standardization of the serum cortisol values after a 1-mg DST and at night was done. As a result, using current criteria, the diagnosis of 11 out of 92 SCS cases was changed to “non-SCS”, and all of 189 non-SCS cases remained non-SCS after calibration. After all, diagnostic concordance rate before and after calibration was 96.1%, suggesting that the actual diagnosis did not change dramatically, by calibration. The cortisol values after a 1-mg DST were compared based on the presence or absence of complications (hypertension, impaired glucose tolerance or diabetes, and hypercholesterolemia). As a result, when serum cortisol after a 1-mg DST was stratified by increments of 1.0 μg/dL, the coincidental occurrence of hypertension and impaired glucose tolerance was more frequently observed in the 2-2.99 μg/dL group than in the 0-0.99 μg/dL group (39.3% vs. 23.5%, p=0.018), suggesting that the threshold for the onset of complications of adrenal tumors may be serum cortisol of 2-3μg/dL after a 1-mg DST. Under the consideration of international consistency, serum cortisol ≥1.8 μg/dL after a 1-mg DST may be useful for the detection of ‘not completely healthy’ subjects with adrenal tumor. Additionally, in the present study, almost all of the respective criteria, such as basal ACTH

Familial dysalbuminemic hyperthyroxinemia (FDH) is caused by abnormal human serum albumin (HSA) with an increased thyroxine (T4) affinity leading to euthyroid hyperthyroxinemia. In Japanese FDH patients with the HSAR218P mutation, not only one-step but also two-step immunoassays for free T4 (FT4) can yield false-positive results. Therefore, it is difficult to distinguish FDH from syndrome of inappropriate secretion of TSH, even when multiple assays are used. Patient 1 was a 29-year-old pregnant woman. A radiographic examination and hormone stimulation test were not performed. We suspected that the patient had FDH because of her family history such as abnormal thyroid function and hyperthyroxinemia (Total T4 level was greater than the measurement sensitivity). Genetic analysis using direct sequencing for HSA revealed that she was consistent with FDH. She experienced a normal delivery. Other patients were performed the thyroid test with Chief complaints of infertility or depression and their thyroid function abnormalities were pointed out. Thyroid function tests revealed elevated FT4 and FT3 levels; their TSH level was within the reference range in all patients. To investigate T4 to HSA binding, gel filtration high-performance liquid chromatography was used for the biochemical analyses. Furthermore, FT4 was measured in FDH patients using one-step method LUMIPULSE (Fujirebio) using T3 as an antigen and an anti-T4 antibody as a label. The genomic analysis revealed a heterozygous missense mutation in HSA(R218P). In FDH patient sera, the albumin effluent corresponded to the peaks for total T4 (TT4); approximately 60% of the T4 in the effluent was detected as FT4. Mean FT4 level measured with LUMIPULSE was 1.28 ng/dL within the reference value range. In the FDH patients, a relatively larger quantity of T4 was bound to abnormal HSA. This bound T4 was measured as FT4 during the analysis. When thyroid function abnormality without clinical findings is observed, it is considered preferable to understand the antigen and antibody to be used and to select measurement method.

Background Dopamine replacement therapy is an established treatment for motor symptoms of Parkinson's disease, but its long-term use is often limited by the eventual development of motor complications, including levodopa-induced dyskinesia. Genetic background, particularly polymorphisms of dopamine metabolism genes, may affect the occurrence of dyskinesia in Parkinson's disease patients. Methods We investigated polymorphisms of dopamine metabolism genes, including catechol-O-methyltransferase, monoamine oxidase B, dopamine beta-hydroxylasedopamine, dopamine receptors D1, D2, and D3, and dopamine transporter, in 110 patients with Parkinson's disease. Cox proportional hazards regression was used to detect associations between genotypes and levodopa-induced dyskinesia. Results Monoamine oxidase B rs1799836 was the only polymorphism correlated with risk of dyskinesia. Patients with an AG or GG genotype were more likely to have dyskinesia than those with an AA genotype (adjusted hazard ratio, 3.41; 95% confidence interval, 1.28–9.10). Also, Kaplan-Meier curves demonstrated that patients with an AG or GG genotype developed dyskinesia earlier than those with an AA genotype (log-rank test, p = .004). Conclusions In Parkinson's disease patients, the monoamine oxidase B rs1799836 G allele is associated with a greater likelihood of developing dyskinesia than the A allele, possibly due to its association with lower monoamine oxidase B activity in the brain. Thus, detection of monoamine oxidase B polymorphisms may be useful for determining the optimal dosing of antiparkinson medications., Graphical abstract Unlabelled Image, Highlights • Average dose of L-dopa induced dyskinesia in Parkinson's disease was over 400 mg/day. • MAO-B rs1799836 G allele increases risk of L-dopa induced dyskinesia in PD. • 50% of PD with MAO-B G allele developed L-dopa induced dyskinesia within 8 years.

Background Panitumumab is the first human combinatorial antibody for the treatment of metastatic colorectal carcinoma. Dermatologic toxicity of all grades occurs in more than 90% of patients. However, there are few reports of purpura induced by anti-epidermal growth factor receptor antibody. Renal failure is also uncommon as an adverse event of anti-epidermal growth factor receptor antibody. Case presentation A 67-year-old Japanese man with advanced colon cancer received monotherapy with panitumumab. General malaise, bilateral edema of his legs, and bilateral purpura of his forearms developed 2 days after the second cycle of panitumumab. A skin biopsy was performed to evaluate the purpuric lesions on his left leg and leukocytoclastic vasculitis was diagnosed. Blood tests showed grade III acute renal failure with a blood urea nitrogen level of 33.8 mg/dL and a creatinine level of 3.10 mg/dL. Conclusions This is the first reported case of leukocytoclastic vasculitis followed by purpura and acute renal failure associated with panitumumab.

We herein report a 75-year-old woman with insulin-treated diabetes and metastatic anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer who received ceritinib, a second-generation ALK inhibitor, and achieved dramatic tumor reduction. However, her fasting blood glucose increased, particularly markedly in the first two weeks after ceritinib administration, and did not normalize even increasing the total insulin dose. After discontinuing ceritinib, her glucose levels rapidly reduced. Ceritinib can aggravate hyperglycemia in patients with diabetes who lack compensatory insulin secretion, due to its inhibitory effects on the insulin receptor. Careful monitoring for ceritinib-induced hyperglycemia should be performed, especially in the first two weeks after ceritinib administration.

// Sohei Kobayashi 1 , Tyuji Hoshino 2 , Takaki Hiwasa 3 , Mamoru Satoh 4 , Bahityar Rahmutulla 1, 5 , Sachio Tsuchida 4 , Yuji Komukai 2 , Tomoaki Tanaka 1 , Hisahiro Matsubara 6 , Hideaki Shimada 7 , Fumio Nomura 4 , Kazuyuki Matsushita 1, 8 1 Department of Molecular Diagnosis, Graduate School of Medicine, Chiba University, Chiba City, Chiba 260-8670, Japan 2 Department of Physical Chemistry, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan 3 Department of Biochemistry and Genetics, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan 4 Divisions of Clinical Mass Spectrometry and Clinical Genetics, Chiba University Hospital, Chiba 260-8670, Japan 5 Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba City, Chiba 260-8670, Japan 6 Department of Academic Surgery, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan 7 Department of Gastroenterological Surgery, Toho University Omori Medical Center, Tokyo 143-8541, Japan 8 Department of Laboratory Medicine & Division of Clinical Genetics and Proteomics Chiba University Hospital, Chiba 260-8670, Japan Correspondence to: Kazuyuki Matsushita, email: kmatsu@faculty.chiba-u.jp Keywords: auto-antibodies, cancer biomarker, colorectal cancer, far-upstream element-binding protein-interacting repressor (FIR) = poly(U)-binding-splicing factor (PUF60) Received: June 29, 2016 Accepted: October 12, 2016 Published: October 15, 2016 ABSTRACT Anti-PUF60, poly(U)-binding-splicing factor, autoantibodies are reported to be detected in the sera of dermatomyositis and Sjogren’s syndrome that occasionally associated with malignancies. PUF60 is identical with far-upstream element-binding protein-interacting repressor (FIR) that is a transcriptional repressor of c-myc gene. In colorectal cancers, a splicing variant of FIR that lacks exon2 (FIRΔexon2) is overexpressed as a dominant negative form of FIR. In this study, to reveal the presence and the significance of anti-FIRs (FIR/FIRΔexon2) antibodies in cancers were explored in the sera of colorectal and other cancer patients. Anti-FIRs antibodies were surely detected in the preoperative sera of 28 colorectal cancer patients (32.2% of positive rates), and the detection rate was significantly higher than that in healthy control sera (Mann–Whitney U test, p < 0.01). The level of anti-FIRs antibodies significantly decreased after the operation ( p < 0.01). Anti-FIRs antibodies were detected in the sera of early-stage and/or recurrent colon cancer patients in which anti-p53 antibodies, CEA, and CA19-9 were not detected as well as in the sera of other cancer patients. Furthermore, the area under the curve of receiver operating characteristic for anti-FIRs antibodies was significantly larger (0.85) than that for anti-p53 antibodies or CA19-9. In conclusions, the combination of anti-FIRs antibodies with other clinically available tumor markers further improved the specificity and accuracy of cancer diagnosis.

Purpose In a 10-week proof-of-concept study (LINC 1), the potent oral 11β-hydroxylase inhibitor osilodrostat (LCI699) normalized urinary free cortisol (UFC) in 11/12 patients with Cushing’s disease. The current 22-week study (LINC 2; NCT01331239) further evaluated osilodrostat in patients with Cushing’s disease. Methods Phase II, open-label, prospective study of two patient cohorts. Follow-up cohort: 4/12 patients previously enrolled in LINC 1, offered re-enrollment if baseline mean UFC was above ULN. Expansion cohort: 15 newly enrolled patients with baseline UFC > 1.5 × ULN. In the follow-up cohort, patients initiated osilodrostat twice daily at the penultimate efficacious/tolerable dose in LINC 1; dose was adjusted as needed. In the expansion cohort, osilodrostat was initiated at 4 mg/day (10 mg/day if baseline UFC > 3 × ULN), with dose escalated every 2 weeks to 10, 20, 40, and 60 mg/day until UFC ≤ ULN. Main efficacy endpoint was the proportion of responders (UFC ≤ ULN or ≥50 % decrease from baseline) at weeks 10 and 22. Results Overall response rate was 89.5 % (n/N = 17/19) at 10 weeks and 78.9 % (n/N = 15/19) at 22 weeks; at week 22, all responding patients had UFC ≤ ULN. The most common AEs observed during osilodrostat treatment were nausea, diarrhea, asthenia, and adrenal insufficiency (n = 6 for each). New or worsening hirsutism (n = 2) and/or acne (n = 3) were reported among four female patients, all of whom had increased testosterone levels. Conclusions Osilodrostat treatment reduced UFC in all patients; 78.9 % (n/N = 15/19) had normal UFC at week 22. Treatment with osilodrostat was generally well tolerated. Electronic supplementary material The online version of this article (doi:10.1007/s11102-015-0692-z) contains supplementary material, which is available to authorized users.

Surgical resection is the preferred treatment for locoregional recurrence of differentiated thyroid cancer (DTC). However, some recurrences are unresectable because of their aggressive invasion or severe adhesions. On the other hand, stereotactic radiotherapy (SRT) enables high-dose irradiation to target lesions, and its usefulness for various cancers has been reported. The objective of the present study was to investigate the feasibility and efficacy of SRT as salvage treatment for locoregional recurrence of DTC. Between August 2011 and December 2017, 52 locoregional recurrent lesions in 31 patients with recurrent DTC were treated by SRT using the CyberKnife system. Information on the adverse events associated with SRT was retrospectively collected from the patients’ medical records. Of the 52 lesions, 33 could be evaluated for therapeutic effectiveness by follow-up CT, and response was assessed using the RECIST criteria. Twenty-five patients had papillary carcinoma, 5 had follicular carcinoma, and 1 had poorly differentiated cancer. SRT was delivered in one to 20 fractions, and the median dose was 30 Gy (range 15–60 Gy). Adverse events were not frequent, but 1 patient developed bilateral vocal cord palsy that required emergent tracheostomy. The median follow-up period of 33 lesions was 14 months (range 1–54 months). Complete response, partial response, stable disease, and progressive disease were seen in 10, 11, 9, and 3 patients, respectively. The 3-year local control rate was 84.6%. SRT using the CyberKnife system was found to be a feasible and effective treatment to suppress the growth of locoregional recurrence of DTC.

New diagnostic criteria and the treatment policy for adrenal subclinical Cushing's syndrome (SCS) are proposed on behalf of the Japan Endocrine Society. The Japanese version has been published, and the essential contents are presented in this English-language version. The current diagnostic criteria for SCS have elicited two main problems: (i) the relatively low reliability of a low range of serum cortisol essential for the diagnosis by an overnight 1-mg dexamethasone suppression test (DST); (ii) different cutoff values for serum cortisol after a 1-mg DST compared with those of other countries. Thus, new criteria are needed. In the new criteria, three hierarchical cortisol cutoff values, 5.0, 3.0 and 1.8 μg/dL, after a 1-mg DST are presented. Serum cortisol ≥5 μg/dL after a 1-mg DST alone is considered sufficient to judge autonomous cortisol secretion for the diagnosis of SCS, and the current criterion based on serum cortisol ≥3 μg/dL after a 1-mg DST can continue to be used. Clinical evidence suggests that serum cortisol ≥1.8-2.9 μg/dL after a 1-mg DST is not always normal, so cases who meet the cutoff value as well as a basal adrenocorticotropic hormone (ACTH) level

To assess the efficacy, safety, and pharmacokinetics of metyrosine (an inhibitor of catecholamine synthesis) in patients with pheochromocytoma/paraganglioma (PPGL), we conducted a prospective, multi-center, open-label study at 11 sites in Japan. We recruited PPGL patients aged ≥12 years requiring preoperative or chronic treatment, receiving α-blocker treatment, having baseline urinary metanephrine (uMN) or normetanephrine (uNMN) levels ≥3 times the upper limit of normal values, and having symptoms associated with excess catecholamine. Metyrosine treatment was started at 500 mg/day and modified according to dose-adjustment criteria up to 4,000 mg/day. The main outcome measure was the proportion of patients who achieved at least 50% reduction in uMN or uNMN levels from baseline. Sixteen patients (11 males/5 females) aged 12-86 years participated. After 12 weeks of treatment and at the last evaluation of efficacy, the primary endpoint was achieved in 31.3% of all patients, including 66.7% of those under preoperative treatment and 23.1% of those under chronic treatment. Sedation, anemia, and death were reported in 1 patient each as serious adverse drug reactions during the 24-week treatment. Metyrosine was shown to be tolerated and to relieve symptoms by reducing excess catecholamine in PPGL patients under both preoperative and chronic treatment.

Context Necrolytic migratory erythema (NME) occurs in approximately 70% of patients with glucagonoma syndrome. Excessive stimulation of metabolic pathways by hyperglucagonemia, which leads to hypoaminoacidemia, contributes to NME pathogenesis. However, the molecular pathogenesis of glucagonoma and relationships between metabolic abnormalities and clinical symptoms remain unclear. Patient A 53-year-old woman was referred to our hospital with a generalized rash and weight loss. NME was diagnosed by histopathological examination of skin biopsy tissue. Laboratory tests revealed diabetes, hyperglucagonemia, marked insulin resistance, severe hypoaminoacidemia, ketosis, and anemia. Enhanced computed tomography scans detected a 29-mm pancreatic hypervascular tumor, which was eventually diagnosed as glucagonoma. Preoperative treatment with octreotide long-acting release reduced the glucagon level, improved the amino acid profile, and produced NME remission. Surgical tumor excision normalized the metabolic status and led to remission of symptoms, including NME. Interventions Whole-exome sequencing (WES) and subsequent targeted capture sequencing, followed by Sanger sequencing and pyrosequencing, identified biallelic alteration of death-domain associated protein (DAXX) with a combination of loss of heterozygosity and frameshift mutations (c.553_554del:p.R185fs and c.1884dupC:p.C629fs) in the glucagonoma. Consistently, immunohistochemistry confirmed near-absence of DAXX staining in the tumor cells. Tumor expression of glucagon and somatostatin receptor subtype 2 and 3 messenger RNA was markedly upregulated. Conclusions This is a report of glucagonoma with biallelic inactivation of DAXX determined by WES. The tumor manifested as glucagonoma syndrome with generalized NME. This case showed the relationship between hypoaminoacidemia and NME status. Further investigations are required to elucidate the underlying mechanisms of NME onset and glucagonoma tumorigenesis.

The number of patients who need thyroid surgery has increased worldwide in recent decades. Patients with thyroid disease experience globus pharyngeus as a result of direct compression and edema of the surrounding organs. Thyroid surgery is needed to improve these symptoms or as treatment for thyroid cancer. After thyroid surgery, globus symptoms may become worse and may affect the daily life of the patient for a long time. Psychogenic problems have also been thought to cause the globus sensation. A prospective analysis of globus symptoms and psychogenic factors following thyroidectomy was performed.Patients scheduled to undergo thyroid surgery between February and September 2016 completed the foreign-body sensation in the throat score (FBST; range 0-8.2) and the self-rating depression scale (SDS; range 0-100) preoperatively and three days, one month, three months, six months, and 12 months postoperatively.Long-term follow-up was completed in 616 patients (491 females). A total of 365 patients had thyroid cancer, 169 had benign tumors, and 82 had diffuse goiters with Graves' disease. The percentage of patients who complained about neck discomfort (FBST2) was 29.4% before surgery. A preoperative high FBST showed a significant direct correlation with a high SDS, but thyroid volume did not. A postoperative high FBST was seen in 75.3% of patients at two days and 78.9% at one month after surgery, and it then gradually decreased to 49.3% at 12 months after surgery. At three days after the operation, the median FBST was significantly higher in patients who had total thyroidectomy with lateral neck dissection or total thyroidectomy only compared to those who had lobectomy only (p 0.05). These differences were still present 12 months after surgery. A higher preoperative SDS score was also identified as an independent predictor for a high FBST at 12 months after surgery, but not at one or three months postoperatively, on multivariate analyses.Preoperative globus symptoms appear directly related to psychological factors. The area of the surgical procedure and preoperative psychological factors were related to persistent neck discomfort.

Osteoporosis not only increases bone fracture risk but also affects survival in postmenopausal women. Although osteoporosis is diagnosed based on low bone mineral density (BMD) determined by dual energy X-ray absorptiometry (DXA), BMD measurement is sometimes difficult because DXA is not widely available in the community. The Fracture Risk Assessment tool (FRAX) can predict 10-year major osteoporotic fracture risk and hip fracture risk with or without femoral neck BMD. The FRAX has not been investigated adequately in community-dwelling Japanese women. We administered the FRAX tool in 13,421 Japanese women who underwent DXA-based forearm BMD measurement in Chiba Bone Survey, a population-based, multicenter, cross-sectional study of postmenopausal osteoporosis conducted in Chiba, Japan. Mean age was 57.77 ± 9.24 years. Mean forearm BMD was 87.94 ± 17.00% of young adult mean (YAM). Mean FRAX major osteoporotic fracture risk without femoral neck BMD was 7.06 ± 5.22%. BMD decreased and percentage of osteoporosis increased from age 55 onward. Age distribution of percentage of subjects with FRAX major osteoporotic fracture risk >15% was similar to that of percentage of osteoporosis subjects. We identified the cutoff value of FRAX major osteoporotic fracture risk for diagnosis of osteoporosis as 7.2%. With this cutoff, the positive likelihood ratio was over 1.0 at age 55 and above but accuracy was low. In conclusion, FRAX without femoral neck BMD reflects bone status, and may be useful to diagnose osteoporosis in Japanese women aged 55 and above, although the sensitivity was low for osteoporosis screening, especially in middle-aged women.

Many patients with primary aldosteronism (PA) show a significant decline in kidney function after adrenalectomy. Thus, PA patients who undergo surgery are at greater risk of both postoperative renal damage and new-onset metabolic events associated with renal insufficiency. The aim of this study was to explore postoperative changes in serum lipid levels and to identify risk factors associated with postoperative new-onset dyslipidemia in PA patients. The records of 57 Japanese patients who underwent unilateral laparoscopic adrenalectomy for PA were retrospectively surveyed. Clinical and biochemical data were evaluated at baseline and 12 months after surgery. Preoperative and postoperative estimated glomerular filtration (eGFR) and serum lipid profile, including triglycerides, high-density lipoprotein (HDL)-cholesterol and low-density lipoprotein (LDL)-cholesterol levels, were compared. Furthermore, uni- and multivariate analyses were performed to determine the predictors for postoperative new-onset dyslipidemia. A significant decrease in eGFR and deterioration of serum lipid levels was identified postoperatively in most patients. Of the 39 patients without pre-existing dyslipidemia, 18 developed new-onset dyslipidemia postoperatively. Multivariate analysis identified preoperative lower eGFR and higher body mass index as independent predictors for new-onset dyslipidemia after surgery. On univariate analyses, additional factors associated with new-onset dyslipidemia included older age, male sex, higher LDL-cholesterol, and higher LDL/HDL ratio. PA patients had a higher risk of postoperative new-onset or progressive dyslipidemia. Clinicians should pay attention to not only follow-up of renal impairment but also total management of new-onset metabolic events associated with renal insufficiency in PA patients.

Aims/introduction Although high-dose glucocorticoids have been reported to cause new-onset diabetes mellitus (glucocorticoid-induced diabetes mellitus), its risk factors have remained to be determined. We investigated the risk factors related to glucocorticoid-induced diabetes mellitus diagnosed within 2 months after the high-dose treatment (newly treated with an initial high dose of > 20 mg prednisolone (PSL) equivalent per day for at least more than 6 months) in collagen vascular diseases. Methods A total of 2,631 patients with collagen vascular diseases was registered between 1986 and 2006 in the Chiba-Shimoshizu Rheumatic Cohort. We analyzed 681 patients newly treated with high-dose glucocorticoid who did not have diabetes mellitus and/or its previous diagnosis (age: 46.3 ± 16.7 years, PSL dose: 40.0 ± 14.1 mg/day). Glucocorticoid-induced diabetes mellitus was diagnosed by two or more glucose measurements in patients with fasting glycaemia ≥ 7 mmol/L and 120 minutes post-load glycaemia ≥ 11.1 mmol/L. Results Glucocorticoid-induced diabetes mellitus was observed in 26.3% of patients, and the glucocorticoid-induced diabetes mellitus group had higher age, higher BMI, lower rates of females and systemic lupus erythematosus, higher rates of smoking, alcohol use, and microscopic polyangiitis. Multivariate logistic regression analysis demonstrated that the risk of glucocorticoid-induced diabetes mellitus was independently higher in every 10-year increment of initial age with adjusted odds ratio (OR) 1.556 (95% confidence interval: 1.359 - 1.783), in every 1 kg/m2 increment of BMI with OR 1.062 (1.002 - 1.124), in current smoking with OR 1.664 (1.057 - 2.622), and in every 10 mg increment of initial dose of prednisolone with OR 1.250 (1.074 - 1.454). Conclusions High-dose glucocorticoids caused diabetes mellitus with high prevalence within a short period, and current smokers should be considered at higher risk of glucocorticoidinduced diabetes mellitus in addition to age, BMI, and initial dose.

Objectives To examine the difference in improvement of lower urinary tract symptoms between morning and evening dosing of α1-blocker naftopidil. Methods A total of 177 male patients with nocturia were included in the present study and randomized to morning or evening dosing of naftopidil. The International Prostate Symptom Score, quality of life index and nocturia quality of life index were compared between the two study groups at 12 weeks. Results A total of 143 patients (morning group: n = 70, evening group: n = 73) were analyzed as a result of the dropout of 34 patients because of failure to give consent, adverse events and failure to attend. Nocturia, quality of life index and nocturia quality of life index at 12 weeks were significantly better in the evening group compared with the morning group. In a multivariate model, both the dosing time of naftopidil and the initial nocturia quality of life index were significantly associated with change in nocturia quality of life index. Conclusions Evening dosing of naftopidil seems to be more effective in treating nocturia in male patients with lower urinary tract symptoms.

Background A functional pituitary adenoma can produce multiple anterior-pituitary hormones, such as growth hormone (GH) -producing adenomas (GHoma) with prolactin or thyrotropin stimulating hormone production in the same lineage. However, it is very rare that acromegaly shows subclinical Cushing’s disease (SCD) beyond the lineage. Here we describe the involvement of intratumoral coexistence with 2 types of hormone-producing cells associated with different lineage in acromegaly concomitant with SCD. Case presentation In our study, we performed clinical evaluation of the patient showing acromegaly with SCD. To elucidate the mechanisms of this pathology, we analyzed immunohistochemistry and gene expression of anterior-pituitary hormones and transcriptional factors in the resected pituitary tumor. On immunohistochemical staining, most of the tumor cells were strongly stained for GH antibody, while some cells were strongly positive for adrenocorticotropic hormone (ACTH). Gene expression analysis of a transsphenoidal surgery sample of the pituitary gland revealed that ACTH-related genes, such as POMC, Tpit, and NeuroD1 mRNA, had higher expression in the tumor tissue than the nonfunctional adenoma but lower expression compared to an adenoma of typical Cushing’s disease. Further, double-labeling detection methods with a fluorescent stain for ACTH and GH demonstrated the coexistence of ACTH-positive cells (GH-negative) among the GH-positive cells in the tumor. Additionally, Pit-1 expression was reduced in the ACTH-positive cells from tumor tissue primary culture. Conclusion Here we described a case of a pituitary tumor diagnosed with acromegaly associated with SCD. We performed quantitative-expression analyses of transcriptional factors of the tumor tissue and immunohistochemistry analysis of tumor-derived primary culture cells, which suggested that the multihormonal pituitary adenoma concomitant with Pit-1 and Tpit lineage cells caused acromegaly associated with SCD.

Although advanced thyroid carcinoma patients who cannot be cured by conventional therapy have lacked effective treatment, multitargeted tyrosine kinase inhibitors have recently become available. Phase 3 trials of lenvatinib showed a median time to objective response of 2 (95 % confidence interval (CI) 1.9-3.5) months, demonstrating that shrinks tumors rapidly. The phenomenon of immediate tumor shrink is known as early tumor shrinkage (ETS) which is related to clinical outcome in other malignancies. However, precisely when within 8 weeks lenvatinib starts to affect tumors remains unclear. In tumors near the carotid arteries, trachea, or esophagus, a rapid therapeutic effect can induce fistula formation or arterial bleeding. To prevent such treatment-emergent serious adverse events (SAE), early imaging evaluation seems to be very important. In this study, the point in time when lenvatinib started to shrink tumors was retrospectively investigated. The subjects were 16 patients who started lenvatinib administration between May and August 2015. Tumor size was evaluated by computed tomography (CT) scans frequently within the first 8 weeks according to the Response Evaluation Criteria In Solid Tumors (RECIST) guideline. Initial tumor response was defined as ≥ 10% tumor reduction. Serum thyroglobulin (Tg) level was monitored in 8 differentiated thyroid carcinoma (DTC) without TgAb patients. At the first evaluation, 13 patients (83.3 %) showed tumor reduction and that decreased with time. Thirteen patients (83.3 %) showed >10 % tumor reduction within 8 weeks. In all DTC patients, serum Tg level was markedly decreased. In conclusion, lenvatinib immediately shrinks tumors, the so-called ETS phenomenon. Therefore, careful attention should be paid to fistula formation from the early phase.

SummaryAdrenal tumors with more than one cellular component are uncommon. Furthermore, an adrenal tumor composed of a pheochromocytoma and a malignant peripheral nerve sheath tumor is extremely rare. A composite pheochromocytoma with malignant peripheral nerve sheath tumor in a 42-year-old man is reported here. After adequate preoperative control, left adrenalectomy was performed simultaneously with resection of the ipsilateral kidney for spontaneous rupture of the left adrenal tumor. Pathological findings demonstrated pheochromocytoma and malignant peripheral nerve sheath tumor in a ruptured adrenal tumor. To date, there have been only four reported cases of composite pheochromocytoma with malignant peripheral nerve sheath tumor, so the present case is only the fifth case in the world. Despite the very poor prognosis of patients with pheochromocytoma and malignant peripheral nerve sheath tumors reported in the literature, the patient remains well without evidence of recurrence or new metastatic lesions at 36 months postoperatively.

T1 rho and T2 mapping are magnetic resonance imaging (MRI) techniques to detect early degenerative changes in cartilage. Recent advancements have enabled 3D acquisition for both techniques. The objective of the present study was to examine the correlation of 3D T1 rho and 3D T2 mapping with macroscopic and histological characteristics of knee cartilage. Twenty-one patients who underwent total knee arthroplasty due to osteoarthritis with involvement of the medial compartment but with minimum involvement of the lateral compartment were enrolled. Prior to surgery, five series of MRI were acquired with a 3-T scanner. 3D T1 rho/T2 analyses were performed following determination of regions to be assessed using in-house software that incorporated three series of MRI acquisitions data (3D-MERGE, 3D-SPGR, and 3D-CUBE). During surgery, the cartilage of the lateral compartment was macroscopically assessed with the International Cartilage Research Society (ICRS) articular classification system. The extracted specimens were histologically assessed using the OARSI histology score. Three regions of interest (ROI) were assessed for each slice (two slices per knee): the central lateral femoral condyle (cLFC), the posterior portion of the lateral femoral condyle (pLFC), and the lateral tibia plateau (LTP). For each ROI, the mean T1 rho and T2 relaxation time, the ICRS grade, and the OARSI score were compared. Neither the T1 rho nor the T2 reflected the macroscopic grading. The T1 rho could discriminate between histological grades 1 and 2. However, the T2 could not. The T1 rho relaxation time was higher in the pLFC than in the cLFC even in the same grade. Compared to T2 mapping, T1 rho mapping may have an advantage in differentiating grades I and II cartilage degeneration on OARSI histological grading system.

Summary Background The number of antihypertensive drug classes cannot accurately reflect the total consumption of antihypertensive drugs used to control blood pressure. The defined daily dose has been adopted to permit consumption analysis of many prescribed drugs. The aim of the present study was to assess postoperative changes in antihypertensive drug consumption in patients with primary aldosteronism using the defined daily dose as the unit of measurement. Methods This retrospective study included 110 Japanese patients who underwent unilateral laparoscopic adrenalectomy between 1995 and 2012. Antihypertensive drug doses were calculated according to the standard of the defined daily dose recommended by the World Health Organization to compare drug use. After assessing postoperative changes in antihypertensive drug consumption, univariate and multivariate analyses were performed to identify clinical predictors for a 75% or greater decrease in the defined daily dose. Results Consumption of antihypertensive drugs decreased postoperatively in 95.4% of patients. The median decrease in the defined daily dose was 76.8%. A postoperative decrease of 75% or greater in the defined daily dose was confirmed in 52.7% of patients. Multivariate analysis identified no medical history of cardiovascular disease, low body mass index, and short duration of hypertension as independent predictors of a postoperative decrease of 75% or greater in the defined daily dose. Conclusion The defined daily dose is a useful tool for assessing total changes in the consumption of antihypertensive drugs in patients with primary aldosteronism. Using the defined daily dose, clinicians could explain in detail to patients with primary aldosteronism the predicted postoperative change in antihypertensive drug consumption.

BACKGROUND NEDD9 is one of the Crk-associated substrate (Cas) family proteins that mediate downstream signaling processes including cytoskeletal organization, cell-cycle and tumorigenesis. While NEDD9 plays a crucial role in epithelial–mesenchymal transition (EMT), the functional mechanism underlying NEDD9-mediated EMT in prostate cancer (PCa) remains uncertain. METHODS The expression levels of NEDD9 and its downstream molecules in PC-3, LNCaP, and VCaP cells exposed to transforming growth factor-β (TGF-β) were determined by western blotting. The invasion of these cells with ectopic overexpression of NEDD9 or silencing of NEDD9 expression was measured by transwell invasion assay. Human tissue samples comprising 45 PCa specimens and ten specimens of normal prostatic tissue were used for immunohistochemical (IHC) analysis of NEDD9 expression. RESULTS Both NEDD9 and its downstream signaling molecules associated with EMT were strongly induced by TGF-β in PCa cells. PC-3 cells with stable overexpression of NEDD9 had a mesenchymal phenotype and significantly enhanced cell invasion, despite their decreased cell proliferation. Knockdown of endogenous NEDD9 expression completely diminished TGF-β-triggered tumor invasion in several PCa cell lines. The IHC data revealed a significant positive correlation between the NEDD9 staining score and tumor aggressiveness (e.g., Gleason grade, serum PSA level). The NEDD9 staining score in primary PCa with bone metastasis was significantly higher than that in PCa without metastasis. CONCLUSIONS NEDD9 may be a key mediator involved in TGF-β-mediated EMT and cell motility in PCa cells and a novel target in the treatment of metastatic PCa and prevention of spread of localized PCa cells to other organs. Prostate 74:901–910, 2014. © 2014 Wiley Periodicals, Inc.