Diagnostic potential of miR-483 family for IGF-II producing non-islet cell tumor hypoglycemia.

OBJECTIVE: In insulin-like growth factor II (IGF-II) producing non-islet cell tumor hypoglycemia (NICTH), high molecular weight forms of IGF-II (big IGF-II) are produced as a cause of spontaneous hypoglycemia. MicroRNA (miRNA)-483 family, encoded in an intron lesion of IGF2 gene, is suggested to be co-expressed with IGF-II. Here, we tested whether serum miR-483-5p and -3p levels are associated with the presence of big IGF-II in NICTH. DESIGN: Serum samples from patients who were suspected to have IGF-II producing NICTH (n = 42) were tested. MiR-483-5p and -3p levels were evaluated using quantitative PCR. IGF-II level was analyzed using ELISA. The presence of big IGF-II was identified by Western blotting. RESULTS: Big IGF-II was detected in the sera of 32 patients. MiR-483-5p (P = 0.0015) and -3p (P = 0.027) levels were significantly higher in sera with big IGF-II (n = 32) than in those without (n = 10), whereas serum IGF-II level (P = 0.055) was not significantly different between the groups. The median serum concentration of miR-483-5p was ~10 times higher than that of miR-483-3p. Although a strong correlation was observed between the two miRNAs (r = 0.844, P < 0.0001), but neither of which was correlated with serum IGF-II level. The areas under the receiver operating characteristic curves of miR-483-5p (0.853) and -3p (0.722) were higher than that of IGF-II (0.694) for detecting the presence of big IGF-II. CONCLUSION: The associations of serum miR-483-5p and -3p levels with the presence of big IGF-II suggest the diagnostic potential of these miRNAs for IGF-II producing NICTH.

Levels of glucose-regulatory hormones in patients with non-islet cell tumor hypoglycemia: including a review of the literature.

Non-islet cell tumor hypoglycemia (NICTH) is one of the causes of spontaneous hypoglycemia. The pathogenesis of NICTH is thought to be an excessive production by tumors of big insulin-like growth factor (IGF)-II. This study investigated the levels of glucose-regulatory hormones in patients with NICTH with high serum levels of big IGF-II (big IGF-II group) and compared these with profiles of patients with spontaneous hypoglycemia with normal IGF-II (normal IGF-II group). Circulating IRI, CPR, ACTH, cortisol, GH, and IGF-I levels measured during hypoglycemic episodes were examined retrospectively in 37 patients with big IGF-II producing NICTH and 6 hypoglycemic patients with normal IGF-II. The hormone profile data of 15 patients with NICTH from published case reports were reviewed and included in the analyses. Mean plasma glucose levels (36 vs. 29 mg/dL), serum IRI (0.53 vs. 0.37 µIU/mL), CPR (0.15 vs. 0.20 ng/mL), IGF-I SDS (-3.55 vs. -3.18 SD) and ACTH levels (27.3 vs. 33.8 pg/mL) were not significantly different between the big and normal IGF-II groups. However, mean serum GH (0.85 vs. 9.62 ng/mL) and plasma cortisol levels (16.2 vs. 34.5 µg/dL) were significantly lower in the big IGF-II group than in the normal IGF-II group (both p<0.05). In conclusion, although the magnitude of the decrease in insulin and IGF-I levels did not differ between spontaneous hypoglycemic patients caused by other etiologies, patients with NICTH tended to have low basal GH levels during hypoglycemic episodes. These differences in hormone profile may be helpful for selecting patients who require analysis of IGF-II.

Continuing efforts to standardize measured serum growth hormone values in Japan.

Determination of serum growth hormone (GH) levels is mandatory for diagnosis of GH deficiency and excess. In the present study, we, the Study Committee for GH and Its Related Factors, The Foundation for Growth Science, Japan measured GH values in serum samples using all the commercially available kits in Japan. Significant discrepancies in the GH values were observed among the kits in spite of using the unified recombinant human GH-based standards. To deal with the discrepancies, we established a formula using a linear structural relationship model and were able to standardize the GH values. We propose to use the formula to diagnose GH deficiency and excess in Japan.

Late recurrence of a malignant hypoglycemia-inducing pelvic solitary fibrous tumor secreting high-molecular-weight insulin-like growth factor-II: A case report with protein analysis.

The present study reports a case of recurrent malignant pelvic solitary fibrous tumor (SFT) that induced non-islet cell tumor hypoglycemia via high-molecular-weight insulin-like growth factor-II in a 72-year-old male patient. The tumor recurred ~12 years after the complete resection of the original mass. The recurrent tumor, which had directly invaded the left ureter and perirectal fat tissue, could not be completely excised due to its fragility and adhesiveness. At 13 days post-surgery, the patient presented with rectal perforation, and an urgent rectal resection and colostomy was performed. Neither recurrence of the tumor nor hypoglycemic symptoms were observed 9 months after the surgery. High molecular weight insulin-like growth factor-II was detected in the serum and tumor specimens by western blot analysis and immunohistochemistry. The present case report suggests that certain SFTs can relapse even ≥10 years after a presumed complete resection of the primary tumor, and that performing a safe and complete resection of these tumors can be challenging, due to their adhesiveness or physical presentation; therefore, the indications for surgery should be considered with caution.

Hypoglycemia Observed on Continuous Glucose Monitoring Associated With IGF-2-Producing Solitary Fibrous Tumor.

CONTEXT: Tumors producing IGF-2 (IGF-2oma) are a major cause of spontaneous hypoglycemia. The treatment mainstay is surgical resection. Many case reports note resolution of hypoglycemia after IGF-2oma resection; however, outcomes are variable according to tumor type. We report a case of resolving hypoglycemia, observed on continuous glucose monitoring, after resection of an IGF-2-producing solitary fibrous tumor of pleura and review the current literature. CASE REPORT: A 69-year-old woman presented with impaired consciousness because of hypoglycemia. An IGF-2oma was diagnosed as the cause for hypoglycemia because of decreased serum insulin and IGF-1, the presence of a pleural tumor, and a high-molecular-weight form of serum IGF-2 detected by Western immunoblot. Surgical resection was performed; pathological examination demonstrated a solitary fibrous tumor with low-grade malignancy. Continuous glucose monitoring showed reversal of hypoglycemia after tumor resection. Approximately 2 years after resection, the patient has no signs of tumor recurrence or hypoglycemia. CONCLUSIONS: An IGF-2-producing solitary fibrous tumor of pleura in this case caused hypoglycemia. From a search of the literature of 2004-2014, 32 cases of IGF-2oma with hypoglycemia that underwent radical surgery were identified; in 19 (59%) patients, hypoglycemia was reversed, and there was no subsequent recurrence. The remaining 13 (41%) patients experienced tumor recurrence or metastasis an average of 43 months after initial tumor resection. The tumor of the present case was a low-grade malignancy. Regular follow-up with biomarker monitoring of glucose metabolism and assessment of hypoglycemic symptomatology, in conjunction with imaging tests, is important for detecting possible tumor recurrence and metastasis.

Candidemia Diagnosed from Peripheral Blood Smear: Case Report and Review of Literature 1954-2013.

BACKGROUND: Yeast with pseudohyphae or those that have been phagocytized by white blood cells are coincidentally found in peripheral blood smears. The clinical diagnostic value and outcome of candidaemia diagnosed from peripheral blood smears (CPBSs) are unclear. CASE PRESENTATION: A 45-year-old man with diabetes and panhypopituitarism for 20 years received 10 mg of hydrocortisone and 100 µg of levothyroxine sodium hydrate daily. He has been admitted seven times because of adrenal failure triggered by infections and was admitted for pneumonia. On day 56, some budding yeast was found microscopically in a peripheral blood smear with May-Giemsa staining. Some of them were phagocytized by white blood cells. The two blood cultures yielded Candida parapsilosis. Despite antifungal treatment and removal of an intravenous catheter, on day 98 (42 days after the candidaemia diagnosis), the patient died. CONCLUSION: We analysed 36 cases including the present case. Almost all CPBS patients (96.5 %, n = 29) were using an intravenous catheter. The most frequently isolated species was C. parapsilosis (35.1 %), followed by C. albicans (29.7 %). The overall mortality rate was 53.6 % (n = 28). The time from the discovery of yeast-like pathogens using peripheral blood smears to death ranged from a few hours to 93 days (median 19 days). The present results suggest that intravenous catheter use and the underlying conditions of patients are responsible for CPBSs. The detection of yeast in peripheral blood smears suggests advanced infections with uncontrollable complications, which means a poor prognosis. Rapid detection methods besides blood culture are needed.

Adult growth hormone deficiency: current concepts.

The clinical syndrome of adult growth hormone deficiency (AGHD) was widely recognized in the 1980s. In this review, we first describe the clinical features and diagnosis of AGHD and then state the effects of growth hormone (GH) therapy for these patients. The main characteristics of AGHD are abnormal body composition, dyslipidemia, insulin resistance, and an impaired quality of life (QoL) due to decreased psychological well-being. For diagnosing AGHD, the international consensus guidelines have suggested that an insulin tolerance test (ITT) is the gold standard, but in Japan, the growth hormone releasing peptide-2 (GHRP-2) test is available and is recommended as a convenient and safe GH stimulating test. The cut-off for diagnosing severe AGHD is a peak GH concentration of 9 g/L during the GHRP-2 test. Since 2006, GH therapy has been approved for Japanese patients with severe AGHD. For adults, GH replacement therapy should be initiated at a low dose (3 g/kg body weight/day), followed by individualized dose titration while monitoring patients' clinical status and serum insulin-like growth factor-I (IGF-I) concentrations. A variety of favorable effects of GH replacement have been indicated; however, it has not yet been established fully whether there is a direct effect of GH treatment on reducing mortality.

Mechanism of repression of 11ß-hydroxysteroid dehydrogenase type 1 by growth hormone in 3T3-L1 adipocytes.

11ß-Hydroxysteroid dehydrogenase type 1 (11ß-HSD1) is an NADPH-dependent reductase that converts cortisone to cortisol in adipose tissue. We previously reported that GH and IGF-I decrease 11ß-HSD1 activity and mRNA levels in adipocytes. Hexose-6-phosphate dehydrogenase (H6PDH) is involved in the production of NADPH, which is a coenzyme for 11ß-HSD1. The aim of the present study was to clarify further the mechanism of repression of 11ß-HSD1 activity by GH using linsitinib, an IGF-I receptor inhibitor. The suppression of 11ß-HSD1 mRNA by IGF-I was attenuated in the presence of 1 µM linsitinib (17.2% vs. 53.3% of basal level, P<0.05). 11ß-HSD1 mRNA levels in cells treated with GH in the presence of 1 µM linsitinib were not different from those in absence of linsitinib (35.9% vs. 33.9%). The increase in IGF-I mRNA levels with GH and 1 µM linsitinib was not different from that in the absence of linsitinib (359% vs. 347%). H6PDH mRNA levels were significantly decreased in cells treated with IGF-I for 8 and 24 h (55.6% and 33.7%, P<0.05). In the presence of 1 µM linsitinib, there was no repression of H6PDH mRNA (111.4%). H6PDH mRNA levels were significantly decreased in cells treated with GH in the absence of linsitinib for 24 h (55.9%, P<0.05), but not for 8 h (89.5%). The presence of 1 µM linsitinib also prevented repression of H6PDH mRNA by GH over 24 h (107.8%). These results suggest that GH directly represses 11ß-HSD1 mRNA rather than acting via the IGF-I receptor, and that GH represses H6PDH through locally produced IGF-I.

Adult growth hormone deficiency: current concepts.

The clinical syndrome of adult growth hormone deficiency (AGHD) was widely recognized in the 1980s. In this review, we first describe the clinical features and diagnosis of AGHD and then state the effects of growth hormone (GH) therapy for these patients. The main characteristics of AGHD are abnormal body composition, dyslipidemia, insulin resistance, and an impaired quality of life (QoL) due to decreased psychological well-being. For diagnosing AGHD, the international consensus guidelines have suggested that an insulin tolerance test (ITT) is the gold standard, but in Japan, the growth hormone releasing peptide-2 (GHRP-2) test is available and is recommended as a convenient and safe GH stimulating test. The cut-off for diagnosing severe AGHD is a peak GH concentration of 9 g/L during the GHRP-2 test. Since 2006, GH therapy has been approved for Japanese patients with severe AGHD. For adults, GH replacement therapy should be initiated at a low dose (3 g/kg body weight/day), followed by individualized dose titration while monitoring patients' clinical status and serum insulin-like growth factor-I (IGF-I) concentrations. A variety of favorable effects of GH replacement have been indicated; however, it has not yet been established fully whether there is a direct effect of GH treatment on reducing mortality.

Clinical features and therapeutic outcomes of acromegaly during the recent 10 years in a single institution in Japan.

Untreated acromegaly is associated with a twofold to fourfold increased mortality risk compared to the population. Recently, new therapeutic modalities have been developed and may contribute to an improvement in treatment outcomes in patients with acromegaly. In the current study we determined the clinical features and recent therapeutic outcomes in patients with acromegaly. The initial symptoms, selected therapeutic modalities, and outcomes in 125 patients with acromegaly (M/F, 49/76, 19-86 years) who were admitted to our institution between 2001 and 2010 were analyzed using medical charts. The basal GH levels and IGF-I SD scores in the patients ranged from 0.17 to 90.21 µg/L and 1.9-13.6, respectively. Acral enlargement (face, hands, and feet) without overt complications was essential to the diagnosis in 49 % of the patients. In these cases, it required 5 years to establish the diagnosis of acromegaly after symptom onset. Twenty (16 %) and 13 (10 %) patients had diabetes mellitus and hypertension 6 years prior to the diagnosis of acromegaly, respectively. In 35 patients with microadenomas, the rate of controlled cases following transsphenoidal surgery was 93 %. In 90 patients with macroadenomas, the remission rate was 79 % with multidisciplinary treatment. In cases in which the tumor extended beyond the lateral tangent of the internal carotid artery (Knosp grade ≥3), the remission rate was 33-56 %. Improvements in surgical techniques and medical therapies may contribute to increased rates of controlled cases in patients with acromegaly, although advanced lateral extension of the tumor remains a critical determinant of the therapeutic outcome.

DNA mismatch repair protein (MSH6) correlated with the responses of atypical pituitary adenomas and pituitary carcinomas to temozolomide: the national cooperative study by the Japan Society for Hypothalamic and Pituitary Tumors.

CONTEXT: Temozolomide (TMZ) is an alkylating agent and was a first-line chemotherapeutic agent for malignant gliomas. Recently, TMZ has been documented to be effective against atypical pituitary adenomas (APAs) and pituitary carcinomas (PCs). OBJECTIVE: The clinical and pathological characteristics of APAs and PCs treated with TMZ in Japan were surveyed and analyzed retrospectively. DESIGN: Members of the Japan Society of Hypothalamic and Pituitary Tumors were surveyed regarding the clinical characteristics of APAs and PCs treated with TMZ. Stored tumor samples were gathered from the responders and were assessed by the immunohistochemistry of Ki-67, O(6)-methyl-guanine-DNA methyltransferase, p53, MSH6, and anterior pituitary hormones. Responses to TMZ treatment were defined as complete response (CR), partial response (PR), progressive disease (PD), and stable disease (SD) according to RECIST (Response Evaluation Criteria in Solid Tumors) version 2.0. SUBJECTS: Three samples from 3 subjects with APA and 11 samples from 10 subjects with PC were available. RESULTS: The 13 subjects had APAs and PCs consisting of 5 prolactin-producing tumors, 5 ACTH-producing tumors, and 3 null cell adenomas. The clinical response to TMZ treatment was as follows: 4 cases of CR and PR (31%), 2 cases of SD (15%), 6 cases of recurrence after CR and PR (46%), and 1 case of PD (8%). However, considerable subjects had recurrent disease after a response to TMZ. The immunohistochemical findings of Ki-67, O(6)-methyl-guanine-DNA methyltransferase, and p53 did not show any significant correlation with the efficacy of TMZ. However, the immunopositivity of MSH6 was positively correlated with TMZ response (P = .015, Fisher's exact test). CONCLUSIONS: This study showed that preserving MSH6 function was contributory to the effectiveness of TMZ in malignant pituitary neoplasms. It is necessary to survey more cases and evaluate multifactor analyses.

Efficacy, safety, and pharmacokinetics of sustained-release lanreotide (lanreotide Autogel) in Japanese patients with acromegaly or pituitary gigantism.

The somatostatin analog lanreotide Autogel has proven to be efficacious for treating acromegaly in international studies and in clinical practices around the world. However, its efficacy in Japanese patients has not been extensively evaluated. We examined the dose-response relationship and long-term efficacy and safety in Japanese patients with acromegaly or pituitary gigantism. In an open-label, parallel-group, dose-response study, 32 patients (29 with acromegaly, 3 with pituitary gigantism) received 5 injections of 60, 90, or 120 mg of lanreotide Autogel over 24 weeks. Four weeks after the first injection, 41% of patients achieved serum GH level of <2.5 ng/mL and insulin-like growth factor-I (IGF-I) level was normalized in 31%. Values at Week 24 were 53% for GH and 44% for IGF-I. Dose-dependent decreases in serum GH and IGF-I levels were observed with dose-related changes in pharmacokinetic parameters. In an open-label, long-term study, 32 patients (30 with acromegaly, 2 with pituitary gigantism) received lanreotide Autogel once every 4 weeks for a total of 13 injections. Dosing was initiated with 90 mg and adjusted according to clinical responses at Weeks 16 and/or 32. At Week 52, 47% of patients had serum GH levels of <2.5 ng/mL and 53% had normalized IGF-I level. In both studies, acromegaly symptoms improved and treatment was generally well tolerated although gastrointestinal symptoms and injection site induration were reported. In conclusion, lanreotide Autogel provided early and sustained control of elevated GH and IGF-I levels, improved acromegaly symptoms, and was well tolerated in Japanese patients with acromegaly or pituitary gigantism.

Recurrent solitary fibrous tumor of the pleura with malignant transformation and non-islet cell tumor-induced hypoglycemia due to paraneoplastic overexpression and secretion of high-molecular-weight insulin-like growth factor II.

A 41-year-old man was diagnosed with a solitary fibrous tumor (SFT) of the pleura in the posterior mediastinum. Despite two surgeries for excision, the SFT recurred and progressed with direct invasion of the chest wall and bone metastases. He was hospitalized because of cerebral infarction and presented with recurrent severe hypoglycemia fourteen years later. High-molecular-weight (HMW) insulin-like growth factor II (IGF-II) was identified in the serum and tumor using Western blotting and immunohistochemistry. These findings suggested that the cause of the recurrent severe hypoglycemia was SFT production of HMW IGF-II, a mediator of non-islet cell tumor-induced hypoglycemia (NICTH).

Development and validation of a new questionnaire assessing quality of life in adults with hypopituitarism: Adult Hypopituitarism Questionnaire (AHQ).

OBJECTIVE: To develop and validate the Adult Hypopituitarism Questionnaire (AHQ) as a disease-specific, self-administered questionnaire for evaluation of quality of life (QOL) in adult patients with hypopituitarism. METHODS: We developed and validated this new questionnaire, using a standardized procedure which included item development, pilot-testing and psychometric validation. Of the patients who participated in psychometric validation, those whose clinical conditions were judged to be stable were asked to answer the survey questionnaire twice, in order to assess test-retest reliability. RESULTS: Content validity of the initial questionnaire was evaluated via two pilot tests. After these tests, we made minor revisions and finalized the initial version of the questionnaire. The questionnaire was constructed with two domains, one psycho-social and the other physical. For psychometric assessment, analyses were performed on the responses of 192 adult patients with various types of hypopituitarism. The intraclass correlations of the respective domains were 0.91 and 0.95, and the Cronbach's alpha coefficients were 0.96 and 0.95, indicating adequate test-retest reliability and internal consistency for each domain. For known-group validity, patients with hypopituitarism due to hypothalamic disorder showed significantly lower scores in 11 out of 13 sub-domains compared to those who had hypopituitarism due to pituitary disorder. Regarding construct validity, the domain structure was found to be almost the same as that initially hypothesized. Exploratory factor analysis (n = 228) demonstrated that each domain consisted of six and seven sub-domains. CONCLUSION: The AHQ showed good reliability and validity for evaluating QOL in adult patients with hypopituitarism.

Standardized centile curves and reference intervals of serum insulin-like growth factor-I (IGF-I) levels in a normal Japanese population using the LMS method.

Measurements of insulin-like growth factor-I (IGF-I) are useful not only for diagnosis and management of patients with growth hormone (GH)-related disorders but also for assessing nutritional status. We reported population-based references of serum IGF-I in 1996. However, they did not properly reflect data in the transition period from puberty to maturity. The aim of the present study was to re-establish a set of normative data for IGF-I for the Japanese population. The study included 1,685 healthy Japanese subjects (845 males, 840 females) from 0 to 83 years old. Subjects suffering from diseases that could affect IGF-I levels were excluded. Obese or extremely thin adult subjects were also excluded. IGF-I concentrations were determined by commercially available immunoradiometric assays. The reference intervals were calculated using the LMS method. Median IGF-I levels reached 310 ng/mL in males at the age of 14 years and 349 ng/mL in females at the age of 13 years, falling to 124 ng/mL and 103 ng/mL, respectively, by the age of 70 years. The mean pretreatment IGF-1 SD scores in patients with severe GH deficiency (GHD) obtained from the database of the Foundation for Growth Science and from clinical studies for adult GHD were -2.1±1.6 and -4.9±2.5, respectively. The present study established age- and gender-specific normative IGF-I data for the Japanese population and showed the utility of these references for screening patients with severe GHD.

Effects of GH assay standardization on evaluation of treatment outcomes for acromegaly in Japan.

In Japan, the growth hormone (GH) assay has been standardized since April 2005 through use of a uniform recombinant human GH (rhGH) standard. Since then, GH values measured using the rhGH standard have been approximately 40% lower than previous values measured using kit standards based on the WHO standards for hGH of pituitary origin. However, the Japanese criteria for evaluating treatment outcomes for acromegaly have remained the same: a nadir GH during a 75 g OGTT <1 µg/L is considered cured, 1≤GH<2.5µg/L is considered inadequately controlled, and ≥2.5 µg/L is considered poorly controlled, instead of these levels were lowered to 60%, i.e. from 1 to 0.6 µg/L for cured and from 2.5 to 1.5µg/L for inadequately controlled (termed as "newly proposed criteria" in this study). We investigated the effects of standardization of the GH assay on the evaluation of post-surgical disease activity in 50 patients with acromegaly (M/F 19/31, 21-72 yr.). Post-surgical nadir GH levels during OGTT were positively correlated with the IGF-I SD score 3 months after TSS. Five of 6 patients whose post-surgical nadir GH levels ranged between 0.6 and 1 µg/L had normal serum IGF-I levels 3 months after TSS. Rates of improvement in glucose metabolism did not differ when patients were classified based on the present criteria vs. the newly proposed criteria. In conclusion, the current Japanese remission criteria for acromegaly still accurately reflect post-surgical disease activity in most patients, though long-term observation is still required.