ACTA ENDOCRINOLOGICA (BUC)

Previous studies have correlated the expression of PAR proteins with breast cancer invasiveness. The scope of this study was to evaluate the expression of PAR-1 in human breast cancer specimens and investigate possible correlations with tumor size, grade and lymph node status, as well as covariations with estrogen and progesterone receptors, c-erbB-2 protein and lysosomal protease Cathepsin D. Formalin-fixed paraffin-embedded sections of 75 mastectomy specimens deriving from patients with primary breast carcinomas were implemented. Expression of PAR-1 was detected employing immunohistochemical assays utilizing a goat polyclonal PAR-1 antibody. The granular pattern of cytoplasmic immunoreaction was considered indicative for the protein?s expression. Statistical assessment was performed using SPSS 13.0 statistical package, Pearson?s correlation, &#967;2 and Fisher?s exact test. Expression of PAR-1 protein had a statistically significant correlation (p<0.001) with tumor grade, while in invasive tumors a similar relationship (p<0.001) was documented between PAR-1 expression and presence of positive axillary lymph nodes. However, PAR-1 expression did not exhibit a significant correlation with tumor size or with the expression of ER, PR, c-erbB-2, or Cathepsin D molecules. PAR-1 possesses a role in tumor invasion and contributes to the metastatic potential of certain types of breast carcinomas. The disassociation between expression of PAR-1 and that of the ER, PR, c-erbB-2, or Cathepsin D might imply participation in alternative pathways of malignant transformation and tumor progression.

Obesity is an important risk factor for obstructive sleep apnea syndrome (OSAS). One would expect that effective treatment by continuous positive airway pressure (CPAP) would lead to weight loss due to decreased daytime sleepiness and improved physical activity. However, many papers suggest that shortage of sleep is a risk factor for obesity.\r\nAim. To assess the weight change after 1 year of effective CPAP treatment for OSAS.\r\nMethods. In this retrospective study OSAS was diagnosed in 109 subjects (50 women, 59 men; age 58?13 years). Eighty subjects used CPAP > 5 h per night in > 70% of nights and were considered treatment subjects. Twenty-nine subjects used CPAP < 5 hours per night or < 70% of nights and were considered control subjects. Patients were diagnosed using complete full-night or split-night polysomnography (70 and 39 patients respectively). Mean effective titrated CPAP pressure was 9.8 cm H2O. CPAP compliance was assessed through downloadable data from CPAP machine (19 patients) or clinical exam (90 patients). Body mass\r\nindex (BMI) was determined at the time of diagnosis and 1 year later (range 10-15 months).\r\nResults. Treatment and control subjects were similar regarding age, sex, BMI and apnea hypopnea index (AHI) at baseline. Weight increased in CPAP users (n=80) by 1.3 kg (CI 95% 0.4, 2.25; p<0.01) but not in control subjects (n=29) (mean difference in controls 0.37 kg, CI 95% -1.8, 2.5; p>0.05). BMI significantly increased in men (p<0.005), in subjects with severe OSAS (AHI>30 events/hour) (p<0.009) and in those younger than 65 years (p<0.01). Sleep architecture was investigated by full-night polysomnography in 50 regular CPAP users and 20 controls. In the subgroup of 18 treatment patients with lack of slow wave sleep (SWS) the increase in body weight was 2.6 kg (CI 95% 0.4, 4.9, p=0.02), more than double as compared with patients with SWS at baseline (n=32).\r\nConclusion. Effective CPAP treatment leads to a modest, but significant weight gain after 1 year in OSAS patients, especially in men with severe sleep apnea. This seems to be in relation to lack of SWS at baseline. An independent medical intervention for weight loss should be associated with CPAP treatment in sleep apnea syndrome.

Context. Adrenocortical carcinoma (ACC) is a rare neoplasm with an aggressive course and poor prognosis. The worldwide incidence is about 0.5 to 2 cases per million population per year. Oncocytic adrenocortical carcinoma is a rare histopathological variant of ACC with only a few reported cases in the literature. Case report. We report a case of an oncocytic variant of adrenocortical carcinoma in a 21-year-old male patient who presented with a left adrenal mass. Imaging studies confirmed a large left adrenal mass with involvement of the left renal vein and inferior vena cava. Endocrine workup showed mildly elevated serum cortisol levels. Discussion. Oncocytic AAC is a rare histopathological variant of ACC, as well as a rare subgroup of oncocytic adrenal neoplasms Hormonally active or functioning adrenocortical carcinomas most commonly secrete cortisol whereas co-secretion of multiple steroid hormones is a rare phenomenon. Conclusions. Surgery remains the mainstay of treatment, but most of the patients present late with large masses and eventually become unsuitable for curative resection.

As the medical utility of injectable therapeutic peptides is expanding, so is the challenge of developing technologies that allow the administration of such molecules via alternative routes, considering that chronic patients requiring treatment with parenteral formulations are less adherent and compliant to the therapeutic regimens. Hence, substantial efforts have been made to develop technologies that allow the oral formulation of peptides. Due to their importance in the field of pharmaceutical technology, we describe the latest advancements made in the development of oral salmon calcitonin and oral semaglutide, in co-formulation with absorption enhancers such as 8-[(5-chloro-2-hydroxybenzoyl) amino] octanoic acid (or 5-CNAC) and N-[8-(2-hydroxybenzoyl) amino] caprylate (or SNAC). Oral semaglutide is considered to be a landmark for oral peptide delivery technology, as it is one of the very few successful examples of peptides that can be administered orally. Unlike semaglutide, oral calcitonin is still not approved by the regulatory authorities because it failed to demonstrate the anticipated effects in phase III clinical trials conducted so far. However, the efforts for obtaining an oral form of calcitonin have significantly contributed to the development of technologies that facilitate the absorption of peptide-structure macromolecules.

Hyperinsulinism/hyperammonemia (HI/HA) syndrome is caused by activating mutations in GLUD1 gene, and causes fasting as well as protein sensitive symptomatic hypoglycemia, in addition to persistently elevated plasma ammonia levels. First-line treatment is diazoxide, and most patients respond well to this agent, however side effects may be observed. The most frequent side effect of diazoxide is fluid retention and hypertrichosis, while hyperuricemia and hematologic side effects are observed less often. Herein, we report a case who had a heterozygous mutation of GLUD1 gene and who developed diazoxide related neutropenia 8 years after the start of treatment. On follow-up, leucopenia and mild neutropenia persisted and the treatment was changed to somatostatin analogues. However, she developed persistent severe symptomatic hypoglycemia and required diazoxide retreatment. A lower dose of diazoxide (6 mg/kg/day) successfully controlled hypoglycemia and cell counts increased even though they were not normalized. Neutropenia in current case presented after a long period of time of diazoxide use and this period is the longest defined in the literature. Long-term endocrine and hematologic follow-up of this patient up to 18 years old will also be presented.

Triple A syndrome is an autosomal recessive inherited multisystem disorder that was first described in 1978. Triple A syndrome has a high genotypic and phenotypic heterogeneity and has been linked with mutations in the AAAS gene, which has been identified on chromosome 12q13. A 14 years old male patient applied to outpatient clinic complaining of weakness and darkening of skin color since 4 months. On physical examination hyperpigmentation was observed on both the skin and mucosa. The morning cortisol level was 1.8 μg/dL and ACTH was >1250 ng/L. Schirmer test showed absence of tears. In the patient’s esophagoscopy, mucosal paleness and stenosis of the cardia were observed. Molecular genetic analysis of AAAS gene confirmed the diagnosis of triple A syndrome caused by homozygous mutation: c.1368_1372delGCTCA (p.Gln456HisfsTer38). This variant is considered to be a possible pathogenic because it causes a frame shift that changes the protein structure. As a result of the genetic analysis of the patient’s parents, the AAAS gene was detected as heterozygous in both parents for the c.1368_1372delGCTCA mutation. To the best of our knowledge, this is the first report of homozygous mutation: c.1368_1372delGCTCA (p.Gln456HisfsTer38).

Context. Diabetes insipidus (DI) is rare in the neonatal period but of great importance due to increased renal risk and mental retardation despite treatment. Objective. This report describes the case of a patient with congenital nephrogenic diabetes insipidus (NDI). Detection of this pathology during the neonatal period, especially in premature newborns, is difficult because of the electrolyte variations that occur as a result of the immature kidney function. Subjects and methods. The subject was a preterm infant with very low birth weight (VLBW) and persistent hypernatremic hyperosmolarity that developed polyuria and polydipsia in the first weeks of life. Results. Taking into account blood and urine laboratory tests, vasopressin levels, as well as family history, the infant was diagnosed with congenital NDI. Early treatment allowed a good development, proving that the prevention of long-term complications is possible through multidisciplinary care and frequent monitoring. The particularity of this case was the presence of persistently elevated presepsin levels. This association prompted the investigation into underlying renal hypernatremia. Conclusions. NDI is a rare condition and the onset in the neonatal period is a sign of severity and hereditary causality. Early diagnosis, symptomatic treatment and multidisciplinary monitoring may decrease the risk of longterm complications.

Purpose. Assessing cardiovascular risk in patients with acromegaly using traditional cardiovascular risk factors is inadequate. Endothelial dysfunction seems to be a much better indicator for assessing cardiovascular risk in acromegaly. The study aims to compare from this point of view two groups of patients, with hypertension and with acromegaly. Methods. The first group consists of 54 patients with acromegaly and the second group of 64 hypertensive patients. Endothelial dysfunction was evaluated by the FMD method. The relationship between endothelial dysfunction, specific humoral markers of acromegaly and traditional cardiovascular risk factors was analysed in both groups. Results. Although the presence of cardiovascular risk factors was statistically significantly higher in the group of hypertensives (the most important were age, blood pressure, glycemia, hypertriglyceridemia and SCORE), the presence of endothelial dysfunction was higher in the acromegaly group (61.10% vs. 32.10%, p=0.02). The best correlation with endothelial dysfunction in acromegaly group was the level of GH (28.9±28 vs. 11.7±10.3, p=0.003). Conclusions. The presence of endothelial dysfunction in patients with acromegaly is highly dependent on the level of GH and traditional cardiovascular risk factors are less important. In these patients the cardiovascular risk should not be evaluated in the same way as in normal population.

Craniopharyngiomas (CP) are rare, dysembryoplastic tumors of the hypothalamo-pituitary area. There are two very distinct pathological types: adamantinomatous (ACP) and papillary (PCP). ACP and PCP also have significant clinical differences, pointing to a different pathogenesis. This only began to be elucidated lately and indeed discovered specific, mutually exclusive mutations with pathogenetic role in ACP and PCP, respectively. The vast majority of ACP harbor an activating mutation of the CTNNB1 gene coding for β-catenin (member of the Wnt pathway). The mutation was proved to be pathogenetic in animal models and a tumorigenesis model has already been created. In contrast, in PCP, BRAF (gene coding for a main actor in the MAPkinase pathway) mutations have been found in the majority of cases. These findings can improve the differential diagnosis of intracranian tumors (by specifically designed immunohistochemistry-antibodies) and the design of molecules to inhibit the disordered intracellular pathways. Such molecules are already available and promising for the BRAF/MAPkinase pathway. In conclusion, extremely significant progresses have been made in revealing the complex process of tumorigenesis in CP and they are likely to solve in the foreseeable future many challenges we typically face in the clear positive diagnosis and optimal management of these rare tumors.