No abstract

Abstract. Neuroendocrine tumors (NET) include a spectrum of malignancies arising from neuroendocrine cells throughout the body. The objective of this clinical investigation of retrospectively and prospectively collected data was to describe the prevalence, demographic data, clinical symptoms and methods of diagnosis of NET and the treatment and long-term follow-up of patients with NET. Data were provided by the participating centers and assessed for consistency by internal reviewers. All the cases were centrally evaluated (when necessary) by the pathologists in our group. The tissue samples were reviewed by hematoxylin and eosin and immunohistochemical staining techniques to confirm the diagnosis of NET. In total, 532 cases were documented: 461 gastroenteropancreatic-NET (GEP-NET) and 71 bronchial NET (BNET). All the tumors were immunohistochemically defined according to the World Health Organization (WHO) and European Neuroendocrine Tumor Society criteria. The most common initial symptoms in GEP-NET were abdominal pain, diarrhea, bowel obstruction, flushing, gastrointestinal bleeding and weight loss. The most common tumor types were carcinoid (58.0%), non-functional pancreatic tumor (23.0%), metastatic NET of unknown primary (16.0%) and functional pancreatic tumor (3.0%). Of the BNET, 89.0% were typical and 11.0% atypical carcinoids. Of the patients with GEP-NET, 59.2% had distant metastasis at diagnosis. The locations of the primary tumors in GEP-NET were the small bowel (26.9%), pancreas (25.2%), colon-rectum (12.4%), appendix (7.6%), stomach (6.9%), esophagus (2.8%), duodenum (2.0%) and unknown primary (16.3%). The histological subtypes based on the WHO classification were well-differentiated NET (20.1%), well-differentiated neuroendocrine carcinomas (66.5%) and poorly differentiated neuroendocrine carcinomas (10.3%). Overall, 67.3% of the patients underwent surgery, 41.2% with curative intent and 26.1% for palliative purposes. The 5-year survival rates were 65.1% (95% confidence interval, 58.0-71.4%) in GEP-NET and 100.0% in typical carcinoid of the lung. This observational, non-interventional, longitudinal study aimed to accumulate relevant information regarding the epidemiology, clinical presentation and current practices in the treatment of NET patients in Argentina, providing insight into regional differences and patterns of care in this heterogeneous disease.

Polycystic ovary syndrome (PCOS) is an endocrine disorder. PCOS women are at high risk of developing insulin resistance (IR) and cardiovascular disorders since young age. We aimed to study the reliability of lipid accumulation product (LAP) and visceral adiposity index (VAI) as markers of metabolic disturbances (MD) associated with IR in young reproductive aged PCOS patients. We also evaluated the association between LAP and VAI and the presence of hyperandrogenism. In a cross-sectional study, 110 PCOS patients and 88 control women (18-35 years old) were recruited. PCOS patients were divided into 2 groups, as hyperandrogenic and non-hyperandrogenic considering the signs of hyperandrogenism (clinical or biochemical). Anthropometric measurements were taken and blood samples collected. Metabolic and anthropometric characteristics and their association with IR and associated MD were evaluated and LAP and VAI were calculated. LAP and VAI were compared with TC/HDL-c and TG/HDL-c to define the best markers of MD in this population. Independently of the phenotype, young PCOS patients showed high IR and dyslipidemia. Both LAP and VAI showed to be more effective markers to assess MD and IR in these young women than TG/HDL-c or TC/HDL-c [cut-off values: LAP: 18.24 (sensitivity: 81.43% specificity: 73.49%), positive predictive value (PPV): 75.0%, negative predictive value (NPV): 77.27%, VAI: 2.19 (sensitivity: 81.16% specificity: 72.15% PPV: 74.65% NPV: 72.22%)]. LAP and VAI are representative markers to assess MD associated with IR in young PCOS patients. All PCOS patients, independently of their androgenic condition, showed high metabolic risk.

The high number of unidentified alleles in the nonclassical group suggests that less frequent mutations, or the presence of new ones, might be the cause of the disease in the Argentine population. Alternatively, the cut-off value in the ACTH-stimulated 17-hydroxyprogesterone test might overestimate the diagnosis of the nonclassical form by including some patients with heterozygous status.

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is the most frequent inborn error of metabolism, and accounts for 90–95% of CAH cases. The affected enzyme, P450C21, is encoded by the CYP21A2 gene, located together with a 98% nucleotide sequence identity CYP21A1P pseudogene, on chromosome 6p21.3. Even though most patients carry CYP21A1P-derived mutations, an increasing number of novel and rare mutations in disease causing alleles were found in the last years. In the present work, we describe five CYP21A2 novel mutations, p.R132C, p.149C, p.M283V, p.E431K and a frameshift g.2511_2512delGG, in four non-classical and one salt wasting patients from Argentina. All novel point mutations are located in CYP21 protein residues that are conserved throughout mammalian species, and none of them were found in control individuals. The putative pathogenic mechanisms of the novel variants were analyzed in silico. A three-dimensional CYP21 structure was generated by homology modeling and the protein design algorithm FoldX was used to calculate changes in stability of CYP21A2 protein. Our analysis revealed changes in protein stability or in the surface charge of the mutant enzymes, which could be related to the clinical manifestation found in patients.