HypoparaNet: A Database of Chronic Hypoparathyroidism Based on Expert Medical-Surgical Centers in Italy.

Hypoparathyroidism is a rare disease characterized by low serum calcium levels and absent or deficient parathyroid hormone level. Regarding the epidemiology of chronic hypoparathyroidism, there are limited data in Italy and worldwide. Therefore, the purpose of this study was to build a unique database of patients with chronic hypoparathyroidism, derived from the databases of 16 referral centers for endocrinological diseases, affiliated with the Italian Society of Endocrinology, and four centers for endocrine surgery with expertise in hypoparathyroidism, to conduct an epidemiological analysis of chronic hypoparathyroidism in Italy. The study was approved by the Institutional Review Board. A total of 537 patients with chronic hypoparathyroidism were identified. The leading etiology was represented by postsurgical hypoparathyroidism (67.6%), followed by idiopathic hypoparathyroidism (14.6%), syndromic forms of genetic hypoparathyroidism (11%), forms of defective PTH action (5.2%), non-syndromic forms of genetic hypoparathyroidism (0.9%), and, finally, other forms of acquired hypoparathyroidism, due to infiltrative diseases, copper or iron overload, or ionizing radiation exposure (0.7%). This study represents one of the first large-scale epidemiological assessments of chronic hypoparathyroidism based on data collected at medical and/or surgical centers with expertise in hypoparathyroidism in Italy. Although the study presents some limitations, it introduces the possibility of a large-scale national survey, with the final aim of defining not only the prevalence of chronic hypoparathyroidism in Italy, but also standards for clinical and therapeutic approaches.

Severe hypocalcemia and life-threatening ventricular arrhytmias: case report and proposal of a diagnostic and therapeutic algorithm.

Hypocalcemia is frequent in the setting of endocrine disorders, bone diseases and renal failure. When hypocalcemia is severe it can predispose to life-threatening ventricular arrhythmias; in such cases a rapid admission to hospital and a prompt correction of electrolyte imbalance are needed. We report the case of an old patient suffering from renal failure that was admitted to our cardiac step-down unit because of severe hypocalcemia associated with ventricular arrhythmias. Hypocalcemia was promptly treated and an endocrinologic consult was requested for investigating the causes of this electrolyte imbalance. Our experience suggests the creation of a new synergy between cardiologists and endocrinologists that led us to build a simple and schematic algorithm for the diagnosis and treatment of hypocalcemia.

A New Approach to Ultrasound Study of the Left Adrenal Lodge.

INTRODUCTION: Ultrasound examination of the left adrenal gland is generally associated with relatively low sensitivity and specificity and is strongly influenced by the operator's experience, patient characteristics, and the type of equipment available. In particular, the left adrenal gland remains a structure that is difficult to investigate, even in expert hands. The possibility of improving the ultrasound exploitability of the left adrenal gland and therefore contributing to enhancing the overall diagnostic sensitivity of the technique, allowing for a more widespread application, could be represented by the addition, alongside traditional structural landmarks, of vascular landmarks. The improvement in the diagnostic sensitivity of ultrasound may allow for the use of this technique in selected categories of patients, particularly in the remote monitoring of already-known adrenal pathologies. METHODOLOGY: In ultrasound, the normal adrenal gland is described as a solid formation of 6-8 +/-2 mm in thickness with the shape of an inverted V or Y letter or a λ shape consisting of a thin, linear, hyperechoic (medullary) central area surrounded by a hypoechoic (cortical) layer and possibly by a capsule that delimits it from the surrounding adipose tissue of the adrenal lodge. The ultrasound exploration of the adrenal gland is traditionally performed using a Convex 1-6 mHz probe, using structural landmarks such as the liver, spleen, upper renal pole, and diaphragm. On the right side, the liver provides a good acoustic window to the adrenal space, allowing visualization of the adrenal gland in approximately 90% of cases [1x, 2x]. On the left side, the spleen is used as an acoustic window, but its smaller size compared to the liver often cannot overcome the acoustic barrier represented by residual gas in the gastric and transverse colon/left colic flexure, even after intestinal preparation, reducing the possibility of visualizing the left adrenal gland up to 40-50% [1x, 2xy]. The exploration initially takes place with the patient supine to reduce meteoric overlap, then in the right lateral decubitus position; once the upper pole of the left kidney is identified with longitudinal and coronal sections along the mid and posterior axillary line, the left adrenal gland is located in the triangular space between the spleen, upper renal pole, and diaphragmatic crux by angling the probe anteriorly. As the kidney section decreases and disappears, the adrenal region becomes visible. Once the location is identified, the probe can be rotated on a traverse plane, considering that the left adrenal gland is medially located between the upper renal pole and the renal hilum, with the gland lying between the aorta medially and the kidney laterally. Considering that most adrenal expansions on the left tend to develop downward and inward, the left adrenal gland can also be explored, especially through an anterior approach, both in the long and short axes, using vascular landmarks, given the tight and consistent anatomical relationships of the gland with the large venous and arterial vessels in the region. The presence of gas-filled hollow organs can be partially reduced by conducting the exploration with moderate and constant pressure with the probe to displace them from the field of view. The vascular landmarks are represented by the: 1) abdominal aorta at the level of the emergence of the superior mesenteric artery, 2) the splenic vein, and 3) the vascular pedicle of the left kidney. The adrenal gland is located in the space between the aorta medially, the renal pedicle caudally, and the splenic vein anteriorly. Therefore, with a left paramedian axial section, the abdominal aorta is sought at the level of D12, where the superior mesenteric artery originates. Aligning with the splenic vein, which acts as the roof of the space under examination, the area of interest is explored by tilting the probe superiorly and medially towards the aorta, inferiorly and medially towards the left renal vein, and superiorly and laterally towards the renal border, trying to maintain the view of the splenic vein as the true anterior-lateral margin of the area. This position makes it possible to explore the tail of the pancreas and the Treitz. DISCUSSION: The ultrasound examination of the adrenal gland in adults is considered a method with low sensibility and highly operator -, patient-, and instrument-dependent compared to CT and MRI [3X] and currently has a limited and selective role in the management of patients with adrenal masses [4-6]. According to the International LLGG guidelines, the preferred methods for characterizing adrenal masses are CT, MRI, and PET/TC with 18F-fluorodeoxyglucose [4]. However, exploration of the adrenal glands has been considered an integral part of abdominal ultrasound studies since the 1990s [1X, 2X]. Under favorable conditions, the method is able to detect both neoplastic and non-neoplastic pathologies affecting the organ, contributing to the discovery of incidentalomas in this setting during an examination performed for reasons or symptoms not immediately related to the presence of an adrenal mass. [5]. The prevalence of adrenal incidentalomas detected during abdominal diagnostic investigations is reported to be around 5% of cases [7-10]. The sensitivity, in experienced hands, can be high even for masses smaller than 20 mm, especially on the right side [7]. The ultrasound examination may be indicated if the diagnostic workup of the adrenal mass does not reveal an immediate surgical indication and instead requires periodic monitoring. In cases where the conditions allow for accurate visualization and measurement of the lesion, for the absence of radiation exposure, simplicity of execution, and low cost, ultrasound examination may be preferred to CT for long-term surveillance [6-12], especially in young individuals. CONCLUSION: The addition of non-conventional acoustic windows and vascular landmarks characterized by anatomical constancy to the standard ultrasound examination can contribute to improving the sensitivity of the method, allowing for the identification of a greater number of incidentalomas and expanding the population that may benefit from ultrasound surveillance of known adrenal masses, especially of the left adrenal gland. A comparative study between the gold standard and the ultrasound method enhanced by vascular landmarks is desirable to quantify any potential improvement in sensitivity and specificity of the method in exploring the adrenal gland. This would serve as a premise for its practical application on a larger scale.

Phase 2 placebo-controlled, single-blind trial to evaluate the impact of oral ibandronate on bone mineral density in osteopenic breast cancer patients receiving adjuvant aromatase inhibitors: 5-year results of the single-centre BONADIUV trial.

AIM: We present the final results of the BONADIUV trial, a single-blind, randomised, placebo-controlled phase 2 study to evaluate the impact of ibandronate treatment on bone mineral density (BMD) in osteopenic women taking aromatase inhibitors (AI). PATIENTS AND METHODS: Between 2011 and 2014, 171 osteopenic patients were randomised in a 1:1 ratio to receive either placebo or oral monthly ibandronate (150 mg). Treatment duration was 2 years, with 6-month evaluation. Primary end-point was the 2-year lumbar spine (LS) and total hip (TH) T-score mean differences as measure of BMD variation. Secondary analyses of survival outcomes have been performed at a 5-year median follow-up. CLINICALTRIALS. GOV IDENTIFIER: NCT02616744. RESULTS: Median age of study population was 60.2 years (range 44-75). At the database cut-off time, the median follow-up was 63.3 months (range 2.7-87.3). No difference in terms of T-score was shown at baseline between arms both for TH (P = 0.61) and LS (P = 0.96). At 2-year follow up, the mean change was statistically significant in favour of ibandronate arm both at TH (P = 0.0002) and LS (P < 0.0001). No significant difference in terms of adverse events was observed between arms. At a median follow-up of 63.3 months (range 2.7-87.3), the overall survival (OS) rate was 97.5% in the placebo group and 93.0% in the ibandronate arm (P = 0.19). The invasive disease-free survival (iDFS) rates did not differ between groups (P = 0.42). CONCLUSIONS: Ibandronate compared to placebo improved BMD change in osteopenic women treated with adjuvant AI. Five-year survival analyses showed no difference between arms in terms of OS and iDFS rates.

A novel polymorphism at the GNAS1 gene associated with low circulating calcium levels.

The concentration of calcium in the extracellular fluid is crucial for several physiological functions in humans and in normal conditions its circulating levels are maintained between 8.5-10.5 mg/dl. Among the regulators of calcium homeostasis parathyroid hormone (PTH) acts though the G-protein coupled PTH receptor and a hormone-sensitive adenylate cyclase, with Gsα subunit (stimulatory guanine nucleotide-binding protein alpha-subunit) being responsible for the stimulation of the catalytic complex. Mutations of the Gsα encoding gene, GNAS1, are causal for some forms of congenital hypocalcemia. In the present study genetic variability in the GNAS1 gene was analyzed in a group of hypocalcemic patients collected through the Italian Register of Primary Hypoparathyroidism (RIIP). We identified a new intronic variant of the GNAS1 gene, consisting of a T>C polymorphism. This polymorphism was studied in a group of unrelated healthy subjects for a possible association with bone turnover biomarkers and bone mineral density. The T>C polymorphism was found in 18% of the studied populations, with 15% heterozygous TC and 3% homozygous CC (Pearson χ(2)analysis: p=0.04). A significant association with low serum calcium levels was found in healthy subjects carrying the T > C polymorphism (ANCOVA analysis: p=0.04). These results support segregation of a novel GNAS1 gene intronic variant with low calcium levels in primary hypoparathyroidism, pseudo-hypoparathyroidism and in the general population.

Synchronous occurrence of medullary and papillary carcinoma of the thyroid in a patient with cutaneous melanoma: determination of BRAFV600E in peripheral blood and tissues. Report of a case and review of the literature.

The purpose of this study is to describe a case of concurrent medullary and papillary thyroid carcinoma (MTC and PTC) and cutaneous melanoma and to analyze BRAF(V600E) mutation in plasma and tissues. We report the clinical history and the laboratory, imaging, and histopathological findings of a 47-year-old man affected by multinodular goiter. BRAF(V600E)-mutated DNA was quantified in plasma samples and in cancer sections by quantitative real-time polymerase chain reaction (qPCR). At ultrasound examination, the dominant right nodule of the thyroid was weakly hyperechoic and hypervascularized, while the left one was hypoechoic without internal vascularization. Regional lymphadenomegalia was not detected. Basal plasma calcitonin was elevated, and the patient underwent total thyroidectomy and resection of central cervical lymph nodes. Histopathological examination identified two distinct foci of MTC and PTC and micrometastasis of well-differentiated carcinoma in one of the six resected lymph nodes. RET proto-oncogene germline mutations were not detected. Cutaneous melanoma of the thorax was subsequently diagnosed. BRAF(V600E) tissue DNA was detected in PTC and melanoma but not in MTC. The cell-free plasma percentage of BRAF(V600E) DNA was detected in pre-thyroidectomy peripheral blood and was drastically reduced after cancer treatments. This study confirms the occurrence of synchronous MTC and PTC and is the first evidence of the co-existence of melanoma and distinct thyroid cancers of different origin. BRAF(V600E) allele was detected in PTC and melanoma but not in MTC tissues. BRAF(V600E) molecular quantification in pre- and post-treatment blood supports our previous data, suggesting its possible role in diagnosis and follow-up of BRAF-positive tumors.

A high-resolution melting protocol for rapid and accurate differential diagnosis of thyroid nodules.

A large majority of thyroid nodules are benign, and only 5% have malignant features on cytological examination. Unfortunately, fine-needle aspiration is inconclusive in approximately 30% of all thyroid biopsies, because the cytological features are indeterminate (suspicious for malignancy but not completely diagnostic or nondiagnostic). Wide panels of somatic mutations have been identified in thyroid cancers, and detection of genetic alterations in fine-needle aspirate has been demonstrated to improve diagnostic accuracy. Nevertheless, the relatively high number of genetic targets to be investigated, in comparison with the low percentage of malignant samples, makes the usual diagnostic protocol both time-consuming and expensive. We developed a reliable and sensitive protocol based on high-resolution melting analysis for the rapid screening of mutations of KRAS, HRAS, NRAS, and BRAF oncogenes in thyroid fine-needle aspirations. The entire procedure can be completed in approximately 48 hours, with a dramatic reduction in costs. The proposed protocol was applied to the analysis of 260 consecutive fine-needle aspiration biopsy (FNAB) samples. In 35 of 252 samples, 36 sequence variants were detected for BRAF (17 samples), NRAS (6 samples), HRAS (3 samples), KRAS codon 12 (9 samples), and KRAS codon 61 (1 sample).

Wolfram syndrome. How much could knowledge challenge the fate? A case report.

BACKGROUND: Wolfram syndrome (WS) is a rare, autosomic recessive genetic disorder. The mortality rate of WS is about 65% before 35 years of age. It presents diagnostic challenges in the clinical practice due to its incomplete characterization. This report represents the first case of undiagnosed Wolfram syndrome in a patient over 53 years old. CASE REPORT: A 53-year-old white woman developed a respiratory complication necessitating extended ICU care and respiratory rehabilitation. This respiratory complication proved to be a consequence of undiagnosed WS. CONCLUSIONS: The report discusses the clinical elements that suggested the diagnosis, the problems related to the ICU management of this patient, in particular the weaning difficulties, and the need for rehabilitation. Finally, the report considers the ethical aspect of timely diagnosis on the course and outcome of WS.