Neuroendocrine neoplasms in the context of inherited tumor syndromes: a reappraisal focused on targeted therapies.

PURPOSE: Neuroendocrine neoplasms can occur as part of inherited disorders, usually in the form of well-differentiated, slow-growing tumors (NET). The main predisposing syndromes include: multiple endocrine neoplasias type 1 (MEN1), associated with a large spectrum of gastroenteropancreatic and thoracic NETs, and type 4 (MEN4), associated with a wide tumour spectrum similar to that of MEN1; von Hippel-Lindau syndrome (VHL), tuberous sclerosis (TSC), and neurofibromatosis 1 (NF-1), associated with pancreatic NETs. In the present review, we propose a reappraisal of the genetic basis and clinical features of gastroenteropancreatic and thoracic NETs in the setting of inherited syndromes with a special focus on molecularly targeted therapies for these lesions. METHODS: Literature search was systematically performed through online databases, including MEDLINE (via PubMed), and Scopus using multiple keywords' combinations up to June 2022. RESULTS: Somatostatin analogues (SSAs) remain the mainstay of systemic treatment for NETs, and radiolabelled SSAs can be used for peptide-receptor radionuclide therapy for somatostatin receptor (SSTR)-positive NETs. Apart of these SSTR-targeted therapies, other targeted agents have been approved for NETs: the mTOR inhibitor everolimus for lung, gastroenteropatic and unknown origin NET, and sunitinib, an antiangiogenic tyrosine kinase inhibitor, for pancreatic NET. Novel targeted therapies with other antiangiogenic agents and immunotherapies have been also under evaluation. CONCLUSIONS: Major advances in the understanding of genetic and epigenetic mechanisms of NET development in the context of inherited endocrine disorders have led to the recognition of molecular targetable alterations, providing a rationale for the implementation of treatments and development of novel targeted therapies.

[Intra-articular fracture of the calcaneus associated with injury to lateral collateral ligaments of the ankle]. / Fractura intraarticular de calcáneo asociada a lesión de ligamentos colaterales laterales del tobillo.

Calcaneal fractures are the most frequent of the tarsus (3.5% of all fractures). Young adults are mainly affected, being more frequent in men (5.9:1). On the other hand, ligament injuries associated with fracture of the calcaneus are very infrequent. We describe a case of a 39 year old patient who suffered ankle trauma. He presented instability in plantar flexion and inversion. A fracture of the calcaneus was diagnosed. During surgery, a complete lesion of the lateral ligament complex was found. The reduction and osteosynthesis associated with ligament reconstruction was performed. We consider important to confirm the stability of the ankle after a calcaneus fracture. Lack of diagnosis in this type of injuries can evolve into chronic instability.

Las fracturas de calcáneo son las más frecuentes del tarso (3.5% de todas las fracturas). Afectan a adultos jóvenes, siendo más frecuentes en hombres (5.9:1). Por otro lado, las lesiones ligamentarias asociadas a fractura de calcáneo no son muy frecuentes. Presentamos un caso de un paciente de 39 años que sufrió entorsis de tobillo. Mostraba inestabilidad en flexión plantar e inversión. Radiografías mostraron una fractura de calcáneo. Durante la cirugía se evidenció una lesión completa del complejo ligamentario lateral. Se realizó la reducción y osteosíntesis asociada a la reconstrucción ligamentaria. Ante fracturas de calcáneo es importante corroborar la estabilidad del tobillo. La falta de diagnóstico en este tipo de lesiones puede generar inestabilidades crónicas.

Talus Bipartitus: A Rare Anatomical Variant Presenting as an Entrapment Neuropathy of the Tibial Nerve within the Tarsal Tunnel.

Tarsal tunnel syndrome is an entrapment neuropathy of the tibial nerve within the tarsal tunnel that lies beneath the retinaculum on the medial side of the ankle. It is often underdiagnosed. Talus bipartitus is a rare anatomical variant; only a few cases have been described in medical literature. We report a case of a 36-year-old female with tarsal tunnel syndrome secondary to a talus bipartitus undergoing surgical treatment with good clinical outcome. To our knowledge, talus bipartitus presenting as tarsal tunnel syndrome has no previous reports. Image studies and physical examination are crucial to reach precise diagnosis.

Extensor Tendons Rupture after Volar Plating of Distal Radius Fracture Related to a Dorsal Radial Metaphyseal Bone Spur.

Extensor tendon ruptures due to volar plating in distal radius fractures have mostly been described in relation with technique failures such as screw prominence and drill penetration. We report the case of a 71-year-old female with a C2 distal radius fracture with severe dorsal metaphyseal comminution. The patient underwent surgical treatment with reduction of the large fragments and fixation with a volar locking plate; the small dorsal metaphyseal nonarticular fragments were not reduced. Six months later, the patient developed extensor digitorum communis (EDC) rupture and extensor indicis proprius (EIP) laceration in coincidence with the dorsal comminution turned into a bony spur. The possible association between the extensor tendon injury and the dorsal residual metaphyseal bony spur in the distal radius fractures is unusual but should be taken into account in fracture patterns presenting dorsal comminution.

SIGNAL DECOMPOSITION AND ANALYSIS FOR THE IDENTIFICATION OF PERIODIC AND ANOMALOUS PHENOMENA IN RADON TIME-SERIES.

This work concerns continuous monitoring of radon and thoron specific activity in soil gas within the framework of identifying possible anomalies. It is based on the analysis of a medium-term data record obtained from soil gas in an area of geophysical interest. The RaMonA spectrometric system is also used to measure the climatic parameters and a specific analysis of the alpha spectra is performed to better determine the alpha lines intensity. Since radon emission is also influenced by meteorological parameters, it is mandatory to differentiate the changes due to the deep phenomena. Different procedures are utilized to reach the above objective: statistical analysis using the Empirical Mode Decomposition technique, the Multiple Linear Regression method and the Remote Radon Estimation by using of the thoron trend to eliminate the locally produced radon fraction. The results of such methods are compared to recognize and to highlight radon anomalies.

Thirty years after Chernobyl: Long-term determination of 137Cs effective half-life in the lichen Stereocaulon vesuvianum.

It has been widely shown that nuclear fallout includes substances, which accumulate in organisms such as crustaceans, fish, mushrooms and lichens, helping to evaluate the activity concentration of contaminants accumulated on a long time. In this context, radiocaesium deposited in soil following the Chernobyl accident on 26 April 1986 is known to have remained persistently available for plant uptake in many areas of Europe. Studies on the lichen Stereocaulon vesuvianum show the plant's high capacity to retain radionuclides from the substrate and the air. After the Chernobyl accident, starting from September 1986, at the Radioactivity Laboratory (LaRa) of the University of Naples Federico II, four monitoring campaigns to evaluate the activity concentration of four isotopes of the two elements caesium and ruthenium (134Cs, 137Cs, 103Ru and 106Ru) were carried out until 1999. This study allowed the effective half-life of 134Cs and 137Cs to be estimated. Twenty-eight years after the accident, in December 2014, a further sampling was carried out; only 137Cs was revealed beyond the detection limits, measuring activity concentrations ranging from 20 to 40 Bq/kg, while the other radionuclides were no longer observed due to their shorter half-life. The last sampling allowed more precise determination of the effective half-life of 137Cs (6.2 ± 0.1 year), due to the larger dataset on a large time period.

Track counting and thickness measurement of LR115 radon detectors using a commercial image scanner.

An original optical method for track counting and film thickness determination of etched LR115 radon detectors was developed. The method offers several advantages compared with standard techniques. In particular, it is non-destructive, very simple and rather inexpensive, since it uses a commercial scanner and a free software. The complete analysis and the calibration procedure carried out for the determination of radon specific activity are reported. A comparison with the results of spark counting defines the accuracy and the precision of the new technique.

Dependence of the LR-115 radon detector calibration factor on track density.

The reliability and accuracy of the methodology based on using LR-115 track detectors for radon measurements have been studied by determining the dependence of their calibration factors on radon exposure at levels reaching 13 MBq m(-3) h. This factor results not constant and demonstrated a decreasing exponential trend vs. exposure that has been explained in terms of the saturation effect and verified using a numerical simulation. This dependence does not affect the parameter that normalizes track density vs. film thickness. This parameter results constant and equal to - 0.30±0.02 cm(-2)/µm in the 300-8000 kBq h m(-3) exposure range.

Realization and characterization of a ²²°Rn source for calibration purposes.

The recent interest for measuring (220)Rn activity in air and the following development of the corresponding measurement techniques require the improvement of standards for the calibration and characterization of the measurement devices. Due to the short half-life of the (220)Rn, the adopted techniques for the production of (222)Rn sources are not always reliable. In this paper a methodology for realizing a thoron known activity starting from a (232)Th source will be presented and discussed.

Efficacy and tolerability of Estraderm MX, a new estradiol matrix patch.

OBJECTIVES: To assess the efficacy and tolerability of a new matrix patch delivering 0.05 mg estradiol per day (Estraderm MX 50) in postmenopausal women with moderate to severe postmenopausal symptoms. METHODS: A multicenter, double-blind, randomized, between-patient, placebo controlled trial in 109 postmenopausal women was carried out. Patches were applied twice weekly for 12 weeks. Patients were assessed at 4, 8 and 12 weeks of treatment. The primary efficacy variable was change from baseline in mean number of moderate to severe hot flushes (including night sweats) per 24 h during the last 2 weeks of treatment. Other variables included Kupperman Index, local and systemic tolerability. Plasma concentrations of estradiol (E2), estrone (E1) and estrone sulfate (E1S) were determined before and after treatment. RESULTS: Estraderm MX was significantly superior to placebo (P < 0.001) in reducing mean number of moderate to severe hot flushes (including night sweats) per 24 h after 4, 8 and 12 weeks of treatment. The estimate of treatment group differences after 12 weeks was 4.2 hot flushes (95% confidence interval: 2.6-5.8). Estraderm MX also significantly reduced Kupperman Index at all time points compared to placebo (P < 0.001). Estraderm MX induced increases in mean E2, E1 and E1S plasma levels as expected (E2: baseline 2.7 pg/ml, 12 weeks 38.9 pg/ml; E1: baseline 18.8 pg/ml, 12 weeks 41.6 pg/ml; E1S: baseline 235.6 pg/ml, 12 weeks 765.1 pg/ml). Overall rates of adverse experiences were similar for Estraderm MX and placebo. The number of patients reporting skin irritation was low and similar in both groups. CONCLUSIONS: Estraderm MX 50, a new matrix patch, offers an effective and well tolerated dosage form for transdermal delivery of 0.05 mg E2 per day.

Oxytocin receptor in human fetal membranes at term and during labor.

Human fetal membranes, taken from 30 patients submitted to caesarean section during the final stages of gestation and labor, were examined in order to evaluate the presence and characteristics of the oxytocin receptor. The presence of oxytocin receptors in human fetal membranes, both in the amnion and in the chorion-decidua, was demonstrated in this study. The receptor binding to oxytocin showed a significant increase during early and advanced labor compared with before the onset of labor. When the pre-labor level was taken as the normalized form (control = 100) the increase with respect to the control (10 cases) for the amnion in early labor (2.27 times +/- 0.11, mean +/- SEM, P less than 0.001, 10 cases) and in advanced labor (2.53 times +/- 0.15, 10 cases, P less than 0.001) was highly significant. In the chorion-decidua the increase was 1.61 times +/- 0.09, P less than 0.001 in early labor and 1.66 times +/- 0.19, P less than 0.001 in advanced labor. Scatchard analysis showed a single receptor site for oxytocin in amnion and chorion decidua. The dissociation constant (Kd) did not change during the various stages of labor; the mean values found were 0.228 +/- 0.02 (mean +/- SEM) nM in the amnion and 0.193 +/- 0.03 nM in the chorion-decidua respectively. These findings suggest that human fetal membranes are target organs for oxytocin and that they might play a role in the onset of labor through an increase of receptor binding.

[Partial deficiency in 21-hydroxylase in certain forms of hirsutism]. / A propos du déficit partiel en 21-hydroxylase dans certaines formes d'hirsutisme.

The ACTH test is important when hirsutism occurs in women with a slight 21-hydroxylase deficiency, and normal basal 17-OH Progesterone (17-OH-P/plasma levels). Extensive hormonal assays: LH, FSH, Prolactin, 17 beta-estradiol (E2), Estrone, 17OH-P, Androstenedione, Testosterone, Cortisol (C), Dehydroepiandrosterone-S (DEA-S) were carried out in 36 hirsute women. 13 of these presented hormone levels as found in polycystic ovary syndrome (PCOS), 6 women presented a slight 21-hydroxylase deficiency (increased plasma 17-OH-P and decreased C after ACTH test with significant, p less than 0.01, increase of 17-OH-P/C and 17 women presented idiopathic hirsutism (IH). The hormonal pattern, in the basal condition, is not different in IH or in slight 21-hydroxylase deficiency. The ACTH test is able to differentiate between IH and adrenal hirsutism.

In vitro effects of beta-interferon on steroid receptors and prostaglandin output in human endometrial adenocarcinoma.

The effect of natural beta-interferon (beta-IFN) on steroid receptor levels and output of prostaglandins (PGs) was investigated in human endometrial cancer. beta-IFN determines in endometrial adenocarcinoma explants an increase of cytosolic estradiol (ER) and progesterone (PR) receptors at concentrations ranging from 10 to 1000 IU/ml of culture medium. Only cases in which there was an enhancement of at least 50% with respect to control values were considered. Low concentrations of beta-IFN (10 IU/ml of culture medium) produce an enhancement of ER in 60% and of PR in 42% of cases, while higher concentrations of beta-IFN (1000 IU/ml of culture medium) produce an enhancement of ER in 32%, and of PR in 82% of cases. Since PGs are involved in proliferation control in a large variety of tumors, we evaluated the ratio between PGF2-alpha and PGE2 levels in culture medium. This ratio increased, in our experimental model, after treatment with 10 and 1000 IU/ml of beta-IFN in 38% and 58% of cases respectively. Our data suggest that beta-IFN could affect cellular hormone sensitivity through a modification of ER and PR and it can also determine a variation of PG output in human endometrial cancer.

Estradiol 17 beta-hydroxysteroid dehydrogenase activity in human breast fibroadenomas.

In the human endometrium, the presence of the progesterone-dependent enzyme 17 beta-hydroxysteroid dehydrogenase (E2DH) permits the conversion of an active estrogen, estradiol, into a less active one, estrone. This E2DH activity contributes to the antiestrogenic properties of progesterone. In the present study, E2DH activity was assayed in 54 surgically removed fibroadenomas. This benign breast disease was chosen since it offers rather homogeneous epithelial concentrations and still remains close to normal breast tissue from a pathological and hormonal point of view. E2DH activity was highest in fibroadenomas with high epithelial cell density. In addition, in these high epithelial cell density fibroadenomas (n = 18), E2DH activity increased markedly throughout the luteal phase of the menstrual cycle. Thus, it was 3- to 4-fold higher in fibroadenomas removed at the end of the luteal phase (1520 +/- 166 fmol/mg protein.h) than in those obtained during the follicular phase (375 +/- 95 fmol/mg protein.h). In addition, a striking increase in E2DH activity was observed in fibroadenomas from 5 patients treated with oral progestins (4080 +/- 650 fmol/mg protein.h) and 3 patients receiving progesterone topically applied upon the breast (3830 +/- 475 fmol/mg protein.h). E2DH activity, therefore, appears to be an important mechanism involved in the control by progesterone of estradiol action in breast tissue, as it is in the endometrium. It is also a good index of cellular differentiation and progesterone action at the molecular level. It is hypothesized that E2DH activity might be a specific marker of progesterone receptor itself and could be proposed in the evaluation of the hormone dependence of human breast tissue.

Metodo para a determinacao matematica de prioridades para o controle de riscos. / Method for mathematical determination of priorities for risk control

A fim de oferecer aos tecnicos especializados em Seguranca e Medicina do Trabalho subsidios para a hierarquizacao dos riscos na empresa,e proposto um metodo para a determinacao de prioridades de acao de controle e a respectiva alocacao dos recursos financeiros disponiveis. Atraves desse metodo, e possivel, segundo os autores, determinar matematicamente as prioridades, caracterizando o dano, o nivel de exposicao ao risco, a eficiencia e o custo das medidas de controle. A complementacao deste trabalho, contendo um exemplo ilustrativo, sera publicada em proxima edicao