Neuroendocrine tumors diagnosed at the Antonio Cardarelli hospital (Naples, Italy) between 2006-2009: a single-institution analysis.

Neuroendocrine tumors (NETs) are rare, with an incidence of about 5 per 100,000 inhabitants. As no study on NETs has ever been specifically conducted on the population of Campania, we performed a retrospective analysis of all newly diagnosed NETs at the Antonio Cardarelli hospital between 2006-2009. A search of the registry of the Pathology Department of the Antonio Cardarelli hospital was carried out to retrieve available data on all newly diagnosed NET cases. Two hundred and ninety-nine NET tumors were diagnosed at our Institution from January, 2006 to December, 2009. Globally, 121 patients (40% of the population) had a lung NET, while 92 patients (30% of the population) presented a GEP-NET. The most common primary tumor site varied by sex, with female patients being more likely to have a primary NET in the lung, breast or colon, and male patients being more likely to have a primary tumor in the lung. Also, twenty-three cases of breast NETs were identified, and clinical information regarding therapy and response was available for 22 patients. Our study represents a pioneering effort to provide the medical community in Campania with basic information on a large number of patients with different types of NETs. The Antonio Cardarelli hospital could greatly benefit from cooperation with other hospitals in order to become a highly specialized center for NETs in the region and Southern Italy.

Duchenne's muscular dystrophy involves a defective transsulfuration pathway activity.

Duchenne muscular dystrophy (DMD) is the most frequent X chromosome-linked disease caused by mutations in the gene encoding for dystrophin, leading to progressive and unstoppable degeneration of skeletal muscle tissues. Despite recent advances in the understanding of the molecular processes involved in the pathogenesis of DMD, there is still no cure. In this study, we aim at investigating the potential involvement of the transsulfuration pathway (TSP), and its by-end product namely hydrogen sulfide (H2S), in primary human myoblasts isolated from DMD donors and skeletal muscles of dystrophic (mdx) mice. In myoblasts of DMD donors, we demonstrate that the expression of key genes regulating the H2S production and TSP activity, including cystathionine γ lyase (CSE), cystathionine beta-synthase (CBS), 3 mercaptopyruvate sulfurtransferase (3-MST), cysteine dioxygenase (CDO), cysteine sulfonic acid decarboxylase (CSAD), glutathione synthase (GS) and γ -glutamylcysteine synthetase (γ-GCS) is reduced. Starting from these findings, using Nuclear Magnetic Resonance (NMR) and quantitative Polymerase Chain Reaction (qPCR) we show that the levels of TSP-related metabolites such as methionine, glycine, glutathione, glutamate and taurine, as well as the expression levels of the aforementioned TSP related genes, are significantly reduced in skeletal muscles of mdx mice compared to healthy controls, at both an early (7 weeks) and overt (17 weeks) stage of the disease. Importantly, the treatment with sodium hydrosulfide (NaHS), a commonly used H2S donor, fully recovers the impaired locomotor activity in both 7 and 17 old mdx mice. This is an effect attributable to the reduced expression of pro-inflammatory markers and restoration of autophagy in skeletal muscle tissues. In conclusion, our study uncovers a defective TSP pathway activity in DMD and highlights the role of H2S-donors for novel and safe adjuvant therapy to treat symptoms of DMD.

Inherited predisposition to malignant mesothelioma: germline BAP1 mutations and beyond.

Malignant mesothelioma (MM) is a rare aggressive neoplasm arising from mesothelial lining of body cavities, most commonly pleura and peritoneum. It is characterised by a poor prognosis and limited treatment options. A universally recognised risk factor for the development of MM is exposure to asbestos. However, evidence supporting a genetic susceptibility to the development of MM has been accumulating during the last decades. Intensive research for the identification of MM susceptibility genes has led to the discovery of BAP1 and to the definition of the so-called "BAP1-related tumour predisposition syndrome". Patients carrying germline BAP1 mutations have an increased risk for the early development of tumours, including MMs, uveal melanomas, cutaneous melanocytic lesions, clear cell renal cell carcinomas and basal cell carcinomas. Furthermore, pathogenic variants in tumour suppressor genes with a role in DNA repair have been recently described in families with clustered MM cases. These genetic alterations seem to confer exaggerate sensitivity to asbestos carcinogenic effect and, arguably, increased response to specific chemotherapeutic strategies. While the translational significance of BAP1 alterations is explored in the research field, the identification of families carrying germline BAP1 mutations is mandatory to start appropriate surveillance programs and guarantee the best clinical management to these patients.

Peripheral relaxant activity of apomorphine and of a D1 selective receptor agonist on human corpus cavernosum strips.

Apomorphine is used in the erectile dysfunction therapy and its action has been ascribed to the stimulation of central dopamine receptor. At the present stage, very little is known about the peripheral action of apomorphine on human corpus cavernosum (HCC). We have investigated the peripheral action of apomorphine and the role of dopamine receptors in HCC. We here demonstrate that both D1 and D2 receptors were expressed in the HCC, D1 receptors were two-fold more abundant than D2 and that both receptors were mainly localized on the smooth muscle cell component. Apomorphine in vitro exerted an anti-alpha1 adrenergic activity in human cavernosal strips since it prevented contraction induced by phenylephrine (PE), but not by U46619 or endothelin. Apomorphine elicited endothelium-independent and concentration-dependent relaxation of the strips contracted by PE, U46619 or endothelin. The EC50 values (microM) for apomorphine, in the presence and absence of endothelium, were 51.0+/-16 and 16.0+/-14, 120+/-19 and 150+/-18, 59.0+/-15 and 140+/-50 on PE-, U46619- or endothelin-induced contraction, respectively. Selective dopamine receptor agonist A-68930 (D1-like), but not quinpirole (D2-like), caused concentration-dependent relaxation of the cavernosal strips, which was partially prevented by endothelium removal or by treatment with an inhibitor of nitric oxide (NO) synthase. In conclusion, we show that (1) apomorphine has a peripheral relaxant direct effect as well as an antiadrenergic activity, (2) HCC possesses more D1-like (D1 and D5) than D2-like (D2, D3 and D4) receptors, (3) both D1- and D2-like receptors are mainly localized on smooth muscle cells and (4) the relaxant activity is most probably mediated by D1-like receptor partially through NO release from endothelium.

Bronchoconstrictor effect of thrombin and thrombin receptor activating peptide in guinea-pigs in vivo.

1. Several thrombin cellular effects are dependent upon stimulation of proteinase activated receptor-1 (PAR-1) localized over the cellular surface. Following activation by thrombin, a new N-terminus peptide is unmasked on PAR-1 receptor, which functions as a tethered ligand for the receptor itself. Synthetic peptides called thrombin receptor activating peptides (TRAPs), corresponding to the N-terminus residue unmasked, reproduce several thrombin cellular effects, but are devoid of catalytic activity. We have evaluated the bronchial response to intravenous administration of human alpha-thrombin or a thrombin receptor activating peptide (TRAP-9) in anaesthetized, artificially ventilated guinea-pigs. 2. Intravenous injection of thrombin (100 microkg(-1)) caused bronchoconstriction that was recapitulated by injection of TRAP-9 (1 mg kg(-1)). Animal pretreatment with the thrombin inhibitor Hirulog (10 mg kg(-1) i.v.) prevented thrombin-induced bronchoconstriction, but did not affect bronchoconstriction induced by TRAP-9. Both agents did not induce bronchoconstriction when injected intravenously to rats. 3. The bronchoconstrictor effect of thrombin and TRAP-9 was subjected to tolerance; however, in animals desensitized to thrombin effect, TRAP-9 was still capable of inducing bronchoconstriction, but not vice versa. 4. Depleting animals of circulating platelets prevented bronchoconstriction induced by both thrombin and TRAP-9. 5. Bronchoconstriction was paralleled by a biphasic change in arterial blood pressure, characterized by a hypotensive phase followed by a hypertensive phase. Thrombin-induced hypotension was not subject to tolerance and was inhibited by Hirulog; conversely, hypertension was subject to tolerance and was not inhibited by Hirulog. Hypotension and hypertension induced by TRAP-9 were neither subject to tolerance nor inhibited by Hirulog. 6. Our results indicate that thrombin causes bronchoconstriction in guinea-pigs through a mechanism that requires proteolytic activation of its receptor and the exposure of the tethered ligand peptide. Platelet activation might be triggered by the thrombin effect.

Induction of sperm abnormalities in mice by ifosfamide and trofosfamide.

The antitumor drugs ifosfamide (IF) and trofosfamide (TF) were evaluated for their capability to induce sperm abnormalities in (C3H X C57BL/6)F1 mice. A statistically significant increase in teratospermia was observed at the 35th day after 5 daily consecutive intraperitoneal injections of the drugs at doses of 25, 50, 100 mg/kg b.w. of TF and 100 mg/kg b.w. of IF. Thus, IF and TF are able to interfere with the differentiation process of spermatogenic cells.

Intracystic papillary carcinoma of the male breast. A case report (histochemical, immunohistochemical and ultrastructural study).

We report a case of intracystic papillary carcinoma of the male breast in a 70-year-old male Caucasian. Grossly, the tumor was a cystic lesion measuring 6 cm in diameter. It contained hemorrhagic fluid and a mural nodule with filiform projections. PAS stain with and without digestion revealed small clumps of diastase-resistant material in the cytoplasm of the neoplastic cells. Grimelius stain was positive. Immunoperoxidase stains were negative for neuron-specific enolase, S100 protein, cromogranin and synaptophysin and were positive for carcinoembryonic antigen and epithelial membrane antigen. On ultrastructural examination the neoplastic cells showed membrane-bound, dense-core secretory granules. We believe that this neoplasm, despite negative neuroendocrine markers, is a variant of mammary adenocarcinoma with endocrine differentiation, partly because of the positive Grimelius stain and partly because of the presence of electron-dense granules, which according to some authors represent lactational differentiation.

Adenocarcinoma of the pancreas in childhood (pancreatoblastoma): report of a case with good response to chemotherapy.

Here we report a case of pancreatoblastoma in a 2-year, 4-month-old girl. The child underwent surgical resection and was managed with chemotherapy (cisplatin plus doxorubicin). The patient is currently disease-free 42 months after being taken off chemotherapy.

Intradiscal and intramuscular injection of discogel(®) - radiopaque gelified ethanol: pathological evaluation.

This study assessed the impact and modification of intradiscal, intraforaminal, epidural and intramuscular swine injection of a new material, Discogel(®)- radiopaque gelified ethanol- recently introduced for the mini-invasive treatment of herniated disc. Discogel(®) is a sterile viscous solution containing ethyl alcohol, cellulose derivative product, added to a radio-opaque element, tungsten. The pig was sedated and under fluoroscopy guidance a needle was positioned within disc L1-L2 followed by intradiscal, intraforaminal, epidural and intramuscular injection of 1 ml of Discogel. As disc control level L4-L5 was considered where nothing was injected. The pig was sacrifed 48 h after injection of discogel and the spine from D10 to S1 was removed and fixed in 10% buffered formalin. The anatomical specimens were cut with an electric saw and analyzed by routine technique then stained with formalin. The specimens containing bone material were treated by DEKAL solution. The specimens were stained with hematoxylin-eosin method and then analyzed by histochemical (Masson -Van Gieson PAS and trichromic stains ) and immunochemical methods. Morphostructural examination disclosed a granular material coloured black by hematoxylin-eosin method (tungsten) in paravertebral tissue both in the muscular and connective tissue. Some inflammatory elements like lymphomonocyte cells and venous stasis were found. No alteration was found where discogel was injected, and the nucleus pulposus, disc, chondromixoid and root ganglium were normal. After intradiscal, intraforaminal, epidural and intramuscular injection of Discogel(®) no morpho-structural changes in nuclear tissue and annulus were found. Further studies on pigs with immunohistochemical analysis after treatment will confirm the morphological alterations induced by discogel and its action.

[Splenic hamartoma]. / Amartoma splenico.

The Authors present a case of Splenic Hamartoma. This is a rare unique complex vascular lesion of the spleen. This is also a recently reinterpreted lesion with some persistent confusion regarding its definition, histogenesis and classification. The patient is a young woman who following a check up with a raised erythrocyte sedimentation rate underwent abdominal sonography demonstrating an incidental slightly hypoechoic nodular splenic lesion. The pathologic study of the splenectomy specimen showed a large (10 cm) sharply demarcated mass. Histologically the lesion presented a remarkably angiomatoid lobular-nodular configuration with abundant fibrosclerotic stroma with areas of calcification. The immunohistochemical study revealed within the angiomatoid tissue different types of blood vessels: a) capillaries CD31+, CD34+, CD8-; b) structures consistent with splenic venous sinuses CD31+, CD34+/- , CD8-/+; c) small veins CD31+, CD34+, CD8-. The Authors judge this complex picture as indicative of a Splenic Hamartoma with a peculiar lobular-nodular pattern that seems to coincide with the recently described SANT: Sclerosing Angiomatoid Nodular Transformation of the spleen. In this report the Authors discuss the pathology of the lesion and the problems concerning its vasular profile. It is also emphasized the Hamartoma's great variety of morphologic patterns derived from the preponderant growth of one or another of several histologic components. This is the cause of the presence in literature of some different pathologic entities which today are fairly recognized as part of a large pathologic spectrum of the same lesion. The Authors discuss the differential diagnosis of Splenic Hamartoma with other lesions as haemangiomas and inflammatory pseudotumor.

[Localized primary cutaneous nodular amyloidosis]. / Amiloidosi nodulare cutanea primaria localizzata.

A case of cutaneous nodular amyloidosis in a 60-year-old man is described with reference to histological, immunohistochemical and ultrastructural features. Clinically, the patient presented two brownish nodules on his face. Histologically, a massive dermal collection of eosinophilic, homogeneous material showing positivity for Congo red stain was revealed. Immunoreactivity for both Ig-light chains was detected in dermal plasma cells as well as in amyloid material. Ultramicroscopically, the typical fibrillary pattern of amyloid was found. Clinical and instrumental examinations failed to demonstrate amyloid depositions elsewhere in the body.

[Teratogenic and goitrogenic activity of propineb and propylenethiourea in the rat]. / Attività teratogena e gozzigena di propineb e propilentiourea nel ratto.

The teratogenic and goitrogenic effects of Propineb, dithiocarbamate pesticide and Propylenthiourea (PLTU), its metabolite and degradation product have been studied. The aim of this study was to show the possible correlation between the two activities. Female Sprague-Dawley rats were treated with Propineb and PLTU starting from 6th to 16th day of pregnancy. The functional state of maternal and foetal thyroid, the toxicity of products versus dams and embryotoxic and teratogenic effects were examined. The observed goitrogenic effect may be compared to that reported in the previous studies of the authors, if considering time of sacrifice. In fact, the lesion quickly rises and as rapidly regresses when treatment is stopped. The foetal thyroid has not been affected by the product administered to the dams. PLTU showed a clear teratogenic activity at doses that did not show any maternal toxicity (45 and 90 mg/k).

Evaluation of use patterns of psychotropic drugs in an Italian geriatric hospital.

This study is a survey of psychotropic drug use patterns among 934 elderly patients admitted to the Padua Geriatric Hospital. 34% of the patients took psychotropic drugs during their stay in hospital. The drugs most commonly used are anxiolytics and hypnotics of the benzodiazepine class. Women subjects living alone, and to a lesser extent those suffering from particular disorders, as of the central nervous system and the musculoskeletal apparatus, seem to be at higher risk in the use of psychotropic drugs. Moreover, the results show that psychotropic drugs are prescribed during the stay in hospital and even on discharge to a high percentage of subjects who did not use such drugs before admission to the hospital.