Lower expression of the TWIK-related acid-sensitive K+ channel 2 (TASK-2) gene is a hallmark of aldosterone-producing adenoma causing human primary aldosteronism.

CONTEXT: The molecular mechanisms of primary aldosteronism, a common cause of human hypertension, are unknown, but alterations of K(+) channels can play a key role. OBJECTIVE: The objective of the study was to investigate the following: 1) the expression of the Twik-related acid-sensitive K(+) channels (TASK) in aldosterone producing adenomas (APAs); 2) the role of TASK-2 in aldosterone synthesis; and 3) the determinants of TASK-2-blunted expression in APAs. DESIGN: We analyzed the transcriptome and the microRNA profiles of 32 consecutive APAs and investigated the protein expression and localization of TASK-2 in APA and adrenocortical cell lines (H295R and HAC15) using immunoblotting and confocal microscopy. The functional effect of TASK-2 blunted activity caused by a dominant-negative mutation on steroidogenic enzymes, and aldosterone production was also assessed. TASK-2 regulation by selected microRNA was studied by a luciferase assay. RESULTS: TASK-2 was consistently less expressed at the transcript and protein levels in APAs than in the normal human adrenal cortex. H295R cell transfection with a TASK-2 dominant-negative mutant construct significantly increased the aldosterone production by 153% and the gene expression of aldosterone synthase (CYP11B2, gene expression fold change 3.1 vs control, P < .05) and the steroidogenic acute regulatory protein (gene expression fold change 1.8 vs control, P < .05). Two microRNAs, hsa-miR-23 and hsa-miR-34, were found to decrease the TASK-2 expression by binding to the 3' untranslated region of the TASK-2 gene. CONCLUSIONS: The TASK-2 channel lower expression represents a hallmark of APA and is associated with a higher expression of hsa-miR-23 and hsa-miR-34. The ensuing blunted TASK-2 activity increased the production of aldosterone in vitro and the expression of steroidogenic acute regulatory protein and CYP11B2. Hence, the lower expression of TASK-2 channel in APA cells can explain high aldosterone secretion in human primary aldosteronism despite the suppression of angiotensin II, hypertension, and hypokalemia.

5-Azacytidine makes human preadipocytes able to differentiate into mesoderm-derived cell lineages.

In the present study we have evaluated whether (i) 5-azacytidine (AZA), a well-known demethylating agent, could be able to modify the phenotype of human preadipocytes and (ii) the modified cells could possess multilineage differentiation potential. Human preadipocytes at the 3rd passage were treated for 48 or 96 h with 10 µM AZA and then expanded up to passage 5. Stem cell markers, such as OCT-4, Nanog, and Sox2, were upregulated after 96 h of treatment with the demethylating treatment. Further, decreases in the expression of genes, such as adipose differentiation-related protein, characterizing the preadipocytes were noted. Our data showed that AZA-treated preadipocytes differentiated into cell lineages derived from mesoderm. Indeed, after incubation with inductive media for 3 weeks, osteblast-, chondrocyte-, and myoblast-like cells were detected in the cultures. Interestingly, both upregulation of stem cell markers and differentiation potential were maintained by the treated cultures expanded until the 5th passage. Taken together, our results suggest that AZA, without the use of transduction methods, convert preadipocytes to a less differentiated state that can be induced, under suitable stimuli, to the formation of mesoderm-derived cell lineages.

Perichondritis with or without external otitis and intradermal injection: a new therapeutic approach.

Auricular perichondritis and fiogosis of the external auditory canal are not uncommon pathology of the ear. These inflammatory processes are often accompanied by reactive locoregional lymphadenopathy. An inadequate or insufficient systemic therapy may lead to the persistence of otalgia and of signs of flogosis. The administration of local intradermaltherapy allows a strengthening of the pharmacological effect and a reduction in the quantity of drug used. It provides a rapid improvement in the locoregional signs of infection.Intradermal injection is performed on two pretragral points, two retroauricular points and one in the posterior surface of the pinna. The drugs injected are corticosteroids and antibiotics.The administration of intradermal therapy in the cases presented gave excellent results: control of pain, rapid improvement in the signs of infection, complete recovery from the flogosis, no side-effects.The intradermal lijection of small quantities of drugs allows a rapid and complete recovery from external otitis while the systemic approach leads often to the persistence of the flogosis.

The effects of sulfurous-arsenical-ferruginous thermal water nasal irrigation in wound healing after functional endoscopic sinus surgery for chronic rhinosinusitis: a prospective randomized study.

PURPOSE: Although several publications reported the benefits of nasal irrigation in the management of chronic rhinosinusitis and in sinonasal postoperative care, the available data are poorly controlled. The aim of this prospective randomized study was to compare the effects of sulfurous-arsenical-ferruginous thermal water nasal irrigation vs isotonic sodium chloride solution nasal irrigation after functional endoscopic sinus surgery (FESS) for chronic sinonasal disease considering the histomorphological characteristics of mucosal repair after sinus surgery. MATERIALS AND METHODS: Eighty patients who consecutively underwent FESS were randomly assigned (1:1) to postoperative nasal irrigation with sulfurous-arsenical-ferruginous thermal water or isotonic sodium chloride solution for 6 months. Intraoperative and postoperative (1, 3, and 6 months) mean counts of lymphocytes, neutrophils, eosinophils, plasma cells, histiocytes, and mast cells in ethmoid biopsies were blindly determined by a pathologist. RESULTS: Fifty-six patients underwent at least 2 postoperative biopsies. A statistically significant reduction of eosinophil count was disclosed 6 months postoperatively only after sulfurous-arsenical-ferruginous solution nasal irrigation (P = .04). After isotonic sodium chloride solution nasal irrigation, the mean eosinophil count in 6-month postoperative biopsies did not decrease. After both irrigation modalities, the mean mast cell counts in 6-month postoperative biopsies were significantly lower than in intraoperative biopsies (P < .05). Neutrophils, lymphocytes, histiocytes, and plasma cell counts were not significantly different between intraoperative vs 6-month postoperative biopsies independently from irrigation modality. CONCLUSIONS: Considering the important role of eosinophils in allergic response, we should suggest sulfurous-arsenical-ferruginous solution nasal irrigation in particular, which significantly reduces local eosinophil count, for allergic patients after FESS for chronic rhinosinusitis.

Abducent nerve paralysis: first clinical sign of clivus metastasis from tonsillar carcinoma.

It is known that 15-20% of oropharyngeal carcinomas develop distant metastases that involve most commonly lung, liver and bone. Clival metastasis from oropharyngeal squamous cell carcinoma has not been previously reported in the English literature. We describe the rare occurrence of clival metastasis from tonsillar carcinoma presenting with abducent paralysis and discuss diagnostic and therapeutic rational approaches. Despite neoadjuvant chemotherapy (cisplatinum/etoposide/epirubicin followed by taxotere), extended left tonsillectomy and ipsilateral radical neck dissection and external radiotherapy (60 Gy) for tonsillar carcinoma, the patient developed clival metastasis and died of disease. The overall prognosis of patients with clival metastases is extremely poor, with an overall median survival of about 2.5 years. Cranial nerve palsy occurrence is associated with a poorer prognosis with an average survival of only 5 months.

Nuclear localization of mammary serine protease inhibitor (MASPIN): is its impact on the prognosis in laryngeal carcinoma due to a proapoptotic effect?

PURPOSE: Cell death by apoptosis is considered a regulator of cell number; cancer cells are defective in their response to apoptosis. Many potential markers of apoptosis are under study: M30 immunoreactivity is confined to the cytoplasm of apoptotic epithelial cells and is expressed during early apoptosis. Mammary serine protease inhibitor (MASPIN), a suppressor of tumor growth, seems to be involved in the induction of tumour cell apoptosis. The aim of our preliminary study was to investigate, for the first time, the relations between MASPIN subcellular pattern of expression, nuclear MASPIN expression, M30 expression, and prognosis in laryngeal carcinoma. MATERIALS AND METHODS: Subcellular pattern of distribution of MASPIN and nuclear MASPIN expression were immunohistochemically determined in 66 consecutive cases of laryngeal carcinoma. M30 expression in correspondent carcinoma fields was also calculated. RESULTS: M30 expression was significantly higher in the group of laryngeal carcinomas with MASPIN nuclear localization (P = .024). Our investigation found a reduced carcinoma recurrence rate in the group of patients with MASPIN nuclear localization (P value = .0086). The log-rank test showed a significantly longer disease-free interval in patients with nuclear MASPIN localization (P = .029). CONCLUSIONS: These preliminary results support the hypothesis of an apoptosis-sensitizing effect of nuclear MASPIN in laryngeal carcinoma with the potential perspective of a clinical use of the tumour suppressive proapoptotic function of MASPIN.

Carcinosarcoma de novo of the parotid gland.

Only 29 cases of salivary gland carcinosarcoma de novo have been described in the English-language literature. We present a new case of parotid gland carcinosarcoma de novo and discuss diagnostic and treatment modalities of this pathologic entity. Our patient underwent total parotidectomy with facial nerve preservation, chemotherapy, and radiotherapy. At 26-month follow-up, the patient presented no evidence of recurrence. One-third of the cases of salivary carcinosarcoma de novo died of the disease after a median period of 10 months. Although the number of cases is limited, the combination of radical surgical excision and radiotherapy seems currently the treatment of choice.

Survivin expression is significantly higher in pN+ oral and oropharyngeal primary squamous cell carcinomas than in pN0 carcinomas.

CONCLUSIONS: The preliminary results reported here suggest that survivin expression in primary oral and oropharyngeal squamous cell carcinomas (SCCs) may identify patients at risk of disease disseminating to neck lymph nodes. If these results are confirmed in larger series of patients it may imply that elective neck dissection should be considered in clinically N0 patients with oral and oropharyngeal SCCs who show high expression of survivin. OBJECTIVE: To investigate the expression of survivin, a member of the inhibitor of apoptosis proteins family, in patients with primary oral and oropharyngeal SCCs with and without neck lymph node metastases. MATERIAL AND METHODS: We considered 13 consecutive cases of oral and oropharyngeal SCCs with lymph node metastases (pN + ) and 13 cases of pN0 oral and oropharyngeal SCCs. The survivin reactivity of primary SCCs and lymph node metastases was evaluated immunohistochemically. A lesion was considered positive if >9.5% of the tumour cells showed diffuse strong staining. RESULTS: Sporadic groups of normal basal and parabasal epithelial cells showed weak survivin staining. In SCCs, a nuclear reaction predominated. Eight primary pN+ SCCs were survivin-positive (mean expression 34.7%), compared to 5 primary pN0 SCCs (mean expression 12.3%; p=0.017). Statistical analysis disclosed significantly higher survivin expression in primary oral and oropharyngeal SCCs that developed distant non-lymphatic metastases (p=0.012).

Distant muscular (gluteus maximus muscle) metastasis from laryngeal squamous cell carcinoma.

Clinical evidence of non-lymphatic distant metastasis has been reported in approximately 10% of cases of head and neck squamous cell carcinoma (HNSCC). The lungs are the commonest site of distant metastasis of HNSCC, followed by the bones, liver and skin. A 65-year-old male underwent supraglottic laryngectomy and left modified neck dissection for a carcinoma of the laryngeal surface of the epiglottis extending to both false cords. Eight months later the patient underwent right radical modified neck dissection for hypodermal metastatic disease involving the underlying (sternocleidomastoid) muscle. Thirty-two months later, surgical excision of a lesion in the right gluteus maximus muscle was performed. Histological study diagnosed a muscular metastasis with the same morphological aspect as the laryngeal carcinoma. The patient showed no evidence of cervical or distant recurrence at follow-up after 13 months. Although skeletal muscles represent approximately 50% of total body mass and receive a large proportion of total cardiac output, haematogenous metastases to skeletal muscle are extremely uncommon. Most skeletal muscle metastases are of pulmonary origin. Distant skeletal muscle metastasis from HNSCC is an extremely rare occurrence. Treatment options, depending upon the clinical setting, include observation, radiotherapy, chemotherapy and excision; these approaches rarely alter the patient outcome. The prognosis associated with skeletal muscle metastasis is thought to be poor, consistent with the fact that it generally occurs as a feature of systemic spread.