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.

Radioguided thyroidectomy for follicular tumors: Multicentric experience.

BACKGROUND: The diagnosis of thyroid nodular diseases requires an integrated approach that has been widely established over the past years. This strategy includes: ultrasonography (US) with; implemented Color-Power-Doppler, conventional scintigraphy also with positive indicators, specific pathological studies targeted by immunohistochemically-assays, and the fine needle; aspiration biopsy (FNAB), which, usually, in case of "Follicular Lesions" (10-20%) findings is; unable to distinguish carcinoma from follicular adenoma, then indicating the necessity of surgery to; obtain a correct diagnosis. The aim of this study was to evaluate the role of the scintigraphy with; positive indicators, both preoperatively in diagnostic approach of the thyroid nodules and; intraoperatively as a guide to the extension of the surgical excision. METHODS: On 4482 Thyroidectomy performed, we selected 360 cases of follicular neoplasms (192; females and 168 males). In the preoperative phase, these patients underwent 99 m Tc-sestaMIBI; scintigraphy with both early (10 min) and late (2 h) image acquisition, which were later; compared to the ones obtained by image subtraction of means 99 m Tc-pertechnetate. Following the; sestamibi administration before intervention, we selected the most up-taking nodularity with the; assistance of a specific surgical probe (Neoprobe), quantifying uptake with relation to the surgical pathology, for an amount of 324 total thyroidectomies and 36 hemi thyroidectomies. RESULTS: In all cases of multinodular goiter the benign nodules showed an intraoperative low sestamibi uptake whereas follicular carcinomas showed both a high preoperative uptake and, as a; percentage, the highest values of intraoperative uptake; on the other hand, follicular adenomas had; both pre-and intraoperative mean values of uptake. On the contrary, papillary carcinomas only; showed a mild uptake. CONCLUSIONS: Preoperative sestamibi scintigraphy confirmed its importance in improving the information obtained through different diagnostic investigations. Also intraoperatively, it pointed; out high-risk nodules more accurately. Therefore, radio (Sestamibi) guided surgery could have an; interesting rule in the thyroid follicular lesion treatment.

GPX4 and GPX7 over-expression in human hepatocellular carcinoma tissues.

Hepatocellular carcinoma (HCC) is the most common type of liver cancer and is still one of the most fatal cancers. Hence, it needs to identify always new putative markers to improve its diagnosis and prognosis. The selenium is an essential trace mineral implicated as a key factor in the early stage of cancer and exerts its biological function through the selenoproteins. In the last years our group has been studying the involvement of some selenoproteins in HCC. However, no many data are reported in literature about the correlation between HCC and the glutathione peroxidases (GPXs), both selenium and non selenium-containing GPXs. In this paper we have evaluated the GPX4 and GPX7 expression in some paraffin-embedded tissues from liver biopsy of patients with hepatitis C virus (HCV)-related cirrhosis and HCC by immunohistochemistry and RT-qPCR analysis. Our results evidenced that i) GPX4 and GPX7 had a statistically significant over-expression in HCC tissues compared to cirrhotic counterparts used as non tumor tissues, and ii) their expression was higher in grade III HCC tissues with respect to grade I-II samples. Therefore, we propose to use GPX4 and GPX7 as possible markers for improving HCC diagnosis/prognosis.

Daily Oxygen/O3 Treatment Reduces Muscular Fatigue and Improves Cardiac Performance in Rats Subjected to Prolonged High Intensity Physical Exercise.

Rats receiving daily intraperitoneal administration of O2 and running on a treadmill covered an average distance of 482.8 ± 21.8 m/week as calculated during 5-week observation. This distance was increased in rats receiving daily intraperitoneal administration of an oxygen/O3 mixture at a dose of 100; 150; and 300 µg/kg with the maximum increase being +34.5% at 300 µg/kg and still present after stopping the administration of oxygen/O3. Oxygen/O3 decreased the mean arterial blood pressure (-13%), the heart rate (-6%), the gastrocnemius and cardiac hypertrophy, and fibrosis and reduced by 49% the left ventricular mass and relative wall thickness measurements. Systolic and diastolic functions were improved in exercised oxygen/O3 rats compared to O2 rats. Oxygen/O3 treatment led to higher MPI index starting from the dose of 150 µg/kg (p < 0.05) and more effective (+14%) at a dose of 300 µg/kg oxygen/O3. Oxygen/O3 dose-dependently increased the expression of the antioxidant enzymes Mn-SOD and GPx1 and of eNOS compared to the exercised O2 rats. The same doses resulted in decrease of LDH levels, CPK, TnI, and nitrotyrosine concentration in the heart and gastrocnemius tissues, arguing a beneficial effect of the ozone molecule against the fatigue induced by a prolonged high intensity exercise.

Interplay between Intravitreal RvD1 and Local Endogenous Sirtuin-1 in the Protection from Endotoxin-Induced Uveitis in Rats.

Rat endotoxin-induced uveitis (EIU) is a well-established model of human uveitis. In this model, intravitreal injection of resolvin D1 (RvD1, 10-100-1000 ng/kg) 1 hour after subcutaneous treatment of Sprague-Dawley rats with lipopolysaccharide (LPS, 200 µg/rat) significantly prevented the development of uveitis into the eye. RvD1 dose-dependently increased the expression of sirtuin-1 (SIRT1) within the eye, while it decreased the expression of acetyl-p53 and acetyl-FOXO1. These effects were accompanied by local downregulation of some microRNAs related to the expression and activity of SIRT1. These were miR-195-5p, miR-200a-3p, miR-34a-5p, and miR-145-5p. An increase of manganese superoxide dismutase and decrease of caspase 3 were evident after RvD1 treatment. In another set of experiments, the protective effects of RvD1 (1000 ng/kg) were partly abolished by the pretreatment of the rats with EX527 (10 mg/kg/day, i.p.), a specific inhibitor of SIRT1 activity, for 7 days prior to the induction of EIU in rats. Similarly, the effects of RvD1 (1000 ng/kg) on the SIRT1 protein expression were abolished by Boc2, N-t-butoxycarbonyl-PLPLP, a specific formyl-peptide receptor type 2/lipoxin A receptor antagonist. Therefore, an interplay of the SIRT1 activity on the RvD1 mediated resolution of EIU is argued.

Assessment of the Selenoprotein M (SELM) over-expression on human hepatocellular carcinoma tissues by immunohistochemistry.

Selenium is an essential trace mineral of fundamental importance to human healthy and exerts its biological function through selenoproteins. In particular, Selenoprotein M (SELM) is located in the endoplasmic reticulum and contains the common redox motif of cysteine-X-X-selenocysteine type. It attracts great attention due to its high expression in brain and its potential roles as antioxidant, neuroprotective, and cytosolic calcium regulator. Recently, our group found SELM over-expression  in human hepatocellular carcinoma (HCC) cell lines. In this report some paraffin-embedded tissues from liver biopsy of patients with hepatitis C virus (HCV)-related cirrhosis and HCC were immunohistochemically stained and SELM expression scoring was evaluated. Our results evidence for the first time an increase of SELM expression in HCC liver tissues, and its gradual expression raise associated with an increased malignancy grade. Therefore, we propose to use i) SELM as putative marker for HCC as well as ii) simple immunohistochemistry technique to distinguish between the different grades of malignancy. 

BRAF and PIK3CA genes are somatically mutated in hepatocellular carcinoma among patients from South Italy.

Poor data have been previously reported about the mutation rates in K-RAS, BRAF, and PIK3CA genes among patients with hepatocellular carcinoma (HCC). Here we further elucidated the role of these genes in pathogenesis of primary hepatic malignancies. Archival tumour tissue from 65 HCC patients originating from South Italy were screened for mutations in these candidate genes by direct sequencing. Overall, oncogenic mutations were detected in 15 (23%) patients for BRAF gene, 18 (28%) for PIK3CA gene, and 1 (2%) for K-RAS gene. Using statistical analysis, BRAF mutations were significantly correlated with the presence of either multiple HCC nodules (P=0.021) or higher proliferation rates (P=0.034). Although further extensive screenings are awaited in HCC patients among different populations, our findings clearly indicated that mutational activation of both BRAF and PIK3CA genes does contribute to hepatocellular tumorigenesis at somatic level in Southern Italian population.

Ultrastructural profile of microcystic meningioma.

OBJECTIVE: Microcystic meningioma was originally classified as a subtype of meningioma by the World Health Organization classification of brain tumours in 1993, and accounts for 1.6% of intracranial meningiomas. This subtype is a variety of meningioma in which micro- and macro-cysts are diffuse. The morphologic characteristics are well defined, while the histogenetic mechanism that give rise to these patterns remain unclear. MATERIALS AND METHODS: The authors present an electron microscopic study of an unusual case of fronto-temporal microcystic meningioma, manifesting as history of headache, right paresis and dysphasia in a 73-year-old female. Computer tomography revealed a large hypodense mass in the left fronto-temporal region, with slight contrast enhancement. RESULTS: Ultrastructural observation showed complex alterations among small vessels and intratumoral capillaries in a background of severe modification in vessel permeability. CONCLUSIONS: This electronic microscopy study documented that growth of the cyst was due not only to accumulation of in extracellular fluid, but also to cytolysis consequent to ingravescent hydropic degeneration.

An ultrastructural study of the histogenesis of haemangioblastoma.

Seven cases of cerebellar haemangioblastoma, not associated with von Hippel-Lindau disease (sporadic haemangioblastomas), were studied by light and electron transmission microscopy. Morphological features that might provide information about the histogenesis of the tumour were examined. The ultrastructural data indicate both the common ancestry of the different cytotypes that make up the tumour, and the mesenchymal origin of the elements present, which were also documented by their capacity to synthesise lipid droplets in the cytoplasm (a process of lipidization similar to that of pre-adipocytes).

Unexpected finding of laparoscopic appendectomy: appendix MALT lymphoma in children.

Mucosa-associated lymphoid tissue (MALT) lymphomas comprise a group of indolent B-cell non-Hodgkin lymphomas (NHL), which are rare in pediatric age. The clinical presentation of MALT lymphomas varies according to the location of the lymphoma. We report on a case of MALT lymphoma involving the appendix in a 6-year-old girl. A 6-year-old girl was referred to our institution in May 2005 with a diagnosis of appendicitis. The abdominal ultrasound showed slight effusion in the pelvic fossa. The patient underwent laparoscopic appendectomy using the three-trocar technique. The appendix appeared moderately hyperaemic with slight enlargement of the two-thirds of the distal portion. The postoperative course was uneventful and the girl was discharged on day 1 without any complication. The morphological and immunohistochemical examination showed typical findings of low-grade MALT lymphoma (positivity for CD20, no immunostaing for CD5 and CD10, positivity for anti-lambda light chain and low positivity for Ki-67). Further extensive examinations (abdominal MRI, gastroscopy, colonscopy and capsule endoscopy of the ileum) revealed that the lymphoma was limited to the distal two-third of the appendix (stage IA) and was not associated with any specific infection. At a recent follow-up the patients appeared to be doing well. Appendiceal MALToma is a rather uncommon pathology and, to our knowledge, there is only one report of appendiceal intussusception associated with appendiceal maltoma. According to our experience, low-grade MALToma can be managed by simple appendectomy. The histological examination should be the rule whenever an appendectomy is performed in children.

[Is extrauterine endometriosis confined to the gynecological sphere? A critical review of the experience in a general surgery unit]. / Endometriosi esterna: patologia di esclusivo interesse ginecologico? Il punto di vista del chirurgo generale.

Extrauterine or external endometriosis (e.e.) describes ectopic localization of functional endometrial tissue, a finding whose incidence is increasing due to the diffusion of laparoscopic procedures. The clinical presentation of such disease is often non-specific, even in those cases with a definite surgical indication, depending on the site and pathology of the lesions. Surgical planning is therefore difficult at times, specifically regarding the extent of resection in patients--as young women--willing to maintain fertility. The Authors report on 7 cases observed in their own experience (inguinal endometriosis--1 case, umbilical endometriosis--1 case, abdominal wall endometriosis--3 cases, intestinal endometriosis--1 case, diaphragmatic endometriosis associated with pneumothorax--1 case), representing the wide range of clinical settings related to e.e. Based on literature data, an analysis of clinical and diagnostic issues is carried out. Specifically, the problems related to extent of surgical resection in multifocal cases, possible malignant degeneration and localization on abdominal wall scars are discussed.

Ultrastructural pathology of pediatric myocardium in acute ischemia: bioptic study before and after treatment with cardioplegic solution.

Protecting the myocardium from the risk of acute ischemia during heart surgery is still an unsolved problem; the problem is even more open and more pressing in pediatric heart surgery. To meet this greater risk it is advisable to use a cardioplegic solution with a composition that is better suited to the particular morphofunctional conditions of the myocardium in the child, i.e., a solution offering greater protection. To this purpose the authors experimented with Celsior cardioplegic solution during heart surgery in children to evaluate the efficacy compared to the standard St. Thomas solution. In this comparative study 15 children were treated with Celsior cardioplegic solution and 15 others with St. Thomas cardioplegic solution. Each patient underwent 2 biopsies of the myocardium, the first before cardioplegic treatment and the second immediately after reperfusion. In both groups, focal lesions involving both the cardiomyocytes and the vascular-stromal structures were randomly found. The former had undergone a necrotic-regressive process with changes in the myofibrils and the mitochondria. The vascular-stromal structures showed changes in the permeability of the capillary endothelia, with interstitial edema. The results show the lesions to be similar in the 2 groups both on a quality and quantitative level.

The immunohistochemical outline of p27kip1, cyclin B1 and cyclin D3 in pleomorphic adenomas.

AIM: Pleomorphic adenomas of salivary glands are benign lesions which may sometimes relapse even after complete surgical removal. This risk has led to the search for methods to provide predictive data on the biological behaviour of such neoplasia. The authors intend to evaluate the degree of cellular aggression of these tumours by finding prognostic data using the antigens involved in cellular proliferative activity. Therefore they have chosen for this study: p27kip1, cyclin B1 and Cyclin D3. METHODS: Seventeen mixed tumours, 2 of them relapsed, underwent the direct immunohystochemical PAP technique for the determination of antigens p27kip1, cyclins B1 and D3 of the tissue. RESULTS: The results obtained show that the verification of these markers may reveal a potential risk of biological deviation and that their expression is independent of the degree of cellularity in neoplasias. CONCLUSIONS: On the basis of the results, the conclusion is drawn that there is no relation between the expressivity of the mentioned antigens and histological characters of pleomorphic adenomas.

[Granulomatous mastitis: diagnostic and therapeutic problems. Case report and review of the literature]. / Mastite granulomatosa: problemi di diagnosi e terapia. Presentazione di un caso e revisione della letteratura

The granulomatous mastitis is uncommon inflammatory disease of the breast of unknown etiology. The diagnosis is obtained only through hystopathology. We report a case of woman, 41 years old, showing lesions of the breast, that caused strong pain with ulcerations sero-haematic secretion and axillary omolateral lymphadenopathy. The diagnostic workup (sonography, mammography, multiples FNAB of single lesions, the culture of cells and hormonal profile) showed an inflammatory aspecific lesions with presence of atipic cells in nipple's secretion and in FNAB of periareola lesion. We performed an excisional biopsy. The hystopathologic diagnosis showed a granulomatous mastitis, confirming the validity of our diagnostic and therapeutic choices. The excisional biopsy has allowed to avoid an overtreatment and obtain a good aesthetic result.

A computational search for box C/D snoRNA genes in the Drosophila melanogaster genome.

MOTIVATION: In eukaryotes, the family of non-coding RNA genes includes a number of genes encoding small nucleolar RNAs (mainly C/D and H/ACA snoRNAs), which act as guides in the maturation or post-transcriptional modifications of target RNA molecules. Since in Drosophila melanogaster (Dm) only few examples of snoRNAs have been identified so far by cDNA libraries screening, integration of the molecular data with in silico identification of these types of genes could throw light on their organization in the Dm genome. RESULTS: We have performed a computational screening of the Dm genome for C/D snoRNA genes, followed by experimental validation of the putative candidates. Few of the 26 confirmed snoRNAs had been recognized by cDNA library analysis. Organization of the Dm genome was also found to be more variegated than previously suspected, with snoRNA genes nested in both the introns and exons of protein-coding genes. This finding suggests that the presence of additional mechanisms of snoRNA biogenesis based on the alternative production of overlapping mRNA/snoRNA molecules. AVAILABILITY: Additional information is available at http://www.bioinformatica.unito.it/bioinformatics/snoRNAs.

Recurrent and atypical meningiomas--a multiparametric study using Ki67 labelling index, AgNOR and DNA Feulgen staining.

OBJECTIVE: Histological analysis has limited value to predict the biological behavior of meningiomas. In this study, we investigated the utility of indicators of cell proliferation in the evaluation of histologically benign meningiomas. MATERIALS AND METHODS: For this purpose, 50 meningothelial meningiomas, 50 atypical meningiomas and 8 primary benign meningiomas with their recurrences were studied. For each case the Ki67 labeling index (LI), DNA ploidy and AgNOR were evaluated and the results quantitatively processed and assessed by computerized image analyzer. RESULTS: The Ki67 labelling showed a low index (11.3%) in typical meningiomas and primary meningiomas (13.6%). In contrast, it was higher in atypical (26.6%) and recurrent meningiomas (28%). Similar results were obtained for the AgNOR granule count which showed that typical and primary meningiomas had mean 1.51 - 1.49, whereas recurring meningiomas and atypical meningiomas had mean values of 1.92 and 1.98, respectively. DNA ploidy revealed in the hyperpolyploid region between 4c - 16c: 7.02% of the nuclei in primary meningiomas, 17.98% of the nuclei in recurring meningiomas and 24.63% of the nuclei in atypical meningiomas. CONCLUSION: Our results suggest that evaluation of cell proliferation using Ki67 LI, DNA ploidy and AgNOr, integrated with standard histopathology, can provide better information for a correct grading of meningiomas.

DNA ploidy as a significant prognostic factor after radical resection for large bowel carcinoma: a prospective study.

It is controversial whether cell DNA measurement is a reliable method to predict prognosis in radically resected large bowel carcinomas. A study using strict rules was undertaken on 54 consecutive patients to clarify the usefulness of DNA ploidy by image cytometric analysis as a prognostic indicator. The tumors were 39% diploid and 61% aneuploid. DNA ploidy was not related to more advanced stages and it, with histological grade and Dukes' stage, was an independent covariate and influenced both disease-free and overall survival. Aneuploid tumors showed the worse prognosis in all Dukes' stages. This prospective study shows that DNA ploidy is an important independent prognostic indicator of clinical outcome and recurrence rate, and it should be used to both select high-risk patients and guide postoperative treatments, particularly in early-stage large bowel carcinomas.