A thyroid nodule revealing a paraganglioma in a patient with a new germline mutation in the succinate dehydrogenase B gene

A 32-year-old asymptomatic female was diagnosed with an isolated thyroid nodule of 2.5 cm diameter. Fine needle aspiration suggested a medullary thyroid carcinoma. Consequently, a total thyroidectomy was performed. The nodule stained positive for chromogranin A, neurone-specific enolase and synaptophysin, but not for calcitonin. Finally, pathological analysis showed a thyroid paraganglioma. Although the tumour appeared to be sporadic in a patient with no personal or familial history of paraganglioma and/or pheochromocytoma, we have identified a new mutation (392delC) of the succinate dehydrogenase-B (SDHB) gene in the genomic DNA extracted from the leukocytes of the patient. That mutation induced a shift in the reading frame of the gene creating a premature stop codon (P131fsX135) which was predicted to result in a truncated SDHB protein of 135 amino acids.This report highlights the difficulties of this unexpected diagnosis of hereditary thyroid paraganglioma. It also discusses the clinical involvements in terms of familial screening and the necessary follow-up of the patient.     

Recent progress in the diagnosis, prognostic evaluation and treatment of pheochromocytomas

INTRODUCTION: Pheochromocytoma is a catecholamine-secreting neoplasm of chromaffin tissue. It is a rare disease. Biochemical tests should be performed only in patients at high risk of pheochromocytoma, and an imaging procedure only in those with positive biochemical tests. CURRENT KNOWLEDGE AND KEY POINTS: The most specific and sensitive diagnostic test for the disease is the determination of plasma or urinary metanephrines. The tumor can be located by computerized tomography, magnetic resonance imaging, and specific scintigraphy. Ten to 20% of pheochromocytomas result from hereditary diseases, including multiple endocrine neoplasia type 2, von Hippel Lindau disease, and neurofibromatosis 1. Familial cases are diagnosed earlier, and are more frequently bilateral and recurring than sporadic cases. About 10% of the cases are malignant either at first operation or during follow-up, malignancy being diagnosed by the presence of lymph node, visceral or bone metastases. The probability of a recurrence is positively correlated with the urinary excretion of metanephrines and tumor size. Recurrences are more frequent in cases with ectopic tumors and in those with a low plasma epinephrine to total catecholamine ratio. Patients, especially those with familial tumors or low epinephrine secretion, should be followed-up indefinitely. FUTURE PROSPECTS AND PROJECTS: Treatment for malignant recurrences includes surgery, therapeutic embolization, chemotherapy, and the application of therapeutic doses of metaiodobenzylguanidine. Metyrosine, phenoxybenzamine, or somatostatin analogs may help to control blood pressure and to alleviate symptoms in patients with malignant pheochromocytoma; however such a treatment has no antiproliferative effect.     

Collective effective dose received by the population of Egypt from building materials

Natural radioactivity due to the presence of 226Ra, 232Th and 40K in selected building materials (cement, sand, bricks, gypsum and ceramic) used in Egypt was measured using a gamma-ray spectrometer with an HPGe detector. The average activity concentrations observed in different building materials ranged from 10.0 +/- 1.3 to 109 +/- 6, <2 to 55.8 +/- 2.2 and 5.5 +/- 1.7 to 684 +/- 34 Bq kg(-1) for 226Ra, 232Th and 40K, respectively. Based on these, together with previously reported results, the effective doses received by the residents of different types of house within all Egyptian governorates were assessed using the WinMat computer program. The results were below 1 mSv a(-1) in all cases. The collective effective dose indoors was assessed as 15,000 man Sv and the excess effective dose due to building materials was 0.07 mSv a(-1).     

The role of microvessel density on the survival of patients with lung cancer: a systematic review of the literature with meta-analysis

In order to determine whether angiogenesis is a prognostic marker in lung cancer, we performed a systematic review of the literature to assess the prognostic value on survival of microvessel count in patients with lung cancer. Published studies were identified by an electronic search in order to aggregate survival results, after a methodological assessment using a quality scale designed by the European Lung Cancer Working Party. To be eligible, a study had to deal with microvessel count assessment in lung cancer patients on the primary site and to provide survival analysis according to microvessel count expression. Microvessel count has been assessed on surgical samples by immunohistochemistry using factor VIII in 14 studies, CD34 in 10 and CD31 in eight. Respectively 1866, 1440 and 1093 non-small cell lung cancer patients were considered. The overall median quality scores were respectively 52, 59 and 59% for studies assessing microvessel count via factor VIII, CD34 and CD31, without significant difference between studies evaluable or not for meta-analysis nor between studies with significant or non significant results. Seven 'factor VIII' studies, nine 'CD34' and seven 'CD31' provided sufficient data allowing a meta-analysis on survival and were evaluable for results aggregation. This showed that a high microvessel count in the primitive lung tumour was a statistically significant poor prognostic factor for survival in non small cell lung cancer whatever it was assessed by factor VIII (HR: 1.81; 95% CI: 1.16-2.84), CD34 (HR: 1.99; 95% CI: 1.53-2.58) or CD31 (HR: 1.80; 95% CI: 1.10-2.96). Variations in survival among the individual studies can be explained in addition to patients selection criteria by the heterogeneous methodologies used to stain and count microvessels: different antibody clones, identification of 'hotspots', Weidner or Chalkey counting method, cut-off selection. Microvessel count, reflecting the angiogenesis, appears to be a poor prognostic factor for survival in surgically treated non small cell lung cancer but standardisation of angiogenesis assessment by the microvessel count is necessary.     

Neonatal outcome after exposure to selective serotonin reuptake inhibitors late in pregnancy]

OBJECTIVES: To analyse neonatal effects after in utero selective serotonin reuptake inhibitors exposure and the pertinence of recommendations delivered by our team. MATERIALS AND METHODS: We report a series of 27 pregnancies exposed late in pregnancy including the period of delivery, to the Selective Serotonin Reuptake Inhibitors (SSRI) and having been the subject of a call to the Regional Center of Pharmacovigilance of Tours (CRPV). RESULTS: Twenty-seven children were born without malformation. Twelve children were hospitalized because of prematurity (two), exposure to other drugs imposing particular surveillance (eight) or in view of abnormal neonatal effects (two). Five newborns (18.5%) of which three had also been exposed to other drugs (benzodiazepine, neuroleptic, H1-antagonist) had presented one or more neonatal adverse effects compatible with the role of the SSRI (irritability, agitation, shivering, hypotonia) but with uncertainty about a clear discrimination between withdrawal syndrome and serotonin impregnation. All the symptoms disappeared spontaneously. One of the five children had a described in treated adults but two neonatal observations were published. No child had hemorrhagic symptoms as described in treated adults despite the fact that two neonatal observations were reported. CONCLUSION: This study confirms the relative benignity of SSRI exposure during late pregnancy. Our recommendations for monitoring the newborns during their stay in maternity wards were well respected. The risk of hemorrhagic symptoms or hyponatremia, not well known by pediatricians, deserves to be recalled to medical teams who take in charge newborns exposed to SSRI.     

The effects of interferon-α on the proliferation of CML progenitor cells in vitro are not related to the precise position of the M-BCR breakpoint

We investigated the effects of brief (2 h) and continuous exposure to recombinant interferon-alpha (2a) (rIFN-alpha) on the proliferation of primitive (blast colony-forming cells, Bl-CFC) and committed myeloid progenitor cells (BFU-E and GM-CFC) derived from blood and bone marrow of patients with chronic myeloid leukaemia (CML) and normal subjects. In all three clonogenic assays, rIFN-alpha suppressed colony formation in a dose-dependent manner. No differences were detected in the proliferation of CML or normal Bl-CFC and GM-CFC exposed to rIFN-alpha. Erythroid colony formation by normal, but not by CML BFU-E, was inhibited by relatively low concentrations (100 U/ml) of rIFN-alpha. However, in patients whose blood or marrow contained a mixture of Philadelphia chromosome (Ph)-positive and Ph-negative BFU-E, cytogenetic analysis of individual erythroid colonies showed no differential inhibition by rIFN-alpha. We found no difference in the sensitivity to rIFN-alpha of GM-CFC from patients whose leukaemic cells expressed BCR/ABL mRNA with the b2a2 junction and that of GM-CFC from patients with the b3a2 mRNA. We conclude that (1) rIFN-alpha does not have a significant leukaemia-specific effect on the progenitor cells detected in these assays, and (2) the sensitivity of CML GM-CFC to rIFN-alpha is independent of the type of BCR/ABL message present in the cells. The clinical efficacy of rIFN-alpha could be due to selective toxicity to cells not assayed in this study, to effects on accessory cells or to alterations induced in progenitor cell/stromal cell interactions.     

Mitochondrial succinate is instrumental for HIF1alpha nuclear translocation in SDHA-mutant fibroblasts under normoxic conditions

The genes encoding succinate dehydrogenase (SDH) subunits B, C and D, act as tumour suppressors in neuro-endocrine tissues. Tumour formation has been associated with succinate accumulation. In paraganglioma cells, two forms of SDHA (type I, II) were found which might preclude significant succinate accumulation in the case of a mutation in either form. In fibroblasts only SDHA type I is found. In these cells, SDHA type I mutation leads to SDH deficiency, succinate accumulation and hypoxia-inducible factor 1alpha(HIF1alpha) nuclear translocation. HIF1alpha nuclear translocation was not observed in ATPase-deficient fibroblasts with increased superoxide production and was found to be independent of cellular iron availability in SDHA-mutant cells. This suggests that neither superoxides nor iron were causative of HIF1alpha nuclear translocation. Conversely, alpha-ketoglutarate (alpha-KG) inhibits this nuclear translocation. Therefore, the pseudo-hypoxia pathway in SDH-deficient cells depends on the HIF1alphaprolyl hydroxylase product/substrate (succinate/alpha-KG) equilibrium. In SDH deficiency, organic acids thus appear instrumental in the HIF1alpha-dependent cascade suggesting a direct link between SDH and tumourigenesis.     

In vitro susceptibility testing of amorolfine in pathogenic fungi isolated from dermatomycosis patients in China

The antifungal susceptibility of isolates from Chinese dermatomycosis patients to amorolfine was investigated following National Committee for Clinical Laboratory Standards (NCCLS) protocols. In total, 383 isolates were tested, including 132 strains from tinea pedis, 148 strains from tinea corporis/cruris, and 103 strains from onychomycosis. The minimum inhibitory concentration (MIC) of amorolfine against dermatophytes ranged from 0.01 to 0.08 microg ml(-1). The MIC(50) and MIC(90) of amorolfine for Trichophyton rubrum were both equal to 0.04 micro ml(-1); for T. mentagrophytes these MICs were 0.04 microg ml(-1) and 0.08 microg ml(-1) respectively; and for Epidermophyton floccosum they were 0.02 microg ml(-1) and 0.04 microg ml(-1) respectively. The MIC range of amorolfine against Candida parapsilosis was 0.5-16 microg ml(-1). MIC(50) and MIC(90) for C. parapsilosis were 0.5 and 2 microg ml(-1). MIC ranges of amorolfine against Scopulariopsis spp. and Acremonium spp. were 0.5-4 and 2-8 microg ml(-1), respectively. Candida albicans, Fusarium solani and Aspergillus flavus required relatively higher concentrations of amorolfine to inhibit their growth (MIC 0.125-64 microg ml(-1), MIC(50) and MIC(90) were 4 and 64 microg ml(-1)). The results demonstrated that amorolfine is the only topical agent that has such a potent antifungal activity and a broad spectrum against a wide range of pathogenic fungi.     

Role of Bcl-2 as a prognostic factor for survival in lung cancer: a systematic review of the literature with meta-analysis

The role of the anti-apoptotic protein Bcl-2 in lung cancer remains controversial. In order to clarify its impact on survival in small and non-small cell lung cancer (NSCLC), we performed a systematic review of the literature. Trials were selected for further analysis if they provided an independent assessment of Bcl-2 in lung cancer and reported analysis of survival data according to Bcl-2 status. To make it possible to aggregate survival results of the published studies, their methodology was assessed using a quality scale designed by the European Lung Cancer Working Party (including study design, laboratory methods and analysis). Of 28 studies, 11 identified Bcl-2 expression as a favourable prognostic factor and three linked it with poor prognosis; 14 trials were not significant. No differences in scoring measurement were detected between the studies, except that significantly higher scores were found in the trials with the largest sample sizes. Assessments of methodology and of laboratory technique were made independently of the conclusion of the trials. A total of 25 trials, comprising 3370 patients, provided sufficient information for the meta-analysis. The studies were categorised according to histology, disease stage and laboratory technique. The combined hazard ratio (HR) suggested that a positive Bcl-2 status has a favourable impact on survival: 0.70 (95% confidence interval 0.57-0.86) in seven studies on stages I-II NSCLC; 0.50 (0.39-0.65) in eight studies on surgically resected NSCLC; 0.91 (0.76-1.10) in six studies on any stage NSCLC; 0.57 (0.41-0.78) in five studies on squamous cell cancer; 0.75 (0.61-0.93) and 0.71 (0.61-0.83) respectively for five studies detecting Bcl-2 by immunohistochemistry with Ab clone 100 and for 13 studies assessing Bcl-2 with Ab clone 124; 0.92 (0.73-1.16) for four studies on small cell lung cancer; 1.26 (0.58-2.72) for three studies on neuroendocrine tumours. In NSCLC, Bcl-2 expression was associated with a better prognosis. The data on Bcl-2 expression in small cell lung cancer were insufficient to assess its prognostic value.