Léiomyosarcomes utérins : épidémiologie,histologie, biologie,diagnostic, pronostic et traitement

Uterine leiomyosarcoma is a rare disease with a poor prognosis. The rarity of this tumor needs a specialized management in tertiary reference centers in order to provide patients with optimal diagnostic, prognostic and therapeutic care. The pathological diagnosis relies on the presence of three characteristics in proliferating smooth muscle cells: necrosis, cytologic atypia and mitosis. Despite progress in the knowledge of the biology of these tumors, no oncogenic driver has been found. Prognosis depends mainly on the age of the patient, race, FIGO stage, mitotic index and hormonal receptor expression in the tumor. Surgery is one of the cornerstones of management and cytotoxic chemotherapy is the mainstay of treatment in metastatic disease with a potential role in the adjuvant setting. In locally advanced or metastatic disease, prognosis is poor with a median overall survival of about 12 to 14 months despite a 30% response rate to polychemotherapy regimens. Anti-angiogenics and hormonal therapy have a role to play in the setting of metastatic disease. It is mandatory to include such patients in clinical trials aiming to improve the therapeutic management of these patients. Multimodal therapy can improve the prognosis of selected patients too.     

The neuropeptide 26RFa is expressed in human prostate cancer and stimulates the neuroendocrine differentiation and the migration of androgeno-independent prostate cancer cells

AimAccumulating data suggest that neuropeptides produced by neuroendocrine cells play a crucial role in the progression and aggressiveness of hormone refractory prostate cancer (CaP). In this study, we have investigated the presence and function of the neuropeptide 26RFa in CaP.MethodsWe have localised and quantified tumour cells containing 26RFa and its receptor, GPR103, in CaP sections of various grades. In vitro experiments were performed to investigate the effects of 26RFa on the migration, proliferation and neuroendocrine differentiation of the androgeno-independent (AI) prostate cancer cell line DU145.Results26RFa and GPR103 are present in carcinomatous foci exhibiting a neuroendocrine differentiation, and the number of 26RFa and GPR103-immunoreactive cancer cells increases with the grade of CaP. 26RFa stimulated the migration of native or transdifferentiated AI DU145 cells, but had no effect on their proliferation. Furthermore, 26RFa induced the neuroendocrine differentiation of DU145 cells as assessed by the occurrence of neurite-like extensions and the increase of the expression of the neuroendocrine marker chromogranin A.ConclusionThe present data indicate that 26RFa may participate to the development of CaP at the AI state by promoting the neuroendocrine differentiation and the migration of cancer cells via autocrine/paracrine mechanisms.     

Estimating the risks and prevalence of hypertension in a suburban area of Beijing

Community-oriented primary care (COPC) provides a framework for identifying and addressing a defined community's health and health care needs. The research reported upon here is based on a community health survey in a new suburban neighborhood (Tayuan region) in the Haidian district of Beijing, conducted by the Beijing Medical University Department of Preventive Medicine and Health Care to serve as a basis for planning health care services for the residents in that community. The analyses focus on the prevalence and predictors of hypertension among older adult residents (those 45 years of age and older). Based on logistic regression analyses, the odds ratios (in parentheses) confirm that individuals with a family history of cardiovascular disease were more likely to have been diagnosed as hypertensive (1.57). Hypertensives were also more likely to have uncontrolled systolic (3.85) or diastolic (4.75) blood pressure and associated behavioral and biologic risks, such as obesity (1.87) and renal damage (2.60). These risks were even greater among current or former smokers. These analyses will inform the design of community-oriented primary care interventions in that particular community in the People's Republic of China. They also signal important implications and highlight practical methods for assessing and targeting interventions in U.S. communities facing comparable, but unexamined, risks.     

Multiphoton spectral analysis of benzo[a]pyrene uptake and metabolism in a rat liver cell line

Dynamic analysis of the uptake and metabolism of polycyclic aromatic hydrocarbons (PAHs) and their metabolites within live cells in real time has the potential to provide novel insights into genotoxic and non-genotoxic mechanisms of cellular injury caused by PAHs. The present work, combining the use of metabolite spectra generated from metabolite standards using multiphoton spectral analysis and an “advanced unmixing process”, identifies and quantifies the uptake, partitioning, and metabolite formation of one of the most important PAHs (benzo[a]pyrene, BaP) in viable cultured rat liver cells over a period of 24 h. The application of the advanced unmixing process resulted in the simultaneous identification of 8 metabolites in live cells at any single time. The accuracy of this unmixing process was verified using specific microsomal epoxide hydrolase inhibitors, glucuronidation and sulfation inhibitors as well as several mixtures of metabolite standards. Our findings prove that the two-photon microscopy imaging surpasses the conventional fluorescence imaging techniques and the unmixing process is a mathematical technique that seems applicable to the analysis of BaP metabolites in living cells especially for analysis of changes of the ultimate carcinogen benzo[a]pyrene-r-7,t-8-dihydrodiol-t-9,10-epoxide. Therefore, the combination of the two-photon acquisition with the unmixing process should provide important insights into the cellular and molecular mechanisms by which BaP and other PAHs alter cellular homeostasis.     

Overview and outcome of mucormycosis among children with cancer: Report from the Children's Cancer Hospital Egypt

Mucormycosis represents a real challenge in immunocompromised patients. This study aimed to describe the clinical characteristics, treatment outcome and infection‐related mortality in our patients at the Children's Cancer Hospital 57357, Cairo, Egypt. This is a retrospective study during the period 2007‐2017. Data analysis included demographic data, risk factors, diagnostic workup, treatment and outcome. During the study period, 45 patients developed proven mucormycosis according to EORTC/MSG criteria (2008). Ninety percentof cases were of haematological malignancies. Liposomal amphotericin B was the mainstay of treatment. Posaconazole was used as secondary prophylaxis in 35% of cases. Combination antifungal was used in three cases with progressive mucormycosis. Surgical intervention was achievable in 50% of cases. Therapy was successful in 35 patients (66%). Complications related to mucormycosis were seen in five cases with disfigurement and perforated hard palate. Chemotherapy delay with subsequent relapse of primary malignancy was reported in one case. Mucormycosis‐related mortality was 33% (15 cases). Mucormycosis is a major cause of mortality among patients with haematological malignancies. Early diagnosis of Mucormycosis infection, with rapid initiation of appropriate antifungal therapy and surgical intervention, whenever feasible, is the backbone of mucormycosis treatment.     

The value of postlumpectomy mammogram in the management of breast cancer patients presenting with suspiciouis microcalcifications

PURPOSE: It is recommended that patients with breast cancer who present with mammographically detected microcalcification should undergo postlumpectomy mammogram with magnification views to ensure adequate removal of all clinically demonstrable disease. The value of postlumpectomy mammogram has not been adequately examined in the literature. This report aims to quantify the value of such a study. MATERIALS AND METHODS: Retrospective review identified 90 breast cancer patients referred to our department between 1992 and 1997 who met all of the following criteria: (1) patients were considered for breast conserving management; (2) patients had suspicious microcalcifications on diagnostic mammograms; (3) the mammographic lesions were thought to be removed entirely on postexcision specimen radiographs; (4) surgical excisions were thought to be adequate on the basis of a review of the histologic pathology reports; and (5) postlumpectomy mammograms with magnification views were obtained. Fifty patients had invasive adenocarcinoma and 40 patients had ductal carcinoma in situ. The margins of last resection were clear, close, or focally involved in 70, 13, and seven patients, respectively. Patient records were reviewed to determine whether postlumpectomy mammograms demonstrated residual microcalcifications. RESULTS: Sixteen patients (17%) were found to have residual microcalcifications on postlumpectomy mammograms. Twelve patients underwent either local re-excision (seven patients) or simple mastectomy (five patients). Re-excision was not performed in four patients. Residual malignant cells were found in eight patients (67% of the re-excision group and 9% of the whole group). Six of these patients had their tumors initially resected with clear margins and the remaining two patients had their tumors initially resected with close margins. CONCLUSIONS: Postlumpectomy mammograms with magnification views detected residual clinical disease in a significant proportion of patients. Our result supports the routine use of this test, even when satisfactory postexcision specimen radiographs and adequate lumpectomy resection margins are obtained. This finding is particularly true for patients with ductal carcinoma in situ.     

The inhibition of long-chain fatty acyl-CoA synthetase by enoximone in rat heart mitochondria.

The mechanism by which enoximone, a reported phosphodiesterase inhibitor, inhibits the oxidation of long-chain fatty acids was studied in isolated rat heart mitochondria using a series of 14C-labeled substrates. Enoximone decreased palmitate oxidation in a time- and concentration-dependent manner. Fifty percent inhibition of palmitate oxidation was achieved with 250 microM of enoximone. In contrast to its effect on palmitate, enoximone (250 microM) increased octanoate oxidation by 30%, whereas pyruvate oxidation was unaffected by enoximone. At that dose there was no effect on the oxidation of palmitoyl-CoA and palmitoyl carnitine. The degree of palmitate oxidation inhibited by enoximone was parallel to the inhibition of acyl-CoA synthetase in both rat heart mitochondria and microsomes. These results suggest that enoximone is a reversible inhibitor of long-chain fatty acyl-CoA synthetase. Moreover, the reaction, which is catalyzed by this enzyme, is a rate-limiting step in the pathway of fatty acid oxidation in rat heart mitochondria.     

Familial hematological malignancies: <Emphasis Type="Italic">ASXL1</Emphasis> gene investigation

Purpose

Familial aggregation among patients with several hematological malignancies has been revealed. This emphasizes the importance of genetic factors. Only few genes predisposing to familial hematological malignancies have been reported until now due to the low occurrence. We have described in previous study PRF1 and CEBPA variants that might contribute to the background of genetic factors, which encourage us to extend our investigations to other cooperating genes. The aim of this study is to determine whether germline additional sex combs-like 1 (ASXL1) gene mutations may be involved?

Methods/patients

In this study, we investigated the candidate gene ASXL1 by direct sequencing in 88 unrelated Tunisian and French families with aggregated hematological malignancies.

Results

We report a new p.Arg402Gln germline missense substitution in two related Tunisian patients which has not been previously described. We identified here this variant for the first time in non-Hodgkin lymphoma. The p.Arg402Gln variant was not found in 200 control chromosomes. In silico analysis has predicted potential deleterious effect on ASXL1 protein.

Conclusions

From an extended candidate genes analyzed in the field of familial hematological malignancies, ASXL1 might be involved. This variant should be considered since a potential damaging effect was predicted by in silico analysis, with a view to develop functional assay in order to investigate the biological assessment.

     

Brown spider dermonecrotic toxin directly induces nephrotoxicity

Brown spider (Loxosceles genus) venom can induce dermonecrotic lesions at the bite site and systemic manifestations including fever, vomiting, convulsions, disseminated intravascular coagulation, hemolytic anemia and acute renal failure. The venom is composed of a mixture of proteins with several molecules biochemically and biologically well characterized. The mechanism by which the venom induces renal damage is unknown. By using mice exposed to Loxosceles intermedia recombinant dermonecrotic toxin (LiRecDT), we showed direct induction of renal injuries. Microscopic analysis of renal biopsies from dermonecrotic toxin-treated mice showed histological alterations including glomerular edema and tubular necrosis. Hyalinization of tubules with deposition of proteinaceous material in the tubule lumen, tubule epithelial cell vacuoles, tubular edema and epithelial cell lysis was also observed. Leukocytic infiltration was neither observed in the glomerulus nor the tubules. Renal vessels showed no sign of inflammatory response. Additionally, biochemical analyses showed such toxin-induced changes in renal function as urine alkalinization, hematuria and azotemia with elevation of blood urea nitrogen levels. Immunofluorescence with dermonecrotic toxin antibodies and confocal microscopy analysis showed deposition and direct binding of this toxin to renal intrinsic structures. By immunoblotting with a hyperimmune dermonecrotic toxin antiserum on renal lysates from toxin-treated mice, we detected a positive signal at the region of 33-35 kDa, which strengthens the idea that renal failure is directly induced by dermonecrotic toxin. Immunofluorescence reaction with dermonecrotic toxin antibodies revealed deposition and binding of this toxin directly in MDCK epithelial cells in culture. Similarly, dermonecrotic toxin treatment caused morphological alterations of MDCK cells including cytoplasmic vacuoles, blebs, evoked impaired spreading and detached cells from each other and from culture substratum. In addition, dermonecrotic toxin treatment of MDCK cells changed their viability evaluated by XTT and Neutral-Red Uptake methodologies. The present results point to brown spider dermonecrotic toxin cytotoxicity upon renal structures in vivo and renal cells in vitro and provide experimental evidence that this brown spider toxin is directly involved in nephrotoxicity evoked during Loxosceles spider venom accidents.