Role of radiotherapy in the management of rare gynaecological cancers.

There are a large number of gynaecological cancers with rare histologies, for which the available data are limited and usually retrospective. Because of their rarity and poor prognosis, the management of these cancers must be centralized in expert centres, for both histological diagnosis and treatment. With the exception of sarcomas, most endometrial or cervical cancers with rare histologies respond to the same radiation treatment modalities than cancers with more common histologies, although there are some specificities regarding treatments such as neuroendocrine carcinomas (chemotherapy with platinum and etoposide, major role of surgery). For localized or locally advanced ovarian cancer, external beam radiotherapy has a role in the management of hypercalcaemic small cell carcinoma of the ovary. This article summarizes the current role of external beam radiotherapy and brachytherapy in the management of cancers of the uterine cervix, uterine corpus and ovaries, with rare or very rare histologies, and with localized or locally advanced stages.

[Cervical Pap smear in an epidemiologically exposed population: ideas, facts and arguments]. / Pratique du frottis cervico-utérin dans une population épidémiologiquement exposée : idées reçues, faits et arguments.

OBJECTIVES: To analyse the prevalence of abnormal papsmears in a primary care center and the screening practices. MATERIALS AND METHODS: Single-center retrospective study on 1,430 FCU performed in 1,251 patients between January 2009 and December 2011 with analysis of demographic, clinical and epidemiological chararacteristics of the women, and the monitoring of the patients with pathological papsmears. RESULTS: The study population was predominantly young (under 25), unmarried, nulliparous, and using contraception. Among the 1,244 FCU, nearly 90% of them were interpretable with the junction area interested. Nine percent were pathological with mainly ASC-US and L-SIL (3.5% and 4.5%) with no difference between more and less than 25years. Two factors were significantly associated with the presence of pathological papsmear: first intercourse before age 14 and smoking more than 10 cigarettes per day. Monitoring of patients with a pathological papsmear showed that 33% of patients had not an appropriate follow-up especially younger patients. DISCUSSION: To perform papsmear before 25 years because the patient has associated high risk HPV co-factors does not appear justified by the severity or frequency of cytological lesions, especially as it increases the financial cost and is responsible of potential deleterious actions such as conizations probably excessive among the youngest patients. Personalized monitoring of these patients with a pathological papsmear is required. The French practice recommendations on cervical cancer screening (first screening at age 25, 26 years cytological control then every 3 years up to 65 years in patients who have or have had sex) deserve to be applied in young and disadvantaged patients.

[Pleomorphic lobular intraepithelial neoplasia: clinical, histological and prognostic study of nine cases]. / Néoplasie lobulaire intra-épithéliale de type pléomorphe : analyse clinique, histologique et pronostique d'une série de neuf cas.

INTRODUCTION: Retrospective clinical, histological and prognostic study of nine cases of lobular intraepithelial neoplasia in its pleomorphic subtype (LIN-P). PATIENTS AND METHODS: Analysis of our center database with selection of nine cases of LIN-P from 140 files of patients who underwent surgical excision with a final diagnosis of LIN (2000 to 2011). The medical files were reviewed with a re-analysis of the mammograms and the histological slides. The outcome of the patients was also analyzed according to their clinical and operative data. RESULTS AND DISCUSSION: The average age at diagnosis was 63 years (later than common LIN [LIN-C]). All patients had mammograms classified ACR 4 and 5, mainly due to the presence of microcalcifications (seven cases) with a case of opacity associated with microcalcifications, and two other cases with only isolated opacities. The preoperative diagnosis of these lesions was difficult: five cases on nine core needle biopsies were reviewed and reclassified LIN-P after finding the presence of LIN-P on the surgical specimen. Associated invasive lesions were found in 55% of core needle biopsy and in 33% of cases of surgical resection specimen. The treatment included a wide surgical excision (five lumpectomies and four mastectomies with a patient who had two lumpectomies) with margins of more than 2mm: we noted a recurrence of LIN-P only in one case where margins were very close (1mm). The analysis of our cases confirms that LIN-P if they probably share the same origin as the LIN-C represent a particular form constituting a true precancerous condition warranting at least a wide surgical excision.

[MRI evaluation of residual breast carcinoma after neoadjuvant chemotherapy]. / Cancer du sein traité par chimiothérapie néoadjuvante: évaluation du reliquat tumoral par l'IRM mammaire.

PURPOSE: This study aims to evaluate the sensibility and specificity of MRI in the detection and size measuring of residual breast cancer in patients treated with neoadjuvant chemotherapy before surgery. PATIENTS AND METHODS: This is a retrospective study of 32 women, who underwent breast MRI before and after neoadjuvant treatment. MRI has been confronted to surgical pathology results. RESULTS: The sensibility of MRI to assess pathologic Complete Response (no invasive residual tumor) was excellent (100%) but the specificity was low (55,5%). There was no false negative case and four false positive cases (Two ductal carcinomas in situ and two scars-like fibrosis). When MRI outcomes were compared with the presence or absence of invasive or in situ residual carcinoma, only one false negative case was noticed (one "in situ" residual tumor). The correlation between tumor size measured by MRI and histopathology was low (r=0,32). Underestimations of tumor size were due to non-continuous tumor regression or invasive lobular carcinoma or association of invasive carcinoma and intra ductal breast cancer. Over estimations of tumor size were due to chemotherapy-induced changes. CONCLUSION: MRI is a sensitive but poorly specific method to assess the pathological complete response after neoadjuvant chemotherapy. Estimation of tumor size and detection of isolated residual in situ carcinoma are fare. Therefore, surgical intervention remains necessary whatever the MRI outcomes.

[Atypical epithelial hyperplasia of the breast: current state of knowledge and clinical practice]. / Hyperplasie épithéliale atypique du sein : bilan des connaissances et pratique clinique.

INTRODUCTION: The diagnosis of atypical epithelial hyperplasia (AEH) increases with breast cancer screening. AEH is divided in three groups: atypical ductal hyperplasia, columnar cell lesions with atypia, lobular neoplasia. The management of women with AEH is not consensual because of uncertainty about their diagnosis related to the type of the biopsy sampling (core needle biopsy or surgical excision) and their controversial clinical signification between risk marker and true precursor of breast cancer. MATERIAL AND METHODS: A systematic review of published studies was performed. Medline baseline interrogation was performed with the following keywords: atypical ductal hyperplasia, columnar cell lesions with atypia, lobular neoplasia, core needle biopsy, breast cancer, precursor lesion, hormonal replacement therapy. For each breast lesion, identified publications (English or French) were assessed for clinical practise in epidemiology, diagnosis and patient management. RESULTS: With immunohistochemistry and molecular studies, AEH seems to be precursor of breast cancer. But, epidemiological studies show low rate of breast cancer in women with AEH. AEH were still classified as risk factor of breast cancer. CONCLUSION: Because of high rate of breast cancer underestimation, surgical excision is necessary after the diagnosis of AEH at core needle biopsy. Surgical oncology rules and collaboration with radiologist are required for this surgery. A second operation was not required due to involved margins by AEH (except with pleiomorphic lobular neoplasia) because local control of breast cancer seems to be unchanged. Besides, hormonal replacement therapy for patient with AEH is not recommended because of lack of studies about this subject.

Inhibition of the histamine-induced Ca2+ influx in primary human endothelial cells (HUVEC) by volatile anaesthetics.

BACKGROUND AND OBJECTIVE: Vasoactive substances such as histamine, acetylcholine or ATP increase the [Ca2+]i of endothelial cells, which leads to the activation of nitric oxide synthase (eNOS). The NO produced by this enzyme relaxes the underlying smooth muscle. Evidence suggests that eNOS activation is dependent on agonist-induced Ca2+ entry. Recently we have shown that in human endothelial cells (HUVEC), this Ca2+ entry is sensitive to isoflurane. The objective here was to study the mechanism by which volatile anaesthetics can depress the histamine-induced Ca2+ entry into HUVEC cells. METHODS: HUVECs on coverslips were loaded with the Ca2+ indicator Fluo-3 and inserted in a gastight, temperature-controlled perfusion chamber. Excitation was at 488 nm and fluorescence signals were monitored with a confocal laser scanning microscope (MRC1024, Biorad). Direct measurement of the Ca2+ influx was with Mn2+ as surrogate for calcium at 360 nm in cells loaded with Fura-2. RESULTS: Addition of histamine induces a biphasic [Ca2+]i increase consisting of Ca2+ release from internal stores and a Ca2+ influx from the external medium (plateau phase). The plateau phase was dose-dependently inhibited by enflurane and sevoflurane (13.7 resp. 21.9% inhibition by 1 MAC anaesthetic). Direct measurement of the Ca2+ influx using the Mn2+ quench of the Fura-2 fluorescence gave similar results. The inhibition of the anaesthetics was not reduced by inhibition of the cGMP pathway, inactivation of protein kinase C, depolarization of the cells or the presence of specific Ca2+-dependent K+ channel inhibitors. Interestingly, unsaturated fatty acids inhibit the histamine-induced Ca2+ influx in a similar way as the volatile anaesthetics. CONCLUSIONS: Volatile anaesthetics dose-dependently inhibit the histamine-induced Ca2+ influx in HUVECs by a mechanism that may involve unspecific perturbation of the lipid bilayer.

Indirect activation of adenosine A1 receptors in cultured rat hippocampal neurons by volatile anaesthetics.

BACKGROUND AND OBJECTIVE: Volatile anaesthetics depress excitatory signal transmission by potentiating the inhibitory action of GABAA receptors and there is strong evidence that this is related with anaesthesia. Using primary hippocampal cultures we analyzed the possibility that the volatile anaesthetics enflurane and sevoflurane depress excitatory signal transmission by activation of adenosine A1 receptors. METHODS: Primary rat hippocampal cultures on 4 cm poly-L-lysine coated glass coverslips were loaded with the Ca2+-indicator fluo-3 and incorporated in a gastight, temperature-controlled perfusion chamber. The intracellular Ca2+-concentration was monitored with a confocal laser-scanning microscope (BioRad) using the 488 nm laser line of a krypton-argon laser for excitation and the Lasersharp Acquisition software for analysis. RESULTS: Continuous perfusion in Mg2+-free medium generated spontaneous synchronized calcium oscillations, which were dose dependently depressed by the volatile anaesthetics enflurane and sevoflurane (0.25-1 minimum alveolar concentration). Addition of 100 nmol of 2-chloro-N6-cyclopentyladenosine, a specific adenosine A1 receptor antagonist, partly reversed the anaesthetic-induced inhibition of the oscillation amplitude of the oscillating cells. The effect of the anaesthetics was mimicked by the addition of S-(p-nitrobenzyl)-6-thioguanosine, an adenosine transport inhibitor and by the addition of 5-amino-5-deoxyadenosine, an inhibitor of adenosine kinase. CONCLUSIONS: The volatile anaesthetics sevoflurane and enflurane activate adenosine A1 receptors in primary rat hippocampal cultures. This effect is mediated by liberation of adenosine most likely by an interaction of the volatile anaesthetics with adenosine transport or key enzymes in adenosine metabolism.

[Management system for patients requiring stereotactic macrobiopsies of the breast: report on 100 patients]. / Mise en place de la prise en charge des macrobiopsies stéréotaxiques mammaires: évaluation sur 100 patientes.

PURPOSE: The authors describe and evaluate the management system for patients requiring large core vacuum-assisted biopsies at a dedicated breast center. This process includes mandatory review of all requests by a multidisciplinary team. MATERIAL: and method. Patients were provided questionnaires to evaluate their degree of satisfaction with the management process. Results from biopsy and surgery were retrospectively reviewed. RESULTS: From the 100 patients included in the study (106 macrobiopsies), 95,28% of biopsies were informative. The degree of correlation between the histological diagnosis from biopsy and surgery was 86,95% for the 46 operated cases. The degree of acceptability by patients as well as medical and non-medical staff was satisfactory. CONCLUSION: The original feature of this process is the retrospective review of all charts after the histological results becomes available for final validation of the biopsy results and management. The results of the biopsy and the post biopsy management are provided by the initial referring physician, allowing optimal patient care and follow-up.

The volatile anesthetic isoflurane suppresses spontaneous calcium oscillations in vitro in rat hippocampal neurons by activation of adenosine A1 receptors.

Primary cultures of rat hippocampal neurons were loaded with the Ca(2+)-indicator fluo-3 and studied with a confocal laser microscope. In Mg(2+)-free medium the cultures showed spontaneous synchronized calcium oscillations. These oscillations derived from excitatory signal transmission by N-methyl-D-aspartate and (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid/kainate receptors and were modulated by gamma-aminobutyric acid(A) receptors. The oscillations were dose-dependently depressed by adenosine (IC50=2 microM) or by 2-chloro-N6-cyclopentyladenosine a specific adenosine A1 receptor agonist (IC50=40 nM). These effects were reverted by 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), a specific adenosine A1 receptor antagonist. The volatile anesthetic isoflurane also depressed these spontaneous calcium oscillations in a dose dependent manner (IC50=0.25 MAC, Minimum Alveolar Concentration). The isoflurane-induced inhibition was partly reversed in 29-38% of the neurons by DPCPX, indicating that the anesthetic activates this receptor possibly by increasing the extracellular concentration of adenosine.

Treatment of cells with detergent activates caspases and induces apoptotic cell death.

Due to their amphiphilic properties, detergents readily disrupt cellular membranes and cause rapid cytolysis. In this study we demonstrate that treatment of cells with sublytic concentrations of detergents such as Triton X-100, Nonidet P-40, n-octylglucoside and the bile salt sodium deoxycholate induce typical signs of apoptosis including DNA fragmentation and cleavage of poly(ADP-ribose) polymerase molecules. The detergent concentration required for apoptosis was below the critical micellar concentration. Induction of apoptosis was not restricted to human cells but similarly occurred in a variety of other vertebrate cell lines. Unstimulated peripheral blood mononuclear cells were susceptible to apoptosis induction by detergent suggesting that apoptosis in this circumstance is not mediated by CD95. Cell death was not due to influx of calcium from the medium. Apoptosis was blocked and cytolysis prevented by treatment with peptide inhibitors of caspases. These findings suggest a process of apoptosis that is initiated upon nonspecific alterations at the cell membrane level. Physiologic correlates of this process still have to be defined.

Sphingosine-1-phosphate induces a Ca2+ signal in primary rat astrocytes and a Ca2+ signal and shape changes in C6 rat glioma cells.

Treatment of rat glioma C6 cells with the beta-adrenergic agonist L-isoproterenol leads to a rise in cAMP level and a subsequent change in cell morphology from an epithelial to an astrocytic type of appearance. This morphological response is reverted by the addition of sphingosine-1-phosphate (S1P) with an EC50 of 10 nM. In rat glioma C6 cells loaded with the Ca2+ indicator Fura-2, S1P evoked Ca2+ release from internal stores and Ca2+ influx from the external medium. Half-maximal stimulation of the Ca2+ increase was 10-20 nM. A similar Ca2+ signal was observed in primary rat astrocytes loaded with the Ca2+ indicator fluo-3. Pretreatment of the C6 cells with PMA (162 nM) prevented both the S1P-induced Ca2+ increase and the morphological reversion. Ca2+ ions therefore seem essential for the morphological reversion by S1P. Pretreatment of the cells with the Clostridium botulinum C3 exoenzyme did not affect the reversion of the morphological response by S1P, indicating that the small GTP-binding protein Rho is not involved in the S1P-induced reversion.

The volatile anesthetic enflurane activates capacitative Ca2+ channels in rat glioma C6 cells.

(1) The volatile anaesthetics halothane and enflurane released Ca2+ from thapsigargin sensitive stores in rat glioma C6 cells, but only enflurane induced a significant Ca2+ influx. (2) The reason for this can be explained by a different inhibitory effect of the anesthetics on the capacitative Ca2+ influx. (3) Halothane inhibited the capacitative Ca2+ influx with an IC50 of 1.9 vol.%, whereas enflurane only marginally affected the ion flux through the channel.

Malignant lymphoma of mucosa associated lymphoid tissue: a new etiology of amyloidosis.

Non Hodgkin Malignant lymphomas (NHML) of mucosa associated lymphoid tissue (MALT) are known to have multiple involvement of the digestive tract. We report one case, presenting with an infiltrative process of the jejuno-ileum, associating lymphoplasmacytoid proliferating cells and amyloidosis. The plasmacytoid cells expressed Alpha and scarce Mu heavy chains, and lambda light chain. Lympho-epithelial lesions were more obvious at the second site of involvement, in the gastric mucosa. The amyloid substance was negative with the Amyloid A component antibody and gave a background noise with Alpha, Mu and lambda chains. No similar report of amyloidosis associated with MALT NHML has been found in the literature.

Influence of cadmium ions on endothelin-1 binding and calcium signaling in rat glioma C6 cells.

Cadmium ions did not influence the binding of endothelin-1 (ET-1) to its receptor on the surface of rat glioma C6 and rat aorta A10 cells. This was studied (a) by the binding of 1251-ET-1 to intact cells in the absence or presence of cadmium (Cd2+) and (b) by analysis of the receptor/ET-1 complex after crosslinking with disuccinimidyl suberate (DSS) or ethylene glycol-bis-(succinimidyl succinate) (EGS) on SDS PAGE. Using Fura-2 and Quin-2 loaded C6 rat glioma cells, it was shown that Cd2+ ions strongly interfered with the ET-1 induced Ca(2+)-influx in C6 glioma cells (IC50 approximately 10 microM).

Per operative localization of a carcinoid tumour of the breast using indium-111 pentetreotide and a nuclear surgical probe.

A 69-year-old woman presented with a single enlarged lymph node in the left axilla. Clinical examination and other investigations, including various imaging methods, failed to reveal the primary tumour. However, indium-111 pentetreotide scan revealed a site of uptake in the anterior region of the left thorax. Peroperative imaging with 111In-pentetreotide confirmed the tumour uptake and use of a nuclear surgical probe allowed precise localization of the tumour, which was completely resected.

Plasmacytoid CD8 lymphoma: morphologic and immunologic characterization.

This study describes a 79 year-old female suffering from fever and lymphadenopathy. A lymph node biopsy showed diffuse infiltration of medium-sized cells with plasmacytoid features. The immunologic phenotype determined by cytometric analysis and immunochemistry showed suppressor T antigen (CD2, CD3, CD7, CD8) expression. Absence of CD5 expression characterized this abnormal T cell proliferation. Gamma T cell receptor rearrangement without immunoglobulin heavy-chain gene rearrangement confirmed the T lineage of these plasmacytoid cells and their clonality. Immunological studies are necessary for identification of this T lymphoma with B microscopic findings.