[The accreditation of a surgical pathology and somatic genetic laboratory (LPCE, CHU of Nice) according to the ISO 15189 norm: Sharing of experience]. / L'accréditation selon la norme ISO 15189 d'un laboratoire de pathologie et de génétique somatique (LPCE, CHU de Nice) : retour d'expérience.

Accreditation is going to be vital and unavoidable in the medium term for medical biology laboratories in France. This accreditation will certainly condition the authorization to conduct biological testing in the health care system. All the biological specialities are now affected by this procedure, including the somatic genetics. The anatomo-pathology, which is a medical speciality in France, may be also concerned by the accreditation. However, the nature and the practices of this specialty increase the complexity of this approach to be implemented according to the standard requested by the authorities, i.e. the ISO 15189 normative standard (standard on "specific requirements for quality and competence for medical biology analysis laboratories"). The present article recounts the experience of a hospital laboratory (LPCE, Nice University Hospital) composed of a surgical pathology and a somatic genetics unit: (1) in the accreditation process according to the ISO 15189 standard, (2) at the time of the audit made by the team of "COFRAC" evaluators, and, (3) in evaluating the strategy implemented following the audit.

[What is new in 2010 for electron microscopy in surgical pathology?]. / Que reste t-il de la microscopie électronique pour le diagnostic anatomopathologique en 2010 ?

In the last decades, several ancillary methods, such as immunohistochemistry and molecular biology techniques, have increased the possibilities for the diagnosis and to evaluate the prognosis of lesions observed in a laboratory of pathology. Conversely, the impact of another method largely used a couple of years ago in a laboratory of pathology, the electron microscopy (EM), is currently limited. EM is a difficult, quite expensive and long method, which requires technicians with a high qualification. Therefore, EM is currently rarely available at the hospital in a laboratory of pathology and is essentially established in research centers. However, EM is still an essential tool for the surgical pathologist. This method allows in some circumstances to confirm or, more rarely, to make the diagnosis of a couple of tissular and cellular lesions observed in human pathology. EM is also an interesting method to better understand the etiopathogenesis of emerging human diseases, in particular of emerging infectious diseases. In this review, we report the main indication of EM in human pathology, we lay special emphasize in certain infectious diseases and neoplasia.

[Role of the surgical pathology laboratory in the pre-analytical approach of molecular biology techniques]. / Rôle du laboratoire d'anatomie pathologique dans l'approche pré-analytique des examens de biologie moléculaire réalisés en pathologie tumorale.

The advent of the targeted cancer therapies administered to patients, according to the results of molecular biology techniques (in particular, in situ hybridization, "polymerase chain reaction" amplification and sequencing), has modified the practice of the surgical pathology laboratories. The necessity to answer to the needs of physicians for optimizing the medical care for patients who develop cancer has led to a policy of national debate, spurred by the National Institute of Cancer (INCa), in order to implement new procedures in the pathology laboratories. Thus, in addition to the structuring of molecular biology platforms and their labeling by INCa, the upstream control of the steps present between resection of tumor samples and molecular analysis has proved to be crucial. Indeed, the quality of this upstream time, called "pre-analytical" phase, determines the reliability of the molecular biology results and therefore the therapeutic strategy. We describe here the main steps to be checked in the pre-analytical phase. The optimization of this pre-analytical phase within the surgical pathology laboratory aims to reduce or render insignificant the risk of errors of molecular biology tests. These errors can indeed lead to false negative or false positive results whose therapeutic consequences can be particularly harmful to patients with cancer.

Candidate mechanisms for capecitabine-related hand-foot syndrome.

AIMS: The oral fluoropyrimidine prodrug capecitabine is widely used in oncology. Capecitabine was designed to generate 5FU via the thymidine phosphorylase (TP) enzyme, preferentially expressed in tumoral tissues. Hand-foot syndrome (HFS) is a limiting toxicity of capecitabine. A pilot study on healthy volunteers was conducted in order to test the hypothesis that the occurrence of HFS could be related to tissue-specific expression of drug-metabolizing enzymes in the skin of the palm and sole. To this end, the expression of TP (activating pathway), dihydropyrimidine dehydrogenase (DPD, catabolic pathway) and cell proliferation (Ki67) were measured in the skin of the palm (target tissue for HFS) and of the lower back (control area). METHODS: Two paired 4-mm diameter punch biopsy specimens (palm and back) were taken in 12 healthy volunteers. Immunohistochemical analyses were performed on frozen tissues. RESULTS: Proliferation rate (Ki67 staining) was significantly higher in epidermal basal cells of the palm compared with the back (P = 0.008). Also, TP and DPD expression were significantly greater in the palm relative to the back (P = 0.039 and 0.012, respectively). TP and Ki67 expression were positively and significantly correlated in the palm. CONCLUSIONS: The high proliferation rate of epidermal basal cells in the palm could make them more sensitive to the local action of cytotoxic drugs. TP-facilitated local production of 5FU in the palm during capecitabine treatment could explain the occurrence of HFS. This observation may support future strategies to limit the occurrence of HFS during capecitabine therapy.

[Antiretroviral treatments-related lipodystrophy syndrome: clinico-pathological findings]. / Le syndrome lipodystrophique associé aux traitements antirétroviraux: aspects anatomo-cliniques.

Effective therapies are available that can stop or slow down the progression of HIV infection. Highly active antiretroviral therapy (HAART) is a combination of antiretroviral drugs such as viral protease inhibitors or nucleoside-analogue reverse-transcriptase inhibitors. Among the side effects due to these drugs, lipodystrophy is a pathology characterized by fat wasting in face and limbs, accumulation of visceral fat, breast adiposity, cervical fat-pads, hyperlipidemia (hypertriglyceridemia and hypercholesterolemia), insulin resistance, and lactic acidemia. The main clinical features include peripheral fat loss (presumed lipoatrophy in the face, limbs, and buttocks) and central fat accumulation (within the abdomen, breasts, and over the dorsocervical spine, so-called "buffalo hump"). Histopathological features disclose a peculiar type of involutional lipodystrophy. Skin biopsies generally show thinning of the subcutaneous fat, associated with fibrosis, lipogranuloma and sometimes vessel proliferation. There is still an open debate concerning the precise responsibility of HAART as well as the metabolic pathways and mechanisms that are involved in the onset of lipodystrophy. There is no proven therapy for any component of lipodystrophy syndrome.

Control of the autophagy maturation step by the MAPK ERK and p38: lessons from environmental carcinogens.

Macroautophagy (hereafter referred to as autophagy) is the major degradative pathway of long-lived proteins and organelles that fulfils key functions in cell survival, tissue remodeling and tumor suppression. Consistently, alterations in autophagy have been involved in a growing list of pathologies including toxic injury, infections, neurodegeneration, myopathies and cancers. Although critical, the molecular mechanisms that control autophagy remain largely unknown. We have recently exploited the disruption of autophagy by environmental carcinogens as a powerful model to uncover the underlying signaling pathways. Our work published in Cancer Research revealed that the sustained activation of the MAPK ERK pathway by the carcinogen Lindane or the MEK1(+) oncogene alters autophagy selectively at the maturation step resulting in the accumulation of large defective autolysosomes. Consistent with our findings, a similar defect is observed with other common xenobiotics such as dichlorodiphenyltrichloroethane and biphenol A that specifically activate ERK. Conversely, Pentachlorophenol that activates both ERK and p38, fails to induce autophagic vacuolation. In addition, evidence is provided that abrogation of p38 by SB203580 is sufficient to interfere with the normal autophagic maturation step. Altogether, these findings underscore the critical role played by MAPK ERK and p38 in the tight control of the autophagy process at the maturation step.