[Multiple myeloma : an overview of advances in biology and treatment]. / Le myélome multiple : un tour d'horizon des nouveautés dans sa biologie et son traitement.

Multiple myeloma is the second most common hematological malignancy, characterized by an uncontrollable proliferation of clonal plasma cells. Although progresses in understanding its pathobiology and its treatment are made every day, it remains incurable. Since myeloma is more and more common, especially in the elderly, we would like to propose an overview of its pathobiology, diagnostic criteria and treatment «guidelines¼.

Deuxième pathologie hématologique la plus fréquente, le myélome multiple est une maladie plasmocytaire qui reste actuellement incurable. Pourtant, tous les jours, des progrès sont effectués au niveau de la compréhension de sa physiopathologie et de l'élaboration de stratégies de traitement. Vu son caractère de plus en plus répandu, surtout chez la personne âgée, nous proposons un tour d'horizon de sa physiopathologie, de ses critères diagnostiques et des grandes lignes de sa prise en charge.

Detection of free-living amoebae in domestic cats with and without naturally-acquired keratitis.

Pathogenic free-living amoebae, most notably Acanthamoeba spp., are important pathogens of the human cornea. The importance of infection with free-living amoebae in cats with keratitis is currently unclear. The aim of this study was to determine the frequency of amoeba detection in corneas of cats with naturally-acquired keratitis and in the ocular surface microflora of cats without ocular disease. Clinical ophthalmic and in vivo corneal confocal microscopic examinations were performed on 60 cats with keratitis. Corneal scrapings were analyzed by amoeba culture; cytological evaluation; and Acanthamoeba, Hartmannella, and Vahlkampfia PCR assays. Following ophthalmic examination, conjunctival specimens collected from 60 cats without clinically apparent ocular disease were analyzed similarly. In one cat with ulcerative keratitis, amoeba cysts and trophozoites were detected by in vivo corneal confocal microscopy; an Acanthamoeba sp. was isolated from corneal specimens and detected by Acanthamoeba PCR assay; and suppurative corneal inflammation was present cytologically. An Acanthamoeba sp. was isolated from conjunctival specimens from one cat without clinically apparent ocular disease, but with suppurative inflammation demonstrated cytologically. Both Acanthamoeba isolates belonged to the T4 genotype. Naegleria-like amoebae were isolated in samples from two cats with keratitis and seven cats without clinical ocular disease, but amoebae were not detected by the other assays in these samples. Amoeba detection by culture was significantly (P = 0.01) associated with cytologically diagnosed corneoconjunctival inflammation. This study identified naturally-acquired Acanthamoeba keratitis in cats. Detection of Naegleria-like amoebae in samples from cats with and without keratitis is of uncertain pathological significance.

Survivin drives tumor-associated macrophage reprogramming: a novel mechanism with potential impact for obesity.

PURPOSE: Recent studies point to adipose-derived stem cells (ASCs) as a link between obesity and cancer. We aimed to determine whether survivin, which is highly secreted by ASCs from subjects with obesity, might drive a pro-tumoral phenotype in macrophages. METHODS: The effect of ASC conditioned medium on the macrophage phenotype was assessed by expression studies. Survivin intracellular localization and internalization were examined by subcellular fractionation and immunofluorescence, respectively. Loss- and gain-of-function studies were performed using adenoviral vectors, and gene expression patterns, migration and invasion capacities of cancer cells were examined. Heterotypic cultures of ASCs, macrophages and cancer cells were established to mimic the tumor microenvironment. Survivin-blocking experiments were used to determine the impact of survivin on both macrophages and cancer cells. Immunohistochemical analysis of survivin was performed in macrophages from ascitic fluids of cancer patients and healthy controls. RESULTS: We found that obese-derived ASCs induced a phenotypic switch in macrophages characterized by the expression of both pro- and anti-inflammatory markers. Macrophages were found to internalize extracellular survivin, generating hybrid macrophages with a tumor-associated phenotype that included secretion of survivin. Exogenous expression of survivin in macrophages generated a similar phenotype and enhanced the malignant characteristics of cancer cells by a mechanism dependent on survivin phosphorylation at threonine 34. Survivin secreted by both ASCs from subjects with obesity and tumor-associated macrophages synergistically boosted the malignancy of cancer cells. Importantly, survivin was mainly detected in ascites-associated macrophages from patients with a malignant diagnosis. CONCLUSION: Our data indicate that survivin may serve as a molecular link between obesity and cancer and as a novel marker for tumor-associated macrophages.

Tyrosine kinase inhibition is an important factor for gene expression of CRTH2 in human eosinophils and lymphocytes: A novel mechanism for explaining eosinophils recruitment by the neuro-immune axis in allergic rhinitis.

We recently shown a novel neuro-immune competition between vasoactive intestinal peptide (VIP) and PGD2 for CRTH2 receptor, and that genistein augmented VIP and PGD2-induced eosinophil chemotaxis. However, there are neither studies on the CRTH2 gene expression in allergic rhinitis (AR) nor in the effect of tyrosine kinase inhibitors in CRTH2 gene regulation. Our Objectives were to study the gene expression modulation of CRTH2 receptor in AR patients and the effect of tyrosine kinase inhibitors (TKIs) on CRTH2 gene modulation. Nasal provocation tests, ELISA, qRT-PCR, western blot, flow cytometry and chemotaxis assays in modified micro-Boyden chambers, were all used, to achieve our objectives. Herein we show that AR patients increased the amounts of VIP and PGD2 in their nasal secretions in the early phase reaction, however CRTH2 gene expression from leukocytes recovered in their nasal secretions was upregulated only during the late phase reaction. The TKIs; Genistein, Erbstatin and Herbimycin A, induced the gene expression of CRTH2 and increased the protein content of CRTH2 in both human lymphocytes and eosinophils. This was functional as PGD2/VIP-induced eosinophil chemotaxis was augmented by the TKIs and inhibited by pervanadate, the tyrosine phosphatase inhibitor. These results open channels for therapeutic modalities targeting CRTH2 molecules in AR.

[Current management of marginal zone lymphomas]. / Prise en charge actueLe du lymphome de la zone marginale.

Marginal zone lymphomas (MZL) encompass three sub-types: MALT (Mucosae Associated Lymphoid Tissue) MZL, nodal MZL and splenic MZL. Immunophenotyping is essential for accurate diagnosis. Helicobacter Pylori is frequently associated with gastric localizations and its eradication can be sufficient for cure. Treatment of nodal MZL is similar to that of follicular lymphoma. Eradication of hepatitis C virus, frequently associated with splenic MZL development, can be sufficient. Without HCV infection, splenectomy constitutes first line therapy. As other indolent lymphomas, disseminated MZL are incurable and treatment should be started only in symptomatic patients.

[Diffuse large B cell lymphoma: management in 2012]. / Prise en charge du lymphome B diffus à grandes cellules en 2012.

Diffuse Large B Cells Lymphoma (DLBCL) is the most common non-Hodgkin lymphoma and comprises a large number of different entities with different clinico-pathological characteristics. The role of positron emission tomography is essential during the initial staging and post treatment assessment, and potentially at early- or mid-treatment evaluation of response. First line therapy comprises immuno-chemotherapy with rituximab and different cytotoxic agents that differ for components, dosages and frequency of administration taking worldwide-recognized pre-treatment prognostic variables into account. After relapse, peripheral blood stem cells transplantation remains the only chance of cure. This review attempts to summarize the current state of our knowledge by highlighting the leads pursued to further improve current therapeutic results.

[How I treat... Acute myeloid leukemia in older patients with good performance status]. / Comment je traite...La leucémie myéloblastique aiguë (LMA) du sujet âgé en bon état général.

This article describes the treatment of acute myeloid leukemia in older patients with good performance status, and then discusses briefly some future therapeutic perspectives.

Prostaglandin E2 receptor distribution and function in the gastrointestinal tract.

Prostaglandin E2 (PGE2) is one of the most important biologically active prostanoids found throughout the gastrointestinal tract. Despite the fact that PGE2 regulates many physiological functions of the gut including mucosal protection, gastrointestinal secretion and motility, it is implicated in the pathophysiology of inflammatory bowel diseases (IBD) and colorectal neoplasia. The varied biological functions exerted by PGE2 are through the pharmacologically distinct, G-protein coupled plasma membrane receptors termed EP receptors. Disruptions of various prostanoid receptor genes have helped in unravelling the physiological functions of these receptors. To date, all four subtypes of EP receptors have been individually knocked out in mice and various phenotypes have been reported for each subtype. Similarly, in vitro and in vivo studies using EP receptor agonists and antagonists have helped in uncoupling the diverse functions of PGE2 signalling involving distinct EP receptors in the gut. In this review, we will summarize and conceptualize the salient features of EP receptor subtypes, their regional functions in the gut and how expressions of EP receptors are altered during disease states.

CD26, adenosine deaminase, and adenosine receptors mediate costimulatory signals in the immunological synapse.

Adenosine deaminase (ADA), a protein whose deficit leads to severe combined immunodeficiency, binds to the cell surface by means of either CD26, A(1) adenosine receptors, or A(2B) adenosine receptors. The physiological role of these interactions is not well understood. Our results show that by a 3-fold reduction in the EC(50) for the antigen, ADA potentiated T cell proliferation in autologous cocultures with antigen-pulsed immature or mature dendritic cells. Costimulation was not due to the enzymatic activity but to the interaction of ADA-CD26 complexes in T cells with an ADA-anchoring protein in dendritic cells. From colocalization studies, it is deduced that ADA colocalizing with adenosine receptors on dendritic cells interact with CD26 expressed on lymphocytes. This costimulatory signal in the immunological synapse leads to a marked increase (3- to 34-fold) in the production of the T helper 1 and proimmflamatory cytokines IFN-gamma, TNF-alpha, and IL-6.

Epidemiological survey of melanoma in the Auvergne region (France): is there an increased incidence in Auvergne?

To assess the efficiency of melanoma screening and prevention campaigns in the Auvergne region (France), cases of melanoma have been recorded since 1st June 1998. The epidemiological follow-up of melanoma was carried out using two sentinel networks; one involving the pathologists, and the other, the dermatologists of the region. Incidence was calculated using the capture-recapture method, by cross-matching the data supplied by both dermatologists and pathologists. Between June 1st 1998 and December 31st 2000, 363 cases of melanoma were recorded. The crude incidence rate of melanoma per 100,000 person-years was 17.1 for all melanomas and 14.6 for invasive melanomas. These rates of incidence were higher than the estimated national rate of France, and were close to incidences found in countries of Northern Europe. This might be explained by an increase in screening for melanoma, by more precise estimation of the incidence due to the capture-recapture method, or by geographic factors (mountainous area). An answer may be provided by following the variation in time of incidence and thickness of melanomas; the increase in the number of thin (low Breslow index) melanomas corresponding with increased screening.

Cigarette smoking and attention: processing speed or specific effects?

RATIONALE: It has been evidenced that nicotine acts on some dimensions of human attention. OBJECTIVE: This study was carried out to test whether the positive effects of nicotine usually observed on the posterior system are specific or should rather be explained in terms of an effect of nicotine on eye movement velocity. METHODS: Ten participants were submitted to four tasks assessing attention. The tasks were borrowed from Zimmermann and Fimm's Battery for the Assessment of Attention: alert, eye movements, visual search and incompatibility. The order of the different tasks was balanced among participants. A within-subjects repeated-measure design was used. Participants received a 0.9-mg or 0.1-mg nicotine cigarette. The 0.1-mg cigarette was used as control. The order of administration of doses over sessions was counterbalanced. During the testing day, volunteers smoked their own cigarette and then waited 3 h without smoking. At the end of this abstinence period, participants completed the baseline tests before smoking an experimental cigarette ad libitum. They were then tested again. RESULTS: Participants who received nicotine appeared to respond faster in an eye movement task--a task associated with a non-elaborated attentional process. Similarly, their alert state improved. On the contrary, no effect of nicotine was observed in the incompatibility task and in the visual search task depending on elaborated attentional process. CONCLUSIONS: Data support previous observations and suggest that, first, non-elaborated information processing appeared to be more sensitive to nicotine and, second, this effect is not due to a velocity factor.

[Iodine 131 uptake by a bronchogenic cyst in a patient with differentiated carcinoma of the thyroid gland]. / Fixation à l'iode 131 d'un kyste bronchogénique chez une patiente ayant un carcinome différencié thyroïdien.

BACKGROUND: After thyroidectomy for differentiated thyroid carcinoma, extracervical uptake of iodine 131 is suggestive of metastasic dissemination. False positives can however occur. CASE REPORT: Differentiated thyroid carcinoma was found in a female patient with a non-functional nodule. Two years after subtotal thyroidectomy and an ablative dose of iodine 131, the whole body scan showed abdominal mediastinal uptake with low serum thyroglobulin level. Considering the possibility of tumor recurrence or lymph node metastasis, the mass was excised. The histology diagnosis was mediastinal bronchogenic cyst. DISCUSSION: To date, iodine uptake in a bronchogenic cyst has not been reported among other false-positives previously described. The pathophysiology of this iodine 131 uptake in a bronchogenic cyst is still unknown: the presence of NIS symporter or a protein which can organify iodine in the mucus cells of the cyst remains to be proven.

Defective functional activity and accelerated apoptosis in neutrophils from children with cancer are differentially corrected by granulocyte and granulocyte-macrophage colony stimulating factors in vitro.

We have previously shown that polymorphonuclear leucocytes (PMN) harvested from children with cancer and exposed to chemotherapy exhibit defective bactericidal activities against both Gram-positive and Gram-negative microorganisms as well as accelerated apoptosis. In this study, PMN from children with cancer were evaluated to compare in vitro the corrective effects of the two myeloid colony stimulating factors G-CSF and GM-CSF on these defective pathways. Both G-CSF and GM-CSF were able to increase the defective bactericidal activities against S. aureus and E. coli. However, GM-CSF was consistently superior to G-CSF in correcting PMN microbicidal activity; this correction was incomplete since it did not reach the level observed in normal PMN exposed to GM-CSF. The accelerated apoptosis of PMN was not affected by G-CSF. In contrast, GM-CSF significantly prolonged the survival of the PMN although it did not reach the level of survival observed with normal PMN exposed to GM-CSF. These observations were consistent with other studies indicating that in PMN, microbicidal activities and apoptosis are differentially sensitive to the myeloid growth factors G-CSF and GM-CSF.

Ferritin-associated iron induces neutrophil dysfunction in hemosiderosis.

Neutrophils (PMNs) from patients with secondary iron overload have an increased iron and ferritin content as well as a phagocytosis defect. Several serum components might be incriminated in the cellular iron accumulation. We therefore compared the effects on the PMN phagocytosis of total serum as well as the ferritin and transferrin fractions of serum derived from patients with thalassemia major and healthy control subjects. An incubation system of PMNs was developed. PMN phagocytosis was measured before and after incubation. Total serum from patients with thalassemia induced a defect that was prevented by co-incubation with deferoxamine (DFO). Gel-filtration chromatography was performed to separate the serum fraction containing transferrin and albumin from that containing ferritin. The transferrin-albumin fraction had no effect on PMN phagocytosis. On the contrary, the ferritin fraction of normal serum was deleterious to PMN phagocytosis, and the same fraction from thalassemic serum decreased PMN phagocytosis even more. Co-incubation with DFO or catalase improved this defect. Moreover, a cellular increase in the L-type subunit of ferritin was observed after the incubation of PMNs with the ferritin-containing fraction from thalassemic serum. In conclusion, serum from patients with thalassemia is toxic to PMNs, and this toxicity is due to ferritin-associated iron.

Prolonged but reversible neutrophil dysfunctions differentially sensitive to granulocyte colony-stimulating factor in children with acute lymphoblastic leukaemia.

Treatment of average-risk acute lymphoblastic leukaemia (ALL) in children consists of 6 months of intensive chemotherapy followed by 18 months of maintenance therapy. Polymorphonuclear leucocyte (PMN) functions from children with ALL were studied in order to evaluate and compare the toxicity of the initial intensive treatment with the toxicity of the subsequent less intensive maintenance treatment. H2O2 and O2- production, evaluated by chemiluminescence, were significantly decreased during the intensive period but returned to normal values when maintenance therapy began. In contrast, bactericidal activity against Gram-positive and Gram-negative microorganisms remained at low levels throughout the treatment but returned to normal values in patients off chemotherapy. PMN from patients on maintenance therapy exhibited an excess of morphological changes associated with apoptosis. This was confirmed by standard two-colour flow cytometry which revealed an increase in the number of hypodiploid cells, and increased expression of membrane phosphatidylserine together with a drastic reduction in the expression of the Fcgamma receptor IIIB (CD16). These defective PMN were differentially sensitive to the effects of granulocyte colony stimulating factor (G-CSF): G-CSF induced similar increase in chemiluminescence in control and patient PMN; GSF partially corrected the defective bactericidal activity; G-CSF did not affect the accelerated PMN apoptosis. These observations indicate that ALL children undergoing chemotherapy present PMN defective functions which are partially sensitive or even resistant to G-CSF.

Case study of quality assurance in the administration of chemotherapy.

The purpose of the study was to monitor the quality of chemotherapy administration within the department of oncology, of the university hospitals in Leuven (Belgium), by focusing on prescription and documented administration of chemotherapy. First, the actors and phases of the process were identified. Then selected patient records of three different types of chemotherapy were retrospectively analysed for 453 chemotherapy administrations. Study results indicated an important need to standardize the nursing and medical guidelines concerning chemotherapy administration. A formal task force was established to work on a multidisciplinary basis. The goals were to improve the routine process by identifying practical problems at any level and to standardize procedures by replacing all poorly defined "habits" by well-structured guidelines.

Defective polymorphonuclear leukocyte functions in children receiving chemotherapy for cancer are partially restored by recombinant human granulocyte colony-stimulating factor in vitro.

Granulocyte colony-stimulating factor (G-CSF) has important direct and priming effects on different functions of normal mature polymorphonuclear leukocytes (PMNL). Previous study has shown an alteration in respiratory burst and bactericidal activities of PMNL harvested from children with cancer treated with chemotherapy. The present study evaluates the possibility that recombinant human (rh) G-CSF could correct these defective functions in vitro. Free radical formation in defective PMNL was enhanced by rhG-CSF to a level similar to that found in normal PMNL primed by rhG-CSF. The defective bactericidal activity against Escherichia coli and Staphylococcus aureus was also corrected. This bactericidal activity was not different from that observed in normal PMNL primed by rhG-CSF. In conclusion, correction of the altered free radical-formation pathway by rhG-CSF in these cells contributed to the restoration of normal bactericidal activity against both gram-positive and gram-negative microorganisms.

Granulocyte functions in children with cancer are differentially sensitive to the toxic effect of chemotherapy.

To analyze the toxicity associated to chemotherapy upon granulocytes, different functional assays were performed, within days of drug exposure and at time of bone marrow recovery, on polymorphonuclear neutrophils (PMN) from children with cancer. There were no significant postchemotherapy changes in the expression of the different receptors studied nor in the phagocytosis of Staphylococcus aureus 42D. By contrast, a significant decrease was observed in H2O2 production in PMN recently exposed to chemotherapy with both cytofluorometric and chemiluminescence assays. There was also a decrease in the production of O2- and in chemotaxis; finally, the intracellular killing of S. aureus 42D and Escherichia coli was reduced. In patients having recovered from drug-induced bone marrow aplasia, PMN functions were found to be normal except for bactericidal activity which was still defective. The observations indicate that, in patients exposed to chemotherapy, some PMN functions are transiently altered, whereas microorganism cell killing is continuously impaired.

Role of nurses in cancer chemotherapy administration. Retrospective record analysis to improve role performance.

The purpose of this quality assurance project in the University Hospitals in Leuven, Belgium, was to describe, analyse and improve the actual routine practice of chemotherapy administration. The article focuses on analysis and improvement of role performance of nurses. The process of chemotherapy was systematically assessed by means of a retrospective analysis of patient records. This was done for 61 patient records receiving 453 chemotherapy administrations. Five aspects of the role of oncology nurses were described and analysed: data collection for prescription of chemotherapy, communication of instructions, preparation of the cytotoxic treatment, administration of cytotoxics and post-chemotherapy assessment. Data analysis showed variability in relation to several role aspects. Standardization of procedures and information was introduced to improve role performance in several areas.

Prognostic value of concentration of pregnancy-specific beta 1-glycoprotein (SP1) in serum of patients with breast cancer.

Pregnancy-specific beta 1-glycoprotein (SP1) was assayed by particle counting immunoassay in serum from 46 healthy female blood donors, 33 patients with benign mastopathy and 84 patients with breast cancer before operation and during follow-up. Values greater than 1 micrograms/1 were found more frequently with benign mastopathies (11/33) and in patients with breast cancer at stage 2 (20/48), 3 (4/9), and 4 (7/10) than in healthy female blood donors (3/46). The survival rate after 4 years was significantly lower in patients with SP1 level greater than 1 microgram/1 before tumor resection (52% vs. 87%). The difference remained significant when only patients in stage 2 were taken into account (57% vs. 85%). A highly significant (r = 0.64; N = 46) negative correlation was observed between the concentration of SP1 in serum and the concentration of estrogen receptor in the tumor. The longitudinal study of patients in stage 2 indicated that, of the 15 whose SP1 concentration fell below 1 microgram/1 after operation, 14 survived over 4 years whereas during the same period, 9 of the 10 patients whose SP1 value remained higher than 1 microgram/1 died.