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Resume Introduction Le granulome annulaire profond est une variete peu frequente de granulome annulaire. Elle est rencontree surtout chez l’enfant et atteint principalement les faces anterieures des jambes et le dos des pieds ; sa localisation cephalique est rare. Nous rapportons trois cas de granulomes annulaires profonds multiples de l’enfant exclusivement localises a l’extremite cephalique. Observations Cas 1 : un garcon de 6 ans avait sept nodules cutanes profonds de 1 a 2 cm, couleur chair, insensibles a la palpation, de consistance dure et fixes au plan profond. Les lesions etaient groupees sur la moitie anterieure de la fosse temporale gauche. Une regression spontanee de trois nodules etait observee dans le mois suivant la biopsie cutanee, mais ceux-ci recidivaient quelques mois plus tard. Cas 2 : une fillette de 4 ans avait cinq nodules cephaliques profonds centimetriques, couleur de peau normale, sur la fosse temporale droite. L’enfant etait perdue de vue apres la biopsie. Cas 3 : un nourrisson de 4 mois avait une quinzaine de nodules cutanes profonds groupes de facon lineaire sur le front en regard de la fosse temporale gauche. L’evolution etait marquee par la regression spontanee des nodules un mois apres la biopsie. Dans les trois cas, l’examen histologique confirmait le diagnostic de granulome annulaire profond. Discussion Peu d’observations de granulomes annulaires profonds multiples cephaliques isoles de l’enfant ont ete publiees. Le diagnostic differentiel est large, incluant des tumeurs malignes ; aussi une confirmation histologique est-elle generalement indispensable. Le traitement n’est pas codifie ; une attitude abstentionniste et un simple suivi clinique peuvent souvent etre preconises.

Introduction La survenue d’une insuffisance renale aigue au cours du traitement des leucemies aigues est le plus souvent d’origine pre-renale ou causee par une necrose tubulaire aigue. La persistance d’une insuffisance renale severe est a l’origine d’une morbi-mortalite sur-ajoutee. Nous presentons une etiologie atypique d’insuffisance renale chez un patient presentant une leucemie aigue myeloblastique. Methodes Un patient de 66 ans, hypertendu, diabetique, est pris en charge pour une leucemie aigue myeloblastique (LAM1), non hyperleucocytaire, a caryotype normal, avec surexpression WT1,NPM1, et mutation IDH2. Il s’y associait une gammapathie monoclonale IgG Kappa de faible intensite, sans plasmocytose medullaire, jugee de signification indeterminee, concomitante de l’hemopathie aigue. A l’issue du traitement d’induction par Gemtuzumab-Ozogamicin (inclusion protocolaire) et Cytarabine pour la LAM, une insuffisance renale aigue apparaissait, d’aggravation progressive en quelques semaines, attribuee initialement a une necrose tubulaire aigue dans un contexte d’aplasie febrile avec bacteriemie a Enterocoque traite par Cefepime et Daptomycine. Au decours de la premiere cure de consolidation, devant une alteration progressive de l’insuffisance renale, de profil organique avec une proteinurie glomerulaire, une hematurie microscopique et une leucocyturie, une biopsie renale etait realisee. Resultats obtenus ou attendus L’histologie renale porte le diagnostic de glomerulonephrite proliferative avec depots d’immunoglobuline monoclonale IgG3 Kappa, non organises, non Randall (PGNMID). Devant la presence de cette gammapathie monoclonale de signification renale, la deuxieme cure de consolidation pour la leucemie aigue myeloblastique etait suspendue. Un traitement par Velcade-Cyclophosphamide et Dexamethasone etait debute. La biopsie renale se compliquait d’une fistule arterio-veineuse avec necessite de radio-embolisation, constitution de lesions surajoutees de necrose tubulaire aigue ischemique et toxique amenant a une aggravation de l’insuffisance renale et necessitant le recours a l’epuration extra-renale. Conclusion Nous rapportons donc l’association atypique d’une hemopathie aigue myeloide et d’une hemopathie chronique s’exprimant sous la forme d’une gammapathie monoclonale de signification renale de type PGNMID, compromettant la prise en charge de l’hemopathie aigue.

Resume Objectif Decrire le devenir obstetrical des patientes enceintes presentant une thrombocytemie essentielle. Patientes et methodes Etude retrospective realisee a la maternite Jeanne-de-Flandre (CHRU de Lille), incluant toutes les patientes presentant une thrombocytemie essentielle qui ont accouche entre janvier 2000 et janvier 2008. Treize patientes ont ete incluses, pour lesquelles ont ete repertoriees les modalites de surveillance clinique et biologique, les complications survenues au cours de la grossesse et le traitement recu. Au total, 18 grossesses ont ete suivies pendant cette periode. Resultats Toutes les patientes avaient recu un traitement par antiagregant plaquettaire poursuivi s’il etait deja indique ou institue au moment du diagnostic de grossesse. Une mort in utero, un accouchement premature a 29 semaines d’amenorrhee et six hemorragies de la delivrance (33 %) ont ete observes. Discussion et conclusion Il parait important de traiter les patientes thrombocytemiques par aspirine des la conception. Ce traitement sera poursuivi en post-partum associe a un traitement anticoagulant. Une prise en charge adaptee permet de reduire les complications thrombotiques classiquement decrites. La mise en place d’un registre national des patientes enceintes thrombocytemiques devrait permettre de mieux evaluer les complications lors de la grossesse et le mode de prise en charge optimale.

Deep granuloma annulare is a fairly rare variety of granuloma annulare. It is seen predominantly in children and mainly affects the anterior aspect of the legs and the top of the feet; cephalic presentation is rare. Below, we report three cases of deep granuloma annulare in children presenting solely at the cephalic extremity.Case 1: a six-year-old boy presented 7 cutaneous nodules measuring 1 to 2cm that were flesh-coloured, insensitive to palpation, of hard consistency and deeply attached. The lesions were grouped together on the anterior half of the left temporal fossa. While spontaneous regression of the three nodules was noted in the month following cutaneous biopsy, these nodules recurred a few months later. Case 2: a four-year-old girl with five deep cephalic nodules measuring around one centimetre and the colour of normal skin were seen on her right temporal fossa. The child was lost to follow-up after biopsy. Case 3: a four-month-old infant was presenting some 15 deep cutaneous nodules arranged in linear fashion on the forehead next to the left temporal fossa. These nodules regressed spontaneously one month after biopsy. In all three cases, histological examination confirmed the diagnosis of deep granuloma annulare.There have been few published cases of multiple, cephalic, deep granuloma annulare at a single site in children. The condition has an extensive differential diagnosis that includes malignant tumours; in addition, histological confirmation is normally essential. Treatment is not qualified and therapeutic extension with clinical monitoring alone may frequently be recommended.

A portal vein invasion is no longer a contraindication for resection in pancreatic cancer, but increased morbidity and mortality rates can be encountered. Hereby it is presented the case of a patient diagnosed with a large adenocarcinoma of the uncinate process of the pancreas, who underwent aposterior approach pancreaticoduodenectomy, with en bloctang ential resection of the portal vein, and total mesopan creasexcision. A posterior approach allows a negative resection margins pancreaticoduodenectomy, with a good local control of the disease, despite the in creas.

Resume Les transfusions de concentres erythrocytaires, seul recours therapeutique de nombreux syndromes myelodysplasiques et l’hyperabsorption intestinale du fer, en rapport avec la dyserythropoiese sont source de surcharge martiale. Celle-ci est responsable d’une morbidite et d’une mortalite excessives. Les patients les plus exposes sont : ceux porteurs d’une anemie refractaire, d’une anemie refractaire sideroblastique ou d’un syndrome 5q-, ceux ayant un bon pronostic (score pronostique international faible ou intermediaire faible), ceux recevant plus de 100 concentres erythrocytaires et ceux âges de moins de 70 ans. Le traitement par la deferoxamine est capable de prevenir la surcharge martiale mais il est contraignant puisqu'il necessite des injections sous-cutanees nocturnes sur huit a 12 heures au moyen d'infuseurs ou d'une pompe portable. Si le traitement est bien conduit, il previent la mortalite liee a la surcharge martiale. Il doit etre commence suffisamment tot (en regle generale avant 20 concentres erythrocytaires). La mesure de la ferritine serique et la connaissance du nombre de concentres erythrocytaires sont la plupart du temps suffisants pour apprecier la surcharge en fer. L’intensite du traitement chelateur est adapte en fonction de l’âge, du type de SMD, du score pronostique international, du nombre de concentres erythrocytaires, de la mesure de la ferritine et surtout de la tolerance des patients. La voie sous-cutanee directe, actuellement evaluee en termes d’efficacite de la prevention, au sein du Groupe francais des myelodysplasies, semble un bon compromis en ce qui concerne l’efficacite et l’observance (protocole national en cours).

The diverse effects of all-trans retinoic acid (ATRA) on growth, differentiation and homeostasis of vertebrate organisms are mediated by three distinct isoforms of retinoic acid receptors (RARs). Although it is not known to what extent each RAR contributes to the different effects of ATRA, several studies have demonstrated that ATRA induced granulocytic differentiation in human myeloid leukemic cell lines is mediated by RAR alpha. In this study, we investigated ATRA binding affinity of the endogenous nuclear receptors of HL-60 and NB4 leukemic cells. Scatchard plot analysis yielded an apparent dissociation constant of 5 +/- 0.3 nM and 1400 +/- 80 receptor sites per cell in HL-60 cells, whereas the NB4 promyelocytic leukemic cell line showed a lower affinity (8.5 +/- 0.5 nM and 900 +/- 30 receptor sites per cell). Modulation of RAR alpha protein (5 fold excess) was found in NB4 cells after 24 hours ATRA exposure, whereas HL-60 cells required a 72-hour culture period to weakly increase the RAR alpha protein level. These data were closely related to the ATRA intracellular concentration and kinetics of terminal differentiation of the cells.

To evaluate the management and outcome of pregnancy in women with essential thrombocytemia.We conducted a retrospective study including all the pregnant women with essential thrombocytemia followed between January 2000 and January 2008 in a University Hospital (hôpital Jeanne-de-Flandre, Lille, France). We report our experience of 18 pregnancies in 13 women. The management and the complications of these pregnancies were reported.All the patients were treated with low dose aspirin during the pregnancy. We observed one intrauterine death, one premature delivery at 29 weeks of gestation and six maternal haemorrhages at delivery (33%).It is essential to treat these patients with low dose aspirin as soon as the pregnancy begins. Aspirin will be continued in postpartum with anticoagulant treatment. This management appears to improve the obstetric outcome and decrease the thrombotic complications usually described. A national register seems to be necessary to evaluate the complications occurring during pregnancy and the optimum follow-up.

We report a case of hemoglobinopathy which could be associated with a pseudoxanthoma elastic-like syndrome.We report the case of a 26-year-old male patient with sickle cell anemia for which the supra-aortic-doppler ultrasonography suggested an asymptomatic left carotid artery of 70% stenosis. The magnetic resonance imaging and angiography showed a left megadolichocarotid with plicature suggestive of pseudoxanthoma elastic or a dilatation relative to a high rate of blood explaining the acceleration speed. There was a cutaneous infiltration but other vasculopathies of neither carotide, nor cerebral, nor ocular have been discovered while they were sometimes found in pseudoxanthoma elastic-like syndrome. This acquired form is different of rare hereditary disease by a later diagnosis, a clinical expression often very incomplete and a frequent association with hemoglobinopathies.This observation shows that RMA could be necessary to perform in adults, when cervical and transcranial Doppler ultrasonography is abnormal, particularly before deciding to start long term blood transfusions. The hemoglobinopathy and pseudoxanthoma elastic-like syndrome must not be ignored because the control of cardiovascular factors reduce the risks of arterial complications.

Transfusion of RBC units, the only current treatment for many myelodysplastic syndromes, and excess intestinal absorption of Fe related to dyserythopoiesis often result in iron overload. This condition is associated with high rates of morbidity and mortality. High-risk patients include those with refractory anemia, sideroblastic anemia, 5q-syndrome, patients with a good prognosis (low or lower intermediate international prognosis score), patients having received over 100 RBC units, and patients under the age of 70. Deferoxamine, while it can prevent iron overload, is a strenuous treatment requiring 8-to-12 hour-overnight subcutaneous injections. When patients comply with the regimen, it efficiently prevents mortality due to iron overload, but must be implemented early in the disorder, usually before transfusing 20 RBC concentrates. A simple way of monitoring iron overload is to measure seric ferritin levels and record the number of RBC concentrates. The chelating treatment should be modulated according to age, MDS type, international prognosis score, number of RBC units received, ferritin levels, and most of all, patient tolerance. The direct subcutaneous approach is currently being evaluated by the French Group for Myelodysplasias for its efficiency to prevent disorders, but seems to be both efficient and well complied with (a national protocol is under way). The recent findings on the proteins implied in iron recycling by macrophages after destruction of RBCs, may in the long term, enable us to manage patients with less burdensome treatments and more effective new oral chelates.

A dose-escalation study was realized in order to assess the maximally tolerated dose (MTD) of high-dose mitoxantrone in a single injection combined with cytarabine and etoposide (EMA regimen) in refractory or relapsed acute myelogenous leukemia (AML). Between July 1997 and June 1998, 24 patients with relapsed or refractory AML entered the study. All but one patient had normal left ventricular ejection fraction (LVEF) at baseline. Performance status according to World Health Organization (WHO) criteria was less than two in all cases. All patients have been previously treated by mitoxantrone or anthracyclines. Four cohort of ten patients were scheduled with the following doses: (1) mitoxantrone 36 mg/m 2 on day 1; (2) mitoxantrone 45 mg/m 2 on day 1; (3) mitoxantrone 60 mg/m 2 on day 1; (4) mitoxantrone 75 mg/m 2 on day 1 in combination with cytarabine 500 mg/m 2 per day (days 1–3, and days 8–10), and etoposide 200 mg/m 2 per day (days 8–10). All patients received the full doses of the three drugs. The limiting toxicity was defined as WHO grade 4 nonhematologic toxicity and for impairment of cardiac function by Alexander's criteria (moderate or severe toxicity). The occurrence of limiting toxicity in at least three patients from the same dose level determined the MDT. No limiting toxicity was observed in mitoxantrone dose level 1. Two limiting toxicities were observed in mitoxantrone dose level 2 (one mucositis, one moderate cardiac toxicity), and three limiting toxicities in mitoxantrone dose level 3 (1 high transaminase levels, two moderate cardiac toxicities) ending the assay. Overall, 16 patients (67%) achieved complete remission (CR). One drug-addict patient died from cerebral hemorrhage due to severe aspergillosis and was not considered as a limiting toxicity. After EMA chemotherapy, 13 patients received subsequent chemotherapy courses involving anthracyclines or their derivatives. Six patients underwent allogeneic bone marrow transplantation. No late toxicity occurred. The median survival of the entire cohort was 41.4 weeks. We conclude that (i) EMA chemotherapy using a single injection of mitoxantrone is effective in the treatment of refractory or relapsing AML; (ii) the recommended phase II dose of mitoxantrone is 45 mg/m 2 administered over 30 min as a single dose in combination with cytarabine and etoposide.

P glycoprotein (Pgp) expression is associated with failure of anticancer chemotherapy in acute myeloid leukemia (AML). However, a consensus has been difficult to reach, due to the variable results obtained by different methods. Samples of 27 patients with AML were studied here according to international recommendations (Beck, et al. , Cancer Research 1996; 56: 3010-20). Pgp expression was performed by immunocytochemistry (ICC) using the avidin-biotin peroxidase technique with JSB1 and UIC2 monoclonal antibodies. Flow cytometry (FCM) analysis of Pgp was investigated using UIC2 in an indirect immunofluorescent assay. UIC2 staining was measured by the Kolmogorov-Smirnov statistical test and fluorescence intensity ratio. Finally, the rhodamine 123 test (Rh 123) with or without verapamil was performed to detect functional activity.by ICC, results of JSB1 and UIC2 were consistent in 94% of the cases. In 74% of the cases, concordant conclusions were observed by ICC and FCM. Overall, Pgp expression was detected in 67% of the cases (ICC/JSB1+ and ICC/UIC2+ or FCM/UIC2+). Functional activity of Pgp was shown in 59% of the patients. Rh 123 efflux was correlated with Pgp expression in 70% of the 27 studied cases but 3 cases were Pgp-/Rh 123+ and 5 Pgp+/Rh 123-. In conclusion, assessment of Pgp expression by ICC and FCM using two different monoclonal antibodies coupled with functional efflux test is required to identify discordant expression/function cases suggesting a non functional Pgp or another alteration of drug transport.

Drug resistance often results in failure of anticancer chemotherapy in leukemias. A large number of studies have been published on the effect of P-glycoprotein (Pgp) expression on prognosis in AML. However, a consensus has been difficult to reach, due to the variable results obtained by different laboratories. Pgp expression was investigated here in bone marrow samples from 34 patients with AML including 19 newly diagnosed cases and 15 relapsing patients. Pgp expression was performed by immunocytochemistry (ICC) using the aviding-biotin-peroxydase technique with JSB1 and UIC2 MoAbs. Flow cytometry (FCM) analysis of Pgp expression was performed using UCI2 MoAbs in an indirect immunofluorescent assay without cell permeabilization. Rhodamine 123 (Rh 123) uptake was measured in the presence or absence of verapamil. Result was discordant in only 1/20 samples studied with both JSB1 and UIC2 by ICC. Results of Pgp expression were consistent on FCM and ICC in 23 of the 28 (82%) samples tested. Overall, Pgp expression was observed by ICC or FCM in 23 (67%) patients, including 11 (58%) newly diagnosed patients and 12 (80%) patients in relapse. Functional Rh123 efflux (Rh123+) was observed in 20 cases (59%): 10 de novo AML (53%) vs 10 AML in relapse (67%). The functional efflux was correlated with Pgp expression in 25 of the 34 cases analyzed (p = 0.013). 3 (9%) and 6 (18%) samples were Pgp-/Rh123+ and Pgp+/Rh123- respectively. Nine of the 14 pts (64%) treated with intensive anthracyclin-Ara C chemotherapy achieved complete remission, including 5/5 (100%) Pgp- cases vs 4/9 (44%) Pgp+ cases (p = 0.04) and 4/6 (67%) Rh 123- vs 4/7 (57%) Rh123+ cases (p = 0.5). In conclusion, assessment of Pgp expression by ICC and FMC using 2 different MoAbs coupled with functional efflux analysis confirms that Pgp expression is correlated with disease stage and response to treatment in AML. Discordant Pgp/Rh123 cases suggest a non functional Pgp or another alteration of drug transport.

Drug resistance often results in failure of anticancer chemotherapy in leukemias. A large number of studies have been published on the effect of P-glycoprotein (Pgp) expression on prognosis in AML. However, a consensus has been difficult to reach, due to the variable results obtained by different laboratories. Pgp expression was investigated here in bone marrow samples from 34 patients with AML including 19 newly diagnosed cases and 15 relapsing patients. Pgp expression was performed by immunocytochemistry (ICC) using the aviding-biotin-peroxydase technique with JSB1 and UIC2 MoAbs. Flow cytometry (FCM) analysis of Pgp expression was performed using UCI2 MoAbs in an indirect immunofluorescent assay without cell permeabilization. Rhodamine 123 (Rh 123) uptake was measured in the presence or absence of verapamil. Result was discordant in only 1/20 samples studied with both JSB1 and UIC2 by ICC. Results of Pgp expression were consistent on FCM and ICC in 23 of the 28 (82%) samples tested. Overall, Pgp expression was observed by ICC or FCM in 23 (67%) patients, including 11 (58%) newly diagnosed patients and 12 (80%) patients in relapse. Functional Rh123 efflux (Rh123+) was observed in 20 cases (59%): 10 de novo AML (53%) vs 10 AML in relapse (67%). The functional efflux was correlated with Pgp expression in 25 of the 34 cases analyzed (p=0.013). 3 (9%) and 6 (18%) samples were Pgp-/Rh123+ and Pgp+/Rh123- respectively. Nine of the 14 pts (64%) treated with intensive anthracyclin-Ara C chemotherapy achieved complete remission, including 5/5 (100%) Pgp- cases vs 4/9 (44%) Pgp+ cases (p=0.04) and 4/6 (67%) Rh 123- vs 4/7 (57%) Rh123+ cases (p=0.5). In conclusion, assessment of Pgp expression by ICC and FMC using 2 different MoAbs coupled with functional efflux analysis confirms that Pgp expression is correlated with disease stage and response to treatment in AML. Discordant Pgp/Rh123 cases suggest a non functional Pgp or another alteration of drug transport.

As a first step to evaluate the possibility of gene therapy using adenoviral vectors in hematological malignancies in vivo, we tested the efficacy of gene transfer by a recombinant adenovirus in cell lines and fresh cells from various hematological neoplasms. Thirteen cell lines and samples from 27 patients were studied. Cells were infected by a recombinant adenovirus expressing beta galactosidase gene (Ad RSV betagal) and efficacy of transduction assessed by evaluating betagal expression in cells with a histochemical method. After infection of the cells at a multiplicity of infection (MOI) of 200 p.f.u./cell, the percentage of beta gal-positive cells after 48h was high in two cell lines. K562 (64%) and RPMI 8226 (a myeloma cell line, 65%), relatively large in the two myeloma cell lines tested (41% and 20%, respectively) and in MT4 (an adult T cell leukemia cell line, 38%) and low or absent in other cell lines. In fresh samples from AML, ALL, CLL, NHL, myeloma and MDS, no betagal positive cells were seen 48h and 72h after infection, except in one case of myeloma and one case of CLL (where 10% and 2% of betagal positive cells were seen after infection, respectively). Exposure of fresh malignant cells to GM-CSF before and during adenoviral infection, in three cases, did not increase the number of transfected cells. This suggests that adenoviral vectors, at least in their present form, cannot efficiently be used for direct gene transfer in hematological malignant cells.

With conventional chemotherapy, approximately 70% of AML patients (pts) achieve complete remission (CR), but only about 30% can be cured with current post-remission approaches. Prognostic factors, including age, FAB subtype, initial leukocyte count, immunophenotype and karyotype have helped identify subgroups wiht “favorable” prognosis. However, those “favorable” subgroups generally still have a probability of long remission below 50%. Among cytogenetic findings, presence of inv(16) and its variants [del(16), T(16; 16)] has been associated with favourable prognosis, alto ugh not in all studies [1–4]. We therefore report on the favourable prognosis of our AML with inv(16) or variants.

In France, more than 80% of children with Burkitt's lymphoma or Burkitt's leukemia (ALL3) are now cured with the LMB (B-cell non- Hodgkin's lymphoma and B-ALL) protocols of the Societe Francaise d'Oncologie Pediatrique, but so far, poor results have been obtained in the few adult studies available. We have analyzed the experience with LMB protocols in adult patients. This retrospective study involved 65 adult patients with small noncleaved cell lymphoma or ALL3 treated with the LMB protocols. They were 17 to 65 years old and not previously treated. Human immunodeficiency virus-infected patients were excluded. The diagnoses were made between September 1984 and August 1991. According to the Murphy classification, 12 patients (18%) had stage I or II disease, 25 (38%), stage III disease; 4 (6%), stage IV disease; and 24 (37%), ALL3 (> or = 25% blasts). According to the Ann Arbor classification, 9 patients had stage I disease; 8 patients, stage II; 5 patients, stage III; 21 patients, stage IV disease; and 22 patients, ALL (> or = 30% blasts). Twelve patients had central nervous system (CNS) involvement before treatment. Thirty-nine patients were treated according to the LMB 84 protocol scheme; 14 according to the LMB 86 protocol, and 12 patients received the LMB 84 induction courses followed by the LMB 86 consolidation courses. Three patients underwent bone marrow transplantation (BMT) while in second complete remission (CR) and 3 others had refractory disease. There were some protocol violations caused by empirical medical decisions: local irradiation was performed in 4 patients, 2 patients received prophylactic radiation to the brain that was not specified in the protocol, 13 patients underwent BMT in first CR, and methotrexate doses were modified in 10 patients. Fifty-eight patients (89%) achieved a CR. There were four (6%) primary induction treatment failures, and three (4%) early treatment-related deaths. Eight patients relapsed between 2 and 30 months after CR (median, 4.7 months). Forty-seven patients are alive in CR (45 first CR, 2 second CR) with a median follow-up of 57 months (24 to 93 months). There were five toxicity-related deaths among patients in CR including four BMT-related deaths and five deaths caused by refractory relapses. One patient died in CR at 62 months of rectal cancer. The 3- year overall survival rate is 74% (SE = 5). According to the stages in the Murphy classification, the 3-year survival rates are stages I and II, 100%; stage III, 80% (SE = 7); and stage IV and ALL, 57% (SE = 8). Seven of 12 patients with initial CNS disease are alive with a median survival of 56 months.(ABSTRACT TRUNCATED AT 400 WORDS)