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The prognostic roles of social status and social environment in chronic lymphocytic leukemia have been highlighted in some solid tumors but remain unclear in hematological malignancies. The objective of this study was to evaluate the influence of individual social status (with socioprofessional category, SPC) and social environment (with European deprivation index, EDI) on net survival in a high-resolution population with CLL.We included CLL patients from the Regional Register of Hematological Malignancies in Normandy belonging to the French Network of Cancer Registries (Francim). The SPC variable was divided into 5 categories: farmers, craftsmen, higher employment, intermediate employment, and workers/employees. Net survival was used to estimate the excess of mortality in CLL independent of other possible causes of death using French life tables. Net survival was estimated with a nonparametric method (Pohar-Perme) and with a flexible excess mortality hazard model. Missing data were handled with multiple imputation.A total of 780 patients were included. The median follow-up was 7.9 years. The crude survival at 10 years was 50%, and the net survival at 10 years was 80%. In multivariate analysis, a higher age (EHR: 1.04 [1.01-1.07]), being a craftsman (EHRSocioprofessional category was a prognostic factor for an excess of mortality in CLL. Craftsmen and workers/employees shared a worse prognosis than workers with higher employment. The social environment was not a prognostic factor. Further work should be performed to explore causal epidemiologic or biological factors and other hematological malignancies.

Eser, Sultan (Balikesir Author), Background In 2015, the second cycle of the CONCORD programme established global surveillance of cancer survival as a metric of the effectiveness of health systems and to inform global policy on cancer control. CONCORD-3 updates the worldwide surveillance of cancer survival to 2014. Methods CONCORD-3 includes individual records for 37.5 million patients diagnosed with cancer during the 15-year period 2000-14. Data were provided by 322 population-based cancer registries in 71 countries and territories, 47 of which provided data with 100% population coverage. The study includes 18 cancers or groups of cancers: oesophagus, stomach, colon, rectum, liver, pancreas, lung, breast (women), cervix, ovary, prostate, and melanoma of the skin in adults, and brain tumours, leukaemias, and lymphomas in both adults and children. Standardised quality control procedures were applied; errors were rectified by the registry concerned. We estimated 5-year net survival. Estimates were age-standardised with the International Cancer Survival Standard weights.Findings For most cancers, 5-year net survival remains among the highest in the world in the USA and Canada, in Australia and New Zealand, and in Finland, Iceland, Norway, and Sweden. For many cancers, Denmark is closing the survival gap with the other Nordic countries. Survival trends are generally increasing, even for some of the more lethal cancers: in some countries, survival has increased by up to 5% for cancers of the liver, pancreas, and lung. For women diagnosed during 2010-14, 5-year survival for breast cancer is now 89.5% in Australia and 90.2% in the USA, but international differences remain very wide, with levels as low as 66.1% in India. For gastrointestinal cancers, the highest levels of 5-year survival are seen in southeast Asia: in South Korea for cancers of the stomach (68.9%), colon (71.8%), and rectum (71.1%); in Japan for oesophageal cancer (36.0%); and in Taiwan for liver cancer (27.9%). By contrast, in the same world region, survival is generally lower than elsewhere for melanoma of the skin (59.9% in South Korea, 52.1% in Taiwan, and 49.6% in China), and for both lymphoid malignancies (52.5%, 50.5%, and 38.3%) and myeloid malignancies (45.9%, 33.4%, and 24.8%). For children diagnosed during 2010-14, 5-year survival for acute lymphoblastic leukaemia ranged from 49.8% in Ecuador to 95.2% in Finland. 5-year survival from brain tumours in children is higher than for adults but the global range is very wide (from 28.9% in Brazil to nearly 80% in Sweden and Denmark). Interpretation The CONCORD programme enables timely comparisons of the overall effectiveness of health systems in providing care for 18 cancers that collectively represent 75% of all cancers diagnosed worldwide every year. It contributes to the evidence base for global policy on cancer control. Since 2017, the Organisation for Economic Co-operation and Development has used findings from the CONCORD programme as the official benchmark of cancer survival, among their indicators of the quality of health care in 48 countries worldwide. Governments must recognise population-based cancer registries as key policy tools that can be used to evaluate both the impact of cancer prevention strategies and the effectiveness of health systems for all patients diagnosed with cancer., American Cancer Society Centers for Disease Control and Prevention Swiss Re Swiss Cancer Research foundation Swiss Cancer League Institut National du Cancer La Ligue Contre le Cancer Rossy Family Foundation US National Cancer Institute Susan G Komen Foundation

BACKGROUND: Significant advances in the management of patients with lymphoid and myeloid malignancies entered clinical practice in the early 2000's. The EUROCARE-5 study database provides an opportunity to assess the impact of these changes at the population level by country in Europe. We provide survival estimates for clinically relevant haematological malignancies (HM), using the International Classification of Diseases for Oncology 3, by country, gender and age in Europe. METHODS: We estimated age-standardised relative survival using the complete cohort approach for 625, 000 adult patients diagnosed in 2000-2007 and followed up to 2008. Survival information was provided by 89 participating cancer registries from 29 European countries. Mean survival in Europe was calculated as the population weighted average of country-specific estimates. RESULTS: On average in Europe, 5-year relative survival was highest for Hodgkin lymphoma (81% ; 40, 625 cases), poorest for acute myeloid leukaemia (17% ; 57, 026 cases), and intermediate for non- Hodgkin lymphoma (59% ; 329, 204 cases), chronic myeloid leukaemia (53% ; 17, 713 cases) and plasma cell neoplasms (39% ; 94, 024 cases). Survival was generally lower in Eastern Europe and highest in Central and Northern Europe. Wider between country differences (>10%) were observed for malignancies that benefited from therapeutic advances, such as chronic myeloid leukaemia, chronic lymphocytic leukaemia, follicular lymphoma, diffuse large B-cell lymphoma and multiple myeloma. Lower differences (

Background Primary malignant brain tumours are rare but represent a serious health burden due to their poor survival. This manuscript describes the survival of malignant brain tumours in adults diagnosed 2000–2007 in Europe. Methods For this study we analysed patients archived in 86 European population-based cancer registries, followed up to 31st December 2008. Only primary malignant neuroepithelial brain tumours (with pathological confirmation) and primary malignant unspecified brain tumours without pathological confirmation were included. We estimated 1-year and 5-year relative survival (RS) weighted by age group and country. We also estimated country-specific and age-specific survival, together with survival differences between time periods (for 1999–2001, 2002–2004 and 2005–2007). Results Glioblastoma represents 49% of all brain tumours, followed by other/unspecified astrocytoma (18%), oligodendroglioma/oligoastrocytoma (9%), ependymoma (1.5%) and embryonal tumours (1%). Five-year RS was 20% for all tumours combined, but ranged from 58% for ependymoma to only 6% for glioblastoma and sharply decreased with increasing age. Differences between countries were relatively small, but generally RS in Ireland/United Kingdom (UK) and Eastern Europe was below the average. An increase in 1-year RS (up to 10–12%) was noted over time, being largest in Central and Northern Europe in patients between 45 and 74 years of age. Conclusions Despite an increase in 1-year RS in most European regions, the survival of primary malignant brain tumours is still poor. Disparities between countries were evident, being even larger at the end of the study period than at the beginning, suggesting differences in availability of the latest treatment modalities.

Background Previous population-based studies revealed major variation in survival for patients with colorectal cancer (CRC) in Europe by age and between different countries and regions, but also a sustained improvement in survival for patients with CRC in recent years. This EUROCARE-5 paper aims to update available knowledge from previous studies and to provide the latest survival estimates for CRC patients from Europe. Methods The study analysed data of patients diagnosed with CRC from population-based cancer registries diagnosed in 29 European countries. Estimates of 1-year and 5-year relative survival (RS) were derived for patients diagnosed in 2000–2007 by European region, country and age at diagnosis. Additionally to these cohort estimates, time trends in 5-year RS were obtained for the calendar periods 1999–2001 and 2005–2007, using the period analysis methodology. Results European average 5-year RS for patients diagnosed with colon and rectum cancer was 57% and 56%, respectively. The analyses showed persistent differences in cancer survival across Europe with lowest survival for CRC patients observed in Eastern Europe. The analyses further showed a strong gradient in age-specific survival. Even though the study revealed sustained improvement in patient survival between 1999–2001 and 2005–2007 (absolute increase of 4 and 6 percentage points for colon and rectum, respectively), the differences in the survival for CRC patients observed at the beginning of the millennium persisted over time. Conclusion Although survival for CRC patients in Europe improved markedly in the study period, significant geographic variations and a strong age gradient still persisted. Enhanced access to effective diagnostic procedures and treatment options might be the keys to reducing the existing disparities in the survival of CRC patients across Europe.

Resume Introduction Le laboratoire d’epidemiologie de l’institut de radioprotection et de surete nucleaire (IRSN) en collaboration avec le groupe Areva conduit une etude de morbidite sur l’ensemble des travailleurs actifs du site Areva de La Hague. Les donnees de cette etude sont issues du systeme Chimed d’enregistrement des maladies mis en place par le service de sante au travail (SST) d’Areva. Dans ce contexte, une validation externe des donnees medicales du SST d’Areva a ete realisee grâce aux donnees du registre des cancers du departement de la Manche et a celles du registre specialise des hemopathies malignes de la Basse-Normandie. Materiels et methodes Un cas incident est un travailleur pour lequel une pathologie cancereuse a ete enregistree par un medecin du travail dans la base de donnees Chimed entre le 01/01/1999 et le 31/12/2009. Le croisement entre la base de donnees Chimed et la base de donnees des registres des cancers permet de calculer la sensibilite (capacite a identifier les vrais positifs) et la valeur predictive positive (probabilite qu’un travailleur classe comme malade ait vraiment la maladie). Resultats Les donnees ont ete analysees pour 5211 travailleurs actifs. Apres le croisement des deux bases de donnees, 30 cas de cancer sont presents simultanement dans les deux bases, 23 cas sont retrouves uniquement dans la base de donnees des registres, 4 cas ont ete enregistres uniquement dans Chimed. En prenant comme reference les registres des cancers, la sensibilite du systeme Chimed est de 57 %. La valeur predictive positive est de 89 %. Discussion et conclusion Etant donne sa faible sensibilite, il n’est pas recommande d’utiliser la base de donnees Chimed comme seule source d’information pour la surveillance des cancers chez les travailleurs actifs d’Areva. La surveillance des cancers necessite que des procedures standardisees et systematiques de codage et d’enregistrement des pathologies tumorales soient mises en place dans les SST.

BACKGROUND: Survival differences across Europe for patients with cancers of breast, uterus, cervix, ovary, vagina and vulva have been documented by previous EUROCARE studies. In the present EUROCARE-5 study we update survival estimates and investigate changes in country-specific and over time survival, discussing their relationship with incidence and mortality dynamics for cancers for which organised screening programs are ongoing. METHODS: We analysed cases archived in over 80 population-based cancer registries in 29 countries grouped into five European regions. We used the cohort approach to estimate 5-year relative survival (RS) for adult (⩾15years) women diagnosed 2000-2007, by age, country and region ; and the period approach to estimate time trends (1999-2007) in RS for breast and cervical cancers. RESULTS: In 2000-2007, 5-year RS was 57% overall, 82% for women diagnosed with breast, 76% with corpus uteri, 62% with cervical, 38% with ovarian, 40% with vaginal and 62% with vulvar cancer. Survival was low for patients resident in Eastern Europe (34% ovary-74% breast) and Ireland and the United Kingdom [Ireland/UK] (31-79%) and high for those resident in Northern Europe (41-85%) except Denmark. Survival decreased with advancing age: markedly for women with ovarian (71% 15-44years ; 20% ⩾75years) and breast (86% ; 72%) cancers. Survival for patients with breast and cervical cancers increased from 1999-2001 to 2005-2007, remarkably for those resident in countries with initially low survival. CONCLUSIONS: Despite increases over time, survival for women's cancers remained poor in Eastern Europe, likely due to advanced stage at diagnosis and/or suboptimum access to adequate care. Low survival for women living in Ireland/UK and Denmark could indicate late detection, possibly related also to referral delay. Poor survival for ovarian cancer across the continent and over time suggests the need for a major research effort to improve prognosis for this common cancer.

Introduction La leucemie myeloide chronique (LMC) est une hemopathie maligne qui, avant l’introduction du premier inhibiteur de tyrosine kinase (ITK) l’imatinib en 2000, etait constamment mortelle. Plusieurs essais cliniques ont compare l’imatinib aux autres ITK en premiere ligne de traitement. Leurs resultats ont montre une superiorite du dasatinib et du nilotinib sur l’imatinib sur des criteres biologiques. En revanche, il n’existe pas a l’heure actuelle d’etude basee sur des donnees populationnelles comparant l’efficacite des differents ITK utilises en premiere ligne de traitement. Or, on peut se poser la question de la representativite des populations incluses en essais clinique par rapport aux patients traites en population generale Retrouve-t-on des conclusions semblables a celles issues des essais cliniques, a savoir une meilleure reponse moleculaire des sujets malades traites par des ITK differents de l’imatinib a partir de donnees obtenues en vie reelle ? Objectifs Decrire en population generale les differentes caracteristiques des patients atteints de LMC selon qu’ils ont ou non ete inclus dans un essai therapeutique. Comparer en population generale l’effet de l’imatinib aux autres ITK en premiere ligne de traitements sur l’atteinte de la reponse moleculaire majeure (RMM). Decrire les raisons de passages a une deuxieme ligne de traitement. Methodes Schema d’etude : cohorte retrospective utilisant des donnees issues de trois registres de population ; population : patients atteints de LMC Ph+ diagnostiques entre 2006 et 2013 dans trois regions francaises couvertes par un registre specialise des hemopathies malignes (Gironde, Cote-d’Or et Basse-Normandie). Les cas de LMC atypique ou de LMC « sans autre precision » ont ete exclus ; analyse : tous les patients inclus dans la cohorte ont ete analyses. Description des caracteristiques au diagnostic selon la participation a un essai clinique. Comparaison des traitements a l’aide d’analyse de risque competitif entre l’atteinte de la RMM en premiere ligne de traitement et le passage a une deuxieme ligne de traitement ou le deces. Resultats Au 30 juin 2016, 360 sujets ont ete identifies et 11 ont ete exclus de l’analyse car non traites en premiere ligne par un ITK. Parmi les 349 sujets, 73 sont inclus dans essai cliniques (20,9 %). Les sujets inclus dans un essai clinique etaient plus jeunes (55,8 ans versus 63,1 ans) dans un meilleur etat general et souffrant de moins de comorbidites. L’analyse de risque competitif a montre apres ajustement que les patients traites en premiere ligne de traitement par un ITK de 2e et 3e generation etait plus a risque d’obtenir une reponse au traitement que les sujets traites par l’imatinib (RR : 1,59, IC95 % : [1,05 ; 2,40]) ; 60 % des sujets traites ont necessite une deuxieme ligne de traitement (63 % pour ceux traites par l’imatinib et 51 % pour les ITK de 2e et 3e generation). Les raisons du passage a une deuxieme ligne de traitement etaient majoritairement liees a un echec du traitement pour les patients traites par un ITK de 1re generation (36 % des cas) ou a un effet toxique pour les patients traites par un ITK de 2e ou 3e generation (72 % des cas). Conclusion Divergence de caracteristiques entre sujets inclus et non inclus en essai clinique retrouve ; meilleur taux de reponse au traitement de 2e et 3e generation par rapport a la 1re generation retrouve, mais a nuancer par l’absence d’analyse sur la survie et par la nature observationnelle de l’etude.

hma.2013.0789 Auteur(s) : Alexandra Audemard1, Xavier Troussard1, Francoise Galateau-Salle2, Margaret Macro1 macro-m@chu-caen.fr 1 Hematologie clinique, 2 Departement de pathologie, CHU de Caen 14000-Caen, Universite de Caen Basse Normandie, UFR de medecine, 14000 Caen, France Tires a part : M. Macro La maladie de Gaucher (MG) est une maladie de surcharge lysosomale (MSL), dont la transmission est autosomique recessive. Elle est secondaire a un deficit en beta-glucocerebrosidase (GBA), qui [...]

Introduction/ Background In hematology, actual diagnosis of B chronic lymphocyte-leukemia (CLL) is based on the microscopic analysis of cell morphology from patient blood smear. However, new photonic technologies appear promising to facilitate and improve the early diagnosis, prognostic and monitoring of personalized therapy. The development of automated diagnostic approaches could assist clinicians in improving the efficiency and quality of health services, but also reduce medical costs. Aims The M3S project aims at improving the diagnosis and prognosis of the CLL pathology by developing a multimodal microscopy platform, including Raman spectrometry, dedicated to the automatic analysis of lymphocytes. Methods Blood smears were prepared on glass slides commonly used in pathology laboratories for microscopy. Two types of sample per patient were prepared: a conventional blood smear and a deposit of “pure” lymphocyte subtypes (i.e. normal B, CLL B, T and NK), sorted out in flow cytometry by using the negative double labelling technique. The second sample is used for the construction of a database of spectral markers specific of these different cell types. The preparations were analyzed with the multimodal machine which combines i) a Raman micro-spectrometer, equipped with a 532nm diode laser excitation source; ii) a micro- scope equipped with 40x and 150x lenses and a high precision xyz motorized stage for scanning the blood smear, and localizing x-y coordinates of representative series (~100 for each patient) of lymphocyte cells before registering three Raman spectra; these cells of interest being previously localized by an original method based on the morphology analysis. After the Raman acquisitions, the conventional blood smears were submitted immunolabelling using specific antibodies. For the establishment of the Raman classifiers, this post-acquisition treatment was used as reference to distinguish the different lymphocyte sub-populations. Raman data were then analyzed using chemometric processing and supervised statistical classifiers in order to construct a spectral library of markers highly specific of the lymphocyte type and status (normal or pathological). Results Currently, a total of 60 patients (CLL and healthy) were in- cluded in the study. Various classification methods such as LDA (Linear Discriminant Analysis), PLS-DA (Partial Least Square Discriminant Analysis), RF (RandomForest) and SVM (Support Vector Machine), were tested in the purpose to distinguish tumoral B lymphocytes from other cell types. These classification algorithms were combined with feature selection approaches. The best performances were around 70% of correct identification when a three-class model (B-CLL vs B-normal vs T and NK lymphocytes) was considered, and 80% in case of a two-class model (B-CLL vs B-normal lymphocytes). These encouraging results demonstrate the potential of Raman micro-spectroscopy coupled to supervised classification algorithms for leukemic cell classification. The approach can find interest more generally in the field of cyto-hematology. Further developments will concern the integration of additional modality such as Quantitative Phase Imaging on one hand to speed the exploration process of cells of interest to be probed, and on the other hand to extract additional characteristics likely to be informative for CLL diagnosis. In addition, the identification of prognostic markers will be investigated by confronting the photonic data to clinical patient information., Diagnostic Pathology, Vol 1 No 8 (2016): 13. European Congress on Digital Pathology

International audience; BACKGROUND:The classification of hematological malignancies (HMs) has changed in recent decades. For the first time, the French network of cancer registries (Francim) provides estimates for incidence and trends of HM in France between 1980 and 2012 for major HM subtypes.METHODS:Incidence was directly estimated by modeling the incidence rates measured in the cancer registry area. For each HM subtype, a "usable incidence period" was defined a priori, corresponding to the years for which all the registries collected them in a homogeneous way. For both sexes and each HM subtype, age-period-cohort models were used to estimate national incidence trends.RESULTS:Overall in France, there were an estimated 35,000 new HMs in 2012 (19,400 in men and 15,600 in women). Lymphoid malignancies accounted for more than two-thirds of HM incident cases (n=25,136). The incidence sex ratio (M/F) varied from 1.1 for classical Hodgkin lymphoma to 4.0 for mantle-cell lymphoma. The median age at diagnosis ranged from 62 to 81 years according to the major HM subtypes. Overall in both sexes, the top five most frequent HMs in 2012 were plasma cell neoplasm (about 4900 estimated cases), chronic lymphocytic leukemia/small lymphocytic lymphoma (4500 cases), diffuse large B-cell lymphoma and myelodysplastic syndromes (4100 cases), and acute myeloid leukemia (2800 cases). The incidence rates increased for follicular lymphoma and plasma cell neoplasm during the study period in both sexes. Classical Hodgkin lymphoma was relatively stable in men between 1980 and 2012 and increased in both sexes during the most recent period. Chronic myeloproliferative neoplasms, other than chronic myelogenous leukemia, are the only subtype that showed a slightly downward trend in incidence between 2003 and 2012 in both sexes.CONCLUSION:The striking differences in the incidence patterns by histologic subtype strongly suggest a certain level of etiologic heterogeneity among hematological malignancies and support the pursuit of epidemiologic analysis by subtype for HMs in international studies. Age-standardized incidence rates are essential to analyze trends in risk, whereas the number of incident cases is necessary to make provisions for healthcare resources and to evaluate the overall burden of HM.; Position du problème :La classification des hémopathies malignes a considérablement évolué ces dernières années. Pour la première fois en France, les registres publient l’incidence et les tendances des principaux sous-types d’hémopathies malignes en population entre 1980 et 2012.Méthodes :L’incidence a été estimée directement à partir de la modélisation de l’incidence de la zone registre. Pour chacune des entités, une « période d’incidence utilisable » a été préalablement définie : cette période correspond aux années pour lesquelles l’ensemble des registres du réseau Francim a recueilli de façon homogène l’entité correspondante. En fonction des entités, l’estimation a donc porté sur des périodes de longueur différente.Résultats :En 2012, 35 000 hémopathies malignes ont été diagnostiquées en France (19 400 chez l’homme et 15 600 chez la femme). Les hémopathies lymphoïdes représentaient plus des deux tiers des cas incidents (n=25 136). Le sex-ratio (H/F) variait de 1,1 pour le lymphome de Hodgkin classique, à 4,0 pour le lymphome du manteau. L’âge médian au diagnostic s’échelonnait de 62 à 81ans pour les principales hémopathies. Considérant les deux sexes, les cinq plus fréquents sous-types d’hémopathie maligne en 2012 étaient : le myélome/plasmocytome (4900 cas incidents), la leucémie lymphoïde chronique (4500 cas), le lymphome diffus à grandes cellules B et les syndromes myélodysplasiques (4100 cas), et les leucémies aiguës myéloïdes (2800 cas). Les taux standardisés d’incidence (population Monde) variaient selon le type d’hémopathie maligne considéré et le sexe : l’incidence a augmenté dans les deux sexes pour le lymphome folliculaire et les myélomes, le lymphome de Hodgkin classique est resté relativement stable chez l’homme entre 1980 et 2012 alors qu’il a augmenté dans les deux sexes durant la période la plus récente. À l’inverse, l’incidence a diminué entre 2003 et 2012 uniquement pour les syndromes myéloprolifératifs (hors leucémie myéloïde chronique).Conclusion :Les fortes disparités d’incidence par sous-type histologique suggèrent un certain degré d’hétérogénéité étiologique entre les différentes hémopathies malignes et justifient la poursuite d’études étiologiques par sous-type, en particulier au sein de collaborations internationales. L’estimation de l’incidence et des tendances reste nécessaire pour la planification des soins et l’évaluation de la charge globale des hémopathies malignes.

Introduction/ Background In hematology, actual diagnosis of B chronic lymphocyte-leukemia (CLL) is based on the microscopic analysis of cell morphology from patient blood smear. However, new photonic technologies appear promising to facilitate and improve the early diagnosis, prognostic and monitoring of personalized therapy. The development of automated diagnostic approaches could assist clinicians in improving the efficiency and quality of health services, but also reduce medical costs. Aims The M3S project aims at improving the diagnosis and prognosis of the CLL pathology by developing a multimodal microscopy platform, including Raman spectrometry, dedicated to the automatic analysis of lymphocytes. Methods Blood smears were prepared on glass slides commonly used in pathology laboratories for microscopy. Two types of sample per patient were prepared: a conventional blood smear and a deposit of “pure” lymphocyte subtypes (i.e. normal B, CLL B, T and NK), sorted out in flow cytometry by using the negative double labeling technique. The second sample is used for the construction of a database of spectral markers specific of these different cell types. The preparations were analyzed with the multimodal machine which combines i) a Raman micro-spectrometer, equipped with a 532nm diode laser excitation source; ii) a microscope equipped with 40x and 150x lenses and a high precision xyz motorized stage for scanning the blood smear, and localizing x-y coordinates of representative series (~100 for each patient) of lymphocyte cells before registering three Raman spectra; these cells of interest being previously localized by an original method based on the morphology analysis. After the Raman acquisitions, the conventional blood smears were submitted to immunolabelling using specific antibodies. For the establishment of the Raman classifiers, this post-acquisition treatment was used as reference to distinguish the different lymphocyte sub-populations. Raman data were then analyzed using chemometric processing and supervised statistical classifiers in order to construct a spectral library of markers highly specific of the lymphocyte type and status (normal or pathological). Results Currently, a total of 60 patients (CLL and healthy) were included in the study. Various classification methods such as LDA (Linear Discriminant Analysis), PLS-DA (Partial Least Square Discriminant Analysis), RF (Random Forest) and SVM (Support Vector Machine), were tested in the purpose to distinguish tumoral B lymphocytes from other cell types. These classification algorithms were combined with feature selection approaches. The best performances were around 70% of correct identification when a three-class model (B-CLL vs B-normal vs T and NK lymphocytes) was considered, and 80% in case of a two-class model (B-CLL vs B-normal lymphocytes). These encouraging results demonstrate the potential of Raman micro-spectroscopy coupled to supervised classification algorithms for leukemic cell classification. The approach can find interest more generally in the field of cyto-hematology. Further developments will concern the integration of additional modality such as Quantitative Phase Imaging on one hand to speed the exploration process of cells of interest to be probed, and on the other hand to extract additional characteristics likely to be informative for CLL diagnosis. In addition, the identification of prognostic markers will be investigated by confronting the photonic data to clinical patient information., Diagnostic Pathology, Vol 1 No 8 (2016): 13. European Congress on Digital Pathology

Introduction/objectifs/but En hematologie biologique, l’examen microscopique des frottis de sang, moelle, ganglion… reste la premiere etape du diagnostic et du suivi des patients. Dans le but de fournir une aide pratique et adaptee aux biologistes impliques dans la morphologie cellulaire, le GFHC a mis en place la premiere solution de tele-expertise en cytologie hematologie : le reseau ANDRAL : http://www.gfhc-reseau-andral.fr/ . Pour toute demande soumise (images microscopiques + fiche patient), le reseau propose une relecture par deux experts dans un delai Materiel et methode Le fonctionnement et l’environnement d’ANDRAL sont strictement conformes aux exigences reglementaires. L’hebergement agree des donnees est fourni par syndicat inter-hospitalier Limousin (SILPC). La relecture des dossiers images (lundi/samedi – 8 h/20 h) est assuree par un groupe d’experts benevoles. Le projet est finance par l’ARS Limousin, la Mutualite francaise, la Ligue contre le cancer. Resultats/observations Depuis novembre 2012, ANDRAL a enregistre 350 inscriptions : biologistes liberaux (36 %), hospitaliers CHU (32 %) CH (32 %) en France et hors metropole 12 % UE, Afrique, Oceanie… Les experts traitent environ 2 dossiers/semaine dont 15 % d’urgence. Les delais de prise en charge (mediane 1 h 09) et de reponses (mediane 4 h 55) sont juges tres satisfaisants par les utilisateurs. L’evaluation du service montre que la demarche permet de preciser les resultats patients (78 %) apres des reponses jugees pertinentes et utiles (94 %). La phase d’experimentation valide largement les objectifs initiaux : pertinence de l’organisation et des outils, deploiement large, service rendu reel. Les perspectives d’ANDRAL sont aujourd’hui tres prometteuses : deploiement d’un modele medico-economique, ouverture vers les jeunes biologistes, cooperation avec d’autres reseaux.

International audience; Using biophotonics techniques to retrieve prognostic intracellular signatures : IHMO project aims at developing a multimodal microscopy platform that includes in a single machine Raman micro spectroscopy and multispectral imaging used for tumor diagnosis and prognosis. Lymphocytes from 24 leukaemic patients suffering from hyper leukocytosis Chronic Lymphoid Leukemia and from 11 healthy individual have been studied, using around 90 cells per blood sample. Blood smears were prepared on microscopy slides; cells were localized by optical microscopy, and Raman microspectroscopy spectra were acquired on cell nuclei. Afterward multi-Z stacks images of each cell were acquired for eight bands distributed in the visible spectrum. Raman data's were classified using a Support Vector Machine algorithm that provided a molecular signature that allowed for distinguishing lymphocytes from other nucleated blood components with 99.6% sensibility and 98.8% specificity. Then the algorithm was used for developing a classification model splitting leukaemic and healthy smears; sensibility was 95% and specificity was 87.5% among the spectra used for evaluation: 1540 from 11 leukaemic patients and 516 from seven healthy individual. IHMO project has demonstrated the power of Raman microspectroscopy for cell classification. Morphological descriptors obtained from multi-Z and multispectral images provide another independent classification that still needs to be assessed. The microscopy platform can be used more generally in the field of cytohaematology, however application to cytological and histological pathology would need further developments.

Acquired von Willebrand syndrome is a rare bleeding disorder, which has been related in various diseases including lymphoproliferative disorders or autoimmune diseases. Its diagnosis is an important step before treatment of patients and particularly in case of bleeding. We report four cases from Caen Hemophilia Treatment Center, diagnosed and treated from 1999 to 2008. Mucocutaneous bleeds in every case were the same as in hereditary von Willebrand disease. All patients had no personal or family history of bleeding. Phenotype was identified as type 2 von Willebrand disease with a loss of high molecular weight multimers. Anti-von Willebrand factor inhibitor screening was positive for three patients. The etiological diagnosis was one chronic lymphocytic leukaemia, two monoclonal gammapathies of undetermined significance (MGUS) and one undetermined case. The management of patients need two stages: first infusions of factor von Willebrand/factor VIII concentrates to stop bleeds, then treatment of the underlying disease such as chemotherapy, corticotherapy and treatment with high doses of polyvalents immunoglobulins. In every case, treatment was effective and improved patient's quality of life.

50 patients with a median age of 41 years (range 29–54) underwent allogeneic bone marrow transplantation for multiple myeloma. 35 patients were on second-line treatment, and 15 on first-line treatment. 24 patients were considered refractory to previous treatment. 45 patients received marrow from HLA-matched sibling donors (3 of these from twin donors), and 5 from unrelated or related non-sibling donors. 21 patients entered complete remission, while 15 had persistent disease following repopulation of the marrow. 14 patients were not evaluable for remission status because of early transplantation-related death. The overall median survival from bone marrow transplantation was 27 months, with a projected long-term survival of 34%. Patients who were 40 yr of age or older had a survival that was not different from that of patients between 29 and 40 yr of age. The median disease-free survival of patients who entered complete remissions was 41 months. These patients tended to have a longer survival than patients with persistent disease following repopulation of the marrow. Allogeneic bone marrow transplantation appears to be a promising method for treatment of certain patients with multiple myeloma.

Resume La leucemie lymphoide chronique (LLC) est la plus frequente des leucemies chroniques. Elle est definie par une lymphocytose absolue (> 4 × 109/l) durable avec a l'examen du frottis sanguin des cellules lymphoides matures de petite taille. Le score immunologique RMH etabli sur cinq criteres (positivite du CD5 et du CD23, negativite du FMC7 et expression faible des Igs et du CD22 ou du CD79b) est de 4 ou 5. La classification clinique de Binet definit trois stades d'evolution differente : les stades A (65 % des cas) et B (28 %) sans ou avec au moins trois aires ganglionnaires atteintes en l'absence d'anemie ou de thrombopenie et le stade C avec anemie (hemoglobine inferieure a 10 g/dl) ou thrombopenie (plaquettes inferieures a 10 × 109/l). Certains patients avec un stade A vont progresser rapidement et inversement d'autres vont rester stables et non evolutifs pendant des periodes tres prolongees. Quatre marqueurs a valeur pronostique ont ete recemment identifies et permettent d'adopter de nouvelles strategies therapeutiques en fonction de la presence ou non de criteres de gravite. Ces facteurs sont le temps de doublement des lymphocytes, la thymidine kinase serique, la detection de certaines anomalies cytogenetiques dont les del(11) et del(17), la +12 et la del(13) et les etudes de profil mute ou non des genes des chaines lourdes des immunoglobulines. Les strategies therapeutiques ont evolue ces dernieres annees et font appel, si des criteres de gravite sont presents, a une association chimiotherapie (analogues des purines associes ou non au cyclophosphamide) et immunotherapie (anticorps monoclonaux anti-CD20 et/ou anti-CD52). Les indications therapeutiques doivent etre prises en milieu specialise et en Reunion de concertation pluridisciplinaire (RCP).

Background In Europe skin melanoma (SM) survival has increased over time. The aims were to evaluate recent trends and differences between countries and regions of Europe.Methods Relative survival (RS) estimates and geographical comparisons were based on 241,485 patients aged 15 years and over with a diagnosis of invasive SM in Europe (2000-2007). Survival time trends during 1999-2007 were estimated using the period approach, for 213,101 patients. Age, gender, sub-sites and morphology subgroups were considered. Results In European patients, estimated 5-year RS was 83% (95% confidence interval, CI 83-84%). The highest values were found for patients resident in Northern (88%; 87-88%) and Central (88%; 87-88%) Europe, followed by Ireland and United Kingdom (UK) (86%; 85-86%) and Southern Europe (83%; 82-83%). The lowest survival was in Eastern Europe (74%; 74-75%). Within regions the intercountry absolute difference in percentage points of RS varied from 4% (North) to 34% (East). RS decreased markedly with patients' age and was higher in women than men. Differences according to SM morphology and skin sub-sites also emerged. Survival has slightly increased from 1999 to 2007, with a small improvement in Northern and the most pronounced improvement in Eastern Europe. Discussion SM survival is high and still increasing in European patients. The gap between Northern and Southern and especially Eastern European countries, although still present, diminished over time. Differences in stage distribution at diagnosis may explain most of the geographical differences. However, part of the improvement in survival may be attributed to overdiagnosis from early diagnosis practices.

Background Survival of patients diagnosed with lung and pleura cancer is a relevant health care indicator which is related to the availability and access to early diagnosis and treatment facilities. Aim of this paper is to update lung and pleural cancer survival patterns and time trends in Europe using the EUROCARE-5 database. Methods Data on adults diagnosed with lung and pleural cancer from 87 European cancer registries in 28 countries were analysed. Relative survival (RS) in 2000–2007 by country/region, age and gender, and over time trends in 1999–2007 were estimated. Results Lung cancer survival is poor everywhere in Europe, with a RS of 39% and 13% at 1 and 5 years since diagnosis, respectively. A geographical variability is present across European areas with a maximum regional difference of 12 and 5 percentage points in 1-year and 5-year RS respectively. Pleural cancer represents 4% of cases included in the present study with 7% 5-year RS overall in Europe. Most pleural cancers (83%) are microscopically verified mesotheliomas. Survival for both cancers decreases with advancing age at diagnosis for both cancers. Slight increasing trends are described for lung cancer. Survival over time is higher for squamous cell carcinoma and adenocarcinomas than for small and large cell carcinoma; and better among women than men. Conclusions Despite the generalised although slight increase, survival of lung and pleural cancer patients still remains poor in European countries. Priority should be given to prevention, with tobacco control policies across Europe for lung cancer and banning asbestos exposure for pleural cancer, and in early diagnosis and better treatment. The management of mesothelioma needs a multidisciplinary team and standardised health care strategies.

Background: Overall survival after cancer is frequently used when assessing a health care service’s performance as a whole. It is mainly used by the public, politicians and the media, and is often dismissed by clinicians because of the heterogeneous mix of different cancers, risk factors and treatment modalities. Here we give survival details for all cancers combined in Europe, correlating it with economic variables to suggest reasons for differences. Methods: We computed age and cancer site case- mix standardised relative survival for all cancers combined (ACRS) for 29 countries participating in the EUROCARE-5 project with data on more than 7.5 million cancer cases from 87 population-based cancer registries, using complete and period approach. Results: Denmark, United Kingdom (UK) and Eastern European countries had lower survival than neighbouring countries. Five-year ACRS has been increasing throughout Europe, and substantial increases, between 1999–2001 and 2005–2007, have been achieved in countries where survival was lower in the past. Five-year ACRS for men and women are positively correlated with macro-economic variables like the Gross Domestic Product (GDP) and Total National Expenditure on Health (TNEH) (R2 about 70%). Countries with recent larger increases in GDP and TNEH had greater increases in cancer survival. Conclusions: ACRS serves to compare all cancer survival in Europe taking account of the geographical variability in case-mixes. The EUROCARE-5 data on ACRS confirm previous EUROCARE findings. Survival appears to correlate with macro-economic determinants, particularly with investments in the health care system.

Background This work presents relative survival estimates regarding urinary tract tumours among adult patients (age ⩾ 15 years) diagnosed in Europe. It reports on survival estimates of cases diagnosed in 2000–2007, and on survival time trends from 1999–2001 to 2005–2007. Methods Data on 677,340 adult urinary tract tumour patients, (429,154 cases of invasive and non-invasive bladder and 248,186 cases of invasive kidney cancers) diagnosed between 2000 and 2007 were provided by 86 population-based cancer registries from 29 European countries. The complete approach was used to estimate survival in 2000–2007; the period approach was used to estimate survival over time. Results The age-standardised 5-year relative survival for patients with kidney tumours diagnosed in Europe during 2000–2007 was 60%. The best prognosis was observed in Southern and Central Europe and prognosis improved in all regions along the time period. For invasive and non-invasive patients with bladder tumours combined the age-standardised 5-year relative survival in Europe was 68%. The best prognosis was observed in Southern and Northern Europe. However, in Scotland and The Netherlands the relative survival was significantly lower, although the survival estimates for these two countries were based on invasive tumours only. Conclusions Differences in registration practices affect comparisons of survival values between European countries, especially in patients with urinary bladder cancers. The between-country variation in survival is influenced by the varying use of diagnostic investigation in urinary tract tumours. Further data on stage at diagnosis can help to elucidate the influence of diagnostic intensity or early diagnosis on the survival patterns.

BACKGROUND: Head and neck (H&N) cancers are a heterogeneous group of malignancies, affecting various sites, with different prognoses. The aims of this study are to analyse survival for patients with H&N cancers in relation to tumour location, to assess the change in survival between European countries, and to investigate whether survival improved over time. METHODS: We analysed about 250, 000 H&N cancer cases from 86 cancer registries (CRs). Relative survival (RS) was estimated by sex, age, country and stage. We described survival time trends over 1999-2007, using the period approach. Model based survival estimates of relative excess risks (RERs) of death were also provided by country, after adjusting for sex, age and sub- site. RESULTS: Five-year RS was the poorest for hypopharynx (25%) and the highest for larynx (59%). Outcome was significantly better in female than in male patients. In Europe, age-standardised 5-year survival remained stable from 1999-2001 to 2005-2007 for laryngeal cancer, while it increased for all the other H&N cancers. Five- year age-standardised RS was low in Eastern countries, 47% for larynx and 28% for all the other H&N cancers combined, and high in Ireland and the United Kingdom (UK), and Northern Europe (62% and 46%). Adjustment for sub-site narrowed the difference between countries. Fifty-four percent of patients was diagnosed at advanced stage (regional or metastatic). Five- year RS for localised cases ranged between 42% (hypopharynx) and 74% (larynx). CONCLUSIONS: This study shows survival progresses during the study period. However, slightly more than half of patients were diagnosed with regional or metastatic disease at diagnosis. Early diagnosis and timely start of treatment are crucial to reduce the European gap to further improve H&N cancers outcome.

Background The EUROCARE study collects and analyses survival data from population-based cancer registries (CRs) in Europe in order to provide data on between-country differences in survival and time trends in survival. Methods This study analyses data on liver cancer, gallbladder and extrahepatic biliary tract cancers (“biliary tract cancers”), and pancreatic cancer diagnosed in 2000–2007 from 88 CRs in 29 countries. Relative survival (RS) was estimated overall, by region, sex, age and period of diagnosis using the complete approach. Time trends in 5-year RS over 1999–2007 were also analysed using the period approach. Results The prognosis of the studied cancers was poor. Age-standardised 5-year RS was 12% for liver cancer, 17% for biliary tract cancers and 7% for pancreatic cancer. There were some between-country differences in survival. In general, RS was low in Eastern Europe and high in Central and Southern Europe. For all sites, 5-year RS was similar in men and women and decreased with advancing age. No substantial changes in survival were reported for pancreatic cancer over the period 1999–2007. On average, there was a crude increase in 5-year RS of 3 percentage points between the periods 1999–2001 and 2005–2007 for liver cancer and biliary tract cancers. Conclusions The major changes in imaging techniques over the study period for the diagnosis of the three studied cancers did not result in an improvement in the prognosis of these cancers. In the near future, new innovative treatments might be the best way to improve the prognosis in these cancers.

Background We provide updated estimates of survival and survival trends of male genital tumours (prostate, testicular and penis cancers), in Europe and across European areas. Methods The complete approach was used to obtain relative survival estimates for patients diagnosed in 2000–2007, and followed up through 2008 in 29 countries. Data came from 87 cancer registries (CRs) for prostate tumours and from 86 CRs for testis and penis tumours. Relative survival time trends in 1999–2007 were estimated by the period approach. Data came from 49 CRs in 25 countries. Results We analysed 1,021,275 male genital cancer cases. Five-year relative survival was high and decreased with increasing age for all tumours considered. We found limited variation in survival between European regions with Eastern Europe countries having lower survival than the others. Survival for penile cancer patients did not improve from 1999 to 2007. Survival for testicular cancer patients remained stable at high levels since 1999. Survival for prostate cancer patients increased over time. Conclusions Treatment standardisation and centralisation for very rare diseases such as penile cancers or advanced testicular tumours should be supported. The high survival of testicular cancer makes long-term monitoring of testicular cancer survivors necessary and CRs can be an important resource. Prostate cancer patients’ survival must be interpreted considering incidence and mortality data. The follow-up of the European Randomised Study of Screening for Prostate Cancer should continue to clarify the impact of screening on prostate cancer mortality together with population based studies including information on stage and treatments.

Background Since 25 years the EUROCARE study monitors the survival of cancer patients in Europe through centralised collection, quality check and statistical analysis of population-based cancer registries (CRs) data. The European population covered by the study increased remarkably in the latest round. The study design and statistical methods were also changed to improve timeliness and comparability of survival estimates. To interpret the EUROCARE-5 results on adult cancer patients better here we assess the impact of these changes on data quality and on survival comparisons. Methods In EUROCARE-5 the survival differences by area were studied applying the complete cohort approach to data on nearly nine million cancer patients diagnosed in 2000–2007 and followed up to 2008. Survival time trends were analysed applying the period approach to data on about 10 million cancer cases diagnosed from 1995 to 2007 and followed up to 2008. Differently from EUROCARE-4, multiple primary cancers were included and relative survival was estimated with the Ederer II method. Results EUROCARE-5 covered a population of 232 million resident persons, corresponding to 50% of the 29 participating countries. The population coverage increased particularly in Eastern Europe. Cases identified from death certificate only (DCO) were on average 2.9%, range 0–12%. Microscopically confirmed cases amounted to over 85% in most CRs. Compared to previous methods, including multiple cancers and using the Ederer II estimator reduced survival estimates by 0.4 and 0.3 absolute percentage points, on average. Conclusions The increased population size and registration coverage of the EUROCARE-5 study ensures more robust and comparable estimates across European countries. This enlargement did not impact on data quality, which was generally satisfactory. Estimates may be slightly inflated in countries with high or null DCO proportions, especially for poor prognosis cancers. The updated methods improved the comparability of survival estimates between recently and long-term established registries and reduced biases due to informative censoring.

Some epidemiologic studies suggest a link between hepatitis C virus (HCV) infection and some B-cell non-Hodgkin's lymphomas. We undertook this study after a patient with splenic lymphoma with villous lymphocytes had a hematologic response after antiviral treatment of HCV infection. Nine patients who had splenic lymphoma with villous lymphocytes and HCV infection were treated with interferon alfa-2b (3 million IU three times per week) alone or in combination with ribavirin (1000 to 1200 mg per day). The outcomes were compared with those of six similarly treated patients with splenic lymphoma with villous lymphocytes who tested negative for HCV infection. Of the nine patients with HCV infection who received interferon alfa, seven had a complete remission after the loss of detectable HCV RNA. The other two patients had a partial and a complete remission after the addition of ribavirin and the loss of detectable HCV RNA. One patient had a relapse when the HCV RNA load again became detectable in blood. In contrast, none of the six HCV-negative patients had a response to interferon therapy. In patients with splenic lymphoma with villous lymphocytes who are infected with HCV, treatment with interferon can lead to regression of the lymphoma.

Roles des auteurs Tuteur : Dr J. Jegu, Laboratoire d’epidemiologie et de sante publique, Strasbourg, France. Responsable : Pr M. Velten, Laboratoire d’epidemiologie et de sante publique, centre Paul-Strauss, Strasbourg, France. Etat de la question Le tabac augmente le risque de premier mais aussi de second cancer primitif (SCP). Cette etude a cherche a determiner si le risque de SCP chez les patients atteints d’un cancer lie au tabac a change ces dernieres annees. Materiel et methodes Les donnees de douze registres de cancer francais ont ete utilisees pour constituer une cohorte de tous les patients ayant presente un cancer du larynx, du poumon, de la vessie, de l’oropharynx ou de la cavite orale entre 1989 et 2010 suivis jusqu’au 30 juin 2013. L’approche par personnes–annees a ete utilisee pour estimer des ratios standardises d’incidence (SIR) et des exces absolus de risque (EAR) de second cancer metachrone. Les tendances de SIR par annee de diagnostic et site de premier cancer ont ensuite ete modelisees par des regressions multivariees de poisson en ajustant sur le sexe, l’âge et la duree de suivi. Resultats Parmi les 83 166 patients ayant un premier cancer du larynx, du poumon, de la vessie, de l’oropharynx ou de la cavite orale, 7826 ont developpe un SCP (SIR = 1,99 [1,94–2,03]). Apres analyse multivariee par regression de poisson, seul le risque de cancer du poumon apres un cancer de la vessie etait associe a l’annee de diagnostic du premier cancer, avec un SIR augmentant de 2,51 (95 % CI 2,06–3,02) en 1989–1994 a 3,69 (95 % CI 3,11–4,34) en 2005–2010. Le risque etait stable sur la periode d’etude pour les autres cancers lies au tabac. Conclusion Le risque de second cancer du poumon apres un cancer de la vessie ayant augmente entre 1989 et 2010 et les risques de second cancer apres un premier cancer du larynx, du poumon, de l’oropharynx et de la cavite orale etant restes hauts et inchanges, les interventions pour le sevrage tabagique des patients atteints d’un premier cancer lie au tabac doivent etre poursuivies et renforcees.

International audience

International audience; BACKGROUND: The struggle against social inequalities is a priority for many international organizations. The objective of the study was to quantify the cancer burden related to social deprivation by identifying the cancer sites linked to socioeconomic status and measuring the proportion of cases associated with social deprivation. METHODS: The study population comprised 68 967 cases of cancer diagnosed between 1997 and 2009 in Normandy and collected by the local registries. The social environment was assessed at an aggregated level using the European Deprivation Index (EDI). The association between incidence and socioeconomic status was assessed by a Bayesian Poisson model and the excess of cases was calculated with the Population Attributable Fraction (PAF). RESULTS: For lung, lips-mouth-pharynx and unknown primary sites, a higher incidence in deprived was observed for both sexes. The same trend was observed in males for bladder, liver, esophagus, larynx, central nervous system and gall-bladder and in females for cervix uteri. The largest part of the incidence associated with deprivation was found for cancer of gall-bladder (30.1%), lips-mouth-pharynx (26.0%), larynx (23.2%) and esophagus (19.6%) in males and for unknown primary sites (18.0%) and lips-mouth-pharynx (12.7%) in females. For prostate cancer and melanoma in males, the sites where incidence increased with affluence, the part associated with affluence was respectively 9.6% and 14.0%. CONCLUSIONS: Beyond identifying cancer sites the most associated with social deprivation, this kind of study points to health care policies that could be undertaken to reduce social inequalities.

PURPOSE To evaluate growth, thyroid function, puberty, cardiac function, and the incidence of cataracts in children who received allogeneic bone marrow transplantation (BMT) for acute myeloblastic leukemia (AML) in first complete remission (CR) after a preparation with or without total-body irradiation (TBI). PATIENTS AND METHODS Among 45 children studied, 26 received busulfan-cyclophosphamide (Bu-Cy) in preparation for transplantation and 19 received TBI. TBI was fractionated in nine cases and delivered as a single dose in 10. Four children in the Bu-Cy group and none in the TBI group had received prior cranial radiation. The mean follow-up duration after BMT was 5.9 years for the whole group. RESULTS The mean cumulative changes in height SD score (SDS) were -0.86 at 3 years and -1.56 at 5 years in the TBI group, whereas these changes were only -0.05 and -0.17 in the Bu-Cy group (P < .01 at 3 and 5 years). The 6-year probability of hypothyroidism was 9% +/- 8% in the Bu-Cy group and 43% +/- 15% after TBI (P < .02). Pubertal development after Bu-Cy was assessable in two girls and five boys: both girls had primary ovarian failure, whereas Leydig cell function appeared to be preserved in the five boys. One child who had received anthracycline when he was less than 1 year old developed cardiac dysfunction 4 years after Bu-Cy. The 6-year probability of cataracts was 70% +/- 13% in the TBI group and 0% after Bu-Cy. CONCLUSION The use of Bu-Cy represents an alternative transplant cytoreductive regimen for children with AML in first CR, which can reduce the risk of posttransplant growth impairment, thyroid dysfunction, Leydig cell damage, and the incidence of cataracts.

We studied the immunophenotype and the functional reactivity to cytokines of blood cells from eight patients with Splenic Lymphoma with Villous Lymphocytes (SLVL). Cells from all cases exhibited moderate to high levels of membrane immunoglobulin, CD22 and CD40 antigens and light chain restriction (kappa/lambda: 1.7/1). CD44, CD54 and CD11b expression was detected in all cases whereas CD11c was expressed in only four cases (50%). CD11c+ cells lacked CD21 and CD23 expression whereas CD11c- ce lls expressed both these antigens. Cells from most patients (7/8) responded to IL2 whereas only four responded to IL4 and three to TNFalpha. The response to TNFalpha correlated with spontaneous TNF-RII and CD11c expression. Although two days of culture induced the TNF-RII expression in CD11c- cells, they remained unresponsive to TNFalpha. These two groups of SLVL patients also differed by IL10 mRNA content: the former (CD11c+, TNF-RII+) contained TNFalpha and IL10 mRNA whereas the latter (CD11c-, TNF-RII-) lacked IL10 mRNA, even after two days of culture. There were thus two groups of SLVL patients: CD11c+ and CD11c-, exhibiting different patterns of cytokine response and production. These groups may correspond to different cell origins or different progression stages of the disease.

The t(1;19)(q23;p13) translocation occurs commonly in B-lineage ALL. Previous reports have demonstrated a predominance of cases with expression of cytoplasmic Ig mu (C mu+), and FAB L1/L2 phenotype, a poor prognosis and expression of a fusion transcript involving the E2A and PBX1 genes in C mu+ but not in C mu- cases. Of 38 patients with karyotypically proven t(1;19) (q23;p13) leukaemias, we extensively analysed 18 patients with acute leukaemia including 16 B-lineage ALLs, one T-ALL and one AML M4. The AML was associated with a classic E2A-PBX1 fusion transcript and may represent the human counterpart of the AMLs induced by E2A-PBX1 retroviral infection of murine marrow progenitors. The T-ALL was E2A-PBX1 negative and neither the E2A nor the LYL-1 genes, both situated at chromosome 19 p13, were rearranged. Of the 16 B-lineage ALLs, four had cytological features resembling an 'L3-like' phenotype classically associated with Burkitt's lymphoma, two at diagnosis and relapse and two exclusively at relapse. E2A-PBX1 fusion transcripts were detected by RT-PCR in all 13 C mu+ patients and in 2/3 C mu- cases. The 'L3-like' phenotype did not correlate with a particular stage of maturation arrest (one sIg+, one C mu+, one C mu-) or type of E2A-PBX1 transcript, but was associated in all cases with a trisomy 8. Translocation, rearrangement, amplification or over-expression of the c-myc gene was not observed in these cases, demonstrating that the apparent association with trisomy 8 is not due to deregulation of this gene. We therefore show that the E2A-PBX1 transcript, although occurring predominantly in C mu+ pre-B ALL, also occurs in C mu- early pre-B ALL, sIg+ B-ALL and even in AML. These results suggest that the stage of maturation arrest, and indirectly the prognosis, are not solely due to the type of fusion transcript associated with the t(1;19).

Persistent lymphocytosis is usually associated with a malignant lymphoproliferative disease (MLPD). We report six female patients presenting a chronic, moderate lymphocytosis of 2-16 years duration with atypical binucleated lymphocytes on peripheral blood smears. Further investigation showed a polyclonal increase in serum IgM and HLA-DR7 phenotype in all patients. The B cells were polyclonal because Southern hybridization of DNA and polymerase chain reaction failed to demonstrate a clonal rearrangement of immunoglobulin heavy chain genes. Peripheral blood examination showed binucleated lymphocytes in a family member of two of the cases; taken together with the association with HLA-DR7 these data suggest a genetic predisposition. The identification of this benign syndrome is important in order to prevent its misdiagnosis as a MLPD.

Review on Splenic lymphoma with villous lymphocytes (SLVL), with data on clinics, and the genes involved.

Review on Polyclonal B lymphocytosis with binucleated lymphocytes (PPBL), with data on clinics, and the genes involved.

The study was designed to present the incidence of all the haematological malignancies (HM) in Basse-Normandie (BN) over the period 1997 to 2005 in patients less than 25 years old. BN is an administrative region in the North-West of France, composed of three departments: Calvados, Manche and Orne. We extracted data from the Registre régional des hémopathies malignes de Basse-Normandie, a French registry which belongs to the Association of the French Cancer Registries (Francim).All the HM were coded using the third edition of the International classification for oncologic diseases (ICD-O-3). We compared the clinical and biological descriptive data in patients less than 15 years old to those of young adults (15-24 years old).A total of 305 new cases of HM were recorded over the period 1997 to 2005. HM were more frequent in men (168 cases) than in women (137 cases). Patients less than 25 years old accounted for 4.1% of all HM cases, whereas patients less than 15 years old and young adults (15-24 years old) represented 2.2% and 1.9% of all cases, respectively. In patients less than 25 years old, the overall world-standardized incidence rates (WSR) were 7.67/100,000 (95% CI: 6.31-9.04) in BN (8.08 [6.15-10.02] for men and 7.24 [5.31-9.17] for women). In patients less than 15years, the overall WSR was 7.38/100,000 (6.23-8.52), with no difference between boys (7.57) and girls (7.17). Acute lymphoblastic leukaemia (ALL) was the most frequent HM, WSR=4.02/100,000 (3.16-4.88) (4.30 [3.08-5.53] in men, 3.73 [2.52-4.93] in women), with similar clinical and biological criteria between patients less than 15 years and young adults. In young adults, the overall WSR was 8.21/100,000 (7.47-8.96), similar between men and women (9.02 [7.93-10.12] and 7.37 [6.35-8.38], respectively). Their highest WSR was obtained for Hodgkin lymphomas (HL): 3.37/100,000 (2.89-3.85), similar between men (3.49 [2.8-4.17]) and women (3.25 [2.58-3.93]). The study did not show any significant difference between the Calvados, Manche and Orne departments (except for HL, which seems more frequent in Manche department for 15-24 years old cases). There was no evidence of an increased risk for ALL in the subdistricts Beaumont-Hague and Les Pieux, which respectively have a nuclear waste reprocessing plant and a nuclear power plant on their territory. The subtype of HM was dependent on age whereas clinical and biological data were the same, whatever the age.These results contribute to HM monitoring in an area where the nuclear industry is present and to improve the organization and follow-up of medical care.

We evaluated the performance of the automated body fluid mode of the Sysmex XE-5000 series automated haematology analyzer and compared the performance of the automated method for obtaining white blood cell (WBC), red blood cell (RBC) counts and WBC differential counts with microscopic method. One hundred and seventy-four samples were analysed: 81 ascitic fluid, 32 cerebrospinal fluid (CSF), 26 pleural fluid (PF), 18 synovial fluid (SF), 13 peritoneal fluid (PeF) and 4 other types. The agreement between the automated method and the manual reference showed high correlation, with Pearson correlation coefficients greater than 0.9 for all types of body fluids. We also demonstrate that the automated body fluid analysis on the XE-5000 is an acceptable alternative to the microscopic reference method as far as ascitic fluid, peritoneal dialysis fluid, SF or PF are concerned. Conversely, results for body fluid samples from oncology patients with leukaemia or tumours showed significant differences between both methods, as XE-5000 counted blast cells and neoplastic cells in mononuclear cell count. XE-5000 could represent an attractive method for the automated analysis of WBC, RBC, mononuclear cell count (MNC) and polymorphonuclear (PMN) cells of most body fluids. However, CSFs from patients with leukaemia or lymphoma should be processed with the microscopic reference method in order to detect abnormal leukaemic cells.

Acquired von Willebrand syndrome is a rare bleeding disorder, which has been related in various diseases including lymphoproliferative disorders or autoimmune diseases. Its diagnosis is an important step before treatment of patients and particularly in case of bleeding. We report four cases from Caen Hemophilia Treatment Center, diagnosed and treated from 1999 to 2008. Mucocutaneous bleeds in every case were the same as in hereditary von Willebrand disease. All patients had no personal or family history of bleeding. Phenotype was identified as type 2 von Willebrand disease with a loss of high molecular weight multimers. Anti-von Willebrand factor inhibitor screening was positive for three patients. The etiological diagnosis was one chronic lymphocytic leukaemia, two monoclonal gammapathies of undetermined significance (MGUS) and one undetermined case. The management of patients need two stages: first infusions of factor von Willebrand/factor VIII concentrates to stop bleeds, then treatment of the underlying disease such as chemotherapy, corticotherapy and treatment with high doses of polyvalents immunoglobulins. In every case, treatment was effective and improved patient's quality of life.

The CellaVisiontrade mark DM96 is an automated image analysis system dedicated to locating and preclassifying the various types of white blood cells in peripheral blood smears. The system also partially characterizes of the red blood cell morphology and is able to perform platelet counts. We routinely analyzed the blood samples from 440 patients with quantitative and/or qualitative abnormalities detected by the XE-2100 Sysmextrade mark. Only 2.6% of cells are not identified by DM96trade mark. After classification of the unidentified cells very good correlation coefficients are observed between DM96trade mark and manual microscopy for most hematological parameters and accuracy is judged excellent up to 98%. For most common parameters, false positive and false negative ratios are also very good. Whatever the pathology and the number of blasts on smear, all patients were positive for blast detection on DM96trade mark. The system is a useful tool for assisting in the diagnosis and classification of most acute or chronic leukemia. Automatic cell location and preclassification, along with unique cell views on the computer screen, could reduce the time spent performing differentials and make real-time collaboration between colleagues a natural part of the classification process. The workstation also provides an ergonomically correct and relaxed working environment. We suggest its use in routine analysis; the system could be very helpful for the accurate morphological diagnosis of samples from patients with malignant hematological disease.

The study was designed to present the incidence of all the haematological malignancies in Basse-Normandie over the period 1997-2004. We extracted the data from the "Registre régional des hémopathies malignes de Basse-Normandie (RRHMBN)", a French registry which belongs to the Association of the French Cancer Registries (FRANCIM). All the malignant haematological diseases were coded using the third edition of the International Classification for Oncologic Diseases (ICD-O-3) and the ADICAP classification, a special version adapted in 2001 for haematology. Five thousand five hundred and ten new cases of malignant haematological disorders were registered over the period 1997-2004. Whatever the department constituting the Basse-Normandie (Calvados, Manche and Orne), no significant difference of incidence was detected. In men, the more frequent malignant disorders were non-Hodgkin's malignant lymphomas (NHML) followed by chronic lymphocytic leukemia and other mature neoplasms, myelodysplastic syndromes (MDS), multiple myeloma (MM), myeloproliferative disorders (MPD), acute myeloid leukemias (AML), Hodgkin's lymphomas (HL), Waldenström's macroglobulinemia (WM) and acute lymphoblastic leukemia (ALL). In women, MM is the third more frequent haematological disorders after NHML and lymphocytic leukaemia and other mature neoplasms, MPD, MDS, AML, Hodgkin's lymphomas, WM and ALL. The other haematological disorders are very rare. We provide the incidence for the main haematological disorders and for the first time we also present the incidence of the different subtypes of the Hodgkin's and non-Hodgkin's malignant lymphomas, mature lymphoid neoplasms, MPD and also MDS. These results are useful for the organization and follow-up of medical care. The development of specialized haematology and active protocols can optimize the management of the older patients. A high quality of the collected data remains necessary for a continuous watching and research on patients with malignant haematological diseases.