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Tidigare studier har fokuserat på barn och deras familjers upplevelser i samband med en hematologisk malignitet, framförallt leukemi. Hematologiska maligniteter är ett samlingsnamn för leukemi och några andra blodsjukdomar. Prevalensen för sjukdomarna ökar och främst vuxna drabbas. Syftet med studien var att beskriva patienters upplevelser av att leva med en hematologisk malignitet. Metoden för denna litteraturöversikt var kvalitativ. Fem artiklar och två avhandlingar analyserades. Studiens resultat utvecklades till fyra huvudteman: att få en sjukdom, att genomgå behandling, upplevelse av vårdmöten och att skakas om i sin livsvärld. Resultatet visar att sjukdomen upplevs som ett osynligt hot och att det ibland förekommer ett vårdlidande som beror på bristfälligt engagemang för människan bakom den sjuka kroppen. Att genomgå en svår tid med lidandets olika aspekter, förändrade oftast människors syn på sig själva och sina medmänniskor. Relationer fördjupades. Förbättringar i omvårdnadsarbetet kan göras genom ökad fokus på patienters känslomässiga lidande då studien visar att denna aspekt ibland förbises och detta resulterar i en objektifiering av patienter. / Previous studies have focused on children and their families' experiences in connection with a haematological malignancy, especially leukemia. Hematolocical malignancies is a collective name for leukemia and other blood diseases. The prevalence of diseases is increasing and affects mainly adults. The purpose of this study is to describe patients' experiences of living with a haematological malignancy. The methodology for this literature review was qualitative. Five articles and two dissertations were analyzed. Results of the study, developed into four main themes: to get a disease, to undergo treatment, experience of care meetings and to shake in their life-world. The result shows that the disease is perceived as an invisible threat, and that sometimes there is a health suffering due to inadequate involvement of the person behind the disease body. To undergo a difficult time with various aspects of suffering often alters people's views of themselves and their fellow human beings and relationships deepen. Improvements in care work can be done by increasing the focus on patients' emotional distress when the study shows that this aspect is sometimes overlooked and it results in an objectification of patients.

<p>Tidigare studier har fokuserat på barn och deras familjers upplevelser i samband med en hematologisk malignitet, framförallt leukemi. Hematologiska maligniteter är ett samlingsnamn för leukemi och några andra blodsjukdomar. Prevalensen för sjukdomarna ökar och främst vuxna drabbas. Syftet med studien var att beskriva patienters upplevelser av att leva med en hematologisk malignitet. Metoden för denna litteraturöversikt var kvalitativ. Fem artiklar och två avhandlingar analyserades. Studiens resultat utvecklades till fyra huvudteman:</p><p>att få en sjukdom, att genomgå behandling, upplevelse av vårdmöten och att skakas om i sin livsvärld. Resultatet visar att sjukdomen upplevs som ett osynligt hot och att det ibland förekommer ett vårdlidande som beror på bristfälligt engagemang för människan bakom den sjuka kroppen. Att genomgå en svår tid med lidandets olika aspekter, förändrade oftast människors syn på sig själva och sina medmänniskor. Relationer fördjupades. Förbättringar i omvårdnadsarbetet kan göras genom ökad fokus på patienters känslomässiga lidande då studien visar att denna aspekt ibland förbises och detta resulterar i en objektifiering av patienter.</p> / <p>Previous studies have focused on children and their families' experiences in connection with a haematological malignancy, especially leukemia. Hematolocical malignancies is a collective name for leukemia and other blood diseases. The prevalence of diseases is increasing and affects mainly adults. The purpose of this study is to describe patients' experiences of living with a haematological malignancy. The methodology for this literature review was qualitative. Five articles and two dissertations were analyzed. Results of the study, developed into four main themes:</p><p>to get a disease, to undergo treatment, experience of care meetings and to shake in their life-world. The result shows that the disease is perceived as an invisible threat, and that sometimes there is a health suffering due to inadequate involvement of the person behind the disease body. To undergo a difficult time with various aspects of suffering often alters people's views of themselves and their fellow human beings and relationships deepen. Improvements in care work can be done by increasing the focus on patients' emotional distress when the study shows that this aspect is sometimes overlooked and it results in an objectification of patients.</p>

alpha-TEA (alpha-tocopherol ether linked acetic acid) has been shown to induce apoptosis in human prostate, ovarian and breast cancer cells in culture and in xenograft models by promoting pro-apoptotic pathways and inhibiting anti-apoptotic pathways. Studies investigated the ability of alpha-TEA to induce apoptosis in human hematological malignant cell lines Jurkat, Raji and U266, representing T cell leukemia, B cell lymphoma and multiple myeloma, respectively. The three cell lines were cultured in the presence of different concentrations of alpha-TEA for different time periods, and examined for apoptosis by annexin V – FITC analyses, DAPI staining, and western blotting for poly (ADP-ribose) polymerase cleavage. alpha-TEA induced apoptosis in all three cell lines in a dose and time dependent manner. Levels of pro-apoptotic molecules DR5, c-Jun N-terminal protein kinase (JNK), C/EBP homologous protein (CHOP), caspase 9, and caspase 3 were upregulated in alpha-TEA treated cells in comparison to vehicle controls. Caspase 8 was activated in Jurkat and U266 cells but not in Raji cells. Apoptosis and pro-death signaling mediators were blocked by ceramide inhibitor, desipramine. The anti-apoptotic nuclear factor kappa B (NF-[kappa]B) signaling pathway was down-regulated in alpha-TEA treated Raji and U266 cells. Combinations of omega-3 fatty acid docosahexaenoic (DHA) and alpha-TEA significantly enhanced apoptosis in Jurkat cells in comparison to single treatments and vehicle control. In summary, alpha-TEA induced apoptosis in the malignant hematological cell lines is via shared and distinct pathways. ASMase/ceramide-mediated JNK activation and endoplasmic reticulum (ER) stress mitochondrial dependent apoptosis are involved in alpha-TEA induced apoptosis in the three cell lines; however, the cell lines exhibit cell type-specific responses to alpha-TEA: activation of death receptor/caspase 8 pathway is involved in Jurkat cells, suppression of NF-[kappa]B signaling is involved in Raji cells, and the U266 cells share both of these pathways for the induction of apoptosis. / text

Les mécanismes épigénétiques, tels que la méthylation et les modifications d'histones, sont impliqués dans le contrôle à grande échelle de l'expression du génôme et contribuent à la mise en place des profils d'expression des gènes spécifiques de tissus et de types cellulaires. Dans les cellules en cours ou en fin de différenciation, ces mécanismes sont aussi impliqués dans la mise en place et le maintien de la repression d'un grand nombre de gènes. La transformation oncogénique est presque toujours associée à des anomalies de la signalisation épigénétique cellulaire, dont certaines, comme les méthylations aberrantes de gènes suppresseurs de tumeur, sont considérées comme des événements oncogènes. Un aspect beaucoup moins étudié de ces dérégulations épigénétiques est l'activation aberrante de gènes tissu-spécifiques dans des cellules pré-cancéreuses et transformées. De nombreuses études rapportent l'activation « hors contexte » de gènes spécifiques du testicule dans plusieurs cancers somatiques. Ces gènes sont décrits sous le nom de gènes « cancer testis » ou C/T. Il a été suggéré que ces expressions illégitimes pourraient être de bons indicateurs des cancers, et fournir de nouvelles cibles pour une immunothérapie anticancéreuse. Au cours de cette thèse, nous avons développé une approche basée sur ce concept d'activation ectopique de gènes pour identifier les gènes exprimés de manière aberrante dans les lymphoblastes des patients atteints de leucémies lymphoblastiques aigues (LAL). Nous avons ensuite évalué leur intérêt pour une utilisation comme marqueurs pronostics et de prédiction de la réponse au traitement. Nous avons ainsi identifié une signature de huit gènes spécifiques de la lignée germinale / cellules souches embryonnaires, exprimés de manière aberrante dans les LAL pédiatriques et adultes : 4 gènes prédictifs de mauvais pronostic et 4 gènes associés à une issue favorable. Nous avons par la suite montré qu'une combinaison de l'expression de ces 8 gènes peut identifier les formes agressives de LAL chez les enfants ainsi que chez les adultes. Une étude prospective clinique a mis en évidence que notre système de détection des 8 gènes, basé sur un test RT- qPCR, pourrait aider à prédire la réponse précoce à un traitement (induction) dans un groupe de 31 patients adultes nouvellement recrutés, atteints de LAL. Enfin, en exploitant notre méthode de classification, nous avons découvert des traits biologiques communs entre les formes agressives de LAL chez les enfants et chez les adultes. Nos données montrent que les formes les plus agressives de LAL présentent les caractéristiques de cellules souches hématopoïétiques au repos. Cette information pourrait être utilisée pour adapter les approches thérapeutiques. Enfin, en plus de l'amélioration de la détection et du suivi des patients LAL, ce travail a un fort potentiel dans la définition de nouvelles stratégies thérapeutiques ainsi que d'ors et déjà dans les choix thérapeutiques les plus appropriés pour les patients porteurs des formes les plus agressives. / Epigenetic mechanisms such as methylation and histone modifications are involved in large-scale control of the expression of the genome and contribute to the development of specific gene expression profiles of tissues and cell types. In cells, during and after differentiation, these mechanisms are also involved in the establishment and maintenance of the repression of many genes. Oncogenic transformation is almost always associated with abnormalities of cellular epigenetic signalling, some of which, such as aberrant methylation of tumour suppressor genes, are considered as oncogenic events. One much less studied aspect epigenetic deregulations, is the aberrant activation of tissue-specific genes in pre-cancerous and transformed cells. Many studies have reported the “out of context” activation of specific testicular genes in several somatic cancers. These genes are described as the "cancer / testis" genes or C/T. It has been suggested that these illegitimate expressions could be good indicators of cancer and provide new targets for cancer immunotherapy. In this thesis, based on the concept of ectopic activation of genes, we have identified genes aberrantly expressed in lymphoblasts of patients with acute lymphoblastic leukemia (ALL). We have then assessed their potential for a use as markers for prognosis and prediction of treatment response. We have identified a signature of eight genes specific of germline/embryonic stem cells, aberrantly expressed in adult and paediatric ALL. The ectopic activation of four genes was predictive of poor prognosis and the expression of four other genes was associated with a favourable outcome. We have subsequently shown that the combination of the expression of these eight genes can identify aggressive forms of ALL in children and adults. A prospective clinical study showed that a test based on the detection of these 8 genes, by RT- qPCR could help predicting an early response to treatment (induction) in a group of 31 newly recruited ALL adult patients. Finally, using our classification method, we discovered common biological traits between aggressive forms of ALL in children and adults. Our data show that the most aggressive forms of ALL have characteristics of dormant hematopoietic stem cells. This information could be used to refine therapeutic approaches. Finally, in addition to improving the detection and monitoring of ALL patients, this work has great potentials in the definition of new therapeutic strategies as well as in the choice of the most appropriate therapeutic approaches for patients with aggressive forms of ALL.

Hematologic malignancies account for a substantial percentage of cancers worldwide, and the heterogeneity and biological characteristics of leukemias and lymphomas present unique therapeutic challenges. Although treatment options exist for most of these diseases, many types remain incurable and the emergence of drug resistance is pervasive. Thus, novel treatment approaches are essential to improve outcome. Nearly half of the agents used in cancer therapy today are either natural products or derivatives of natural products. The e l,normous chemical diversity in nature, coupled with millennia of biological selection, has generated a vast and underexplored reservoir of unique chemical structures with biologic activity. This review will describe the investigation and application of natural products derived from higher plants in the treatment of leukemia and lymphoma and the rationale behind these efforts. In addition to the approved vinca alkaloids and the epipodophyllotoxin derivatives, a number of other plant compounds have shown promise in clinical trials and in preclinical investigations. In particular, we will focus on the discovery and biological evaluation of the plant- derived agent silvestrol, which shows potential for additional development as a new therapeutic agent for B-cell malignancies including chronic lymphocytic leukemia.

The lymphocyte-specific transcription factor Interferon (IFN) Regulatory Factor 4 (IRF4) is implicated in certain types of lymphoid and myeloid malignancies. However, the molecular mechanisms underlying its interactions with these malignancies are largely unknown. In this study, we have first profiled molecular signatures associated with IRF4 expression in associated cancers, by analyzing existing gene expression profiling datasets. Our results show that IRF4 is overexpressed in melanoma, in addition to previously reported contexts including leukemia, myeloma, and lymphoma, and that IRF4 is associated with a unique gene expression pattern in each context. A pool of important genes involved in B-cell development, oncogenesis, cell cycle regulation, and cell death including BATF, LIMD1, CFLAR, PIM2, and CCND2 are common signatures associated with IRF4 in non-Hodgkin B cell lymphomas. We confirmed the correlation of IRF4 with LIMD1 and CFLAR in a panel of cell lines derived from lymphomas. Moreover, we profiled the IRF4 transcriptome in the context of EBV latent infection, and confirmed several genes including IFI27, IFI44, GBP1, and ARHGAP18, as well as CFLAR as novel targets for IRF4. These results provide valuable information for understanding the IRF4 regulatory network, and improve our knowledge of the unique roles of IRF4 in different hematological malignancies.

Bakgrund: Det är vanligt förekommande att patienter med hematologiskt maligna sjukdomar går från kurativ till palliativ vård. Hematologiska behandlingar beskrivs i litteraturen som högteknologiska, aggressiva och de mest förödande behandlingar människokroppen kan utsättas för. Tidigare studier visar att arbete inom cancervård, palliativ vård och vård i livets slutskede kan ha ogynnsam effekt på sjuksköterskors fysiska, psykiska och emotionella mående. Befintlig litteratur beskriver sjuksköterskors upplevelser av att vårda dessa patienter palliativt dock råder det avsaknad av beskrivning av sjuksköterskans upplevelse av att vårda patienter i övergången mellan kurativ vård och palliativ vård.   Motiv: Då det råder avsaknad av beskrivning av sjuksköterskors upplevelser av att vårda patienter i övergången mellan kurativ och palliativ vård ansåg författarna att det förelåg en kunskapsbrist gällande sjuksköterskors upplevelser samt hur dessa påverkar sjuksköterskan i den dagliga omvårdnaden av dessa patienter. Syfte: Syftet med studien var att beskriva och förstå sjuksköterskors upplevelser av att vårda patienter med hematologiskt maligna sjukdomar i övergången mellan kurativ och palliativ vård.Metod: Föreliggande studie utfördes som en kvalitativ semistrukturerad intervjustudie med induktiv ansats (n=8). Data analyserades enligt the Framework Analyzis. Resultat: Resultatet omfattar fyra teman som handlar om övergången mellan kurativ och palliativ vård: Konsekvenser av ovisshet i övergången, Kommunikation i övergången, Omvårdnad vid ovisshet i övergången och Sjuksköterskans upplevelser vid ovisshet i övergången. Konklusion: Övergången mellan kurativ och palliativ vård för patienter med hematologisk malignitet kan upplevas som otydlig och präglas av ovisshet, vilket leder till utmaningar i omvårdnaden av dessa patienter. Resultatet pekar på områden i behov av utveckling, till exempel behov av ett utökat teamarbete som i sin tur kan förbättra kommunikationen och öka personcentrering i vården av dessa patienter. / Background: It is common for patients with hematological malignancies to go from curative to palliative care. Hematological treatments are described in the literature as high-tech, aggressive and the most devastating treatments the human body can be subjected to. Previous studies show that work in cancer care, palliative care and end-of-life care can have an adverse effect on nurses' physical, mental and emotional well-being. Existing literature describes nurses' experiences of caring for these patients palliatively, however, there is a lack of description of the nurses' experience of caring for patients in the transition between curative care and palliative care. Motive: As there is a lack of description of the nurses' experience of caring for patients in the transition between curative and palliative care, the authors believed that there was a lack of knowledge regarding nurses' experiences and how these affect the nurse in the daily care of these patients. Aim: The aim of the study was to describe and understand nurses' experiences of caring for patients with hematological malignancies in the transition between curative and palliative care. Methods: The present study was conducted as a qualitative semi-structured interview study with an inductive approach (n=8). Data were analyzed with Framework Analysis. Result: The result includes four themes relating to the transition between curative and palliative care: Consequences of uncertainty in the transition, Communication in the transition, Nursing in the event of uncertainty in the transition and The nurses' experiences in the event of uncertainty in the transition. Conclusion: The transition between curative and palliative care for patients with hematological malignancies can be experienced as unclear and characterized by uncertainty, which leads to challenges in the care of these patients. The results point to areas in need of development, for example the need for increased teamwork which in turn can improve communication and increase person-centered care in the care of these patients.

Les cellules Natural Killer (NK) sont des lymphocytes cytotoxiques innés qui jouent un rôle important dans le contrôle immunitaire de la formation de cellules tumorales et de l'infection virale. Chez les personnes en bonne santé, les cellules NK représentent des populations hétérogènes définies par différents marqueurs phénotypiques et exécutant des fonctions spécifiques. Les cellules NK provenant de patients présentant des tumeurs malignes néoplasiques et une infection virale sont cependant typiquement distinctes des personnes en bonne santé par l'apparition de sous-ensembles de cellules NK, qui sont différenciées par leur profil d'isoformes CD45. CD45 est une tyrosine phosphatase leucocytaire commune abondamment exprimée sur toutes les cellules immunitaires hématopoïétiques nucléées. Un variant d'épissage alternatif a entraîné la génération de l'isoforme CD45RA longue et de l'isoforme courte CD45RO, qui s'expriment différemment sur les cellules T naïves et effectrices / mémoires. L'expression des isoformes CD45 sur les cellules NK est largement inconnue. Nous avons précédemment montré que l'expression différentielle des isoformes CD45RA et CD45RO a identifié des sous-ensembles de cellules NK spécifiques dans les maladies hématologiques. Une question reste floue: comment ces cellules CD45RARO + NK changent-elles lorsque leurs cellules cibles disparaissent? Nous avons utilisé des cellules NK de patients traités avec Lenalidomide et l'anticorps anti-CD20 Obinutuzumab pour étudier cela et montré une réduction des cellules CD45RARO / CD45RO + NK après la clairance des cellules tumorales (Chater 4). Nous avons observé la même chose chez les patients atteints de LMA après une chimiothérapie. Dans ce cas, le sous-ensemble de cellules CD45RARO + NK est fortement corrélé avec la trogocytose du marqueur monocyte / macrophage CD14 (Chapitre 5). L'immunophénotypage de cellules NK provenant de patients infectés par le VIH a révélé la présence de cellules CD45RAdim et CD45RO + avec une expression réduite de CD16 et une diminution de la modulation NKG2D totale. En résumé, les cellules NK des cancers hématologiques et l'infection par le VIH présentaient des caractéristiques dysfonctionnelles et l'analyse du profil isoforme CD45 dans ces conditions pathologiques dévoile ces caractéristiques.Enfin, afin de retrouver la réponse immunitaire anti-tumorale chez les patients cancéreux, nous présentons une méthode efficace pour l'expansion in vitro de cellules NK hautement activées à partir du sang du cordon ombilical (UCB). Ces cellules NK prouvent une cytotoxicité cellulaire dépendante des anticorps (ADCC) importante lorsqu'elles sont utilisées en combinaison avec des anticorps monoclonaux approuvés sur le plan clinique ciblant divers antigènes tumoraux. Ceci ouvre leur utilisation dans les immunothérapies à base de cellules NK allogéniques. / Natural Killer (NK) cells are innate cytotoxic lymphocytes that play an important role in immune control of tumor cell formation and virus infection. In healthy people, NK cell represents heterogeneous populations defined by different phenotypical markers and performing specific functions. NK cells from patients with neoplastic malignancies and viral infection are however typically distinctive from healthy people by the appearance of NK cell subsets, which are differentiated by their CD45 isoform profile. CD45 is a common-leukocyte tyrosine phosphatase abundantly expressed on all nucleated hematopoietic immune cells. Alternative splicing variant resulted in generation of the long-isoform CD45RA and the short-isoform CD45RO, which express differently on naïve and effector/memory T cells. Expression of CD45 isoforms on NK cells is largely unknown. We have previously shown that differential expression of CD45RA and CD45RO isoforms identified specific NK cell subsets in hematological diseases. One question remained unclear: how do these CD45RARO+ NK cell changes when their target cells disappeared? We used NK cells from patients treated with Lenalidomide and the anti-CD20 antibody Obinutuzumab to investigate this and showed a reduction in CD45RARO/CD45RO+ NK cells upon clearance of tumor cells (Chater 4). We observed the same in AML patients after chemotherapy. In this case the CD45RARO+ NK cell subset strongly correlates with trogocytosis of the monocyte/macrophage marker CD14 (Chapter 5). Immunophenotyping of NK cells from HIV-infected patients revealed the presence of CD45RAdim and CD45RO+ cells with reduced CD16 expression and total NKG2D down-modulation. In summary, NK cell from hematological cancers and HIV infection displayed dysfunctional hallmarks and analyzing CD45 isoform profile in these pathological conditions unveils these hallmarks.Finally, in order to regain the anti-tumor immune response in cancer patients, we present an efficient method for expansion of highly activated NK cells from umbilical cord blood (UCB) in vitro. These NK cells prove substantial antibody-dependent cell cytotoxicity (ADCC) when used in combination with clinical-approved monoclonal antibodies targeting various tumor antigens. This paves their use in allogeneic NK cell-based immunotherapies.

A neutropenia induzida pela quimioterapia é o mais comum efeito adverso da quimioterapia sistêmica para o câncer e é frequentemente complicada por neutropenia febril (NF). O uso profilático de fatores de crescimento hematopoiéticos pode reduzir o risco, a severidade e a duração da NF. Na prática clínica atual, a decisão de administrar ao paciente profilaxia com fatores de crescimento é baseada principalmente no potencial mielotóxico dos esquemas de QT, mas riscos específicos dos regimes não são definidos. Em muitos estudos, a toxicidade da quimioterapia é analizada em termos de alta dosagem versus baixa dosagem, sem uma regra geral que considere os diferentes esquemas de QT em uma única escala. O objetivo desse estudo é validar uma classificação de toxicidade de um esquema de QT e avaliar sua utilidade em um modelo de predição de risco de neutropenia febril em pacientes com câncer hematológico no começo de um ciclo de quimioterapia. Foram avaliados prospectivamente duzentos e sessenta e oito pacientes e acompanhados durante 1053 ciclos de quimioterapia na Bélgica, entre 2001 e 2005. Informações relevantes foram coletadas no começo do primeiro ciclo e o número de dias de neutropenia febril foi contabilizado no acompanhamento dos pacientes [dicotomizada (sem neutropenia versus >= dia de NF)]. A relação entre o desfecho e as co-variáveis foi analisada usando a Equação de Estimativa Generalizada (GEE). Um regime de quimioterapia agressiva é o maior preditor de NF [razão de chances (OR) 5.2 (3.2-8.4)]. Os outros preditores independentes são: doença subjacente, o comprometimento de medula óssea, superfície corporal <= 2m², uma contagem pré-tratamento de monócitos <150µl e a interação entre o primeiro ciclo na mesma linha de tratamento e uma dosagem de hemoglobina pré-tratamento. Usando as estimativas dos coeficientes de regressão, uma regra de predição clínica de NF foi desenvolvida com essas características: sensibilidade 78.6%, especificidade 62.3%, valor preditivo positivo de 42.7%% e um valor preditivo negativo de 89.1%. Estudos posteriores são necessários para validar esse escore bem como investigar novos potenciais fatores com o intuito de melhor prever a NF. / Chemotherapy-induced neutropenia is the most common adverse effect of chemotherapy and is often complicated by febrile neutropenia (FN). As prophylactic use of colonystimulating factors (CSF) can reduce the risk, severity, and duration of FN, it is of great importance to identify as soon as possible after or even before the start of chemotherapy, the patients who will develop FN. In the current clinical practice, the decision to give to the patient a colony-stimulating factor (CSF) prophylaxis is mainly based on the myelosuppressive potential of the chemotherapy regimen. The objective of this study is to validate a classification of aggressiveness of a chemotherapy regimen and to evaluate its usefulness in a risk prediction model of FN in patients with hematological cancer at the beginning of a chemotherapy cycle. Two hundred and sixty-six patients were prospectively enrolled and followed during 1053 cycles. Relevant patient informations were collected at the beginning of the first cycle and the number of days of FN were counted in the follow-up [dichotomized (no FN versus>= 1 day of FN)]. Aggressive chemotherapy regimen is the major predictor of FN [odds ratio 5.2 (3.2 - 8.4)]. The other independent predictors are the underlying disease, an involvement of bone marrow, body surface<= 2m², a baseline monocyte count <150/µl and the interaction between the first cycle in the same treatment line and a baseline hemoglobin dosage. A rule of prediction of FN was computed with these characteristics: sensitivity 78.6%, specificity 62.3%, positive predictive value 42.7% and negative predictive value 89.1%. Further studies are needed to validate this score.