Case reports of medication-related osteonecrosis of the jaw (MRONJ) treated with uncultured stromal vascular fraction and L-PRF.

Medication-related osteonecrosis of the jaw (MRONJ) is a challenging affection, considering the absence of a "Gold Standard" treatment. Cell therapy and tissue engineering, using adipose-tissue stromal vascular fraction (SVF) containing mesenchymal stromal cells (MSC) and endothelial progenitor cells (EPC); and a scaffold with healing properties, l-platelet-rich fibrin (L-PRF), could be a therapeutic option. Two cases of MRONJ were treated by tissue engineering. The patients presented respectively a stage-II and a stage-III MRONJ. The protocol consists of SVF injection in the L-PRF applied on the cleaned bone. Patients are followed clinically and by medical imaging (MI) for 18 months. The buccal mucosa was closed within a month. No recurrence was observed during the follow-up. The MI highlighted bone formation. MSC and EPC presence, in the SVF, were confirmed by immunophenotyping. We report the preliminary results of MRONJ patients successfully treated with the association of autologous fresh L-PRF-SVF.

[Monoclonal gammopathy of undetermined significance : when and why to look for them ?] / Les gammapathies monoclonales de signification indéterminée : quand et pourquoi les chercher ?

Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic premalignant plasma cell disorder. MGUS is a common disorder and the diagnosis is often made accidentally when a protein electrophoresis is performed in a routine blood test or during a biological assessment for other conditions. In the absence of biological abnormalities or clinical symptoms suggesting a plasma or lymphoplasma-cell disorder, there is no indication for routine screening of the monoclonal protein. When MGUS is diagnosed, the risk of transformation into myeloma or other lymphoproliferative disorders is estimated at 1 % per year. MGUS can also be associated with diseases that are not malignant disorders and in some cases, the monoclonal gammopathy is the witness of another rare but severe disorder wich will be critical not to be missdiagnosed.

La gammapathie monoclonale de signification indéterminée (MGUS) est une anomalie biologique asymptomatique dont le diagnostic est souvent posé lors d'un bilan réalisé en routine ou pour d'autres symptômes que ceux requérant cette analyse. L'incidence des MGUS est évaluée à au moins 3 % au-dessus de 50 ans et sa fréquence continue à augmenter avec l'âge. La majorité des patients avec une MGUS n'évoluera jamais vers une hémopathie et en l'absence d'anomalies biologiques ou de symptômes évoquant une maladie associée à une immunoglobuline monoclonale, il n'y a pas d'indication d'effectuer une électrophorèse des protéines. Si le diagnostic de MGUS est posé, le risque d'évolution vers un myélome ou une autre hémopathie maligne est de 1 % par an. Une MGUS peut aussi être associée à des pathologies non malignes ou être le reflet d'autres maladies rares et graves dont il est capital de ne pas rater le diagnostic.

[Diagnostic approach of an IgM monoclonal gammopathy and clinical importance of gene MYD88 L265P mutation]. / Approche diagnostique d'une gammapathie monoclonale à IgM et intérêt clinique de la recherche de la mutation L265P du gène MYD88.

INTRODUCTION: An IgM monoclonal gammopathy points to a diagnosis of Waldenstrom's Macroglobulinemia. Other B lymphoproliferatives disorders should be ruled out but the limits are sometimes difficult to define. The discovery of the L265P mutation of the MYD88 gene simplified potentially the situation. POPULATION AND METHODS: 383 patients of the Jules Bordet Institute with an IgM level above 2 g/L were reviewed. For the 49 who had a monoclonal peak, we analysed the underlying pathology in termes of general, clinical and biological characteristics. We checked if the MYD88 mutation had been detected. The overall survival rate was studied. RESULTS: 5 histological groups were identified: Waldenstrom's Macroglobulinemia (MW, N = 27), lymphoplasmacytic lymphoma (LLP, N = 10), marginal zone lymphoma (LMZ, N = 7), monoclonal gammopathy of unknown significance and multiple myeloma (MGUS/MM, N = 5). The MW group was compared to the other groups. Regarding biological characteristics, the IgM level upon diagnosis was statistically higher in the MW group with a median level at 19.5 g/L (2.3-101 g/L) (p-value = 0,0001). Concerning the clinical characteristics, a splenomegaly was more frequent in the LMZ group (p-value = 0,04). The L265P mutation of the MYD88 gene was found in 77 % of patients in the MW group, 60 % of patients in the LLP group and 67 % in the LMZ group (p-value = 0,38). For the 49 patients, the 10-yearoverall survival was 85 % (CI 95 %, 67 % to 94 %) and the 15-year-overall survival was 65 % (CI 95 %, 41 % to 81 %). CONCLUSION: A monoclonal IgM peak suggests a MW but other B lymphoproliferatives disorders should be excluded. Even if the L265P mutation is frequent in the LLP/MW, it is not specific. A precise diagnosis requires collating clinical, histological, immunophenotypical and genetical data.

INTRODUCTION: Une gammapathie monoclonale à IgM évoque généralement le diagnostic de maladie de Waldenström. D'autres syndromes lymphoprolifératifs B doivent être exclus mais les " frontières " entre les différentes entités sont parfois mal définies. La découverte de la mutation L265P du gène MYD88 a potentiellement simplifié cette situation. Population et méthodes : 383 patients de l'Institut Jules Bordet présentant un taux d'IgM supérieur à 2 g/L ont été étudiés. 49 d'entre eux présentaient un pic monoclonal pour lesquels nous avons réalisé l'analyse de la pathologie sous-jacente en terme de caractéristiques générales, cliniques et biologiques et avons identifié si une recherche de mutation MYD88 avait été réalisée. La survie globale a également été étudiée. Résultats : 5 groupes histologiques ont été identifiés : maladie de Waldenström (MW, N = 27), lymphome lymphoplasmocytaire (LLP, N = 10), lymphomes de la zone marginale (LMZ ; tous types confondus, N = 7), gammapathie monoclonale de signification indéterminée et myélome multiple (MGUS/MM, N = 5). Le groupe MW a été comparé aux autres groupes. En terme de caractéristiques biologiques, c'est le taux d'IgM au diagnostic qui est statistiquement plus élevé dans le groupe MW avec un taux médian de 19,5 g/L (2,3-101 g/L) (p-valeur = 0,001). Concernant les caractéristiques cliniques, une splénomégalie est plus souvent présente dans le groupe LMZ (p-valeur = 0,04). La mutation L265P du gène MYD88 est retrouvée chez 77 % des patients du groupe MW, 60 % des patients du groupe LLP et 67 % des patients du groupe LMZ (p-valeur = 0,38). La survie globale des 49 patients est de 85 % à 10 ans (IC 95 %, 67 % à 94 %) et de 65 % à 15 ans (IC 95 %, 41 % à 81 %). CONCLUSION: Un pic d'IgM monoclonal évoque généralement une MW, mais il faut toujours exclure d'autres syndromes lymphoprolifératifs B. Alors que la mutation L265P du gène MYD88 est fortement exprimée chez les patients porteurs d'un LLP/MW, elle n'en est pas pour autant spécifique. Un diagnostic précis nécessite aujourd'hui d'intégrer les données cliniques, histologiques, immunophénotypiques et génétiques.

[Practical approach of lymphomas: major role of general practitioner who has to face all these emerging drugs]. / Approche pratique des lymphomes : rôle majeur du médecin généraliste face à l'explosion des nouvelles thérapeutiques.

Malignant lymphoma and other lymphoproliferative disorders represent a group of malignant hemopathies where immunotherapy has allowed spectacular progresses over the last ten years. The recent W.H.O. classification, based upon tumor immunology, and cytogenetical anomalies, allows a better identification of each lymphoma and the comparison of homogeneous populations within various clinical studies. The increase in the incidence of non-Hodgkin lymphoma is related to the aging of the population as well as to other factors that are still to be analysed - a real challenge for the future. We have tried to offer an overview of the latest therapeutical advances while focusing on the major role of general practitioner. The most frequency askeed questions will be discussed.

[Pitfalls of monoclonal gammopathy]. / Les pièges des gammapathies monoclonales.

Monoclonal gammopathy of undetermined significance (MGUS) is a frequent condition affecting at least 3% of the general population over 50 years. Usually, the diagnosis of MGUS is made accidentally during a biological assessment for other conditions. Although MGUS is most frequently a benign and asymptomatic disorder, it has well been described that MGUS could be a premalignant status and that the risk of transformation into myeloma or other lymphoproliferative disorders is estimated at 1% per year. MGUS can also be associated with other diseases than malignant disorders such as Infections, autoimmune diseases. In some case it could reflect rare but severe disorders that will be crucial not to miss the diagnosis.

Lenalidomide in relapsed refractory myeloma patients: impact of previous response to bortezomib and thalidomide on treatment efficacy. Results of a medical need program in Belgium.

The prognosis of multiple myeloma patients has significantly improved since the introduction of the novel agents thalidomide, bortezomib and lenalidomide. We report the data of a medical need programme with lenalidomide plus dexamethasone, conducted in Belgium between August 2007 and March 2008, and including 98 relapsed refractory multiple myeloma patients. In addition to chemotherapy and steroids, all patients had received prior treatment with bortezomib, and 84% of them had been exposed to thalidomide. In 52 patients response data could be retrieved by post-hoc analysis. A partial remission or better was achieved in 52% (49% partial and 3% complete response) of patients, despite a median of 5 previous anti-myeloma treatment lines. Responses were rapid while the majority of patients received lenalidomide with once weekly (also called low-dose) dexamethasone. Treatment with lenalidomide plus dexamethasone did prolong overall survival by nearly half a year in this population with end-stage myeloma. Overall response and quality of response were independent of previous response to thalidomide and bortezomib, although the time to progression tended to be shorter in thalidomide- and bortezomib-refractory patients. It can be concluded that lenalidomide plus dexamethasone is an effective and safe treatment regimen in highly refractory multiple myeloma patients, and that these responses are irrespective of previous exposure or sensitivity to thalidomide and bortezomib.

[Non Hodgkin's lymphomas: a major breakthrough with immunotherapy]. / Les lymphomes non hodgkiniens: apports considérables de i'immunothérapie.

Non hodgkin's lymphomas are a group of haematological malignancies in which spectacular progress has been made over the last ten years thanks to immunotherapy. Furthermore, the new WHO classification, based upon tumour immunology, the degree of tumour differentiation and cytogenetic abnormalities, has finally improved identification of each lymphoma and has enabled comparison of homogeneous populations between different clinical studies. The increase in the incidence of non hodgkin's lymphoma is related to the aging of the population and to other factors that are yet to be elucidated--a real challenge for the future. We have tried to offer an overview of the latest therapeutic advances, with a focus on (radio-) immunotherapy and haemopoietic stem cell transplantation.

The Belgian 2010 consensus recommendations for the treatment of multiple myeloma.

Since the introduction of novel therapeutic agents including thalidomide, lenalidomide and bortezomib, the prognosis of multiple myeloma (MM) has significantly improved. These agents have been incorporated into numerous treatment schedules for newly diagnosed as well as more advanced MM patients. Hence, the therapeutic options for MM have become more complex and subject to rapid changes. The multiple myeloma study group (MMSG) of the Belgian Hematological Society has established recommendations for the treatment of MM as based on an extensive review of the literature which is also summarized in this paper. The recommendations are the result of a consensus opinion between haematologists with experience in the field and representing most haematology centres in Belgium. Where applicable, reimbursement criteria are also taken into account. The consensus recommendations should be a reference for use by clinical haematologists in daily practice.

Antileukemic activity of valproic acid in chronic lymphocytic leukemia B cells defined by microarray analysis.

Epigenetic code modifications by histone deacetylase inhibitors have recently been proposed as potential new therapies for hematological malignancies. Chronic lymphocytic leukemia (CLL) remains incurable despite the introduction of new treatments. CLL B cells are characterized by an apoptosis defect rather than excessive proliferation, but proliferation centers have been found in organs such as the bone marrow and lymph nodes. In this study, we analyzed gene expression modifications in CLL B cells after treatment with valproic acid (VPA), a well-tolerated anti-epileptic drug with HDAC inhibitory activity. CLL B cells obtained from 14 patients were treated in vitro with a concentration of 1 mM VPA for 4 h. VPA effects on gene expression were thereafter studied using Affymetrix technology, and some identified genes were validated by real-time PCR and western blot. We observed that VPA induced apoptosis by downregulating several anti-apoptotic genes and by upregulating pro-apoptotic genes. Furthermore, VPA significantly increased chemosensitivity to fludarabine, flavopiridol, bortezomib, thalidomide and lenalidomide. VPA inhibited the proliferation of CpG/IL2-stimulated CLL B cells and modulated many cell cycle messenger RNAs. In conclusion, exposure of CLL B cells to VPA induced apoptosis, potentiated chemotherapeutic agent effects and inhibited proliferation. These data strongly suggest the use of VPA in CLL treatment, particularly in combination with antileukemia agents.

Doubling time of soluble CD23: a powerful prognostic factor for newly diagnosed and untreated stage A chronic lymphocytic leukemia patients.

Soluble CD23 (sCD23) levels correlate with the stage, prognosis and overall survival (OS) of patients with chronic lymphocytic leukemia (CLL). Therefore, we prospectively evaluated sCD23 doubling time (sCD23DT) as a prognostic factor for time to treatment (TTT) and OS in 56 newly diagnosed and untreated CLL patients at Binet stage A, and compared it to the most commonly used biological prognostic factors: lymphocyte doubling time, immunoglobulin variable heavy chain (IgVH) mutational status and zeta-associated protein-70 (ZAP-70), CD38, and lipoprotein lipase (LPL) expression. In patients with sCD23DT <1 year, the median TTT and OS were 20 and 83 months compared to 141 and 177 months in patients with sCD23DT >1 year (P<0.0001). Among patients with poor prognostic factors (ZAP-70+, LPL+ and CD38+), an sCD23DT <1 year identified a subpopulation with a shorter TTT. Patients with unmutated IgVH and an sCD23DT <1 year had a median TTT and OS of 14 and 83 months, respectively, whereas these values were 70 and >177 months when sCD23DT was >1 year (P<0.0001 and P=0.0219, respectively). Finally, in a Cox multivariate analysis, sCD23DT was the sole independent prognostic factor for TTT (P=0.0027). Furthermore, sCD23DT refines the prognosis given by other classical prognostic factors. These observations support the introduction of sCD23 evaluation into the routine assessment of CLL patients.

The use of low-energy laser (LEL) for the prevention of chemotherapy- and/or radiotherapy-induced oral mucositis in cancer patients: results from two prospective studies.

BACKGROUND: Low-energy laser (LEL) treatment has been suggested as an effective and safe method to prevent and/or treat oral mucositis induced by chemotherapy and/or radiotherapy; however, it has not gained wide acceptance so far. MATERIALS AND METHODS: We conducted two clinical trials testing the LEL technique: firstly, as a secondary prevention in patients with various solid tumors treated with chemotherapy who all developed severe mucositis after a previous identical chemotherapy and, secondly, as therapeutic intervention (compared to sham illumination in a randomized way) in patients with hematological tumors receiving intensive chemotherapy and having developed low-grade oral mucositis. RESULTS: We entered 26 eligible patients in the first study and 36 were randomized in the second study. The success rate was 81% (95%CI = 61-93%) when LEL was given as a preventive treatment. In the second study, in patients with existing lesions, the therapeutic success rate was 83% (95%CI = 59-96%), which was significantly different from the success rate reached in the sham-treated patients (11%; 95%CI = 1-35%); the time to development of grade 3 mucositis was also significantly shorter in the sham-treated patients (p < 0.001). CONCLUSION: Our results strongly support the already available literature, suggesting that LEL is an effective and safe approach to prevent or treat oral mucositis resulting from cancer chemotherapy.

Reduced intensity conditioning haematopoietic stem cell transplantation with mesenchymal stromal cells infusion for the treatment of metachromatic leukodystrophy: a case report.

We report the case of a 23-year-old woman who presented with an adult form of metachromatic leukodystrophy (MLD) evolving over one year with a progressive neurological deterioration. A non-myeloablative matched related haematopoietic stem cell transplantation (HSCT) with concomitant mesenchymal stromal cells (MSCs) infusion was performed. Engraftment occurred rapidly with no significant toxicity or side effects following the MSC infusion. At a follow up of 40 months, the patient had a stabilisation of all neurological manifestations of her disease. This case report suggests the feasibility and the potential efficacy of reduced intensity conditioning (RIC) allogeneic HSCT combined with MSC infusion for patients with the adult form of MLD.

Low mannose-binding lectin concentration is associated with severe infection in patients with hematological cancer who are undergoing chemotherapy.

BACKGROUND: Mannose-binding lectin (MBL) is a serum lectin involved in innate immune response. Low serum MBL concentration may constitute a risk factor for infection in patients receiving myelosuppressive chemotherapy. METHODS: We conducted a prospective, observational study that assessed MBL concentration as a risk factor for infection in patients with hematological malignancy who were hospitalized to undergo at least 1 chemotherapy cycle. MBL deficiency was defined using an algorithm that considered the serum MBL concentration and the MBL genotype. The primary end point was the ratio of duration of febrile neutropenia to the duration of neutropenia. Secondary end points included the incidence of severe infection (e.g., sepsis, pneumonia, bacteremia, and invasive fungal infection). Logistic regression analysis was conducted, and Fisher's exact test was used to analyze binary outcomes, and Kaplan-Meier estimates and log rank tests were used for time-to-event variables. RESULTS: We analyzed 255 patients who received 569 cycles of chemotherapy. The median duration of neutropenia per cycle was 7 days (interquartile range, 0-13 days). Sixty-two patients (24%) were found to have MBL deficiency. Febrile neutropenia occurred at least once in 200 patients. No difference in the primary outcome was seen. The incidence of severe infection was higher among MBL-deficient patients than among non-MBL-deficient patients (1.96 vs. 1.34 cases per 100 days for analysis of all patients [P=.008] and 1.85 vs. 0.94 cases per 100 days excluding patients with acute leukemia [P<.001]). CONCLUSIONS: MBL deficiency does not predispose adults with hematological cancer to more-frequent or more-prolonged febrile episodes during myelosuppressive chemotherapy, but MBL-deficient patients have a greater number of severe infections and experience their first severe infection earlier, compared with nondeficient patients.

Intrathecal donor lymphocyte infusion for the treatment of suspected refractory lymphomatous meningitis: a case report.

A 43-year-old female with large T-cell non-Hodgkin's lymphoma and central nervous system (CNS) involvement underwent HLA-identical-sibling peripheral blood stem cell transplantation (SCT) during her third complete remission. She presented a possible refractory CNS relapse 5 months after the transplant. She was then treated with intrathecal (IT) donor lymphocyte infusions (DLI). No side effects were observed after three DLI injections. The patient died 13 months later from infectious complications with no evidence of progressive disease. To our knowledge, this is the first case report of IT DLI for possible refractory lymphomatous meningitis.

B-cell lymphoma presenting with renal failure associated to spontaneous tumor lysis syndrome and urinary tract obstruction.

The acute tumor lysis syndrome (ATLS) may be a dramatic complication of anticancer treatment. It occurs mostly in haematological malignancies and less commonly in solid tumors. Spontaneous tumor lysis syndrome (STLS) has been reported more frequently in Burkitt's lymphomas than in other haematological tumors, and exceptionally in solid tumors like small-cell lung carcinoma and germ-cell tumors. We report on the case of a patient with a diffuse large B-cell lymphoma (DLBCL) of the urinary tract involved by acute renal failure due to STLS and complicated by obstructive uropathy subsequent to neoplastic infiltration of the bladder. Hyperhydration, urine alkalinization, urate oxidase administration and continuous veno-venous haemodiafiltration (CVVHDF) permitted to control the initial renal failure and to administer chemotherapy. The patient then developed chemotherapy-induced tumor lysis syndrome (TLS) controlled by urate oxidase administration, hyperhydration and urine alkalinization. The treatment of TLS and the differences between ATLS and STLS are discussed.

[Graft-versus-host disease: Review of 22 cases]. / Maladie du greffon contre l'hôte: revue de 22 cas.

PURPOSE: Graft-versus-host disease (GVHD) is one of the major complications of allogeneic bone marrow transplantation. Twenty-two patients, who had an allogeneic bone marrow transplantion at the Institute J. Bordet, developed a GVHD proven by a biopsy. RESULTS: Twenty-two cases of GVHD were registered; 17 of these patients suffered from the acute form of the disease. All the patients presented the characteristic skin lesions, usually associated with other organ involvement. Most of the cases suffered from relapse after a time-limited response or from resistance to therapy, despite an effective treatment. Uncontrolled GVHD led to the death of two patients. CONCLUSION: GVHD is a frequent pathology that significantly contributes to the morbidity and mortality associated with bone marrow transplantation, despite appropriate management. Recognition of clinical and histopathological features of GVHD is important for dermatologists involved in the care of bone marrow transplant patients. Actually, bone marrow transplantation is now easily and more frequently performed than in the past.

Caspofungin salvage therapy in a neutropenic patient with probable invasive aspergillosis: a case report.

A 47-year-old man with acute lymphocytic leukemia was admitted in intensive care unit (ICU) because of respiratory failure. He had febrile neutropenia and probable invasive pulmonary aspergillosis (IA). Amphotericin B renal toxicity and clinical deterioration prompted a shift to caspofungin and resulted in a successful response.

Biological basis of anemia.

Anemia is a frequent complication in cancer, occurring in more than 50% of patients with malignancies. Several factors can cause anemia in these patients, such as blood loss, hemolysis, bone marrow infiltration, hypersplenism, and nutrient deficiencies. However, in a considerable number of patients, no cause other than malignant disease itself can be implicated. This cancer-related anemia is similar to the anemia observed in other chronic diseases, such as rheumatoid arthritis and some chronic infections. The syndrome of anemia of chronic disease is characterized by a hyporegenerative, normocytic, normochromic anemia associated with reduced serum iron and transferrin saturation but elevated (or normal) ferritin levels. Cancer-related anemia results from activation of the immune and inflammatory systems, leading to increased release of tumor necrosis factor, interferon-gamma, and interleukin-1. The cytokine-mediated relative failure of erythropoiesis has been further investigated, and three different mechanisms of action are proposed: (1) impaired iron utilization; (2) suppression of erythroid progenitor cells differentiation; and (3) inadequate erythropoietin production. In addition, the life span of red blood cells is shortened in cancer-related anemia and production cannot compensate sufficiently for the shorter survival time. Administration of recombinant human erythropoietin (r-HuEPO, epoetin alfa) can not only correct inadequate endogenous erythropoietin production, but also can overcome the suppression of erythroid progenitor cells and impairment of iron mobilization.