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Multiple myeloma (MM) is a hematologic disorder of B lymphocytes characterized by the accumulation of malignant plasma cells (PCs) in the bone marrow. The altered plasma cells overproduce abnormal monoclonal immunoglobulins and also stimulate osteoclasts. The host's immune system and microenvironment are of paramount importance in the growth of PCs and, thus, in the pathogenesis of the disease. The interaction of MM cells with the bone marrow (BM) microenvironment through soluble factors and cell adhesion molecules causes pathogenesis of the disease through activation of multiple signaling pathways, including NF-κß, PI3K/AKT and JAK/STAT. These activated pathways play a critical role in the inhibition of apoptosis, sustained proliferation, survival and migration of MM cells. Besides, these pathways also participate in developing resistance against the chemotherapeutic drugs in MM. The imbalance between inflammatory and anti-inflammatory cytokines in MM leads to an increased level of pro-inflammatory cytokines, which in turn play a significant role in dysregulation of signaling pathways and proliferation of MM cells; however, the association appears to be inadequate and needs more research. In this review, we are highlighting the recent findings on the roles of various cytokines and growth factors in the pathogenesis of MM and the potential therapeutic utility of aberrantly activated signaling pathways to manage the MM disease.
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Citocinas/metabolismo , Mieloma Múltiple/metabolismo , Transducción de Señal , Animales , Médula Ósea/inmunología , Médula Ósea/metabolismo , Médula Ósea/patología , Proliferación Celular , Citocinas/análisis , Citocinas/inmunología , Humanos , Inflamación/inmunología , Inflamación/metabolismo , Inflamación/patología , Mieloma Múltiple/inmunología , Mieloma Múltiple/patología , Invasividad Neoplásica/inmunología , Invasividad Neoplásica/patología , Células Plasmáticas/inmunología , Células Plasmáticas/metabolismo , Células Plasmáticas/patología , Escape del Tumor , Microambiente TumoralRESUMEN
INTRODUCTION: Scleromyxedema (rare cutaneous mucinosis), is characterized by the formation of lichenoid papules and presence of Serum monoclonal IgG in most cases, or all; after repeated testing. PATIENT CONCERNS: The patient is a 51-year-old male presented with thick, disfiguring elephant-like erythematous skin folds over the forehead, papular shiny eruptions over ears and trunk and waxy erythematous papules over arms and hands without dysphagia or respiratory or neurologic symptoms DIAGNOSIS: : Skin biopsy from right arm was consistent with scleromyxedema. Serum cryoglobulin was reported negative. Complete blood count and routine blood biochemistry were normal. Thyroid function tests were normal. Serum protein electrophoresis and immunofixation showed monoclonal band of 14.5âg/L typed as IgG lambda. INTERVENTIONS: Our patient was refractory to lenalidomide however improved clinically on immunoglobulins infusions on monthly basis without change in the MGUS level. OUTCOMES: NGF analysis revealed approximately 0.25% Lambda monotypic plasma cells in the bone marrow expressing CD38, CD138, and CD27 with aberrant expression of CD56 and were negative for CD45, CD19, CD117, and CD81. We also detected 0.002% circulating plasma cells (PCs) in peripheral blood. CONCLUSION: The immunophenotype of circulating tumor cells (CTCs) remain close to the malignant PCs phenotype in the BM. Hence, we report NGF approach as a novel diagnostic tool for highly sensitive MRD detection in plasma cell dyscrasias including scleromyxedema.
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Citometría de Flujo/métodos , Células Neoplásicas Circulantes/patología , Escleromixedema/patología , Oído Externo/patología , Frente/patología , Humanos , Inmunoglobulina G/sangre , Inmunoglobulinas Intravenosas/administración & dosificación , Inmunoglobulinas Intravenosas/uso terapéutico , Masculino , Persona de Mediana Edad , Paraproteinemias/inmunología , Paraproteinemias/patología , Escleromixedema/terapia , Piel/patologíaRESUMEN
Sanguinarine (SNG), a benzophenanthridine alkaloid, has displayed various anticancer abilities in several vivo and in vitro studies. However, the anticancer potential of SNG is yet to be established in multiple myeloma (MM), a mostly incurable malignancy of plasma cells. In this study, we aimed to investigate the potential anti-proliferative and pro-apoptotic activities of SNG in a panel of MM cell lines (U266, IM9, MM1S, and RPMI-8226). SNG treatment of MM cells resulted in a dose-dependent decrease in cell viability through mitochondrial membrane potential loss and activation of caspase 3, 9, and cleavage of PARP. Pre-treatment of MM cells with a universal caspase inhibitor, Z-VAD-FMK, prevented SNG mediated loss of cell viability, apoptosis, and caspase activation, confirming that SNG-mediated apoptosis is caspase-dependent. The SNG-mediated apoptosis appears to be resulted from suppression of the constitutively active STAT3 with a concomitant increase in expression of protein tyrosine phosphatase (SHP-1). SNG treatment of MM cells leads to down-regulation of the anti-apoptotic proteins including cyclin D, Bcl-2, Bclxl, and XIAP. In addition, it also upregulates pro-apoptotic protein, Bax. SNG mediated cellular DNA damage in MM cell lines by induction of oxidative stress through the generation of reactive oxygen species and depletion of glutathione. Finally, the subtoxic concentration of SNG enhanced the cytotoxic effects of anticancer drugs bortezomib (BTZ) by suppressing the viability of MM cells via induction of caspase-mediated apoptosis. Altogether our findings demonstrate that SNG induces mitochondrial and caspase-dependent apoptosis, generates oxidative stress, and suppresses MM cell lines proliferation. In addition, co-treatment of MM cell lines with sub-toxic doses of SNG and BTZ potentiated the cytotoxic activity. These results would suggest that SNG could be developed into therapeutic agent either alone or in combination with other anticancer drugs in MM.
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Sanguinarine (Sang), a plant-derived compound isolated from the roots of Sanguinaria canadensis was evaluated for its potential pro-apoptotic effects in precursor B acute lymphoblastic leukemia (Pre-ALL) cell lines. Treatment of 697, REH, RS4;11, and SupB15 cell lines with Sang exhibited significant inhibition of cell viability via induction of apoptotic cell death. Sang-mediated apoptosis was found to be associated with the increased expression of proapoptotic bax with concomitant decrease of Bcl-2 expression leading to depolarization of mitochondria membrane resulting in loss of mitochondrial membrane potential (MMP). The reduced MMP caused the leakage in mitochondrial membrane and release of cytochrome c into the cytosol. The cytochrome c then mediates the activation of caspase-cascade and subsequently PARP cleavage. Furthermore, pretreatment with z-VAD-FMK, a pan-caspase inhibitor, abrogated Sang-induced inhibition of cell viability, induction of apoptosis. Sang treatment also reduced the phosphorylation of AKT and suppressed the expression of a number of anti-apoptotic genes such as cIAP1, cIAP2, and XIAP. Sang mediates its anti-cancer activity by generation of reactive oxygen species (ROS) due to depletion of glutathione level in leukemic cell lines. Pretreatment of these cells with N-acetyl cysteine (NAC) prevented Sang-induced depletion of glutathione level and mitochondrial-caspase-induced apoptosis. Finally, Sang treatment of Pre-ALL cell suppressed colony formation ability of these cells suggesting Sang has an anti-leukemic potential. Altogether, our data suggest that Sang is an efficient inducer of intrinsic apoptotic cell death via generation of ROS and exhibition of anti-leukemic effect in Pre-ALL cells raises the possibility to develop Sang as a therapeutic modality for the treatment and management of Pre-ALL.
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Antineoplásicos Fitogénicos/farmacología , Apoptosis/efectos de los fármacos , Benzofenantridinas/farmacología , Isoquinolinas/farmacología , Caspasas/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras , Proteínas Proto-Oncogénicas c-akt/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
Sub population of cancer cells, referred to as Cancer stem cells (CSCs) or tumor initiating cells, have enhanced metastatic potential that drives tumor progression. CSCs have been found to hold intrinsic resistance to present chemotherapeutic strategies. This resistance is attributed to DNA reparability, slower cell cycle and high levels of detoxifying enzymes. Hence, CSCs pose an obstacle against chemotherapy. The increasing prevalence of drug resistant cancers necessitates further research and treatment development. The current review presents the essential mechanisms that impart chemoresistance in CSCs as well as the epigenetic modifications that can induce drug resistance and considers how such epigenetic factors may contribute to the development of cancer progenitor cells, which are not killed by conventional cancer therapies.
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Extranodal lymphoma (ENL) occurs in approximately 30%-40% of all patients with non-Hodgkin lymphoma and has been described in almost all organs and tissues. However, diffuse large B-cell lymphoma is the most common histological subtype of non-Hodgkin lymphoma, primarily arising in the retroperitoneal region. In this article, we report a rare case of an adult male diagnosed with primary diffuse large B-cell lymphoma of the gluteal and adductor muscles with aggressive bone involvement. All appropriate radiological and histopathological studies were done for diagnosis and staging. After discussion with the lymphoma multidisciplinary team, it was agreed to start on R-CHOP protocol (rituximab, cyclophosphamide, doxorubicin (Adriamycin), vincristine (Oncovin®), and prednisone) as the standard of care, which was later changed to R-CODOX-M/R-IVAC protocol (rituximab, cyclophosphamide, vincristine (Oncovin®), doxorubicin, and high-dose methotrexate alternating with rituximab, ifosfamide, etoposide, and high-dose cytarabine) due to inadequate response. Due to the refractory aggressive nature of the disease, subsequent decision of the multidisciplinary team was salvage chemotherapy and autologous stem cell transplant. The aim of this case report was to describe and evaluate the clinical presentation and important radiological features of extranodal lymphoma affecting the musculoskeletal system.
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Mixed phenotype acute leukemia (MPAL) is considered as a rare type of leukemia with an incidence of less than 4% of all acute leukemia based on the most recent 2008 WHO classification. Common subtypes are the B/myeloid and T/myeloid; B/T and trilineage MPAL being extremely rare. We present a case of a male in his 20s, whose peripheral blood smears showed 34% blast cells and bone marrow with 70% blasts. Immunophenotyping by multiparametric flow cytometry showed two populations of blasts, the major one with B-lineage and the minor one with T-lineage. Conventional karyotyping revealed complex karyotype with the presence of double Philadelphia chromosome (Ph (+)). BCR/ABL1 rearrangement was confirmed by fluorescent in situ hybridization (FISH) analysis. The BCR/ABL1 ES probe on interphase cells indicated p190 minor m-BCR/ABL fusion in 46% and a second abnormal clone with double Ph (+) in 16% of the cells analyzed confirmed by reverse transcription-PCR (RT-PCR). The case was diagnosed as MPAL with double Philadelphia chromosome Ph (+). The patient was treated with dasatinib, four cycle hyper CVAD/methotrexate cytarabin protocol, and allogeneic transplant. He is still alive in complete hematological, cytogenetic, and molecular remission. Mixed phenotype B/T acute leukemia is an extremely rare disease, particularly those with double Philadelphia chromosomes and clinically presents challenges in diagnosis and treatment.
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OBJECTIVE: Idiopathic thrombotic thrombocytopenic purpura (TTP) is a life-threatening disorder mediated by autoantibodies directed against ADAMTS13. This provides a rationale for the use of rituximab in this disorder. We report our experience and the outcome of 10 cases of TTP (9 refractory and 1 relapsing) successfully treated with rituximab in combination with plasma exchange (PE) and other immunosuppressive treatments. METHODS: The diagnosis of TTP was based on clinical criteria and supported by severe deficiency of ADAMTS13 activity and presence of inhibitors in seven cases. Rituximab was started after a median of 18.6 sessions of PE (range: 5-35) at the dose of 375 mg/m(2)/week for 4-8 weeks. RESULTS: Complete remission was achieved in all patients after a median time of 14.4 days of the first dose (range: 6-30). After a median follow-up of 30 months (range: 8-78), eight patients were still in remission and two developed multiple relapses, treated again with the same therapy, and achieved complete responses; they are alive, and in complete remission after a follow-up of 12 and 16 months. CONCLUSION: Rituximab appears to be a safe and effective therapy for refractory and relapsing TTP. However, longer follow-up is recommended to assess relapse and detect possible long-term side effects of this therapy.
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Tuberculosis (TB) can present with various forms and can occasionally be mistaken for malignancy. Hereby, we report a 53-year-old man diagnosed and treated for Burkitt's lymphoma in 2009 who achieved a complete remission confirmed by a computed tomography (CT) scan. During the follow-up 2 years later, he complained of left hip pain that warranted investigation with magnetic resonance imaging and whole-body (18)F-fludeoxyglucose-positron emission tomography (FDG-PET)/CT which showed a benign lesion in the left hip associated with multiple lymph nodes in the chest and abdomen not amenable for biopsy. A follow-up PET/CT scan a few months later showed intense tracer uptake in the lymph nodes with size progression and appearance of new lymph nodes suspicious of lymphoma relapse. The patient was asymptomatic, and all investigations including viral and connective tissue disease studies were negative. Also the tuberculin skin test and QuantiFERON were negative. Lymph node biopsy was planned; however, the patient presented a few days earlier with fever, headache and photophobia. Cerebrospinal fluid (CSF) examination confirmed meningitis with lymphocytic pleocytosis and elevated protein. The CSF Gram stain, culture, viral and acid-fast bacilli were negative. CSF flow cytometry and cytopathology confirmed polyclonal lymphocytosis and suggested reactive causes. CSF TB culture grew Mycobacterium tuberculosis. Mediastinal lymph node biopsy also confirmed TB lymphadenitis. Four antituberculosis drugs were started. One year later, a PET/CT scan showed regression of all the involved lymph nodes. This case highlights the importance of excluding TB in patients with suspected malignancy, especially if they belong to endemic regions, and the increasing role of (18)F-FDG-PET/CT in the early detection of extrapulmonary TB.
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Aggressive natural killer cell leukemia is an extraordinary rare aggressive malignant neoplasm of natural killer cells. Although its first recognition as a specific entity was approximately 20 years ago, this leukemia has not yet been satisfactorily characterized as fewer than 200 cases have been reported in the literature and up to our knowledge, this is the first case report in Qatar. Reaching a diagnosis of aggressive natural killer leukemia was a challenging experience, because in addition to being a rare entity, the relative scarcity of circulating neoplastic cells, failure to obtain an adequate aspirate sample sufficient to perform flow cytometric analysis, together with the absence of applicable method to prove NK clonality (as it lack specific clonal marker); our case had atypical confusing presentation of striking increase in bone marrow fibrosis that was misleading and complicated the case further. The bone marrow fibrosis encountered may be related to the neoplastic natural killer cells' chemokine profile and it may raise the awareness for considering aggressive natural killer leukemia within the differential diagnosis of leukemia with heightened marrow fibrosis.
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OBJECTIVES: This study aims to identify the presenting symptoms, treatment and outcome of patients with nasal natural killer T (NK/T)-cell lymphoma and to find possible differences in survival based on Ann-Arbor stage and international prognostic index (IPI). PATIENTS AND METHODS: Computed tomography and biopsy results of 23 patients (15 males, 8 females; mean age 41 years; range 22 to 72 years) with extranodal NK/T-cell lymphoma who were treated at the department of clinical hematology between 1995 and 2011 were retrospectively analyzed. RESULTS: The median time from onset of clinical symptoms to histological diagnosis was five months. Most patients presented with nasal obstruction (69%) and rhinism (52%). The site of extranodal NK/T-cell lymphoma primarily involved nasal cavity in 39%. Orbital extension was observed in 26%. Lymphomas were classified as stage IE in 30.4%, stage IIE in 47.8% and stage IVE in 21.7%. Nineteen patients received treatment: 10 received chemotherapy plus radiotherapy, nine received chemotherapy only. We used several regimens of chemotherapy including some protocols containing etoposid, L-asparaginase and others without this drugs. Univariate analysis showed that lower IPI score, low Ann-Arbor stage and responsiveness to treatment with both chemotherapy and radiotherapy were significant factors influencing both OS and PFS. CONCLUSION: Nasal type NK/T-cell lymphoma showed a poor response to the conventional anthracycline-based chemotherapy, thereby an investigation for a novel therapy is urgently needed to improve survival.
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Linfoma de Células T/mortalidad , Linfoma de Células T/terapia , Neoplasias Nasofaríngeas/mortalidad , Neoplasias Nasofaríngeas/terapia , Neoplasias Nasales/mortalidad , Neoplasias Nasales/terapia , Adulto , Anciano , Femenino , Humanos , Linfoma de Células T/diagnóstico , Masculino , Persona de Mediana Edad , Neoplasias Nasofaríngeas/diagnóstico , Células T Asesinas Naturales , Estadificación de Neoplasias , Neoplasias Nasales/diagnóstico , Pronóstico , Estudios Retrospectivos , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
Acquired pure megakaryocytic aplasia is a rare hematological disorder characterized by thrombocytopenia with absent or markedly reduced megakaryocytes in the bone marrow. We report a case of a 25-year-old male diagnosed as acquired pure megakaryocytic aplasia. Treatment with prednisone and intravenous immunoglobulin failed, but he was successfully treated with cyclosporine, with complete remission after 90 days and normal platelet count maintained thereafter.
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From April 2003 to December 2006, 195 patients with de novo symptomatic myeloma and younger than 60 years of age were randomly assigned to receive either tandem transplantation up front (arm A, n = 97) or one autologous stem-cell transplantation followed by a maintenance therapy with thalidomide (day + 90, 100 mg per day during 6 months) (arm B, n = 98). Patients included in arm B received a second transplant at disease progression. In both arms, autologous stem-cell transplantation was preceded by first-line therapy with thalidomide-dexamethasone and subsequent collection of peripheral blood stem cells with high-dose cyclophosphamide (4 g/m(2)) and granulocyte colony stimulating factor. Data were analyzed on an intent-to-treat basis. With a median follow-up of 33 months (range, 6-46 months), the 3-year overall survival was 65% in arm A and 85% in arm B (P = .04). The 3-year progression-free survival was 57% in arm A and 85% in arm B (P = .02). Up-front single autologous transplantation followed by 6 months of maintenance therapy with thalidomide (with second transplant in reserve for relapse or progression) is an effective therapeutic strategy to treat multiple myeloma patients and appears superior to tandem transplant in this setting. This study was registered at www.ClinicalTrials.gov as (NCT 00207805).
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Mieloma Múltiple/terapia , Trasplante de Células Madre/métodos , Talidomida/uso terapéutico , Adulto , Inhibidores de la Angiogénesis/uso terapéutico , Proteínas Sanguíneas/metabolismo , Terapia Combinada , Supervivencia sin Enfermedad , Femenino , Hemoglobinas/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/sangre , Mieloma Múltiple/mortalidad , Mieloma Múltiple/patología , Estadificación de Neoplasias , Selección de Paciente , Análisis de Supervivencia , Factores de Tiempo , Recolección de Tejidos y Órganos/métodos , Trasplante Autólogo , Resultado del TratamientoRESUMEN
Clonal rearrangement of antigen receptor genes is commonly used to characterize the lymphoproliferative diseases. In order to perform molecular characterization in the diagnostics and monitoring of lymphoid malignancies, leukemias and lymphomas in Tunisia, we have introduced the use of chemiluminescent probes for immunoglobulin (IG) and T cell receptor (TR) gene rearrangement detection employing the Southern blot method. The chemiluminescent and radioactive detection methods tested with alkaline phosphatase and 32P labelled probes, respectively, were used for the IG and TR gene rearrangement characterization. Our results show the same pattern of rearrangement. Moreover, the chemiluminescent signal is detected faster and it is as sensitive as the radioactive one. We report the optimized conditions for using IGH, IGK, IGL, TRB and TRG probes in non radioactive detection. We have applied the chemiluminescent Southern blot method to analyze examples of Tunisian leukemias and lymphomas. The results allowed the assessment of clonality and the T or B cell lineage of these cases. The use of non radioactive probes makes chemiluminescent Southern blot detection reliable, safe and sensitive. As the use of radioactivity is not common in our laboratories and the licensing requirements needed for its use prohibitive, the chemiluminescent technique will be of great help for detection and characterization of molecular markers in lymphoid malignancies in Tunisia.