ABSTRACT
Extracellular vesicles (EVs) are nanosized particles that have emerged as mediators for intercellular communication in physiologic and pathologic conditions. EVs carry signaling information on their bilipid membrane as well as cargo within, allowing them to perform a wide range of biologic processes and contribute to pathophysiologic roles in a wide range of diseases, including cancer, autoimmune diseases and coagulopathy. This review will specifically address the function of surface molecules on EVs under normal and diseased conditions, as well as their potential to emerge as therapeutic targets in clinical settings, and the importance of further research on the surface topography of EVs.
Subject(s)
Autoimmune Diseases/immunology , Blood Coagulation Disorders/immunology , Extracellular Vesicles/immunology , Neoplasms/immunology , Signal Transduction/immunology , Autoimmune Diseases/pathology , Blood Coagulation Disorders/pathology , Extracellular Vesicles/pathology , Humans , Neoplasms/pathologyABSTRACT
Following the publication of this article the authors noted that the MRD data under the Table 1 column "Remark" of Aspire should go to that of Pollux. The authors wish to apologize for any inconvenience caused. The corrected table is attached to this correction.
ABSTRACT
A small proportion of patients with multiple myeloma (MM) are diagnosed at a very young age. The clinicopathological characteristics and prognosis of these patients are not well known. This analysis included 52 patients diagnosed with MM at the age of ≤30 years (range: 8-30 years). 68% of patients had International Scoring System (ISS) 1 MM; 22% presented with the light chain-only disease, and 48% with elevated serum lactate dehydrogenase (LDH). 85% of patients were treated with novel agents, and 62% received front-line autologous stem cell transplantation (ASCT). Overall response rate (ORR) to front-line treatment and ASCT were 71% and 90%, respectively. The group was followed-up for the median period of 86 months. The median overall survival (OS) was 166 months (95% CI: 53-222), with 5-year OS rate of 77% (95% CI: 61.0-87.9). This findings suggest that the prognosis in young MM patients may be as good if not better than in the general population of MM patients.
Subject(s)
Multiple Myeloma/epidemiology , Adolescent , Adult , Age Factors , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Child , Combined Modality Therapy , Cytogenetic Analysis , Disease Management , Female , Hematopoietic Stem Cell Transplantation , Humans , Male , Multiple Myeloma/diagnosis , Multiple Myeloma/etiology , Multiple Myeloma/therapy , Outcome Assessment, Health Care , Patient Selection , Retrospective Studies , Treatment Outcome , Young AdultABSTRACT
Despite enormous advances, management of multiple myeloma (MM) remains challenging. Multiple factors impact the decision to treat or which regimen to use at MM relapse/progression. Recent major randomized controlled trials (RCTs) showed widely varying progression-free survivals (PFS), ranging from a median of 4 months (MM-003) to 23.6 months (ASPIRE). Based on these RCTs, next-generation proteasome inhibitors (carfilzomib and ixazomib), next-generation immunomodulatory agent (pomalidomide), and monoclonal antibodies (elotuzumab and daratumumab) were approved for relapsed and refractory MM. Daratumumab, targeting CD38, has multiple mechanisms of action including modulation of the immunosuppressive bone marrow micro-environment. In addition to the remarkable single agent activity in refractory MM, daratumumab produced deep responses and superior PFS in MM when combined with lenalidomide/dexamethasone, or bortezomib/dexamethasone. Other anti-CD38 antibodies, such as isatuximab and MOR202, are undergoing assessment. Elotuzumab, targeting SLAMF7, yielded superior response rates and PFS when combined with lenalidomide/dexamethasone. New combinations of these next generation novel agents and/or antibodies are undergoing clinical trials. Venetoclax, an oral BH3 mimetic inhibiting BCL2, showed single agent activity in MM with t(11;14), and is being studied in combination with bortezomib/dexamethasone. Selinexor, an Exportin-1 inhibitor, yielded promising results in quad- or penta-refractory MM including patients resistant to daratumumab. Pembrolizumab, an anti-PD1 check-point inhibitor, is being tested in combination with lenalidomide/dexamethasone or pomalidomide/dexamethasone. Chimeric antigen receptor-T cells targeting B-cell maturation antigen have yielded deep responses in RRMM. Finally, salvage autologous stem cell transplantation (ASCT) remains an important treatment in MM relapsing/progressing after a first ASCT. Herein, the clinical trial data of these agents are summarized, cautious interpretation of RCTs highlighted, and algorithm for salvage treatment of relapse/refractory MM proposed.
Subject(s)
Antibodies/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Multiple Myeloma/drug therapy , Multiple Myeloma/therapy , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/therapy , Humans , Immunotherapy/methods , Progression-Free Survival , Randomized Controlled Trials as TopicABSTRACT
The prognosis for patients multiple myeloma (MM) has improved substantially over the past decade with the development of new, more effective chemotherapeutic agents and regimens that possess a high level of anti-tumor activity. In spite of this important progress, however, nearly all MM patients ultimately relapse, even those who experience a complete response to initial therapy. Management of relapsed MM thus represents a vital aspect of the overall care for patients with MM and a critical area of ongoing scientific and clinical research. This comprehensive manuscript from the International Myeloma Working Group provides detailed recommendations on management of relapsed disease, with sections dedicated to diagnostic evaluation, determinants of therapy, and general approach to patients with specific disease characteristics. In addition, the manuscript provides a summary of evidence from clinical trials that have significantly impacted the field, including those evaluating conventional dose therapies, as well as both autologous and allogeneic stem cell transplantation. Specific recommendations are offered for management of first and second relapse, relapsed and refractory disease, and both autologous and allogeneic transplant. Finally, perspective is provided regarding new agents and promising directions in management of relapsed MM.
Subject(s)
Multiple Myeloma , Practice Guidelines as Topic , Antineoplastic Agents/therapeutic use , Disease Management , Hematopoietic Stem Cell Transplantation/methods , Humans , Multiple Myeloma/diagnosis , Multiple Myeloma/drug therapy , Multiple Myeloma/pathology , Multiple Myeloma/therapy , Recurrence , Salvage Therapy/methodsABSTRACT
OBJECTIVES: Myeloablative allogeneic hematopoietic stem cell transplantation (allo-HSCT) with a matched sibling donor (MSD) in first complete remission (CR1) is an effective consolidation for adult acute lymphoblastic leukemia (ALL), and matched unrelated donor (MUD) is an alternative stem cell source. METHODS: Based on a search of the English literature for MUD transplant in Philadelphia-negative ALL, this review first compares the treatment outcomes of myeloablative allo-HSCT with MUD and MSD, followed by a mini-review of studies of non-myeloablative, reduced intensity conditioning (RIC) allo-HSCT in ALL, and finally measures to improve outcome of MUD allo-HSCT. RESULTS: Publications are inevitably confounded by inclusion of Philadelphia-positive cases, patients beyond CR1, and mismatched unrelated donors in addition to heterogeneity in the length of follow-up. Despite these limitations, the overall data showed that MUD allo-HSCT resulted in comparable survivals with matched related donor (MRD) transplant. Moreover, Asian studies reported a lower transplant-related mortality (TRM) than Western studies. As graft failure is infrequent even in the MUD setting, acute graft versus host disease (aGVHD) remains a major cause of TRM. In addition, RIC allo-HSCT produced promising long-term disease-free survival (DFS) with a low TRM in adult ALL if transplanted in CR1. DISCUSSION: Potential ways to reduce TRM further include antifungal prophylaxis and optimal management of life-threatening non-infective interstitial pneumonitis. Moreover, harnessing graft-versus-leukemia effect with hypomethylating agents warrants clinical trial. CONCLUSION: Myeloablative MUD allo-HSCT resulted in comparable survivals with MRD transplant. RIC allo-HSCT produced promising long-term DFS with a low TRM in adult ALL.
Subject(s)
Graft vs Host Disease/immunology , Hematopoietic Stem Cell Transplantation , Myeloablative Agonists/therapeutic use , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Transplantation Conditioning/methods , Graft vs Host Disease/mortality , Graft vs Host Disease/pathology , Histocompatibility Testing , Humans , Philadelphia Chromosome , Precursor Cell Lymphoblastic Leukemia-Lymphoma/immunology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/mortality , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Siblings , Survival Analysis , Transplantation, Homologous , Unrelated DonorsSubject(s)
Boronic Acids/administration & dosage , Dexamethasone/administration & dosage , Multiple Myeloma/therapy , Nitrogen Mustard Compounds/administration & dosage , Proto-Oncogene Proteins B-raf/genetics , Pyrazines/administration & dosage , Stem Cell Transplantation , Antineoplastic Agents, Alkylating/administration & dosage , Bendamustine Hydrochloride , Bortezomib , Humans , Immunoglobulin G/blood , Karyotyping , Male , Middle Aged , Multiple Myeloma/drug therapy , Mutation , Recurrence , Signal Transduction , Transplantation, Autologous , Treatment Outcome , ras Proteins/geneticsABSTRACT
Abnormal expression of microRNAs (miRNAs) has been implicated in carcinogenesis. Here we report a novel BCR (breakpoint cluster region)-ABL (c-abl oncogene 1, non-receptor tyrosine kinase)/GATA1/microRNA-138 (miR-138) circuitry in chronic myeloid leukemia (CML). miR-138 expression is downregulated in K562 cells and primary CML samples, which is restored after imatinib treatment. The tumor suppressor activity of miR-138 is demonstrated by the induction of cell cycle arrest at G0/G1, inhibition of cell proliferation and colony forming unit granulocyte-macrophage colony formation and enhanced imatinib-induced apoptosis in K562 and Ku812 cells overexpressing miR-138. Moreover, overexpression of miR-138 led to the downregulation of BCR-ABL. Based on luciferase assay, ABL and BCR-ABL are shown to be the target genes regulated by miR-138. Furthermore, miR-138 binding to ABL was shown to localize to the coding region instead of 3'-untranslated regions (3'-UTR) of ABL mRNA. In addition, CCND3 is another target of miR-138, which represses CCND3 expression by binding to its 3'-UTR. Finally, upregulation of miR-138 upon imatinib treatment is associated with the enhancement of GATA1 activity, which binds to the miR-138 promoter. In conclusion, miR-138 is a tumor suppressor miRNA underexpressed in CML. miR-138 represses expression of both BCR-ABL and CCND3 via binding to the coding region and 3'-UTR, respectively. miR-138 expression is activated by GATA1, which in turn is repressed by BCR-ABL. Therefore, miR-138, by virtue of a BCR-ABL/GATA1/miR-138 circuitry, is a tumor suppressor miRNA implicated in the pathogenesis of CML and its clinical response to imatinib.
Subject(s)
Carcinogenesis/genetics , Fusion Proteins, bcr-abl/metabolism , GATA1 Transcription Factor/metabolism , Gene Expression Regulation, Neoplastic , MicroRNAs/genetics , Antineoplastic Agents/pharmacology , Apoptosis , Base Sequence , Benzamides/pharmacology , Binding Sites , Carcinogenesis/metabolism , Cell Proliferation , Down-Regulation , Fusion Proteins, bcr-abl/genetics , G1 Phase Cell Cycle Checkpoints , Gene Expression , HEK293 Cells , Humans , Imatinib Mesylate , K562 Cells , Leukemia, Myelogenous, Chronic, BCR-ABL Positive , MicroRNAs/metabolism , Open Reading Frames , Piperazines/pharmacology , Promoter Regions, Genetic , Pyrimidines/pharmacology , RNA InterferenceABSTRACT
Circulating Epstein-Barr virus (EBV) DNA is a biomarker of EBV-associated malignancies. Its significance in natural killer/T-cell lymphoma treated with the novel regimen SMILE was investigated. EBV DNA was quantified with a World Health Organization EBV standard in 910 plasma samples collected during 230 courses of SMILE in 56 patients. Median presentation EBV DNA was 1900 (0-1.4 × 10(7)) IU/ml. Presentation EBV DNA was significantly associated with tumor load and treatment response. To examine lymphoma chemosensitivity, EBV DNA changes after SMILE were evaluated. EBV DNA after SMILE (I) significantly correlated with tumor load and treatment response. Two dynamic parameters were further analyzed: negative EBV DNA after SMILE (I) and EBV DNA change patterns during treatment (A: persistently undetectable; B: persistently detectable
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , DNA, Viral/blood , Herpesvirus 4, Human/isolation & purification , Killer Cells, Natural/pathology , Lymphoma, T-Cell/drug therapy , Lymphoma, T-Cell/virology , Adolescent , Adult , Aged , Aged, 80 and over , Asparaginase/administration & dosage , Dexamethasone/administration & dosage , Etoposide/administration & dosage , Female , Humans , Ifosfamide/administration & dosage , Lymphoma, T-Cell/mortality , Lymphoma, T-Cell/pathology , Male , Methotrexate/administration & dosage , Middle Aged , PrognosisABSTRACT
Multiple myeloma is characterized by underlying clinical and biological heterogeneity, which translates to variable response to treatment and outcome. With the recent increase in treatment armamentarium and the projected further increase in approved therapeutic agents in the coming years, the issue of having some mechanism to dissect this heterogeneity and rationally apply treatment is coming to the fore. A number of robustly validated prognostic markers have been identified and the use of these markers in stratifying patients into different risk groups has been proposed. In this consensus statement, the International Myeloma Working Group propose well-defined and easily applicable risk categories based on current available information and suggests the use of this set of prognostic factors as gold standards in all clinical trials and form the basis of subsequent development of more complex prognostic system or better prognostic factors. At the same time, these risk categories serve as a framework to rationalize the use of therapies.
Subject(s)
Multiple Myeloma/diagnosis , Multiple Myeloma/drug therapy , Consensus Development Conferences as Topic , Humans , PrognosisABSTRACT
Treatment in medical oncology is gradually shifting from the use of nonspecific chemotherapeutic agents toward an era of novel targeted therapy in which drugs and their combinations target specific aspects of the biology of tumor cells. Multiple myeloma (MM) has become one of the best examples in this regard, reflected in the identification of new pathogenic mechanisms, together with the development of novel drugs that are being explored from the preclinical setting to the early phases of clinical development. We review the biological rationale for the use of the most important new agents for treating MM and summarize their clinical activity in an increasingly busy field. First, we discuss data from already approved and active agents (including second- and third-generation proteasome inhibitors (PIs), immunomodulatory agents and alkylators). Next, we focus on agents with novel mechanisms of action, such as monoclonal antibodies (MoAbs), cell cycle-specific drugs, deacetylase inhibitors, agents acting on the unfolded protein response, signaling transduction pathway inhibitors and kinase inhibitors. Among this plethora of new agents or mechanisms, some are specially promising: anti-CD38 MoAb, such as daratumumab, are the first antibodies with clinical activity as single agents in MM. Moreover, the kinesin spindle protein inhibitor Arry-520 is effective in monotherapy as well as in combination with dexamethasone in heavily pretreated patients. Immunotherapy against MM is also being explored, and probably the most attractive example of this approach is the combination of the anti-CS1 MoAb elotuzumab with lenalidomide and dexamethasone, which has produced exciting results in the relapsed/refractory setting.
Subject(s)
Antineoplastic Agents/therapeutic use , Multiple Myeloma/drug therapy , HumansABSTRACT
Plasma cell leukemia (PCL) is a rare and aggressive variant of myeloma characterized by the presence of circulating plasma cells. It is classified as either primary PCL occurring at diagnosis or as secondary PCL in patients with relapsed/refractory myeloma. Primary PCL is a distinct clinic-pathological entity with different cytogenetic and molecular findings. The clinical course is aggressive with short remissions and survival duration. The diagnosis is based upon the percentage (≥ 20%) and absolute number (≥ 2 × 10(9)/l) of plasma cells in the peripheral blood. It is proposed that the thresholds for diagnosis be re-examined and consensus recommendations are made for diagnosis, as well as, response and progression criteria. Induction therapy needs to begin promptly and have high clinical activity leading to rapid disease control in an effort to minimize the risk of early death. Intensive chemotherapy regimens and bortezomib-based regimens are recommended followed by high-dose therapy with autologous stem cell transplantation if feasible. Allogeneic transplantation can be considered in younger patients. Prospective multicenter studies are required to provide revised definitions and better understanding of the pathogenesis of PCL.
Subject(s)
Leukemia, Plasma Cell/diagnosis , Leukemia, Plasma Cell/therapy , Disease Progression , Female , Humans , Leukemia, Plasma Cell/pathology , Male , Middle AgedABSTRACT
BACKGROUND: Invasive fungal disease (IFD) is an important problem complicating the therapy of haematologic patients. AIM: This study aimed to provide data on the epidemiology of IFD in an Asian teaching hospital, as well as the prescription practice of antifungal drugs. METHOD: We conducted a retrospective review of 275 haematologic patients who were prescribed antifungal drugs in a 4-year period (2007-2010), of whom 130 (47%) had undergone haematopoietic stem cell transplantation. RESULTS: Antifungal prophylaxis with either fluconazole or itraconazole was given in 214 patients (78%). There were 414 prescriptions of antifungal drugs (including liposomal amphotericin B, voriconazole, caspofungin, micafungin, anidulafungin), of which 361 prescriptions were empirical. There were 14 patients with proven IFD, 11 of whom had breakthrough infection while on itraconazole prophylaxis. Interestingly, seven of these cases were due to infection by itraconazole-sensitive candida. CONCLUSION: These results provide important epidemiologic data necessary for the formulation of strategies for prevention and treatment of IFD in Asian patients.
Subject(s)
Antifungal Agents/therapeutic use , Hematologic Diseases/drug therapy , Hematologic Diseases/epidemiology , Hospitals, Teaching/trends , Mycoses/drug therapy , Mycoses/epidemiology , Adult , Aged , Aged, 80 and over , Asia/epidemiology , Female , Hospitals, Teaching/methods , Hospitals, University/trends , Humans , Male , Middle Aged , Retrospective Studies , Young AdultSubject(s)
Blood Protein Electrophoresis , Immunoglobulin lambda-Chains/blood , Multiple Myeloma/blood , Myeloma Proteins/analysis , Oligoclonal Bands/blood , Adult , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Combined Modality Therapy , Dexamethasone/administration & dosage , Diagnosis, Differential , Doxorubicin/administration & dosage , Female , Hematopoietic Stem Cell Transplantation , Humans , Immunoglobulin Isotypes/blood , Immunoglobulin Isotypes/genetics , Immunoglobulin lambda-Chains/genetics , Multiple Myeloma/drug therapy , Multiple Myeloma/pathology , Multiple Myeloma/surgery , Myeloma Proteins/genetics , Oligoclonal Bands/genetics , Recurrence , Remission Induction , Transplantation, Autologous , Vincristine/administration & dosageSubject(s)
Methicillin-Resistant Staphylococcus aureus , Pyomyositis/microbiology , Staphylococcal Infections/complications , Anti-Bacterial Agents/therapeutic use , Female , Humans , Middle Aged , Multimodal Imaging , Pyomyositis/diagnostic imaging , Pyomyositis/drug therapy , Radionuclide Imaging , Staphylococcal Infections/diagnostic imaging , Staphylococcal Infections/drug therapy , Vancomycin/therapeutic useABSTRACT
OBJECTIVE: To perform a multivariate analysis by Cox proportional hazard model of the impact of JAK2 V617F mutation on thrombosis and myeloid transformations in patients with essential thrombocythemia (ET). PATIENTS AND METHODS: The clinicopathologic features and outcome of a cohort of Chinese ET patients were retrospectively reviewed. JAK2 V617F mutation was detected by allele-specific polymerase chain reaction. Potential risk factors including JAK2 V617F that might impact on thrombosis and outcome were studied by multivariate analysis with Cox proportional hazard model. RESULTS: Of 141 patients studied, JAK2 V617F was found in 80 cases (57%). JAK2 V617F was positively correlated with hemoglobin and leukocyte count at diagnosis. Univariate analysis showed significant thrombotic risks to be JAK2 V617F (P=0.006), hemoglobin >13 g/dl (P=0.015), and age >55 years (P=0.011). However, in multivariate analysis, only age and hemoglobin were independent risk factors. JAK2 V617F was unrelated to survival or leukemic/myelofibrotic transformation. CONCLUSION: In Chinese patients with ET, JAK2 V617F was positively associated with age, hemoglobin, and leukocyte count, but was not an independent risk for thrombosis.
Subject(s)
Janus Kinase 2/genetics , Leukemia, Myeloid/genetics , Point Mutation , Thrombocythemia, Essential/complications , Thrombocythemia, Essential/genetics , Thrombosis/genetics , Adult , Aged , Aged, 80 and over , Aging , Female , Genetic Association Studies , Hemoglobins/analysis , Humans , Leukemia, Myeloid/etiology , Leukocyte Count , Male , Medical Records , Middle Aged , Multivariate Analysis , Retrospective Studies , Risk Factors , Survival Analysis , Thrombocythemia, Essential/mortality , Thrombocythemia, Essential/physiopathology , Thrombosis/etiology , Young AdultABSTRACT
A loss-of-function mutation of TET2, CBL and CEBPA has been implicated in the pathogenesis or leukaemic transformation of myeloproliferative neoplasm. As tumour suppressor genes may potentially be inactivated by promoter hypermethylation, the authors studied the methylation status of these genes in three cell lines and diagnostic marrow samples from 45 patients with myeloproliferative neoplasm (MPN) (essential thrombocythaemia, N=34; polycythaemia vera, N=7 and primary myelofibrosis, N=4) by methylation-specific PCR. TET2 was heterozygously methylated in MEG-01 and K562 but completely unmethylated in HEL. On the other hand, both CBL and CEBPA were completely unmethylated in all three cell lines. In the primary marrow samples, methylation of TET2 occurred in two (5.9%) patients with essential thrombocythaemia (4.4% of all patients), both without JAK2 V617 mutation, but not in polycythaemia vera or primary myelofibrosis. There was no association between TET2 methylation with the type of MPN (p=0.713). Hypermethylation of CBL or CEBPA was not detected in any patients. In summary, methylation of TET2, CBL and CEBPA is infrequent in MPN at diagnosis. The role of methylation of these genes at the time of leukaemic transformation warrants further study.
Subject(s)
CCAAT-Enhancer-Binding Proteins/genetics , DNA Methylation , DNA-Binding Proteins/genetics , Myeloproliferative Disorders/genetics , Oncogene Protein v-cbl/genetics , Proto-Oncogene Proteins/genetics , Adult , Aged , Aged, 80 and over , Base Sequence , CpG Islands/genetics , Dioxygenases , Female , Humans , Male , Middle Aged , Molecular Sequence Data , Polycythemia Vera/genetics , Polymerase Chain Reaction/methods , Primary Myelofibrosis/genetics , Thrombocythemia, Essential/geneticsABSTRACT
BACKGROUND: Methylation of genes regulating cell-cycle check-point (INK4 cyclin-dependent kinase inhibitors), apoptosis (XAF1), adhesion (CDH13), JUNB and Wnt signalling (soluble Wnt inhibitors) has been implicated in pathogenesis of haematological and epithelial cancers. METHOD: The authors studied the methylation status of CDKN2A, CDKN2B, XAF1, CDH13, JUNB and a panel of soluble Wnt inhibitors including WIF1, DKK3, APC, SFRP1, SFRP2, SFRP4 and SFRP5 by methylation-specific PCR in 31 bone marrow and 21 peripheral blood samples of patients with essential thrombocythaemia. RESULTS AND DISCUSSION: There was no evidence of hypermethylation of all these genes in both the BM and PB samples. Therefore, in contrast to myeloid leukaemias, methylation of these genes regulating the cell cycle, apoptosis, adhesion and Wnt signalling does not play an important role in the pathogenesis of myeloproliferative diseases. Whether differential methylation may occur in the progenitor or mature blood cell compartments remains to be verified. Our study contributes to the literature on methylation in chronic myeloproliferatve diseases.
Subject(s)
Cyclin-Dependent Kinase Inhibitor Proteins/genetics , DNA Methylation , Intercellular Signaling Peptides and Proteins/genetics , Intracellular Signaling Peptides and Proteins/genetics , Thrombocythemia, Essential/genetics , Adaptor Proteins, Signal Transducing , Adult , Aged , Aged, 80 and over , Apoptosis Regulatory Proteins , Base Sequence , Bone Marrow/metabolism , Cadherins/genetics , Cadherins/metabolism , Cyclin-Dependent Kinase Inhibitor Proteins/metabolism , Female , Humans , Intercellular Signaling Peptides and Proteins/metabolism , Intracellular Signaling Peptides and Proteins/metabolism , Male , Middle Aged , Molecular Sequence Data , Neoplasm Proteins/genetics , Neoplasm Proteins/metabolism , Polymerase Chain Reaction/methods , Proto-Oncogene Proteins c-jun/genetics , Proto-Oncogene Proteins c-jun/metabolism , Sequence Alignment , Signal Transduction/physiology , Thrombocythemia, Essential/metabolism , Wnt Proteins/physiologyABSTRACT
Bortezomib-based regimens have significant activities in multiple myeloma (MM). In this study, we tested the efficacy of a total therapy with a staged approach where newly diagnosed MM patients received vincristine/adriamycin/dexamethsone (VAD). VAD-sensitive patients (> or =75% paraprotein reduction) received autologous hematopoietic stem cell transplantation (auto-HSCT), whereas less VAD-sensitive patients (<75% paraprotein reduction) received bortezomib/thalidomide/dexamethasone (VTD) for further cytoreduction prior to auto-HSCT. On an intention-to-treat analysis, a progressive increase of complete remission (CR) rates was observed, with cumulative CR rates of 48% after HSCT. Seven patients progressed leading to three fatalities, of which two had central nervous system disease. The 3-year overall survival and event-free survival were 75.1% and 48.3%, respectively. Six patients developed oligoclonal reconstitution with new paraproteins. In the absence of anticoagulant prophylaxis, no patients developed deep vein thrombosis. The staged application of VAD+/-VTD/auto-HSCT resulted in an appreciable response rate and promising survivals. Our approach reduced the use of bortezomib without compromising the ultimate CR rate and is of financial significance for less affluent communities.
Subject(s)
Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Boronic Acids/therapeutic use , Hematopoietic Stem Cell Transplantation , Multiple Myeloma/diagnosis , Multiple Myeloma/therapy , Pyrazines/therapeutic use , Thalidomide/therapeutic use , Adult , Aged , Angiogenesis Inhibitors/therapeutic use , Antibiotics, Antineoplastic/therapeutic use , Bortezomib , Dexamethasone/therapeutic use , Disease Progression , Disease-Free Survival , Doxorubicin/therapeutic use , Female , Humans , Immunoglobulins/blood , Male , Middle Aged , Multiple Myeloma/pathology , Multiple Myeloma/physiopathology , Treatment Outcome , Vincristine/therapeutic useABSTRACT
miR-34a is a transcriptional target of p53 and implicated in carcinogenesis. We studied the role of miR-34a methylation in a panel of hematological malignancies including acute leukemia [acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL)], chronic leukemia [chronic lymphocytic leukemia (CLL) and chronic myeloid leukemia (CML)], multiple myeloma (MM) and non-Hodgkin's lymphoma (NHL). The methylation status of miR-34a promoter was studied in 12 cell lines and 188 diagnostic samples by methylation-specific polymerase chain reaction. miR-34a promoter was unmethylated in normal controls but methylated in 75% lymphoma and 37% myeloma cell lines. Hypomethylating treatment led to re-expression of pri-miR-34a transcript in lymphoma cells with homozygous miR-34a methylation. In primary samples at diagnosis, miR-34a methylation was detected in 4% CLL, 5.5% MM samples and 18.8% of NHL at diagnosis but none of ALL, AML and CML (P = 0.011). In MM patients with paired samples, miR-34a methylation status remained unchanged at progression. Amongst lymphoid malignancies, miR-34a was preferentially methylated in NHL (P = 0.018), in particular natural killer (NK)/T-cell lymphoma. In conclusion, amongst hematological malignancies, miR-34a methylation is preferentially hypermethylated in NHL, in particular NK/T-cell lymphoma, in a tumor-specific manner, therefore the role of miR-34a in lymphomagenesis warrants further study.