VEGF与血液学恶性疾病

VEGF作为一种血管新生的主要病理生理性调节因子，触发了白血病细胞及多发性骨髓瘤细胞的生长、存活及移动，在造血过程中起重要作用。VEGF的表达及其信号转导，对血液学恶性疾病，尤其是对多发性骨髓瘤的发病机制及临床特性都有重要作用。针对VEGF及其受体直接或间接的治疗，有可能为临床提供一种新的有效的治疗方法。     

Molecular diagnosis in hematologic malignancies

Recent advances in molecular diagnosis in the hematological laboratory have greatly contributed to the diagnosis and treatment of hematologic malignancies, such as leukemia and lymphoma. The pathogenesis of leukemia and lymphoma has been disclosed by the analyses of genetic abnormalities in patients; abnormal gene expression may induce derangement in the control of cellular proliferation. Based on these genetic abnormalities, gene-targeted therapy has been introduced as a new approach to treating hematologic malignancies. We discuss here the usefulness of the molecular diagnosis in clinical hematology.     

CD44 and hematologic malignancies

The expression of CD44 was upregulated in some hematological malignancies and is associated with metastasis and prognosis. The ligation of CD44 with specific monoclonal antibodies can trigger terminal differentiation of leukemic blasts in some subtypes, so it is probable to develop an anti-CD44 based differentiation therapy in leukemia. The effects of CD44 and its monoclonal antibodies are discussed in this review. Cellular ＆ Molecular Immunology.     

ABO blood groups in hematologic malignancies

This article examines the genetic predisposition of individuals to lymphoma and leukemia with regard to the ABO blood groups. Blood samples from 558 patients suffering from various forms of lymphoma and leukemia were collected and typed for ABO blood groups. The ABO blood group phenotype frequencies of lymphoma patients were similar to those in control samples. Among leukemia patients, a significant increase in the frequency of the A2 phenotype was found in chronic lymphocytic leukemia. Possible mechanisms underlying the predisposition of individuals with the A2 blood group to chronic lymphocytic leukemia suggested by these preliminary results are discussed.     

Novel immunotherapies for hematologic malignancies

The immune system is designed to discriminate between self and tumor tissue. Through genetic recombination, there is fundamentally no limit to the number of tumor antigens that immune cells can recognize. Yet, tumors use a variety of immunosuppressive mechanisms to evade immunity. Insight into how the immune system interacts with tumors is expanding rapidly and has accelerated the translation of immunotherapies into medical breakthroughs. Herein, we appraise novel strategies that exploit the patient's immune system to kill cancer. We review various forms of immune-based therapies, which have shown significant promise in patients with hematologic malignancies, including (i) conventional monoclonal therapies like rituximab; (ii) engineered monoclonal antibodies called bispecific T-cell engagers; (iii) monoclonal antibodies and pharmaceutical drugs that block inhibitory T-cell pathways (i.e. PD-1, CTLA-4, and IDO); and (iv) adoptive cell transfer therapy with T cells engineered to express chimeric antigen receptors or T-cell receptors. We also assess the idea of using these therapies in combination and conclude by suggesting multi-prong approaches to improve treatment outcomes and curative responses in patients.     

Applications of next-generation sequencing in hematologic malignancies

In the last decade, next-generation sequencing (NGS) has rapidly progressed from a research method to a core component of standard-of-care clinical testing. In oncology, tumor sequencing provides a critical tool to detect somatic driver mutations that not only characterize disease but also impact therapeutic decision-making. Here, we review the important role of NGS in the evaluation of hematopoietic neoplasms. We discuss technical and practical considerations relevant in somatic mutation testing, emphasizing issues unique to blood cancers. Then, we describe how NGS data is being used to facilitate diagnosis, inform prognosis, guide therapy selection, and even monitor disease. This broad overview highlights the transformative impacts NGS data provides throughout the clinical course of patients with hematologic malignancies.     

Immunoglobulin allotypes Gm and Km in hematologic malignancies

Immunoglobulin allotypes of the Gm and Km systems have been compared in patients with various forms of hematologic malignancies and healthy controls of the same ethnographic background. These comparisons found an increased frequency of the haplotype Gm and a decreased frequency of Gm in patients with Hodgkin's disease; a decreased frequency of Gm in diffuse, large-cell lymphoma patients; a decreased frequency of Gm and an increased frequency of Gm in acute myeloid leukemia patients; a decreased frequency of Gm in chronic myeloid leukemia patients, and an increased frequency of the phenotype Km(1+) in chronic lymphocytic leukemia patients. These results support previous suggestions of the involvement of immunoglobulin allotypes in the susceptibility to some forms of human hematologic malignancy.     

Acquired hemophilia in patients with hematologic malignancies

OBJECTIVES: To evaluate the occurrence of acquired hemophilia in patients with hematologic malignancies and to assess their response to treatment. DESIGN: Data on 8 patients with hematologic neoplastic disorders and inhibitor against factor VIII were analyzed retrospectively. SETTING: Three large tertiary-care centers. RESULTS: All 8 patients presented with spontaneous or posttraumatic hemorrhages. The mean inhibitor titer at the time of diagnosis was 79 Bethesda units (BU), and residual factor VIII activity was detectable in 3 patients. The inhibitor disappeared in 5 patients after a mean of 92 days, but persisted in the 3 other patients. The patients who achieved complete resolution of their circulating anticoagulant had lower mean inhibitor titers at the time of diagnosis than those who had persistent inhibitor (27 BU vs. 167 BU, respectively). Two patients died as a result of major hemorrhages that did not respond to treatment. CONCLUSIONS: Antibodies against factor VIII may be responsible for some bleeding episodes in patients with lymphoid or myeloid malignancies. Acquired hemophilia in this setting should be differentiated from other causes of bleeding because the approach to treatment is different. No conclusion can be drawn regarding the association between the activity of the underlying illness and the inhibitor titer, although it appears that at least in some patients such a relationship may exist. The underlying pathogenetic mechanisms responsible for the production of autoantibodies against factor VIII remain unclear, but we provide a few explanations in this article.     

Interstitial 9q- deletions in hematologic malignancies

Sixteen patients with interstitial deletions of the long arm of chromosome #9 (9q-). were studied. From our observations and the findings of ten other cases in the literature, it can be deduced that the anomaly is almost exclusively found in myeloproliferative disorders and that it rarely occurs as the sole anomaly; however, in more than one-third of the cases, it was associated with a t(8;21) and occurred as a secondary event. The deletion appears to be interstitial, the breakpoints are somewhat variable, and the region carrying the abl oncogene was never involved.     

外泌体microRNAs在恶性血液系统疾病中的研究进展

<正>外泌体(exosome)是一类脂质双分子层结构的封闭性膜性囊泡,直径约为30~150 nm~([1]),外泌体的形成最初是由于细胞内吞,细胞膜内化产生核内体,随后在核内体膜的入鞘部分形成许多小囊泡,这样的核内体称之为多泡体,最后多泡体与细胞膜融合,并释放核内体小囊泡到细胞外间隙成为外泌体~([2-3])。外泌体最早是在1983年由Pan和Johnstone发现~([4]),由细胞主动分泌、释放。研究至今,已发现淋巴细胞、血小板、内皮细胞、肥大细     

Candida guilliermondii fungemia in patients with hematologic malignancies

The microbiological, clinical, and epidemiological features of most non-Candida albicans Candida species are well known, but much less is known about species such as Candida guilliermondii, an uncommon pathogen causing a variety of deep-seated infections in immunocompromised hosts. To characterize C. guilliermondii fungemia in patients with hematological malignancies and its susceptibility to antifungal drugs, all cases of C. guilliermondii fungemia diagnosed in our department between 1983 and 2005 were retrospectively analyzed and the literature was reviewed. C. guilliermondii caused 29/243 (11.7%) candidemia episodes diagnosed during the study period. Central venous catheters were the documented sources of candidemia in 19/29 episodes (65.5%), and invasive tissue infections were documented in 2 (6.9%). In the remaining eight, the catheter was not removed and the source of the fungemia remained obscure. Seven episodes ended in death, but only one could be attributed to invasive C. guilliermondii infection. Molecular typing data reveal no evidence of common infection sources. Isolates displayed high rates of in vitro susceptibility to amphotericin B (100%), voriconazole (95%), and fluconazole (90%) and lower rates of in vitro susceptibility to flucytosine (86%), itraconazole (76%), and caspofungin (33%). Our literature review confirms that C. guilliermondii is a significantly more frequent cause of candidemia among cancer patients compared with the general hospital population. It accounted for <1% of the total number of Candida bloodstream isolates reported in the articles we reviewed, with higher rates in Europe (1.4%) and Asia (1.8%) compared with North America (0.3%).     

Inversion of chromosome 12 and lineage promiscuity in hematologic malignancies

Rearrangements of the short arm of chromosome 12 are among the most common aberrations found in hematologic malignancies, including myelodysplastic syndromes, acute myelocytic leukemias, acute lymphoblastic leukemias, and non-Hodgkin lymphomas. We report on a group of 46 patients with a variety of myelocytic and lymphoid malignancies, all with an inversion of chromosome 12. Both pericentric and paracentric inversions occurred. The identified hotspots for breakage were p13 and q24. These correspond to gene-rich areas of known chromosome instability. The inv(12) is difficult to detect and may be misinterpreted as a partial deletion by routine cytogenetics. Fluorescence in situ hybridization studies revised the G-banding interpretations of a deleted 12p in some cases to an inversion. The inv(12) may occur as the sole abnormality in both myelocytic and lymphoid malignancies, suggesting lineage promiscuity as seen with MLL and ETV6 gene disruptions. The majority of patients with the inv(12) had complex karyotypic changes that predicted a poor prognosis. Of the 24 patients with known clinical follow-up, many were refractory to chemotherapy and overall survival was short.     

Lymphoproliferative disorders and hematologic malignancies following organ transplantation

Eleven allograft recipients (one cardiac, one hepatic, nine renal) at the Massachusetts General Hospital developed a lymphoproliferative disorder or leukemia. Six (all renal) patients received conventional immunosuppressive therapy (CIT), four received cyclosporin A (CsA) (one cardiac, one hepatic, two renal), and one received CIT for his first transplant and CsA for his second transplant (both renal). The interval from transplant to onset of the hematologic disorder ranged from 2 mo to 3 yr in the CsA group and from 6 mo to 9 yr in the CIT group and was 16 yr in the patient with two allografts. There were eight malignant lymphomas, seven of which were extranodal, (four immunoblastic, one large noncleaved cell, one small noncleaved cell, one plasmacytoma, one unclassifiable), one case of polymorphic diffuse B cell hyperplasia and two cases of acute myeloid leukemia. Frozen section immunohistochemistry in six cases showed monotypic immunoglobulin in four lymphomas, (including the plasmacytoma), an immunoglobulin-negative B cell phenotype in one lymphoma, and polytypic immunoglobulin in the case of polymorphic hyperplasia. One lymphoma showed a monotypic immunoglobulin-producing B cell population in one site and an immunoglobulin-negative B cell population in another site. With an immunoglobulin heavy chain gene-specific probe, Southern blot analysis of tissue from these two sites revealed two distinct rearrangements. When tissue from a second case of lymphoma was analyzed by Southern blot, identical rearrangements of the heavy chain gene were found in tumor from two separate sites. Similar to the experience of others, we find an increased incidence of lymphoma and a slightly increased incidence of acute myeloid leukemia in allograft recipients. In contrast to other reports, we found a predominance of monoclonal B cell malignancies, a more polymorphous histologic appearance of the lymphoproliferative disorders in CsA patients, and one case each of "multiclonal" and "monoclonal" lymphomas when tumor from separate sites was tested for gene rearrangement.     

Role of the ubiquitin proteasome system in hematologic malignancies

Ubiquitination is a post-translational modification process that regulates several critical cellular processes. Ubiquitination is orchestrated by the ubiquitin proteasome system (UPS), which constitutes a cascade of enzymes that transfer ubiquitin onto protein substrates. The UPS catalyzes the destruction of many critical protein substrates involved in cancer pathogenesis. This review article focuses on components of the UPS that have been demonstrated to be deregulated by a variety of mechanisms in hematologic malignancies. These include E3 ubiquitin ligases and deubiquitinating enzymes. The prospects of specific targeting of key enzymes in this pathway that are critical to the pathogenesis of particular hematologic neoplasia are also discussed.     

荧光原位杂交在恶性血液病中的研究进展

荧光原位杂交(fluorescence in situ hybtidization,FISH)可对分裂中期及间期的细胞进行染色体与基因异常检测,具有直观、快速、敏感性和特异性高以及方便灵活等优点,对白血病、淋巴瘤、多发性骨髓瘤、骨髓增生异常综合征等恶性血液病的诊断、分型、临床治疗选择和预后判断提供重要依据.     

荧光原位杂交在恶性血液病中的研究进展

荧光原位杂交(fluorescence in situ hybtidization,FISH)可对分裂中期及间期的细胞进行染色体与基因异常检测,具有直观、快速、敏感性和特异性高以及方便灵活等优点,对白血病、淋巴瘤、多发性骨髓瘤、骨髓增生异常综合征等恶性血液病的诊断、分型、临床治疗选择和预后判断提供重要依据.     

Translocation (2;3) in hematologic malignancies

Cytogenetic studies have revealed nonrandom involvement of some chromosomes in specific structural abnormalities in human neoplasias. In this report we present three patients with t(2;3) associated with hematologic malignancies, and review the pertinent literature. These findings lead us to regard the region between 3q26 and 3q29 as implicated in chromosomal changes in these disorders, whereas, no vulnerable point has been observed in chromosome #2. We suggest that these translocations may activate genes on chromosome #3 related to these neoplasias.     

Constitutional chromosome aberrations as pathogenetic events in hematologic malignancies

A predisposition to tumor development is associated with some constitutional chromosomal abnormalities. Investigations of families with an apparent hereditary cancer and constitutional chromosome rearrangements have led to the molecular identification of tumor suppressor genes. Under the somatic mutation theory for the development of cancer, two mutational events are required. The first step may be a constitutional event and the second an acquired genetic mutation. Cytogenetic studies were performed on 5633 bone marrow specimens from patients with hematologic malignancies from a single institution. Fifty cases of constitutional chromosome aberrations were detected. Data collected from the literature and from our series are reviewed and compared with the incidence of specific constitutional chromosome aberrations in the newborn population. Possible mechanisms that may predispose individuals with constitutional chromosome aberrations to the development of a hematologic malignancy are reviewed.