Risk of leukemic transformation in PV and ET patients

Despite a prolonged survival of around 15 years linked to a prolonged complete remission induced by myelosuppression, myeloproliferative syndromes such as polycythemia vera (PV) and essential thrombosis (ET) remain at risk of lethal adverse affects such as thrombotic events and acute transformation. The major risk at diagnosis, in the absence of treatment, is essentially thrombosis. Different therapeutic trials have shown the necessity to maintain circulating blood cells (RBC and platelets counts) near normal levels to avoid thrombosis. Phlebotomies alone in PV lead in the long run to metaplasia and increased platelet counts and should only be kept for emergency cell count reduction. Myelosuppression is thus until recently the most widely accepted effective alternative. However, the effects of long term chronic administration of myelosuppresive agents needs to be analyzed and monitored as the biological changes which appear during the course of these diseases linked or not to the intrinsic clonal haematopoietic abnormality may lead to malignant transformation. Thus, alternative therapies need to be evaluated and predisposition factors taken in account.     

5q- syndrome in a patient with chronic exposure to ionizing radiation

A report is presented on an interstitial deletion of the long arm of chromosome #5(5q-), associated with refractory anemia in a patient who had been exposed to chronic ionizing radiation. Six years of follow-up did not disclose any evolution toward leukemia.     

恶性髓系血液病-7/7q-异常的分子细胞遗传学分析

目的 分析染色体-7／7q-在骨髓增生异常综合征(myelodysplastic syndrome，MDS)和急性髓细胞白血病(acute myeloblastic leukemia，AMI，)中的发生频率；探讨荧光原位杂交技术(fluorescence in situ hybridization，FISH)在检测和鉴定-7／7q-异常中的价值。方法 回顾性分析所有接受细胞遗传学分析(conventional cytogenetic analysis，CCA)的MDS／AML患者的核型特征，其中70份进行FISH分析。应用双色荧光直接标记的7号着丝粒探针(CEP7，光谱绿)和7q31基因序列探针(D7S486，光谱桔红)，15份正常样本作为对照。结果 -7／7q-在AML和MDS中出现频率分别为4．5l％(31／687例)和5．7l％(28／490例)，分别占异常核型病例的5．68％和l0．29％。7q-常见的缺失区域为7q21—22(10例)和7q31—35(10例)。FISH证实伴有克隆性-7／7q-异常，但在随机性-7／7q-异常或正常核型中未检出-7／7q-异常。在核型分析出现7q-异常的病例中，FISH检出7／11例可同时伴有-7克隆的出现，而且7q-异常的细胞数显著高于-7异常细胞数(42．5％vs8．4％，P=0．025)。1例核型为del(7)(q22)患者FISH证实为染色体易位；1例7q 患者FISH显示dup(7q)；1例复杂异常核型，FISH确定其累及7q。结论 FISH是鉴定或确定7q结构异常的强有力工具，能精确地评价-7／7q-。7q-异常通常与-7异常在同一个样本中共存，且7q-细胞数显著增高，推测-7克隆衍生于7q-的丢失。     

Cytogenetic abnormalities and leukemic transformation in hydroxyurea-treated patients with Philadelphia chromosome negative chronic myeloproliferative disease

Eighty-one consecutive hydroxyurea-treated patients with Philadelphia (Ph) chromosome negative chronic myeloproliferative disease were followed prospectively from 1981 to 1989; 35 of them had polycythemia vera, 32 had essential thrombocythemia, 12 had myelofibrosis, and 2 had myeloproliferative syndromes. The 81 patients were treated with hydroxyurea for a total of 3,804 months during the observation time. Only three patients had been treated with alkylating agents or 32P before start of hydroxyurea treatment. Four patients transformed into acute myeloid leukemia or myelodysplastic syndromes; three of these patients had essential thrombocythemia, and one had a myeloproliferative syndrome. Two patients died of solid cancers. Five out of 53 evaluable patients (9%) had pretreatment clonal cytogenetic abnormalities involving chromosomes 1, 9, 20, and 21. At follow-up, during or after hydroxyurea treatment, 15% had cytogenetic abnormalities, an unexpectedly low frequency compared to the previously reported frequency in patients with polycythemia vera treated with alkylating agents. None of our patients who developed cytogenetic clonal changes during hydroxyurea therapy had polycythemia vera. However, follow-up is too short to draw any conclusions about the mutagenic potential of hydroxyurea compared to alkylating agents.     

Region-specific alteration in brain glutamate: Possible relationship to risk-taking behavior

Risk-taking behaviors involve increased motor activity and reduced anxiety in humans. Total sleep deprivation (SD) in animals produces a similar change in motor and fear behaviors. Investigators studied region-specific brain levels of glutamate in rats after TSD, an animal model of risk-taking behavior. We investigated the effects of sleep deprivation on these behaviors and associated levels of brain glutamate. Compared to the controls, the sleep-deprived rats spent a significantly greater percentage of time in the open arms of the elevated plus maze (EPM), demonstrating reduced fear-like and increased risk-taking behaviors. Additionally, sleep deprivation was associated with a significant increase in glutamate levels in the hippocampus and thalamus. An inverse relationship between glutamate in the medial prefrontal cortex and risk taking in the EPM and a positive association between the ratio of glutamate in the hippocampus to medial prefrontal cortex and risk taking was revealed. The role of sleep deprivation-induced changes in brain glutamate and its relationship to anxiety, fear, and posttraumatic stress disorder (PTSD) is discussed.     

Deletion of 5q31 is observed in megakaryocytic cells in patients with myelodysplastic syndromes and a del(5q), including the 5q- syndrome

One of the most common structural rearrangements in myelodysplastic syndrome (MDS) is a deletion of the long arm of chromosome 5, del(5q). The 5q- syndrome is a distinct entity, that presents with specific morphologic abnormalities of the megakaryocytic lineage. Thus, we evaluated the presence or absence of the del(5q) in these cells. We performed fluorescence in situ hybridization analysis using unique sequence probes (one for 5q31, the other for the 5p telomeric band), and tested bone marrow specimens from 10 patients with MDS (including 6 patients with the 5q- syndrome) and a del(5q). Megakaryocytes were identified by nuclear morphology, size, and ploidy index. Our results demonstrate the presence of the del(5q) in the megakaryocytic lineage and, thus, the involvement of these cells in the disease process.     

Phenotypic alteration in malignant transformation of colonic villous tumours: with special reference to a comparison with tubular tumours

AIMS: To clarify the cellular differentiation of colorectal villous tumours in malignant transformation, compared with that of tubular tumours (tubular adenoma and adenocarcinoma arising in tubular adenoma). METHODS AND RESULTS: Forty-nine cases of colorectal villous tumours [six cases of low-grade villous adenoma, 21 of high-grade villous adenoma (VA), nine of invasive carcinoma in villous adenoma (CIVA), and 13 of pure villous carcinoma (PVC)] and 46 cases of tubular tumours [14 cases of low-grade and 17 of high-grade tubular adenoma (TA), and 15 cases of carcinoma in tubular adenoma (CITA)] were selected for this study based on their expression patterns of CD10 (small intestinal brush border), MUC2 (intestinal goblet cell), and HGM (gastric foveolar epithelium). HGM was more frequently expressed in the adenomatous components of villous tumours (63%) than in those of tubular tumours (14%) (P < 0.05). CD10 expression of high-grade TAs (47%) and carcinomas arising in TA (60%) was significantly higher than that of villous tumours (0%) (P < 0.05). CONCLUSIONS: There were significant differences in the phenotypic expression of adenoma and adenocarcinoma between villous and tubular tumours, respectively. Villous tumours have a pathway of malignant transformation different from that of tubular tumours. Because of biological differences, colorectal villous tumours should be distinguished from tubular neoplasia. The analysis of the phenotype of colorectal neoplasms is useful for the evaluation of tumour progression.     

Combined immunophenotyping and FISH identifies the involvement of B-cells in 5q- syndrome

The 5q- syndrome is a distinct subtype of myelodysplastic syndrome (MDS) characterized by refractory anemia, deletion of the long arm of chromosome 5, del(5q), as the sole cytogenetic abnormality, and a low frequency of transformation to acute leukemia. Using combined immunophenotyping and fluorescence in situ hybridization (FISH), studies were carried out on bone marrow smears of three 5q- syndrome cases to identify the cell lineages carrying the 5q deletion. In all three cases, the granulocytic, monocytic, and erythroid lineages possessed the del(5q) clonal marker, whereas the T-lymphocytes did not. Interestingly, in one case, cells of B-lymphoid lineage also showed the presence of the del(5q). This is the first report to date showing involvement of an acquired 5q deletion associated with MDS in B-cells. This result suggests that in some cases, MDS arises in a multipotent cell with a capacity to differentiate into both myeloid and lymphoid cells.     

Transformation of the 5q- syndrome to acute lymphoblastic leukemia: a report of two cases and review of the literature

Myelodysplastic syndrome (MDS) with an isolated deletion of the long arm of chromosome 5 (5q- syndrome) is a distinct subtype of MDS with an indolent course that rarely transforms to acute leukemia. Deletion of the long arm of chromosome 5 has also been reported in rare cases of de novo B-lymphoblastic leukemia. We present two cases of 5q- syndrome with a similar and unusual course of transformation to lymphoblastic leukemia while on Lenalidomide. These two patients achieved an initial response; however, later acquired a second cytogenetic abnormality, became refractory to treatment and evolved into acute leukemia. At the time of transformation, both patients had recurrence of the 5q- abnormality. Review of the literature and the mechanisms of transformation of the 5q-syndrome into an acute leukemia are discussed. Although the relationship between the events in our cases remains unclear, the intriguing similarity between the two cases raises a question whether immune modulators can alter the natural course of MDS. To our knowledge, no similar cases were previously reported in the literature.     

6p+ and 9q- in two chromosomally distinct clones occurring in a case of myelodysplastic syndrome evolving to acute nonlymphocytic leukemia

Different and unrelated chromosome changes were found to occur in a patient with a myelodysplastic syndrome with rapid evolution to acute nonlymphocytic leukemia. A 6p anomaly was found during the chronic phase and a del(9q) characterized the cells in the leukemic phase. Deletions with a breakpoint in 9q31 appeared to be associated with more aggressive disease.     

Clinical and immunological features of patients with interleukin-5-producing T cell clones and eosinophilia

Recent work suggests that in some patients with the hypereosinophilic syndrome, a clone of abnormal T cells produces large amounts of interleukin-5. In this study, we examined 60 patients with idiopathic eosinophilia. Sixteen patients had circulating T cells with an aberrant immunophenotype that, in most cases, were associated with different forms of skin inflammation. The abnormal T cells produced large amounts of interleukin-5, which may have increased eosinophil differentiation in the bone marrow of these patients.     

Large histiocytes in the choroid of leukemic patients

We identified large histiocytes as a prominent feature in the choroid of eyes obtained at autopsy in seven of nine patients who died of leukemia. The eyes of four of the seven patients affected had leukemic choroidal infiltrates, and a majority had similar-appearing histiocytes identified in spleen or bone marrow. The significance of these cells is undetermined; we postulate that these macrophages are ingesting debris of degenerating leukemic cells.     

基于子波变换阿尔茨海默病脑电信号多尺度定量特征的研究

目的：研究阿尔茨海默病（AlzheimerDisease,AD）脑电信号的多尺度定量特征和相位平均波形。方法：采集32例重度AD患者,30例轻度AD患者和30例正常对照的清醒安静闭目状态下的脑电信号,进行Gauss连续子波变换,提取脑电信号的时频分布特征和多尺度功率谱分布特征;应用条件采样和相位平均的方法提取脑电信号分尺度相位平均波形。结果：AD脑电信号的时频结构特征表现为尺度单一,节律性活动紊乱,而正常对照脑电信号尺度结构丰富,在0．1Hz、1Hz和10Hz频带上形成稳定的节律性活动。AD患者脑电信号的多尺度功率谱分布特征表现为在1Hz附近出现窄而高的功率峰,而正常对照老年人脑电信号表现为在0．1Hz、1Hz和10Hz附近出现三个宽而低的功率峰。多尺度相位平均波形的结果显示,不同导联脑电信号第9尺度（频率中心10Hz）的相位平均波形的波长在重度AD组、轻度AD组和正常对照组三组之间比较存在显著差异（P〈0．01）,组间两两比较也存在显著差异（P〈0．05）。不同导联脑电信号第9尺度的相位平均波形的波长与简易智能精神状态量表（MMSE）评分之间存在负相关（P〈0．01）,说明这一参数与病情严重程度相关。结论：子波分析适用于痴呆病人脑电信号的定量分析,研究表明脑电信号的时频结构、多尺度功率谱分布和第9尺度相位平均波形的波长可以作为AD诊断和评估的定量电生理指标。     

Cytogenetic features of 5q deletion and 5q- syndrome in myelodysplastic syndrome in Korea; marker chromosomes proved to be chromosome 5 with interstitial deletion by fluorescence in situ hybridization

We characterized the cytogenetic changes and prognostic characteristics of 133 Korean patients with myelodysplastic syndrome (MDS), focusing on 5q− syndrome and MDS with chromosome abnormalities involving 5q deletion according to World Health Organization 2008 classification. In all patients, G banding and fluorescence in situ hybridization for 5q were performed, and in MDS patients with 5q deletion, the deleted region on chromosome 5 was mapped with fluorescence in situ hybridization for EGR1, CSF1R, and PDGFRB. The frequency of isolated del(5q) syndrome and 5q deletion was 2.2% (3 of 137 patients) and 15.3% (21 of 137 patients), respectively. International Prognostic Scoring System (IPSS) groups were low risk (5.8%), intermediate 1 (51.1%), intermediate 2 (27.8%), and high risk (15.3%). The patients with del(5q) were significantly older (62 years) and showed an unfavorable survival compared to patients without del(5q). Half (53%) of the patients with del(5q) also had complex chromosome abnormalities, including chromosome 7 abnormalities. Of the patients with del(5q), 93.3% were deleted for all three regions on 5q, compared to 66.7% of patients with isolated del(5q). Marker chromosomes proved to be chromosome 5 with interstitial deletion of q arm by fluorescence in situ hybridization in three patients. The biological characteristics of MDS in Korea seem to be markedly different from those of Caucasians, with Koreans having a younger age, lower frequencies of 5q− syndrome, higher frequencies of complex cytogenetic abnormalities including del(5q), and poorer prognosis. We infer that additional chromosome abnormalities contribute to the adverse prognostic impact in patients with del(5q).     

Immunogenetic analysis of the HLA complex with alloreactive T cell clones

Recently developed technologies to clone alloreactive human lymphocytes have provided a powerful tool for the immunogenetic analysis of the HLA region. Alloreactive T cell clones can be used as specific reagents for HLA encoded cellular determinants detected in secondary proliferation assays such as the primed lymphocyte test (PLT) and, in cell-mediated lympholysis (CML). Lymphocyte clones can also be used for functional assays (e.g., for suppressor or helper activity) to determine the influence of HLA specific restriction.     

Characterization of the 5q- breakpoint in an acute nonlymphocytic leukemia patient using pulsed-field gel electrophoresis

Multiple genes of hematopoietic importance have been localized to the long arm of chromosome 5 including granulocyte-macrophage colony stimulating factor (GM-CSF) and interleukins (IL) 3, 4 and 5 to 5q23-31, colony stimulating factor 1 (CSF1) to 5q33.1 and its receptor (c-fms ) to 5q33.3. The genes coding for platelet-derived growth factor receptor (PDGFR) and acidic fibroblast growth factor (FGFA) have been localized to 5q31-32 and 5q31.3-33.2, respectively. These genes fall in the region of chromosome 5 which is deleted in the 5q- refractory anemia syndrome (5q- RA) and acute nonlymphocytic leukemia (ANLL). We have characterized this region in a 5q- patient with therapy-related ANLL (t-ANLL) by pulsed-field gel electrophoresis and Southern blotting analysis utilizing DNA probes for PDGFR, c-fms , and FGFA. A single 300 kbp MluI restriction fragment was detected in the patient using a PDGFR probe as compared to a 200 kbp fragment in normal controls. BssHII digestions also showed restriction fragment length difference. Similar data for both MluI and BssHII digestions were also obtained when c-fms was used as a probe. Southern blotting analysis of EcoRI-digested DNA showed that each of the PDGFR, c-fms , and FGFA alleles were deleted. These results suggested that one chromosome 5 has a large deletion involving PDGFR, c-fms and FGFA, which is consistent with the cytogenetic analysis of the patient. In contrast, the other chromosome 5, which appeared normal cytogenetically, may have a smaller deletion (or alteration) in proximity to but not involving any of these 3 genes.