Clinical significance of autorosette-forming cells in T-cell lymphoma

The capability to form rosettes with sheep erythrocytes (E), antibody-complement-sensitized ox erythrocytes (EAC) and autologous erythrocytes (ARFC), and surface immunoglobulin determinations were studied using 21 lymph nodes and one tonsil with pathologically-proven non-Hodgkin's lymphoma and 10 lymph nodes with benign pathology. Fourteen of 22 non-Hodgkin's lymphoma patients (64%) had a high incidence of E-rosette formation and they were further differentiated into ARFC-positive and ARFC-negative lymphomas. The clinicopathological findings of the latter were compatible with those of adult T-cell leukemia. ARFC-positive lymphoma was regarded as non-Hodgkin's lymphoma of T-cell type and one patient showed lymphoblastic lymphoma with high ARFC counts. ARFC counts were very low in B-cell and non-T, non-B lymphomas. The results from benign lymph nodes were too variable to draw any conclusion, although ARFC counts were relatively high in lymphadenitis and hyperplasia.     

Genetic profile of adult T-cell leukemia/lymphoma in Okinawa: Association with prognosis,ethnicity, and HTLV-1 strains

Genetic alterations in adult T-cell leukemia/lymphoma (ATLL), a T-cell malignancy associated with HTLV-1, and their clinical impacts, especially from the perspective of viral strains, are not fully elucidated. We employed targeted next-generation sequencing and single nucleotide polymorphism array for 89 patients with ATLL in Okinawa, the southernmost islands in Japan, where the frequency of HTLV-1 tax subgroup-A (HTLV-1-taxA) is notably higher than that in mainland Japan, where most ATLL cases have HTLV-1-taxB, and compared the results with previously reported genomic landscapes of ATLL in mainland Japan and the USA. Okinawan patients exhibited similar mutation profiles to mainland Japanese patients, with frequent alterations in TCR/NF-ĸB (eg, PRKCB, PLCG1, and CARD11) and T-cell trafficking pathways (CCR4 and CCR7), in contrast with North American patients who exhibited a predominance of epigenome-associated gene mutations. Some mutations, especially GATA3 and RHOA, were detected more frequently in Okinawan patients than in mainland Japanese patients. Compared to HTLV-1-taxB, HTLV-1-taxA was significantly dominant in Okinawan patients with these mutations (GATA3, 34.1% vs 14.6%, P = .044; RHOA, 24.4% vs 6.3%, P = .032), suggesting the contribution of viral strains to these mutation frequencies. From a clinical viewpoint, we identified a significant negative impact of biallelic inactivation of PRDM1 (P = .027) in addition to the previously reported PRKCB mutations, indicating the importance of integrated genetic analysis. This study suggests that heterogeneous genetic abnormalities in ATLL depend on the viral strain as well as on the ethnic background. This warrants the need to develop therapeutic interventions considering regional characteristics.     

Lymphomatous Presentation of CD4+/CD8+ HTLV-1-Related Adult T-cell Leukemia/Lymphoma in an Iranian Woman

Adult T-cell leukemia/lymphoma (ATLL) remains an uncommon disorder outside well-defined risk groups. We describe the case of an Iranian woman, who presented with isolated meningeal relapse of diffuse large-cell lymphoma. The malignant cells coexpressed CD4 and CD8 and HTLV-1 seropositivity was confirmed. Despite combination chemotherapy disseminated lymphoma developed. Preterminally the characteristic features of ATLL were noted; hypercalcemia, with normal parathyroid hormone-related protein and vitamin D levels, and peripheral blood leukemic involvement.     

Malignant lymphomas in Japan: Epidemiological analysis of adult T-cell leukemia/lymphoma (ATL)

The incidence of malignant lymphomas in Japan is relatively low compared to that in western European countries and the United States. However, in limited areas in Japan a specific type of lymphoid malignancy called adult T-cell leukemia/lymphoma (ATL), which is caused by human T-cell leukemia virus type I (HTLV-I), is highly prevalent, and there are also many healthy carriers of HTLV-I in the same areas. A cross-sectional seroepidemiological study of HTLV-I showed that the age-specific proportion of healthy HTLV-I carriers in these ATL-endemic areas increased with age, especially over 40, and was higher in females than in males. Three main routes of HTLV-I transmission are recognized: 1) vertical transmission from mother to child mainly through breast milk; 2) horizontal transmission from man to woman through semen, and; 3) parenteral transmission from carrier donor to non-carrier recipient. The annual incidence rate of ATL among HTLV-I carriers is estimated at 2.0 in males and 0.5 in females, and the cumulative risk for ATL in HTLV-I carriers during a 70-year life span is 1%–5%. Possible risk factors for ATL in addition to HTLV-I infection were considered, i.e. genetic factors, environmental factors, nutritional condition, thymus involution etc., but none of these were found to be clearly associated with ATL. To determine whether there exist particularly susceptible hosts for ATL in the ATL endemic areas, HLA types were examined, but no conclusive results on the positive relationships between HLA types and ATL manifestation or HTLV-I infection were obtained. From follow-up studies on the age-specific distribution of HTLV-I carriers in Japan, it is now speculated that the HTLV-I infection rate might have decreased naturally in the more recent generational cohort groups, even in the ATL-endemic areas. However, ATL in Japan is an important subject for study in the field of cancer epidemiology, and several trial intervention programs for the prevention of ATL, such as controls of vertical transmission from mother to child through breast milk, are now ongoing in the ATL-endemic areas of Japan.     

IL2/IL-4, OX40L and FDC-like cell line support the in vitro tumor cell growth of adult T-cell leukemia/lymphoma

Adult T-cell leukemia/lymphoma (ATLL) is a peripheral T-cell neoplasm with an extremely poor prognosis. Maintaining ATLL cells in vitro is difficult and little is known about how they maintain themselves or grow in patients. Elucidating the interaction between ATLL cells and surrounding host factors might therefore provide important insights into pathophysiology. We cultured primary ATLL cells in various culture conditions using IL-2, IL-4 and feeder cells, and established two cell lines dependent on IL-2, IL-4 and a follicular dendritic cell-derived cell line, HK, in which OX40-ligand was induced. Our study indicates the importance of microenvironment in the homeostasis of ATLL.     

CD4+/CD8+比值在乳腺癌患者临床病理分析及预后评估中的意义

目的:初步探讨外周血中CD4+/CD8+的比值与乳腺癌患者临床病理及与总生存时间的关系,分析其临床意义。方法:回顾性分析2010年5月1日至2015年12月31日辽宁省肿瘤医院134例行乳腺癌根治术乳腺癌患者临床病理资料;采用Kaplan-Meier 生存分析法绘制生存曲线,比较两组不同患者的5年生存率,分析患者临床病理因素与总生存时间的关系。结果:低CD4+/CD8+组和高CD4+/CD8+组两组非三阴性乳腺癌患者在肿瘤分期方面,差异具有统计学意义（P＜0.05）;三阴性乳腺癌和非三阴性乳腺癌两组患者生存率方面相比较,5年生存率差异均不具有统计学意义（P＞0.05）。结论:乳腺癌中CD4+/CD8+比值可作为乳腺癌预后不良的危险因素,为乳腺癌的治疗寻找新的治疗靶点。     

High expression of the longevity gene product SIRT1 and apoptosis induction by sirtinol in adult T-cell leukemia cells

Adult T-cell leukemia-lymphoma (ATL) is an aggressive peripheral T-cell neoplasm that develops after long-term infection with human T-cell leukemia virus (HTLV-1). SIRT1, a nicotinamide adenine dinucleotide(+) -dependent histone/protein deacetylase, plays a crucial role in various physiological processes, such as aging, metabolism, neurogenesis and apoptosis, owing to its ability to deacetylate numerous substrates, such as histone and NF-κB, which is implicated as an exacerbation factor in ATL. Here, we assessed how SIRT1 is regulated in primary ATL cells and leukemic cell lines. SIRT1 expression in ATL patients was significantly higher than that in healthy controls, especially in the acute type. Sirtinol, a SIRT1 inhibitor, induced significant growth inhibition or apoptosis in cells from ATL patients and leukemic cell lines, especially HTLV-1-related cell lines. Sirtinol-induced apoptosis was mediated by activation of the caspase family and degradation of SIRT1 in the nucleus. Furthermore, SIRT1 knockdown by SIRT1-specific small interfering RNA caused apoptosis via activation of caspase-3 and PARP in MT-2 cells, HTLV-1-related cell line. These results suggest that SIRT1 is a crucial antiapoptotic molecule in ATL cells and that SIRT1 inhibitors may be useful therapeutic agents for leukemia, especially in patients with ATL.     

Leukemia of T-helper lymphocytes: Clinical and functional features

Leukemia of T-lymphocytes is rare. Chronic and subacute forms of T-cell leukemia have been described including Sézary cell leukemia, T-cell leukemia of Japan, and rare cases of chronic lymphocytic leukemia, prolymphocytic leukemia and hairy cell leukemia. Several studies have analyzed the functional capacity of lymphocytes from patients with T-cell leukemias. In many cases Sézary cells appear to be “helper” T-cells which cooperate with B-lymphocytes in immunoglobulin synthesis. In contrast, lymphocytes from the Japanese form of T-cell leukemia have been reported to function as suppressor cells. We describe an unusual leukemia in a 40-year old man, whose clinical course was characterized by fever, jaundice, hepatosplenomegaly, anemia and neutropenia. Lymph node enlargement and skin infiltration were notably absent. The leukemic cells were atypical mononuclear cells with a high nuclear-cytoplasmic ratio and convoluted nuclei. Immunologic studies of these cells demonstrated them to be T-lymphocytes with receptors for sheep erythrocytes. They reacted with an anti-thymocyte serum and responded to T-cell mitogens and to alloantigens. The leukemic T-cells had helper activity and could cooperate with B-lymphocytes in pokeweed mitogen (PWM) stimulated immunoglobulin synthesis. Concanavalin-A (Con-A) inducible suppressor cell activity was absent. The clinical and immune studies suggest that this case represents a previously undescribed form of T-cell leukemia.