Thrombotic microangiopathy associated with monoclonal gammopathy.

Thrombotic microangiopathy (TMA) is a rare disease comprising of a diverse set of disorders linked by a common histologic finding of endothelial injury. Monoclonal immunoglobulins may act as a potential trigger in the pathogenesis of TMA. To determine the prevalence of monoclonal gammopathy and clinicopathological features of TMA associated with monoclonal immunoglobulin, we performed a retrospective study in adults (18 and older) with a clinical diagnosis of TMA. Of 146 patients with TMA, we detected monoclonal immunoglobulin in 20 patients (13.7%). Among patients 50 and older, the prevalence of monoclonal gammopathy was 21%, which is approximately five-fold higher than the 4.2% expected rate in this population. Fifteen patients had monoclonal gammopathy of undetermined significance, one had multiple myeloma, one with smoldering myeloma, two had POEMS syndrome, and one had T-cell lymphocytic leukemia. Renal biopsy was performed in 15 cases, of which six showed thrombi, 11 showed mesangiolysis, and all showed double contours along glomerular capillary walls. Acute tubular injury was present in 12 cases. Treatment options were varied and included therapeutic plasma exchange in 11 patients. Ten patients progressed to end-stage renal disease, of which two received kidney transplant. Thus, our study shows an unexpectedly high prevalence of monoclonal gammopathy in patients with TMA, suggesting a potential pathogenetic mechanism. This study underscores the importance of evaluating for a monoclonal gammopathy in patients with TMA as well as the potential for targeting the underlying hematologic disorder as an approach to treating TMA.

Clustering of missense mutations in the ataxia-telangiectasia gene in a sporadic T-cell leukaemia.

Ataxia-telangiectasia (A-T) is a recessive multi-system disorder caused by mutations in the ATM gene at 11q22-q23 (ref. 3). The risk of cancer, especially lymphoid neoplasias, is substantially elevated in A-T patients and has long been associated with chromosomal instability. By analysing tumour DNA from patients with sporadic T-cell prolymphocytic leukaemia (T-PLL), a rare clonal malignancy with similarities to a mature T-cell leukaemia seen in A-T, we demonstrate a high frequency of ATM mutations in T-PLL. In marked contrast to the ATM mutation pattern in A-T, the most frequent nucleotide changes in this leukaemia were missense mutations. These clustered in the region corresponding to the kinase domain, which is highly conserved in ATM-related proteins in mouse, yeast and Drosophila. The resulting amino-acid substitutions are predicted to interfere with ATP binding or substrate recognition. Two of seventeen mutated T-PLL samples had a previously reported A-T allele. In contrast, no mutations were detected in the p53 gene, suggesting that this tumour suppressor is not frequently altered in this leukaemia. Occasional missense mutations in ATM were also found in tumour DNA from patients with B-cell non-Hodgkin's lymphomas (B-NHL) and a B-NHL cell line. The evidence of a significant proportion of loss-of-function mutations and a complete absence of the normal copy of ATM in the majority of mutated tumours establishes somatic inactivation of this gene in the pathogenesis of sporadic T-PLL and suggests that ATM acts as a tumour suppressor. As constitutional DNA was not available, a putative hereditary predisposition to T-PLL will require further investigation.

A new and frequent human T-cell leukemia virus indeterminate Western blot pattern: epidemiological determinants and PCR results in central African inhabitants.

Human T-cell leukemia virus (HTLV) indeterminate Western blot (WB) serological patterns are frequently observed in plasma/serum from persons living in intertropical areas. In the framework of ongoing projects on HTLV-1/2 and related viruses in Central Africa, we systematically analyzed plasma from villagers living in South Cameroon by WB. The group included 1,968 individuals (mean age, 44 years; age range, 5 to 90 years; 978 women/990 men), both Bantus (1,165) and Pygmies (803). Plasma samples were tested by WB analysis (MPD HTLV Blot 2.4) and interpreted according to the manufacturer's instructions. Only clear bands were considered in the analysis. Among the 1,968 plasma samples, 38 (1.93%) were HTLV-1, 13 (0.66%) were HTLV-2, and 6 (0.3%) were HTLV WB seropositive. Furthermore, 1,292 (65.65%) samples were WB sero-indeterminate, including 104 (5.28%) with an HTLV-1 Gag-indeterminate pattern (HGIP) and 68 (3.45%) with a peculiar yet unreported pattern exhibiting mostly a strong shifted GD21 and a p28. The other 619 (31.45%) samples were either WB negative or exhibited other patterns, mostly with unique p19 or p24 bands. DNA, extracted from peripheral blood buffy coat, was subjected to PCR using several primer pairs known to detect HTLV-1/2/3/4. Most DNAs from HTLV-1- and HTLV-seropositive individuals were PCR positive. In contrast, all the others, from persons with HTLV-2, HGIP, new WB, and other indeterminate patterns, were PCR negative. Epidemiological determinant analysis of the persons with this new peculiar WB pattern revealed that seroprevalence was independent from age, sex, or ethnicity, thus resembling the indeterminate profile HGIP rather than HTLV-1. Moreover, this new pattern persists over time.

Guidelines for the management of mature T-cell and NK-cell neoplasms (excluding cutaneous T-cell lymphoma).

The peripheral T-cell neoplasms are a biologically and clinically heterogeneous group of rare disorders that result from clonal proliferation of mature post-thymic lymphocytes. Natural killer (NK) cell neoplasms are included in this group. The World Health Organization classification of haemopoietic malignancies has divided this group of disorders into those with predominantly leukaemic (disseminated), nodal, extra-nodal or cutaneous presentation. They usually affect adults and are more commonly reported in males than in females. The median age at diagnosis is 61 years with a range of 17-90 years. Although some subtypes may follow a relatively benign protracted course most have an aggressive clinical behaviour and poor prognosis. Excluding anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL), which has a good outcome, 5-year survival for other nodal and extranodal T-cell lymphomas is about 30%. Most patients present with unfavourable international prognostic index scores (>3) and poor performance status. The rarity of these diseases and the lack of randomized trials mean that there is no consensus about optimal therapy for T- and NK-cell neoplasms and recommendations in this guideline are therefore based on small case series, phase II trials and expert opinion.

Human T-cell leukemia virus type 1 infection among Japanese immigrants and their descendants living in Southeast Brazil: A call for preventive and control responses.

Human T-cell leukemia virus type 1 (HTLV-1) has worldwide distribution and is considered endemic in southwestern Japan. HTLV-1 infection has been associated with adult T-cell leukemia/lymphoma (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) besides other diseases. This cross-sectional study aimed to investigate the prevalence, risk factors and molecular characterization of HTLV-1, among the world's largest population of Japanese immigrants and their descendants outside of Japan, in São Paulo, Southeast Brazil, as well as to analyze the phylogenetic relationship among isolates of HTLV-1. From July to December 2017, 2,139 individuals from five Japanese associations were interviewed and submitted to blood collection. All serum samples were first tested for the presence of anti-HTLV-1/2 antibodies by ELISA and then peripheral blood from individuals with positive serological results were analyzed for the presence of HTLV-1 5'LTR proviral DNA. Partial sequencing of the 5'LTR region of HTLV-1 proviral DNA was performed by Sanger. The prevalence of HTLV-1 infection was 5.1% (CI 95%: 4.2-6.0). In the multiple logistic regression model, HTLV-1 infection was associated with age ≥ 45 years, female sex, being first and second-generation Japanese immigrants, and having sexual partners with history of blood transfusion. The phylogenetic analysis revealed that all HTLV-1 were classified as Cosmopolitan (1a) subtype. Of them, 47.8% were classified as Transcontinental (A) subgroup and 52.2% as belonging to the Japanese (B) subgroup. Although most HTLV-1-infected patients were asymptomatic (97.3%), blurred vision was associated with HTLV-1 infection. The high prevalence of HTLV-1 infection found in this studied population and especially the intra- and interfamily HTLV-1 transmission presents an urgent call for preventive and control responses of this infection in Brazil.

Aggressive natural killer cell leukemia: report of a Chinese series and review of the literature.

Aggressive natural killer cell leukemia (ANKL) is a rare Epstein-Barr virus (EBV)-associated fulminating disease that is widely disseminated at diagnosis. Because of its typically extranodal presentation, differing degrees of NK cell involvement, and varying bone marrow pathology, ANKL can be confused with a reactive process. These features, coupled with a rapidly fatal course, have hampered systematic study of the pathogenesis of ANKL. Nine cases of ANKL were diagnosed and characterized by a single laboratory over a 2-year period. Constant features at presentation included disseminated disease, high fever, bone marrow involvement, and a high lactate dehydrogenase index. All cases were positive for EBV early region protein and negative for latent membrane protein 1, and all had a germline T-cell receptor gene configuration. Peripheral blood counts were variable, with severe thrombocytopenia being the most frequently encountered abnormality (7 of 9 cases). Hematophagocytosis, dyserythropoiesis, and stromal degeneration were the most frequent findings in the bone marrow. Neoplastic cells in the bone marrow were consistently CD2+, CD56+, CD45+, CD34-, CD117-, CD4-, and surface CD3-. Most cases were HLA-DR+ (8/9) and CD8- (8/9). Complex clonal cytogenetic abnormalities were found in 8 of 9 cases. Because of its aggressive course, rapid and accurate diagnosis of ANKL is essential for a better understanding of the etiology, pathogenesis, and treatment of the disease.

Characterization of T-cell large granular lymphocyte leukemia associated with Sjogren's syndrome-an important but under-recognized association.

OBJECTIVE: Patients with T-cell (CD3+) large granular lymphocyte (LGL) leukemia have a high prevalence of autoantibodies and associated autoimmune diseases. Sjogren's syndrome may not be diagnosed unless specifically looked for. We set to determine the prevalence of Sjogren's syndrome in LGL leukemia and its cytokine profile. METHODS: Every patient with a confirmed diagnosis of LGL leukemia diagnosed at a single academic medical center over the last 15 years was evaluated for Sjogren's syndrome by questioning about sicca symptoms. In symptomatic patients, Schirmer's test, rose bengal corneal staining, salivary flow rate measurement, autoantibody screening, and minor salivary gland biopsy were performed. Supernatants obtained from T-LGL leukemic cells following phytohemagglutinin (PHA) activation were analyzed for cytokine production by enzyme-linked immunosorbent assay and patients with or without Sjogren's syndrome were compared with controls. RESULTS: Of 48 patients, 21 reported sicca symptoms and were enrolled in the study. In 8 patients Sjogren's syndrome was ruled out. Thirteen patients had clear evidence of Sjogren's syndrome according to accepted criteria (27%). None had rheumatoid arthritis, but 1 had limited scleroderma. Thus, 12/48 patients had primary Sjogren's syndrome. Other autoimmune diseases were frequently present, in particular, immune cytopenias (n=7) or thyroid autoimmunity (n=6). Supernatants of T-LGL leukemia cells incubated with PHA revealed markedly increased levels of multiple cytokines (especially soluble interleukin 2 receptor, tumor necrosis factor alpha, IL-6, IL-8) compared with healthy controls. However, this increase was common to LGL leukemia patients with or without Sjogren's syndrome. CONCLUSIONS: Sjogren's syndrome was commonly identified in the patients with T-cell LGL leukemia in this study. Upregulated cytokine production by the neoplastic cells may underlie some of the immune-mediated disorders common in these patients.

Prevalence of infection by HTLV-I/II among pregnant women and high-risk groups in the Peloponnese peninsula, Greece.

Although screening for human T-cell lymphotropic virus types I and II (HTLV-I/II) antibodies in volunteer blood donors has been systematic in Greece since 1995, the epidemiology and the determinants of HTLV-I/II infection are not well defined among population groups. During 1997-2005, the prevalence of HTLV-I/II infection was investigated in a sample of 2016 pregnant women, 102 multitransfused haematologic and oncologic patients, 93 thalassaemic patients and 57 intravenous drug users originating from four geographic areas of Pelopennese peninsula, Greece. One recipient of HTLV-I infected blood and the relatives of a woman died from adult T-cell leukaemia/lymphoma (ATTL) related to HTLV-I have also been tested. The subjects were initially screened by an enzyme immunoassay whereas Western blot, INNO-LIA HTLV, polymerase chain reaction and nucleotide sequencing confirmed the infection. One thalassaemic patient had proved HTLV-I infection giving an overall prevalence of 11 per 1000. In the recipient of the infected blood and in two of the five relatives of the woman died from ATTL, HTLV-I infection was also detected. In none of the pregnant women, multitransfused patients and intravenous drug users HTLV-I/II infection was confirmed. These data suggest that HTLV-I is present in Greece among populations at high-risk. However, they would not support the need for HTLV-I/II antenatal screening in Greece.

Primary prevention of HTLV-1 in Japan.

The Nagasaki Prefecture, Japan (population: 1.5 million), is one of the hot endemic foci of Human T-lymphotropic virus type 1 (HTLV-1). Prevalence of HTLV-1 carriers are approximately 10% in the age group over 40 years old (40,000 individuals), approximately 10 times of the national average. Annual registry of adult T-cell leukemia (ATL) in the Prefecture is approximately 60 cases (estimated incidence: 100 cases), or a half percent of total deaths. A effective measure to control the endemic cycle of HTLV-1 has been imperative, since practical ways to prevent or control ATL are not available. A prefecture wide intervention at Nagasaki by refrain from breast-feeding blocked approximately 80% of mother-to-child transmission of HTLV-1.

Distribution of human leukocyte antigens in a population of black patients with human T-cell lymphotrophic virus type I-associated adult T-cell leukemia/lymphoma.

Human leukocyte antigens (HLAs) play an important role in regulating the immune response to infectious agents and determinants of malignant transformation. We compared the HLA frequencies of 25 black patients with adult T-cell leukemia/lymphoma (ATL) referred to the National Cancer Institute for therapy with a racially similar, asymptomatic control population of human T-cell lymphotrophic virus, type I (HTLV-I)-seropositive individuals (n = 45). Serological typing was performed for MHC class I and II antigens. Antigen frequencies were calculated, and corresponding gene frequencies were estimated using the maximum likelihood method. Comparisons between the ATL and control group were made with chi 2 or Fisher's exact test. Three antigens (A36, B18, and DR53) were found to have a higher frequency in the ATL patients than in the controls (uncorrected two-tailed P < 0.05). The gene frequencies for these antigens also were statistically significant in the uncorrected analysis. However, only A36 approached statistical significance after correction of the P value for multiple comparisons (P = 0.08). The results of this pilot study indicate that black patients with ATL may have increased frequencies of certain class I HLA when compared with a racially similar HTLV-I-positive reference population. This suggests that either these antigens may represent markers for a population at greater risk of developing ATL once infected with HTLV-I or that they were acquired at some point in the process of malignant transformation or progression from the carrier state to onset of ATL. These antigens should be targeted in larger studies to confirm or refute these findings.

Human T cell lymphotropic virus type I genomic expression and impact on intracellular signaling pathways during neurodegenerative disease and leukemia.

HTLV-I has been identified as the etiologic agent of neoplasia within the human peripheral blood T lymphocyte population, and a progressive neurologic disorder based primarily within the central nervous system. We have examined the role of HTLV-I in these two distinctly different clinical syndromes by examining the life cycle of the virus, with emphasis on the regulation of viral gene expression within relevant target cell populations. In particular, we have examined the impact of specific viral gene products, particularly Tax, on cellular metabolic function. Tax is a highly promiscuous and pleiotropic viral oncoprotein, and is the most important factor contributing to the initial stages of viral-mediated transformation of T cells after HTLV-I infection. Tax, which weakly binds to Tax response element 1 (TRE-1) in the viral long terminal repeat (LTR), can dramatically trans-activate viral gene expression by interacting with cellular transcription factors, such as activated transcription factors and cyclic AMP response element binding proteins (ATF/CREB), CREB binding protein (CBP/p300), and factors involved with the basic transcription apparatus. At the same time, Tax alters cellular gene expression by directly or indirectly interacting with a variety of cellular transcription factors, cell cycle control elements, and cellular signal transduction molecules ultimately resulting in dysregulated cell proliferation. The mechanisms associated with HTLV-I infection, leading to tropical spastic paraparesis (TSP) are not as clearly resolved. Possible explanations of viral-induced neurologic disease range from central nervous system (CNS) damage caused by direct viral invasion of the CNS to bystander CNS damage caused by the immune response to HTLV-I infection. It is interesting to note that it is very rare for an HTLV-I infected individual to develop both adult T cell leukemia (ATL) and TSP in his/her life time, suggesting that the mechanisms governing development of these two diseases are mutually exclusive.

The epidemiology of diseases associated with HTLV-I and HTLV-II.

Considerable progress is being made in the understanding of at least two diseases associated with HTLV-I, ATLL and TSP. While laboratory methodology has not yet permitted comparable advances in identifying diseases associated with HTLV-II, if any, it is likely that a greater understanding of this and other retroviruses will result from the increasing focus of attention in this area. As illustrated by a recent meeting on retroviruses in the nervous system, which included discussions on polymyositis and multiple sclerosis as well as TSP, ATLL, and AIDS, the number of diseases associated with retroviruses is likely to increase and, if the applications of research data to the control of malignancies associated with hepatitis B virus and Epstein-Barr virus are applicable, the future for improving control of HTLV-I-associated disease should be quite promising.

High prevelance of chronic magnesium deficiency in T cell lymphoblastic leukemia and chronic zinc deficiency in children with acute lymphoblastic leukemia and malignant lymphoma.

Magnesium and zinc are the elements having essential roles in regulation of cell growth, division and differentiation. There have been some studies in the literature suggesting an association between the deficiency of these elements and the development of malignant disorders. In this study hair and serum zinc and magnesium levels were investigated in children with acute lymphoblastic leukemia (ALL) and malignant lymphoma (ML) at the time of initial diagnosis. Ten children with T-cell ALL, 10 children with B-precursor ALL, 5 children with Burkitt's Lymphoma (BL), 11 children with Hodgkin's lymphoma (HL), 10 children with non-Burkitt non-Hodgkin's lymphoma (NBNHL) and 12 age and sex matched healthy children as a control group were included in the study. Mean hair magnesium levels in all of the groups of the patients were lower than the levels in the control group but the difference was statistically significant only in the children with T cell ALL comparable to the controls (28.9+/-3.9 microg/g and 87.6+/-18.5 microg/g respectiveley, p<0,05). Mean serum magnesium levels in all the cohorts were not significantly different than those in controls (p>0.05 in each comparison). Mean hair zinc levels in the patients with T-cell, B-precursor ALL, BL, HL, NBNHL were 103.4+/-14.6 microg/g, 100.9+/-7.8 microg/g, 91.1+/-19 microg/g, 72.5+/-9.1 microg/g, 103.2+/-12.2 microg/g respectively. Each of these levels were significantly lower than the mean hair zinc levels of the control group (141.2+/-9.6 microg/g, p<0.05 in each comparison). Although mean serum zinc levels in all of the groups were also decreased, the differences were statistically significant only in the groups with B-precursor ALL, HL and NBNHL (75.9+/-5.29 microg/dl, 68.6+/-7.3 microg/dl, 85.7+/-5.5 microg/dl respectively) when compared with controls (105.1+/-9.9 microg/dl, p<0.05 in each comparison). Hair magnesium and zinc levels showed a positive correlation with each other in all the groups (r congruent with 0.5). No significant difference was found in the mean hair/serum magnesium and zinc levels between malnourished and nonmalnourished patients. In conclusion, regarding the results of our study and previous data in the literature chronic magnesium and zinc deficiency seems to be associated with the development of ALL and malignant lymphoma in a group of patients.

Prevalence of human T-cell leukemia virus type 1 (HTLV-I) in family members of adult T-cell leukemia (ATL) patients in non-ATL-endemic Hokkaido of Japan.

Family members of patients with adult T-cell leukemia (ATL) in non-ATL-endemic Hokkaido, the northernmost part of Japan, were assessed for the prevalence of HTLV-I infection. Immunofluorescence assay showed that 53 out of 133 (39.8%) healthy family members of 23 ATL patients were positive for antibodies to HTLV-I. When general inhabitants in Hokkaido were examined, 3 out of 18 (16.7%) family members of 5 seropositive healthy persons had HTLV-I antibodies. The overall seropositivity in Hokkaido was 0.7%. Of 26 family members of 6 patients with non-T-cell leukemia seroconverted by blood transfusion, none (0%) was seropositive.

Prevalence of human T-cell leukemia virus type 1 (HTLV-I) in general inhabitants in non-adult T-cell leukemia (ATL)-endemic Hokkaido, Japan.

In contrast to adult T-cell leukemia (ATL)-endemic southwestern Japan, the northernmost island Hokkaido has a small number of ATL patients annually. In this study, we surveyed 32,587 healthy inhabitants throughout Hokkaido for antibodies to human T-cell leukemia virus type 1 (HTLV-I). Only 244 individuals (0.8%) were seropositive as HTLV-I carriers; 0.6% (123 of 19,512) in males and 0.9% (121 of 13,075) in females. In some areas, however, the inhabitants had relatively high seropositivity (> 2%). The highest rate was 5.2% with a cluster of ATL patients in a certain town of the Hidaka area near the Pacific Ocean, in southeast Hokkaido.

Prevalence of human T-cell leukemia virus type 1 (HTLV-I) in adult T-cell leukemia (ATL) in non-ATL-endemic Hokkaido of Japan.

Sera and peripheral blood lymphocytes of 40 adult T-cell leukemia (ATL) patients in non-ATL-endemic Hokkaido were examined for the prevalence of human T-cell leukemia virus type 1 (HTLV-I). All patients had HTLV-I-specific antibodies. When the peripheral lymphocytes were assessed after short-term cultivation, HTLV-I antigens and virus particles were detected. The seroprevalence in 96 cases of non-T-cell leukemias and lymphomas and in 30,056 healthy individuals in Hokkaido were 3.1% and 0.7%, respectively. HTLV-I seropositive inhabitants of Hokkaido can be estimated at about 40,000, and one out of every few thousand HTLV-I carriers is likely to develop ATL.

Adult T-cell leukemia.

Adult T-cell leukemia (ATL) was first reported in Japan, where it has a high incidence in the southwestern region. The retrovirus, human T-lymphotropic virus type I (HTLV-I), is the causative agent of ATL. In ATL-endemic areas, the rate of HTLV-I carriers is high. A definite diagnosis of ATL is based on the presence of HTLV-I proviral DNA in the tumor cell DNA. ATL cells originate from the CD4 subset of peripheral T cells. ATL shows diverse clinical features but can be divided into four subtypes:acute, chronic, smoldering, and lymphoma type. Chemotherapy is not effective; the acute and lymphoma types have a poor prognosis. Familial occurrence of ATL is common. HTLV-I infection is caused by transmission of live infected lymphocytes from mother to child, from man to woman, or by blood transfusion. Infection with HTLV-I can lead to other diseases, including HTLV-I-associated myelopathy/tropical spastic paraparesis and HTLV-I uveitis.

Epidemiology of anti-human T-cell leukemia virus type I antibody and characteristics of adult T-cell leukemia in China.

We analyzed the data from seroepidemiologic survey of anti-HTLV-I serum antibody (HTLV-1 Ab) and 16 adult cases of T-cell leukemia (ATL) in China (1984-1994). The results showed that the positive rate of HTLV-I Ab of the population of China was 0.54%, the birth or residence places of HTLV-I carriers and all the patients with ATL were mainly distributed in the coastal provinces and the northeast China, and a small endemic area of HTLV-I and ATl was found in Fujian Province (HTLV-I Ab positive rate, 2.1%). The HTLV-I in China may be transmitted from Japan or originated from China. The clinical characteristics of the cases included onset in adulthood; frequent skin lesions, lymphadenopathy and hepatosplenomegaly; no mediastinal mass; the ATL cells from peripheral blood with polymorphism nuclei and mature T cell immunophenotype HTLV-IAb positive in most of the cases tested (5/8); mostly acute type; with a median survival period of 3.5 months.