[Analysis of the ethical issues raised by a ten-year epidemiology program in French Guiana: limitations of the current legal framework and solutions adopted]. / Analyse des enjeux éthiques soulevés au cours d'un programme de recherche épidémiologique de dix années en Guyane française : limites de l'encadrement actuel et solutions adoptées.

BACKGROUND: This paper discusses the ethical aspects of a large research program in virology, conducted since 1994 and which has evolved in parallel with the elaboration of bioethics laws in France. This research, which involved the collection of a considerable amount of epidemiological data in the field, focused on epidemiological determinants (mother to child transmission, genetic susceptibility/resistance) of the human oncogenic retrovirus human T cell lymphotropic virus type 1 (HTLV-1). Data were collected from a specific population (Noirs Marrons) living in remote areas in French Guiana (South America). This ethnic group of African descent is highly endemic for HTLV-1 and associated adult T cell leukemia/lymphoma. The population has lived for two centuries on either side of the Maroni river, which constitutes the frontier between French Guiana and Surinam. The low socioeconomic and education levels of a large part of this population are mainly explained by a recent housing/residence fixation on the French side of the Maroni river. It is also linked to significant immigration from Surinam due to the civil war, which lasted for five years in the late 1990s, in this country. Conducting epidemiological surveys in this peculiar context illustrates the limitations of the available current legal framework in France for such studies. Indeed, several important ethical issues arose concerning not only individual and population benefits, but also specificities of the given information and of the informed consent. Another question concerns individual information feed-back in such a context of persistent viral infection, with a very low disease incidence, in a population with a relatively low education level. The goal of this work was mainly to report several of the ethical issues encountered and to discuss possible ways of achieving better information deliver and consent procedures in such a context. Indeed, these procedures should include new ideas and regulations promoting a real partnership, in order to conduct long-term epidemiological studies in populations with a low education level.

HTLV-1 associated adult T-cell leukemia/lymphoma in Israel: report of two patients of Romanian origin.

Human T-lymphotropic virus type 1 (HTLV-1) was the first human oncovirus isolated by Gallo et al. in 1980 and established as an etiological agent for adult T-cell leukemia/ lymphoma (ATL). Although more than 15 million individuals are infected by HTLV-1 through the world, the spread of the virus is highly endemic. The HTLV-1 infection is prevailing in southwestern Japan, inter-tropical Africa, Central and South America. In Kyushu district, Japan, the seroprevalence reaches >30% in the adult population. In the US, Europe and the Middle East the HTLV-1 infection is very rare, and cases of ATL have been reported sporadically. We describe here acute ATL in two patients of Jewish- Romanian origin. The epidemiological anamnesis and screening indicate that both patients acquired the HTLV-1 from their mothers leaving in Romania.

HTLV-I associated adult T cell leukemia/lymphoma: report of two cases from an Amerindian population in coastal northwest British Columbia.

Epidemiological studies of HTLV-I infection have demonstrated the presence of this virus in certain Amerindian populations in Central and South America. We have recently reported the first evidence of endemic HTLV-I infection in North American Amerindians from the coastal regions of British Columbia, Canada. While the predominant HTLV-I-associated disease observed in British Columbia Amerindians is the HTLV-I associated neurological disease (HTLV-I-associated myelopathy/tropical spastic paraparesis), we report here the first two cases of HTLV-I-associated adult T cell leukemia/lymphoma (ATL). Clinical and PCR evidence to support the diagnosis of HTLV-I-associated ATL in these two Amerindians is presented. Both cases of ATL were found in the same tribe although neither patient was directly related to each other. While reports of HTLV-I-associated ATL have been reported in Circumartic native peoples, reports of ATL in North American single ancestry Amerindians have not been previously made to our knowledge.

Six Colombian patients with adult T-cell leukemia/lymphoma.

Six Colombian patients with adult T-cell leukemia/lymphoma (ATL) are presented. The clinical and hematological features, the familial clusters of human T lymphotropic virus type 1 (HTLV-I) carriers and the prognoses of the Colombian ATL patients were similar to those previously reported for Japanese ATL patients. The only difference was the mean age of onset, which was more than 20 years younger than in Japanese patients. Three patients with ATL were suffering from strongyloidiasis. In one patient it was suggested that ATL developed after horizontal transmission from his wife. In addition, there was a familial case of ATL and HAM/TSP. It seems that in some areas of Colombia, not only HTLV-I infection and HAM/TSP but also ATL are highly endemic.

Experience of human lymphotropic virus type I (HTLV-I) in an East London hospital.

We describe the experience of The Royal London Hospital with human T-cell lymphotropic virus type 1 (HTLV-1) related disease. Twelve patients presented from 1988-1993, nine of them in 1993. None were born in the U.K. and 11 were of West Indian origin. Ten had overt lymphomas, one tropical spastic paraparesis/HTLV-1 associated myelopathy (TSP/HAM) and one atypical lymphocytosis and Strongyloidiasis. Five presented acutely ill to Casualty and three died shortly after presentation. Four had been referred to rheumatologists and five had predominantly gastrointestinal symptoms. The population of Caribbean origin served by the hospital is 23,700 and one would only expect one or two cases of lymphoma and one or two cases of TSP/HAM per year. Overall the spectrum of clinical disease at presentation was varied. Suspicion of HTLV-1 infection is merited in patients of West Indian origin between the ages of 30-65 years, who present with a sarcoid-like illness, gastrointestinal symptoms, leukaemia/lymphoma, myelopathy or myositis like-illness.

[Adult T-cell leukemia and non-malignant adenopathies associated with HTLV I virus. Apropos of 17 patients born in the Caribbean region and Africa]. / Leucémies à cellules T de l'adulte et adénopathies non malignes associées au virus HTLV I. A propos de 17 malades originaires des Caraïbes et d'Afrique.

Adult T-cell leukaemia is the first blood disease caused by a retrovirus: HTLV-1. The authors report the first French series of 15 patients, of whom 9 came from the classical endemic areas--the Antilles and outer Caribbean Islands--and 6 from Africa where the serological prevalence of HTLV-1 is high but few cases of adult T-cell leukaemia have been reported. Emphasis is laid on the importance of immunodeficiency (refractory strongyloidiasis, Pneumocystis carinii pneumonia, polyclonal B lymphoproliferative syndrome) and of other pathologies associated with the retrovirus (polyarthritis, lymphocytic interstitial pneumonia). The authors also describe the presence of adenopathy in healthy carriers: either adenitis suggestive of retroviral infection, or Castelman's disease adenopathy. These clinical presentations are similar to those described in lymphadenopathy syndromes due to the human immunodeficiency viruses. Aggressive lymphomas require chemotherapy, but sooner or later resistance develops, and the prognosis is very poor. The indications for allogeneic bone marrow transplantation are still to be determined. The diagnosis of adult T-cell leukaemia must be considered in all patients with blood disease coming from the endemic areas.

Loss of Foxp3 is associated with CD30 expression in the anaplastic large cell subtype of adult T-cell leukemia/lymphoma (ATLL) in US/Caribbean patients: potential therapeutic implications for CD30 antibody-mediated therapy.

Adult T-cell leukemia/lymphoma (ATLL) is caused by the HTLV-1 virus, endemic to Japan and the Caribbean, and is likely derived from cells with the T-regulatory phenotype. The malignant cells express IL2 receptor α (CD25), and the majority express transcription factor Forkhead box P3 (Foxp3), in addition to T-cell markers. Occasional cases express CD30. Whereas Japanese cases are predominantly of the acute and chronic leukemic types, the less well-studied Caribbean cases are more often lymphomatous. We performed immunohistochemical analysis for CD25, Foxp3, and CD30 on samples from 42 US/Caribbean ATLL patients and correlated these markers with morphologic subtype and clinical characteristics. In the 16/42 patients who had successive biopsies, we determined the expression stability of these markers. Foxp3 was expressed in 26 of the 42 (62%) initial biopsies, and its intensity correlated with CD25 expression. It was more frequent in pleomorphic small-sized and medium-sized cell types than in large cell tumors but did not correlate with patients' clinical attributes. Foxp3 expression and morphology were unchanged in successive biopsies in 13 of 16 patients. Four initial biopsies had features of anaplastic large cell T lymphomas, all of which were Foxp3. Successive biopsies from 2 patients with pleomorphic medium cell variant showed diminishing expression of originally weak Foxp3 expression and de novo CD30 expression, whereas they showed morphologic progression to the anaplastic cell variant. A third patient's second biopsy revealed progression from pleomorphic medium to anaplastic large cell morphology with loss of Foxp3, but it remained CD30. Foxp3 expression correlates with pleomorphic small and medium cell types and may be lost with large cell transformation. The evolution of the latter type can be associated with the gain of CD30 expression; such ATLL tumors might respond to anti-CD30 monoclonal antibody therapies.

In contrast to HIV, KIR3DS1 does not influence outcome in HTLV-1 retroviral infection.

While most carriers of human T-cell leukemia virus type 1 (HTLV-1) remain asymptomatic throughout their lifetime, infection is associated with the development of adult T-cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The exact parameters that determine these outcomes are unknown but are believed to include host genetic factors that control the immune response to infection. Host response to fellow retroviridae member HIV is influenced by the expression of members of the Killer Immunoglobulin Receptor (KIR) family including KIR3DS1. In this study we examined the association of KIR3DS1 with the outcome of HTLV-1 infection in three geographically distinct cohorts (Jamaican, Japanese and Brazilian). Despite increased prevalence of KIR3DS1 in the HAM/TSP patients of the Jamaican cohort, we found no evidence for a role of KIR3DS1 in influencing control of proviral load or disease outcome. This suggests that unlike HIV, KIR3DS1-mediated regulation of HTLV-1 infection does not occur, or is ineffective.

Adult T-cell lymphoma in Israeli patients of Iranian origin.

The clinical and laboratory features of four Israeli patients with adult T-cell lymphoma-leukemia (ATL) are presented. In three of them evidence for human T-cell lymphotropic leukemia virus (HTLV-I) infection was obtained. Interestingly, all of the patients immigrated to Israel from the same regions in Iran. Except for lack of skin involvement, the clinical course was typical for ATL as described worldwide. This is the first report of ATL in an Iranian cohort. This observation suggests that Iranian patients with ATL-like illness should be studied for the presence of HTLV-I infection.

Human T-cell lymphotropic virus type I associated adult T-cell leukaemia/lymphoma in Taiwan Chinese.

Twenty-five Chinese patients with human T-cell lymphotropic virus type I (HTLV-I) associated adult T-cell leukaemia/lymphoma (ATLL) were identified in Taiwan. No patients had been outside Taiwan and none were descendants of Japanese heritage. Their ages ranged from 28 to 71 years. There were 17 men and eight women. Main clinical and laboratory features at presentation were lymphadenopathy (16), skin lesions (11), hepatosplenomegaly (11), pulmonary lesions (11), hypercalcaemia (10) and bone marrow infiltration (14). Peripheral blood was characterized by leucocytosis with presence of pleomorphic abnormal lymphocytes but rare anaemia or thrombocytopenia. The clinical subtypes were acute in 15, chronic in three, smouldering in one, and lymphoma type in six. The immunophenotypes of the ATLL cells were characterized by the expression of CD2+, CD4+, CD7-, CD8- and CD25+. The overall prognosis was poor with a median survival of 5 months. The acute form had a significantly shorter survival (2 months) than lymphoma type (13 months). Susceptibility to various infections was common. Pulmonary complications accounted for 73% of the causes of death. The clinicopathologic features of ATLL in Taiwan are indistinguishable from those in HTLV-I endemic areas. The present series adds to the knowledge of the worldwide pattern of the disease.

Retrovirus-associated adult T-cell leukemia-lymphoma: an epidemiologic study of five cases among Hawaii-born offspring of migrant Japanese.

Adult T-cell leukemia-lymphoma (ATLL) is a distinct clinicopathologic entity etiologically linked to HTLV-I infection. We have identified five cases of retrovirus-associated ATLL among Hawaii-born first generation offspring (nisei) of migrant Japanese. Four patients were offspring of migrant Japanese (issei) who emigrated to Hawaii from Okinawa, an HTLV-I endemic area. The fifth patient was born of parents who emigrated to Hawaii from Fukushima and Miyagi prefectures, HTLV-I nonendemic areas. Epidemiologic implications and family studies with regard to HTLV-I antibody testing of the index cases are discussed. The high rate of HTLV-I antibody seropositivity among family members and relatives indicates that the risk of acquiring HTLV-I infection and of developing ATLL persists long after migration. Documentation of ATLL among offspring of Japanese immigrants to Hawaii is an important observation because it confirms the potential for long latency between putative exposure to virus and the development of overt disease. Changing marriage patterns among the Hawaii-Japanese may weaken the risk of vertical virus transmission to the descendents of migrants from southern Japan, while increasing the risk to children born of mixed marriages. In addition, blood products derived from high-risk donors will constitute a continuing hazard if they are not subject to screening.

Adult T-cell leukaemia lymphoma in an aborigine.

A 44-year-old Aborigine with Adult T-cell Leukaemia/Lymphoma (ATLL) due to HTLV-I is reported. He presented with transverse myelitis of subacute onset, and subsequently developed frank T-cell leukaemia complicated by splenomegaly and hypercalcaemia. Cell surface marker studies showed a phenotype of CD3+ CD4+ CD8- CD25+, and serological and molecular studies confirmed HTLV-I infection. This is the first report of ATLL in an Australian Aborigine.

TEL-AML1 fusion gene frequency in paediatric acute lymphoblastic leukaemia in Brazil.

We analysed 67 samples from Brazilian children of diverse ethnic origins with acute lymphoblastic leukaemia (ALL) for the presence of the TEL-AML1 fusion gene transcripts using reverse transcription polymerase chain reaction (RT-PCR). All 12 positive cases (20% of the 60 B-cell precursor ALL) had common (CD10+) ALL with a mean age of 4 years (range 1-10 years). We conclude that the frequency, age, distribution and clinical features of the TEL-AML1 fusion gene-positive ALL is similar in the diverse ethnic backgrounds of the Brazilian children to that in other countries with predominantly white Caucasian or oriental ethnicity. Apparent exceptions to this generality are discussed.

Adult T-cell leukaemia/lymphoma in Brazil and its relation to HTLV-I.

In a series of fourteen patients with adult T-cell lymphoma-leukaemia (ATLL) in Brazil the main features were lymphadenopathy, hepatosplenomegaly, hypercalcaemia, and high leucocyte counts, with abnormal lymphoid cells which had irregular nuclei. The series included the youngest patient with ATLL so far (18 months). Analysis with monoclonal antibodies showed a mature T-cell phenotype (CD4+, CD8-). Antibodies to HTLV-I and/or integration of HTLV-I proviral DNA were found in eleven patients. In the other three HTLV-I DNA could not be demonstrated even by means of the polymerase chain reaction; they therefore had HTLV-I-negative ATLL. This report of ATLL in Brazil corroborates serological reports that HTLV-I may be endemic in some parts of that country. Follow-up studies are required to identify precisely the main route of transmission of HTLV-I in South America and the risk factors for the development of ATLL in carriers.

The first report of familial adult T-cell leukaemia lymphoma in the United Kingdom.

We describe two siblings who developed adult T-cell leukaemia lymphoma (ATLL) within 4 years. Both were black of Afro-Caribbean extraction, but one had been born in the United Kingdom and had visited the Caribbean only once. Both patients were HTLV-1 seropositive, as was their mother; their father and brother were negative. The older sibling had the lymphoma form of ATLL, whilst the younger had chronic ATLL. The former was unresponsive to chemotherapy and died of progressive disease; the latter experienced transient responses to various treatments and is alive 5 years after presentation. Immunophenotyping showed a CD4+, CD25+ phenotype; Southern blot demonstrated a monoclonal integration of HTLV-I in the tissues involved. This report, of the first familial ATLL in the U.K., supports the suggestion of transmission of HTLV-I from mother to child and documents the development of ATLL in second-generation Caribbean immigrants.