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Non-Hodgkin lymphoma (NHL) is the most common hematologic malignancy and the fifth most common type of cancer in more developed regions of the world (1). Numerous NHL subtypes with distinct combinations of morphologic, immunophenotypic, genetic, and clinical features are currently recognized (2,3). The incidence of NHL subtypes varies substantially by age, sex, and race/ethnicity (4–7). However, the etiological implications of this biological, clinical, and epidemiological diversity are incompletely understood. The importance of investigating etiology by NHL subtype is clearly supported by research on immunosuppression, infections, and autoimmune diseases, which are the strongest and most established risk factors for NHL. Studies of solid organ transplant recipients and individuals infected with HIV demonstrate that risks are markedly increased for several—but not all—NHL subtypes (8–13). Some infections and autoimmune diseases are associated with a single specific subtype [eg, human T-cell lymphotropic virus, type I (HTLV-I) with adult T-cell leukemia/lymphoma (14), celiac disease with enteropathy-type peripheral T-cell lymphoma (PTCL) (15–17)], whereas others [eg, Epstein–Barr virus, hepatitis C virus (HCV), Sjogren’s syndrome (18–21)] have been associated with multiple subtypes. In the last two decades, reports from individual epidemiological studies of NHL have suggested differences in risks among NHL subtypes for a wide range of risk factors, but most studies have lacked the statistical power to assess any differences quantitatively and have not systematically evaluated combinations of subtypes. One study assessed multiple risk factors and found support for both etiologic commonality and heterogeneity for NHL subtypes, with risk factor patterns suggesting that immune dysfunction is of greater etiologic importance for diffuse large B-cell lymphoma (DLBCL) and marginal zone lymphoma than for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and follicular lymphoma (22). However, that analysis was limited to approximately 1300 NHL cases and considered only the four most common NHL subtypes. Pooling data from multiple studies through the International Lymphoma Epidemiology Consortium (InterLymph) have provided substantial insight into associations between specific risk factors and NHL subtypes, with evidence that family history of hematologic malignancy, autoimmune diseases, atopic conditions, lifestyle factors (smoking, alcohol, anthropometric measures, and hair dye use), and sun exposure are associated with NHL risk (19,21,23–32). However, no previous study has compared patterns of risk for a range of exposures for both common and rarer NHL subtypes. We undertook the InterLymph NHL Subtypes Project, a pooled analysis of 20 case–control studies including 17 471 NHL cases and 23 096 controls, to advance understanding of NHL etiology by investigating NHL subtype-specific risks associated with medical history, family history of hematologic malignancy, lifestyle factors, and occupation. The detailed risk factor profiles for each of 11 NHL subtypes appear in this issue (15–17,33–40). In this report, we assess risk factor heterogeneity among the NHL subtypes and identify subtypes that have similar risk factor profiles.

Loss of CD4 T lymphocytes is central to the pathogenesis of HIV infection. Without intervention, helper T-cell function declines, followed by broad alterations in immune responses. HIV replication is efficiently controlled in most subjects by use of highly active antiretroviral therapy (HAART), which frequently results in undetectable HIV RNA and recovery of CD4 T-cell counts. However, a substantial proportion of treated subjects appear to have a higher risk for non–AIDS-defining illnesses and a life span that is estimated to be 10 years shorter, compared with HIV-negative populations [1–5]. Low CD4 T-cell counts during HAART are associated with increased risk of cancer, liver disease, and cardiovascular disease [6–8]. Persistent activation of CD4 and CD8 T cells, detected by expression of CD38 and HLA-DR, appears to be associated with limited recovery of CD4 T-cell counts [9]; current hypotheses suggest that disease progression may be more closely associated with immune activation levels than with HIV replication levels [10–12]. The trend for a higher risk of non–AIDS-related illnesses has also been observed among participants in the Women's Interagency HIV Study (WIHS), even in the presence of virologic control and initial recovery of CD4 T-cell counts [13–16]. Interleukin 10 (IL-10) is a type II cytokine initially characterized as an inhibitor of helper T-cell subtype 1 cytokines [17]. A major immunoregulatory effect of IL-10 is inhibition of antigen presentation, acting primarily on dendritic cells and monocytes [18, 19]. IL-10 may also decrease apoptosis of B and T lymphocytes [20–22]. As a consequence, several clinical studies have investigated treatment with recombinant IL-10 for subjects with inflammatory conditions such as psoriasis, Crohn disease, or rheumatoid arthritis [23]. Toll-like receptors (TLRs) are critical components of innate immunity and play a key role in pathogen defense [24]. TLR3, the receptor for double-stranded RNA, and TLR4, the receptor for bacterial lipopolysaccharide (LPS), have recognized roles in antiviral and antibacterial immunity [25, 26]. Bacterial products leaking from the intestinal mucosa [27] and residual HIV replication [28] may contribute to chronic inflammation in treated HIV infection. We investigated the ex vivo capacity of peripheral blood mononuclear cells (PBMCs) from HIV-infected women to respond to TLR3 and TLR4 ligands, representing innate responses to pathogens of intracellular or extracellular origin, respectively. Dysregulated inflammatory cytokine responses in HIV-infected women have been reported in the WIHS [29, 30]. We observed that spontaneous release of inflammatory cytokines in vitro was demonstrable in >60% of HIV-infected women but that responses to TLR3 and TLR4 stimulation were reduced in women with HIV/hepatitis C virus (HCV) coinfection, compared with women with HIV monoinfection [29]. In contrast, IL-10 responses to TLR4 stimulation were enhanced in women with HIV monoinfection, compared with women with HIV/HCV coinfection or noninfected controls. High production of IL-10 in untreated HIV infection has been considered detrimental for virus control because of IL-10 inhibition of the antiviral activity of helper T-cell subtype 1 cytokines [31]. However, the implications of altered cytokine responses, including IL-10 production, in HAART recipients are incompletely understood. The aim of this analysis was to investigate the possible influence of cytokines produced by cells of the innate immune compartment on levels of CD4 T cells over time in treated HIV infection.

Background The impact of HAART on the natural history of human papillomavirus (HPV) remains uncertain following conflicting reports. Prior studies, however, did not consider patients’ adherence to their regimen, or HAART effectiveness (viral suppression).

Background: Women infected with human immunodeficiency virus (HIV) have an increased risk of persistent squamous intraepithelial lesions (SILs) of the cervix. We assessed the association between use of highly active antiretroviral therapy (HAART) and regression of SIL in HIV-infected women enrolled in the Women's Interagency HIV Study, a large, multicenter, prospective cohort study. Methods: Of 2059 HIV-infected participants, 312 HIV-infected women had normal cervical cytology at baseline and were subsequently diagnosed during 7 years of follow-up with incident SIL. Pap smears, CD4+ T-cell counts, and information regarding use of HAART were obtained every 6 months. The outcome of interest was lesion regression, defined as two consecutive normal Pap smears 6 months apart. Incidence rates of SIL regression were computed among person-years at risk, both before and after HAART initiation. All statistical tests were two-sided. Results: Of 312 women, 141 had lesions that regressed to normal cytology, with a median time to regression of 2.7 years. Overall, the incidence of regression increased (P trend = .002) over time after HAART was introduced. At incident SIL, median CD4+ T-cell counts were lower in women whose lesions did not regress than in women whose lesions regressed (230 versus 336 cells/μL; P

Little is known about the epidemiology of human herpesvirus 8 (HHV-8) infections among women. A cross-sectional study was conducted of HHV-8 infection among human immunodeficiency virus (HIV)-infected and high-risk HIV-uninfected women. Serological tests with noninduced (latent) and induced (lytic) HHV-8 antigens were used to detect infection among 2483 participants of a multisite cohort. Reactivity to latent antigen was present in 4.1% and to induced antigens in 12.0% of women. Seven of 8 women who reported Kaposi's sarcoma had HHV-8 antibodies. Among HIV-positive women, HHV-8 infection was associated with use of crack, cocaine, or heroin (76% vs. 65%; P

tients was higher than that expected in the usual population of HIV-infected patients, the data are skewed by the fact that the authors included patients with known malignancy at presentation. The more interesting question relates to the follow-up of these patients over time: will they, in fact, develop B cell malignancies at a rate higher than that expected in the usual population of HIV-infected individuals or higher than that described in the usual population of HIV-uninfected individuals with MGUS? This question cannot yet be answered. It is of interest, however, that 1 individual with MGUS in this study did go on to develop Hodgkin lymphoma, which is also a B cell neoplasm. Nonetheless, the Hodgkin disease was apparently diagnosed after a follow-up duration of only 2 months

The multifactorial etiology of Kaposi's sarcoma (KS), which is seen primarily in men, includes genetic predisposition and immunosuppression. Recently, the KS seen in association with human immunodeficiency virus (HIV) infection has been shown to be mediated by the production of certain growth factors. HIV per se may also play an etiologic role via its tat gene. Therapeutic options include irradiation for local or cosmetic control, interferon-alpha, combinations of antiretroviral agents and interferon-alpha, and chemotherapy. The use of antineoplastic agents, either individually or in combination, in cases of advanced disease has been somewhat successful, but resultant immunosuppression and neutropenia may predispose patients to further infection, thereby adversely affecting survival. AIDS-related lymphoma, a late manifestation of HIV infection, often presents with widespread extranodal disease; the median survival time in all series has been approximately 6 months. Two-thirds of patients may have central nervous system involvement at some time in the course of illness. Intensive chemotherapeutic regimens are associated with an increased likelihood of opportunistic infection and do not prolong survival. Combinations of antineoplastic agents given at low doses for short periods may be associated with long-term remissions.

In this issue of Clinical Infectious Diseases, Soler and col­ leagues [1] described a 14-year-old female from Zaire who had vertically acquired HIV infection and severe immune defi­ ciency, as was manifested by multiple opportunistic infections and a CD4 cell count ofOzmnr'. She was said to have developed Kaposi's sarcoma (KS) lesions that slowly increased in size and number over a 4-month period. At the age of 14.3 years, she developed painful oral ulcers, for which she was given topical and systemic corticosteroids. The dose of these agents and the duration ofadministration are not specified. After corti­ costeroid therapy for the oral ulcers failed, the patient began receiving a 3-week course of thalidomide; during this time, the size of the existing KS lesions decreased while no new KS lesions developed. Thalidomide therapy was continued over the next 2 months, and the number of KS lesions decreased from 29 to 13.

The uptake of free and liposome-entrapped methotrexate (MTX) by human chronic lymphocytic leukemia cells was compared under incubation conditions resembling those encountered in vivo. Liposome encapsulation enhanced up to 200 times the association of MTX with these cells. Autoradiographic studies established an association of [3H]MTX liposomes with the cells. Such a mode of delivery did not significantly increase the amount of drug available to inhibit dihydrotolate dehydrogenase, which suggested that the liposome content was not readily available to the cytoplasmic sites of action. Increased doses of encapsulated MTX resulted in enzyme inhibitions that were similar to those obtained with the free drug. This finding demonstrates that higher doses of MTX delivered by liposomes could be potentially useful in overcoming drug-transport resistance.

The demographic characteristics of "classic" Kaposi's sarcoma (KS) and of "epidemic" KS in Los Angeles, CA, were compared with the use of data from the Cancer Surveillance Program, the population-based tumor registry in Los Angeles County. The data obtained document the magnitude of the excess risk of classic KS for Jewish men of European (especially Eastern and Southern European) origin. The data also show in a systematic way the magnitude of the increase in acquired immune deficiency syndrome-related KS in one large urban area of the United States. In addition, they demonstrate that the demographic risk factors of religion and birthplace for classic KS are unrelated to epidemic KS and that the clinical presentation in terms of stage and primary site of classic KS is distinct from that of the epidemic form of the disease.