Proliferation and apoptosis in the evolution of endemic and acquired immunodeficiency syndrome-related Kaposi's sarcoma

Kaposi's sarcoma (KS) is a multifocal lesion that occurs predominantly in the skin, most frequently in people infected with HIV-1, and that evolves through early stages (patch and plaque) to a tumor-like late stage (nodular). Both, endemic African (EKS) and AIDS-associated (AKS) KS expressed human herpesvirus 8 (HHV-8) as shown by PCR. By immunohistochemistry the expression of cellular Bcl-2 and c-myc was confined in early stages of both EKS and AKS to relatively few endothelial cells (EC) whereas in nodular KS most of spindle cells (SC) strongly expressed both genes. CD40 was usually strongly expressed in SC at all KS stages as well as in EC of non-involved tissue whereas CD40L (CD154) was not demonstrable. Fas (CD95) was moderately to weakly expressed by SC whereas p53 and Waf-1 were found in less than 5% of the SC. In both AKS and EKS at nodular stage almost no apoptotic SC were detected. In most AKS and EKS low levels of cell proliferation were seen but AKS showed consistently higher values compared to EKS. All clinical types and stages of KS showed a diploid cellular DNA content by flow cytometric analysis of microselected lesions. Thus, we conclude that KS during evolution represents diploid, probably reactive, cell proliferation, which progressively increases the expression of strong cellular and also viral (HHV-8) antiapoptotic factors. These authors have contributed equally to this work.     

Supernatants of acquired immunodeficiency syndrome-related Kaposi's sarcoma cells induce endothelial cell chemotaxis and invasiveness

Kaposi's sarcoma (KS) in general, and acquired immunodeficiency syndrome-related KS (AIDS-KS) in particular, is a highly invasive and intensely angiogenic neoplasm of unknown cellular origin. We have recently established AIDS-KS cells in long term culture and reported the development of KS-like lesions in nude mice inoculated with these cells. Here, we have examined the in vitro invasiveness of basement membrane by AIDS-KS cells, as well as the effect(s) of their supernatants on the migration and invasiveness of human vascular endothelial cells. AIDS-KS cells were highly invasive in the Boyden chamber invasion assay and formed invasive, branching colonies in a 3-dimensional gel (Matrigel). Normal endothelial cells form tube-like structures on Matrigel. AIDS-KS cell-conditioned media induced endothelial cells to form invasive clusters in addition to tubes. KS-cell-conditioned media, when placed in the lower compartment of the Boyden chamber, stimulated the migration of human and bovine vascular endothelial cells across filters coated with either small amounts of collagen IV (chemotaxis) or a Matrigel barrier (invasion). Basic fibroblast growth factor could also induce endothelial cell chemotaxis and invasion in these assays. However, when antibodies to basic fibroblast growth factor were used the invasive activity induced by the AIDS-KS-cell-conditioned media was only marginally inhibited, suggesting that the large quantities of basic fibroblast growth factor-like material released by the AIDS-KS cells are not the main mediators of this effect. Specific inhibitors of laminin and collagenase IV action, which represent critical determinants of basement membrane invasion, blocked the invasiveness of the AIDS-KS cell-activated endothelial cells in these assays. These data indicate that KS cells appear to be of smooth muscle origin but secrete a potent inducer of endothelial cell chemotaxis and invasiveness which could be responsible for angiogenesis and the resulting highly vascularized lesions. These assays appear to be a model to study the invasive spread and angiogenic capacity of human AIDS-related KS and should prove useful in the identification of molecular mediators and potential inhibitors of neoplastic neovascularization.     

Human herpesvirus 8 seropositivity and risk of Kaposi's sarcoma and other acquired immunodeficiency syndrome-related diseases.

BACKGROUND: The incidence of Kaposi's sarcoma (KS) is increased severalfold in individuals infected with human immunodeficiency virus-1 (HIV). Human herpesvirus 8 (HHV8) has also been implicated in KS. We investigated several factors that may determine the onset of KS, particularly HHV8 infection in individuals after becoming seropositive for HIV. METHODS: We studied 366 individuals belonging to different HIV-exposure categories (i.e., homosexual activity, intravenous drug use, and heterosexual contact) for whom a negative HIV serologic test and then a positive HIV serologic test were available within a 2-year period. HHV8 antibody testing was performed by use of an immunofluorescence assay on the first serum sample available after the first positive HIV test. Actuarial rates of progression of KS and of other acquired immunodeficiency syndrome (AIDS)-defining diseases were estimated by use of time-to-event statistical methods. All statistical tests were two-sided. RESULTS: Twenty-one of the 366 study participants developed AIDS-related KS, and 83 developed AIDS without KS. One hundred forty (38.3%) participants had detectable anti-HHV8 antibodies. The actuarial progression rate to KS among persons co-infected with HIV/HHV8 was nearly 30% by 10 years after HIV seroconversion. Increasing HHV8 antibody titers increased the risk of developing KS (for seronegative versus highest titer [1:125 serum dilution], adjusted relative hazard [RH] = 51.82; 95% confidence interval [CI] = 6.08-441.33) but not of other AIDS-defining diseases (adjusted RH = 1.14; 95% CI = 0.72-1.80). HHV8-seropositive homosexual men compared with HHV8-seropositive participants from other HIV-exposure categories showed an increased risk of KS that approached statistical significance (adjusted RH = 6.93; 95% CI = 0.88-54.84). CONCLUSIONS: Approximately one third of individuals co-infected with HIV/HHV8 developed KS within 10 years after HIV seroconversion. Progression to KS increased with time after HIV seroconversion. Higher antibody titers to HHV8 appear to be related to faster progression to KS but not to other AIDS-defining diseases.     

Acquired immunodeficiency syndrome-related Kaposi's sarcoma: clinical features, staging, and treatment

The clinical course of acquired immunodeficiency syndrome (AIDS)-related Kaposi's sarcoma (KS) is highly variable, ranging from minimal stable disease to explosive growth. Although KS is primarily a cutaneous disease, extracutaneous spread is common; the oral cavity, gastrointestinal (GI) tract, lungs, and lymph nodes are often involved. The psychosocial burden associated with KS may be profound. The initial evaluation of a patient with KS consists mainly of a thorough physical examination with special attention paid to those areas typically affected by the disease, the testing of stool for occult blood, and a chest x-ray. Treatment options depend greatly on the tumor (extent of tumor and rate of growth), human immunodeficiency virus type I (HIV-I) viral load, and host factors (CD4+ T-lymphocyte count and overall medical condition). Limited cutaneous disease may be treated with topical alitretinoin gel, intralesional vinblastine, radiation therapy, laser therapy, or cryotherapy. The high benefit-to-risk ratio of liposomal anthracyclines (daunorubicin and doxorubicin) and paclitaxel have tremendously simplified the management of patients in whom systemic therapy is warranted. Additionally, epidemiologic evidence of a marked decline in new KS since the widespread use of highly active antiretroviral therapy (HAART) advocates its use. KS herpes virus/human herpes virus 8 (KSHV/HHV-8), sex hormones, and the processes of angiogenesis and cellular differentiation all serve as targets for pathogenesis-based clinical trials. Virtually all patients with KS can benefit from the many approved and investigational agents developed through years of collaborative translational and clinical research.     

Epidemiology of Kaposi's sarcoma in Sweden prior to the acquired immunodeficiency syndrome

We studied retrospectively 529 cases of Kaposi's sarcoma (KS) reported to the Swedish Cancer Registry between 1958 and 1982 to determine incidence rates, survival and rate ratios, together with the frequency and types of associated malignancies. The age-standardized (Swedish population 1970) incidence rate generally increased over the time period, with a mean of 0.27 cases per 100,000 population per year (males 0.40, females 0.14). The incidence rate ratio (based on 5-year intervals and relative to the earliest period) reached 2.06 for males and 3.76 for females in the 1968-1972 interval, while the actual peak occurred between 1971 and 1974 for both sexes. Poisson regression modelling suggested a transient shift in the age-specific male incidence rate pattern with a relative increase of the disease in younger age groups (p = 0.05) up to 1968-1972. The age-adjusted male:female ratio did not change significantly from 2.9 during the period of study. In relation to the general population, 18% fewer men and 24% fewer women were alive 10 years after the diagnosis had been made. Ninety-nine (19%) cases had other primaries, of which 17 were neoplasms of lymphocytic origin. Lymphoproliferative malignancy was 2.5 times (95% CI 1.38, 4.37) more common than expected in patients with KS (in particular in females) but a definite increase in other malignancies was not apparent. It is questionable whether immune dysfunction due to other malignant disease or drug therapy can account for the epidemiologic changes in KS, which began almost 2 decades prior to the AIDS epidemic in Sweden.     

Treatment of the acquired immune deficiency syndrome-related Kaposi's sarcoma with bleomycin as a single agent.

A nonrandomized trial was conducted to assess the efficiency and toxicity of bleomycin as a single agent in treatment of non-life-threatening AIDS-related Kaposi's sarcoma (KS). Sixty patients were enrolled in this study. They all had a disseminated and progressive non-life-threatening AIDS-related KS associated with systemic symptoms and/or CD4 lymphocyte count less than 400/mm3. Thirty patients were treated with intramuscular bleomycin (5 mg/d for 3 days every 2 or 3 weeks) and 30 others with a slow continuous intravenous infusion of bleomycin (6 mg/m3/d for 4 days every 4 weeks). The mean duration of therapy was 5 months (range, 2 to 24 months). A partial response was observed in 29 patients (48.3%) and the disease was stabilized in 18 additional patients (30%). Bleomycin failed in 21.6% of patients. Therapy had to be discontinued in two patients because of side effects. Thus bleomycin as a single agent is a good alternative therapy for AIDS-related KS.     

Weekly docetaxel is safe and effective in the treatment of advanced-stage acquired immunodeficiency syndrome-related Kaposi sarcoma

BACKGROUND: Intravenous paclitaxel, 100 mg/m(2), given over 3 hours every 2 weeks is associated with a response rate of 59% in patients with recurrent or refractory acquired immunodeficiency syndrome (AIDS)-related Kaposi sarcoma (KS). However, this regimen is associated with significant myelosuppression, and the inconvenience of a 3-hour infusion. Moreover, no effective therapies have been defined for use after treatment failure with this agent. A Phase II trial was conducted with weekly docetaxel in patients with advanced-stage KS to assess safety and antitumor activity. METHODS: Docetaxel was administered at a dose of 25 mg/m(2) intravenously over 15-30 minutes weekly for 8 weeks. Thereafter, if the patient experienced stable disease or better response, treatment doses were given every other week until complete disease remission, disease progression, or unacceptable toxicity occurred. RESULTS: Twelve patients were accrued-9 had > 25 mucocutaneous lesions, 1 had lymphedema, and 2 had visceral involvement. Ten patients (83%) had previous systemic chemotherapy, including 4 who received previous paclitaxel. Treatment was well tolerated, with no Grade 4 toxicity of any type. Grade 3 neutropenia occurred in 33% of patients but no patient had neutropenic fever. Five patients (42%) achieved a partial response, including 1 who had previously failed to respond to paclitaxel. The median time to disease progression was 26 months (range, 5-53 months). With a median follow-up period of 45 months, the median survival point had not been reached. CONCLUSIONS: Weekly docetaxel is safe, with reasonable antitumor activity in patients with advanced-stage, recurrent, or refractory AIDS-related KS.     

Immunological variables as predictors of prognosis in patients with Kaposi's sarcoma and the acquired immunodeficiency syndrome

Multivariate analysis was used to identify which of a large number of pretreatment immunological parameters correlated with therapeutic response, subsequent development of opportunistic infection, and survival from the time of diagnosis in a group of 70 patients with Kaposi's sarcoma and acquired immunodeficiency syndrome treated with recombinant leukocyte A interferon. In a logistic regression model, delayed type hypersensitivity response to one or more recall antigens and high proliferative response to Escherichia coli were significant predictors for response to recombinant leukocyte A interferon (for the model, P = 0.01). For prediction of the development of opportunistic infection, the model selected low proliferative responses to phytohemagglutinin and E. coli (P less than 0.001). Favorable factors predicting survival in the Cox regression model were the absence of endogenous serum interferon activity and a high proliferative response to E. coli (P less than 0.001). The estimated median survival for the group with endogenous serum interferon activity and low E. coli response was 12 months; the median has not yet been reached for the group with no serum interferon and a high E. coli response. We conclude that immunological parameters may be useful in predicting prognosis in patients with Kaposi's sarcoma and acquired immunodeficiency syndrome.     

Trends in the incidence of acquired immunodeficiency syndrome-related malignancies in Thailand

BACKGROUND: Thailand was one of the first Asian countries to be affected by the epidemic of human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS). Furthermore, Thailand possesses a national cancer surveillance system based upon regional cancer registries. METHODS: Data from five population-based cancer registries, covering one-fifth of the national population, were used to study trends in the incidence of malignancies related to HIV/AIDS in Thailand during the period 1989-2001. RESULTS: Although the incidence of Kaposi sarcoma (KS) increased slightly from 1989-1991 to 1995-1997, KS remains a very rare malignancy in Thailand compared with other countries in which the prevalence of HIV/AIDS is much lower. The authors reported a marked increase in the incidence of non-Hodgkin lymphoma (NHL), and particularly high-grade/diffuse NHL. However, the largest increases in incidence were noted among individuals age >/= 55 years and in regions with a relatively low prevalence of HIV/AIDS. CONCLUSIONS: The rarity of KS presumably reflected the low prevalence of the causative agent (i.e., KS-associated herpesvirus) in the Thai population. The increasing incidence of NHL may be related to the AIDS epidemic, although a similar increase is observed in many countries worldwide and is not specifically linked to the HIV/AIDS epidemic.     

Kaposi's sarcoma and the acquired immunodeficiency syndrome: treatment with high and low doses of recombinant leukocyte A interferon

The efficacy of recombinant leukocyte A interferon (rIFN-alpha A [Roferon-A, Hoffman-La Roche, Nutley, NJ]) treatment of Kaposi's sarcoma in patients with acquired immunodeficiency syndrome was evaluated in sequential trials using high doses (36 X 10(6) units) and low doses (3 X 10(6) units) of interferon. A major response was seen in 38% of patients treated at the high dose, with a median response duration of 18 months. At the low dose, the major response rate was 3%; dose escalation to 36 X 10(6) units resulted in an additional major response rate of 17% in low-dose nonresponders, with a median response duration of 10 months. Four of 11 patients who achieved a complete response remain free of disease, whereas all partial responders have shown disease progression. Unacceptable toxicity occurred in 27% of patients initially treated at the high dose and only in 10% of those who had progressive dose escalation up to 36 X 10(6) units. Prior opportunistic infections correlated negatively with therapeutic response, whereas large tumor burden and gastrointestinal involvement did not. Responding patients showed a significantly longer survival and a lower incidence of subsequent opportunistic infections than nonresponders. However, from our study we cannot determine whether rIFN-alpha A has an effect on the natural history of Kaposi's sarcoma in patients with the acquired immunodeficiency syndrome.     

Impact of highly active antiretroviral therapy on the presenting features and outcome of patients with acquired immunodeficiency syndrome-related Kaposi sarcoma

BACKGROUND: The objective of the current study was to evaluate the impact of highly active antiretroviral therapy (HAART) on clinical characteristics of presentation and the natural history of Kaposi sarcoma (KS) in patients already receiving HAART at the time of KS diagnosis. METHODS: The authors conducted a retrospective cohort study comparing epidemiologic, clinical, and outcome data for 160 patients who were naive to HAART at the time of KS diagnosis (KS-naive) with the corresponding data for 51 patients already receiving HAART at the time of KS diagnosis (KS-HAART). The analysis included all patients with a diagnosis of KS since January 1996 within two Italian cohorts of patients with human immunodeficiency virus. RESULTS: Immunologic and virologic status at the time of KS diagnosis were significantly more favorable in the KS-HAART group than in the KS-naive group. The frequency of cutaneous involvement was similar in both groups, but cutaneous disease was more indolent among KS-HAART patients, with 1 anatomic site of involvement in 9 patients (21%) and less than 10 lesions in 26 patients (60%), compared with 16 patients (12%; P = 0.06) and 47 patients (34%; P = 0.01), respectively, in the KS-naive group. A smaller proportion of KS-HAART patients presented with visceral disease (24% vs. 39%; P = 0.06); in particular, gastrointestinal tract involvement was significantly less frequent among KS-HAART patients (14%) compared with KS-naive patients (28%; P = 0.05). Median survival was not reached in either group, and the 3-year survival rates of KS-HAART patients (64%) and KS-naive patients (78%) were not significantly different. CONCLUSIONS: The data from the current study indicate that KS exhibits a less aggressive presentation in patients already receiving HAART compared with patients who are naive to HAART at KS diagnosis. Natural history and outcome do not appear to be influenced by the initiation of HAART before development of KS.     

Oral Kaposi's sarcoma in acquired immunodeficiency syndrome. Review of management and report of the efficacy of intralesional vinblastine

Treatment of palatal Kaposi's sarcoma (KS) with intralesional injection of vinblastine was seen to provide effective palliation. Of the ten patients studied, four had a 25% to 50% response, two 50% to 75% response, and four had 75% to 100% response with one or two intralesional injections of vinblastine. Response to treatment was followed for a mean of 3.6 months, with recurrence of lesions in two of ten patients.     

The role of HHV-8 in Kaposi's sarcoma.

The epidemiology of Kaposi's sarcoma (KS) amongst North American and Northern European patients with AIDS suggests that an infectious agent other than HIV is involved in its pathogenesis. Several lines of evidence indicate that human herpesvirus 8 (HHV-8), also termed Kaposi's sarcoma associated herpesvirus, is the sought after agent. DNA of HHV-8 is invariably found in all forms of KS where the virus is present in the KS spindle cell. In contrast, HHV-8 DNA is not regularly detected in most other malignancies. Antibodies against HHV-8 are more frequently found in groups at risk of KS, and HHV-8 seroconversion precedes KS development. Several HHV-8 genes have been identified that exhibit transforming potential in cell culture systems. In addition, the virus encodes and induces several cytokines and angiogenic factors. This is of particular interest as models of KS pathogenesis developed before the discovery of HHV-8 emphasized the importance of inflammatory cytokines. Although the expression pattern of viral genes in KS is not certain yet, it appears likely that the pathogenetic role of HHV-8 in KS may be rather complex and differs from other virus-induced malignancies. 1999 Academic Press.     

High risk of Kaposi's sarcoma and central nervous system lymphoma in the same individuals: A finding related to acquired immunodeficiency syndrome

Kaposi's sarcoma and central nervous system (CNS) lymphoma are the 2 most common malignancies related to HIV infection. To investigate the association between Kaposi's sarcoma and CNS lymphoma, a population-based retrospective cohort study was conducted. Using U.S. Surveillance, Epidemiology and End Results Program data, the gender-specific age- and calendar year-adjusted standardized incidence ratios were calculated for the pre-AIDS (1973–1980) and AIDS (1981–1990) eras, as an estimate of the relative risk (RR) of developing one condition following another. For the AIDS era in men, the RR of CNS lymphoma following Kaposi's sarcoma was 979.7 and that of Kaposi's sarcoma following CNS lymphoma was 231.1. There were no instances of the co-occurrence of these malignancies in women in either era or in men for the pre-AIDS era. The extremely high RRs for the co-occurrence of Kaposi's sarcoma and CNS lymphoma in men during the AIDS era suggests that the association of these malignancies occurs within the same HIV-infected individuals. © 1996 Wiley-Liss, Inc.     

The role of immunosuppression and immune-activation in classic Kaposi's sarcoma.

Immunodeficiency and elevated levels of cytokines have been associated with the development of Kaposi's sarcoma (KS) lesions in patients with AIDS and iatrogenic immunodeficiency. However, their role in classic KS (CKS) is unclear. We measured peripheral blood cell levels, including T-cell subsets, as well as neopterin and beta(2)-microglobulin in 91 HIV-negative Greek patients with histologically confirmed CKS and in 107 controls matched for age and sex. CKS cases had slightly lower leukocyte counts (p = 0.08) and lymphocyte counts (p = 0.02). Although the percentage of CD4 and CD8 T-lymphocytes were not significantly different from controls (p = 0.10 and p = 0.45, respectively), CD4 T-lymphocytes were lower in cases than controls (812 cells/microliter and 1,009 cells/microliter, respectively; p = 0.01); part of this difference resulted from the lower lymphocyte counts (p = 0.07 after adjusting for lymphocyte counts). However, neopterin and beta(2)-microglobulin were both considerably elevated [geometric mean (95% CI): 8.35 (7.27-9.73) nmol/L and 2,904 (2,479-3,401) microgram/L in cases and 5.86 (5.40-6. 35) nmol/L and 2,042 (1,880-2,218) microgram/L in controls, respectively]. We conclude that CKS patients are predominantly characterised by immune activation, although an element of minor immunosupression may also be present.     

A multicenter phase II study of the intravenous administration of liposomal tretinoin in patients with acquired immunodeficiency syndrome-associated Kaposi's sarcoma

BACKGROUND: A multicenter trial was conducted to determine the efficacy and toxicity of escalating dosages of liposomal tretinoin (all-trans-retinoic acid) administered once or three times weekly in patients with acquired immunodeficiency syndrome (AIDS)-associated Kaposi sarcoma. METHODS: Seventy-six patients with acquired immunodeficiency syndrome (AIDS)-associated Kaposi sarcoma were randomized to receive the study drug either once (n = 30) or 3 times weekly (n = 46). The starting dosage was 60 mg/m(2), which was escalated to 90 mg/m(2) and then 120 mg/m(2) if the drug was well tolerated (相似文献