Kaposi's Sarcoma Patients Research Articles

Relationship between human herpesvirus 8 loads and disease stage in classic Kaposi sarcoma patients

Human herpesvirus 8 (HHV-8), also known as Kaposi sarcoma (KS)-associated herpesvirus, is causally implicated in all forms of KS, including the classic form. Our objective was to investigate the relationship between HHV-8 load in peripheral blood mononuclear cells (PBMCs) and the stage of the disease in classic KS (CKS) patients. HHV-8 loads were measured in 41 PBMC samples from CKS patients with different Krigel-based classification stages using a quantitative real-time polymerase chain reaction assay. Low HHV-8 DNA loads reaching a maximum of 75.5 copies/10 5 cells were detected in 73.2% of the patients. HHV-8 loads in patients with stages I and II were similarly distributed. An increased detection rate of HHV-8 DNA, although not statistically significant, was evident in patients diagnosed with CKS stages III and IV. We conclude that the measurements of HHV-8 load in PBMCs provide a limited correlation with the clinical stage of KS.

Risk factors for human Herpesvirus 8 infection and AIDS‐associated Kaposi's sarcoma among men who have sex with men in a European multicentre study

We aimed to identify risk factors for Kaposi's sarcoma (KS) among HIV-positive patients and behaviors associated with human Herpesvirus 8 (HHV-8) infection, as well as to assess KS incidence and mortality rates longitudinally. To fulfill the first objective, a European case-control study was designed in the early 1990s (each KS case was matched to 2 controls with another AIDS indicative disease). After the discovery of HHV-8, serology testing enabled us to assess risk factors for KS development among HHV-8 and HIV-1 coinfected men who have sex with men (MSM), as well as risk factors for HHV-8 infection. HHV-8 seroprevalence was determined using a latent immunofluorescence assay. Relevant information was obtained by means of a questionnaire and medical charts review. Assessment of risk factors for KS development and HHV-8 infection was performed using conditional and unconditional logistic regression models, respectively. A low CD4 count was the only significant risk factor for KS. HHV-8 infection was most strongly linked to the number of life-time sex partners, and multiple body fluids such as saliva and semen are quite likely involved in sexual transmission. Longitudinal follow up showed a significant protective role for highly-active antiretroviral therapy (HAART) both on KS development and mortality of KS patients. Although more conclusive data from cohort studies are needed to better define specific transmission mechanisms for HHV-8, our results contribute to explain why KS incidence is higher among MSM, and the decreasing KS incidence trend observed in countries with universal access to HAART.

Intracellular Tat of Human Immunodeficiency Virus Type 1 Activates Lytic Cycle Replication of Kaposi's Sarcoma-Associated Herpesvirus: Role of JAK/STAT Signaling

Human immunodeficiency virus type 1 (HIV-1) infection significantly increases the risk of Kaposi's sarcoma (KS) occurrence in individuals infected with Kaposi's sarcoma-associated herpesvirus (KSHV). KSHV infection appears to be necessary but not sufficient for KS development without other cofactors. However, factors that facilitate KSHV to cause KS have not been well defined. Previously, we determined that human herpesvirus 6 was one of the cofactors that activated lytic cycle replication of KSHV. Here, we demonstrate that the Tat protein of HIV-1 is a potentially important factor in the pathogenesis of KS, as determined by production of lytic phase mRNA transcripts and viral proteins in BCBL-1 cells. Mechanistic studies showed ectopic expression of Tat induced the production of human interleukin-6 (huIL-6) and its receptor (huIL-6Ra) and activated STAT3 signaling. Neutralization of huIL-6 or huIL-6R or inhibition of STAT3 signaling enhanced the replication. In addition, IL-4/STAT6 signaling also partially contributed to Tat-induced KSHV replication. These findings suggest that Tat may participate in KS pathogenesis by inducing KSHV replication and increasing KSHV viral load. These data also suggest that JAK/STAT signaling may be of therapeutic value in AIDS-related KS patients.

Successful secondary prophylaxis for primary effusion lymphoma with human herpesvirus 8 therapy

Successful secondary prophylaxis for primary effusion lymphoma with human herpesvirus 8 therapy

Kaposi Sarcoma in Patients with Diabetes and Wounds

Kaposi Sarcoma in Patients with Diabetes and Wounds

Kaposi's sarcoma-associated herpesvirus infection and Kaposi's sarcoma in Brazil

Kaposi's sarcoma (KS) became a critical health issue with the emergence of acquired immunodeficiency syndrome (AIDS) in the 1980s. Four clinical-epidemiological forms of KS have been described: classical KS, endemic KS, iatrogenic KS, and AIDS-associated KS. In 1994, Kaposi's sarcoma-associated herpesvirus (KSHV) or human herpesvirus type 8 was identified by Chang and colleagues, and has been detected worldwide at frequencies ranging from 80 to 100%. The aim of the present study was to evaluate the frequency of KSHV infection in KS lesions from HIV-positive and HIV-negative patients in Brazil, as well as to review the current knowledge about KS transmission and detection. For these purposes, DNA from 51 cases of KS was assessed by PCR: 20 (39.2%) cases of classical KS, 29 (56.9%) of AIDS-associated KS and 2 (3.9%) of iatrogenic KS. Most patients were males (7.5:1, M/F), and mean age was 47.9 years (SD = +/- 18.7 years). As expected, HIV-positive KS patients were younger than patients with classical KS. On the other hand, patients with AIDS-associated KS have early lesions (patch and plaque) compared to classical KS patients (predominantly nodular lesions). This is assumed to be the result of the early diagnose of KS in the HIV-positive setting. KSHV infection was detected by PCR in almost all cases (48/51; 94.1%), irrespectively of the clinical-epidemiological form of KS. These results show that KSHV is associated with all forms of KS in Brazilian patients, a fact that supports the role of this virus in KS pathogenesis.

Correlations between synthetic peptide‐based enzyme immunoassays and immunofluorescence assay for detection of human herpesvirus 8 antibodies in different Argentine populations

Human herpesvirus 8 (HHV-8) antibody tests vary in sensitivity and specificity, depending on the population tested and on the type of assay. In this study, we evaluated the sensitivity and specificity of two peptide enzyme immunoassays using a multiple antigenic peptide (PK8.1-MAP) or a chimeric peptide (PK8.1-orf65) as the antigens and determined the HHV-8 seroprevalence in different Argentine populations using an immunofluorescence assay (IFA) as reference. For analysis, when either or both of the peptide EIAs were positive, the specimen was considered positive (PEIA). We estimated the sensitivity and specificity of PEIA to be 97% using Kaposi's sarcoma (KS) patients and healthy individuals as positive and negative controls respectively. Then, we expanded the control groups to include IFA positive men who have sex with men (MSM) and IFA negative blood donors. The sensitivity decreased to 83% but specificity remained high at 98%. Concordance between PEIA and IFA was 77% for 1/40 IFA titers and increased to 90% for titers >or=1/160. Seroprevalences for HHV-8 performed in the HIV positive MSM were (IFA 73.1%; PEIA55.2%); heterosexuals (52.5%, 22.2%), which includes injecting drug users (IDU) (54.0%, 32.4%) and non-IDU (51.6%, 16.1%). The inclusion of non-KS HHV-8 IFA positive individuals to the positive controls may be a substantial improvement towards the realistic assessment of assay sensitivity. These peptide EIAs can be used for trends in populations with high probability of being HHV-8 infected and negative results should be confirmed by IFA. IFA test is still the most suitable test for populations with low probabilities of being infected.

The Kaposi's Sarcoma–Associated Herpesvirus G Protein–Coupled Receptor as a Therapeutic Target for the Treatment of Kaposi's Sarcoma

The Kaposi's sarcoma-associated herpesvirus (KSHV) encodes a G protein-coupled receptor (vGPCR) that has been implicated in the initiation of Kaposi's sarcoma, identifying vGPCR as an attractive target for preventing Kaposi's sarcoma. However, as only a fraction of cells in advanced Kaposi's sarcoma lesions express vGPCR, it is unclear whether this unique viral oncogene contributes to Kaposi's sarcoma progression. We therefore set out to determine whether the few cells that express vGPCR in established tumors represent an appropriate therapeutic target for the treatment of patients with preexisting Kaposi's sarcoma. To this end, we generated endothelial cell lines stably expressing vGPCR or key KSHV latently expressed proteins (vCyclin, vFlip, and LANA1). The endothelial cell line expressing vGPCR was rendered sensitive to treatment with the nucleoside analogue ganciclovir by using a bicistronic construct coexpressing the herpes simplex virus 1 thymidine kinase. S.c. injection into nude mice with mixed-cell populations formed tumors that approximate the ratio of vGPCR-expressing and KSHV latent gene-expressing cells. These mice were then treated with ganciclovir to specifically target only the vGPCR-expressing cells. Surprisingly, despite the expression of KSHV latent genes in the vast majority of tumor cells, specifically targeting only the few vGPCR-expressing cells in established tumors resulted in tumor regression. Moreover, we observed an increase in apoptosis of latent gene-expressing cells after the pharmacologic deletion of the vGPCR-expressing cells. These findings indicate that vGPCR may play a key role in Kaposi's sarcoma progression and provide experimental justification for developing molecular-based therapies specifically targeting vGPCR and its effectors for the treatment of Kaposi's sarcoma patients.

Kaposi's Sarcoma and HIV-Tat: Challenges to Antiangiogenesis Research

Kaposi's sarcoma (KS) is characterized by an abnormal growth of blood vessels. KS was found mainly in older men of Mediterranean or African origin (classic KS) or in patients after organ transplantation (iatrogenic KS). However, in the early 1980s, an aggressive epidemic form, linked to AIDS, was noticed and was one of the first clues to the existence of HIV-1 pandemy. The link between KS occurrence and HIV has raised multiple hypotheses. The drastic reduction of KS after the introduction of HAART, suggests HIV as a powerful co-factor for KS progression. We and others have contributed to the elucidation of KS cell nature and the possible involvement of extracellular HIV Tat. Tat is proangiogenic and is a true promoter of KS lesions acting as a VEGFR2 ligand both on KS and endothelial cells, in addition Tat is able to bind and activate chemokine receptors on monocytes and granulocytes causing a pro-inflammatory status. Evaluation of the effects of extracellular Tat on KS cells by microarray analysis after 24 h of incubation shows an interesting clustering of gene products involved in signal transduction, especially GTP-ase, Kinase and cAMP activity, confirming that Tat acts extracellularly by ways that are probably unrelated to its nuclear activity. KS occurrence is reduced by HAART but still present and in Africa is one of the most frequent oncologic disease. To find suitable drugs with low toxic impact on KS patients, we have tested several drugs and gene therapy approaches in in vivo models. from 2005 International Meeting of The Institute of Human Virology Baltimore, USA, 29 August – 2 September 2005

Prevealence of HIV in Kaposi's Sarcoma (KS) Patients

Results 94.6% of the KS patients were HIV positive whereas 5.4% were HIV negative. The former had epidemic KS while the latter had endemic KS. The mean ages for the two types of KS were 34.9 years(standard deviation = 9.46) for epidemic KS and 34.5 years(standard deviation = 14.4) for endemic KS. The peak incidence of the former type of KS was in the age range 30 to 39 years whereas for the latter type it was more or less uniformly distributed in all the age groups from 10 to 59 years, with a slight peak in the 20 year age range(hence the large standard deviation). The male(M) to female(F) sex distribution for epidemic KS was 1.4:1 while for endemic KS it was 2:1. Also, endemic KS was more common in the low socioeconomic class unlike the epidemic type which cut across all socioeconomic strata.

Serological and molecular detection of HHV-8 in Brazilian populations

Little is known about human herpesvirus 8 (HHV-8) distribution in Brazil. We used indirect immunofluorescence serological assays to determine HHV-8 seroprevalence in two Amerindian tribes from the Amazon region, and blood donors and Kaposi’s sarcoma (KS) patients from the Campinas/SP (Southeastern region). Anti-HHV-8 antibodies were detected in 56.8% of the Amerindians (558/982), in all ages (0-81 years old) and both sexes. In these populations, high prevalence in children younger than 2 years old (44.4%) and children from 2 to 9 years old (35.0%) suggests non-sexual routes of HHV-8 transmission, through vertical transmission or contact to contaminated secretions. HHV-8 seroprevalence in blood donors from Campinas/SP was low (2.8%) and all positive cases were male (9/319) in the fourth and fifth decades of life. Curiously, these individuals were negative to routine serological tests applied in blood banks. Every KS patient assessed in our study was male, with average age of 37 years (27 to 79 years) and anti-HHV-8 positive assays in all cases. In order to determine HHV-8 molecular prevalence, we analyzed DNA from three Amerindian tribes from the Amazon region, KS patients from Campinas/SP and HIV patients from Salvador/BA (Northeastern region). We used Nested-PCR to amplify HHV-8 ORF-26 region by molecular screening. Every ORF-26 amplified sample was also amplified to hypervariable ORF-K1 region for HHV-8 genotyping. We analyzed 384 DNA samples from Amerindian tribes and detected HHV-8 sequences in 3.8% (13/384). KS patients had all DNA samples from skin biopsies and 45.5% from peripheral blood (PBMC) amplified. DNA samples from 148 HIV positive patients were analyzed and HHV-8 sequences were detected in 4% of cases (6/148). Almost all positive DNA samples were amplified to ORF-K1 and determined HHV-8 subtypes. Molecular techniques for amplification and sequencing of two fragments (VR1 and VR2) from ORF-K1 region made possible to build up phylogenetic trees and determine HHV-8 main viral subtypes (A, B, C, D and E) and its variants. Patients with KS from Campinas had subtypes A, B and C detected, with greater frequency of subtype C. Subtypes A and E were detected in Amazon Amerindians. This study is the first to perform genotyping in samples of HIV positive patients from Salvador, detecting subtype B and an unclassified subtype. Thus, it was possible to determine that HHV-8 subtypes A, B, C and E are present in Brazilian populations. As Brazil is a large country with variable population, culture and different geographical characteristics, more HHV-8 epidemiological studies are necessary to establish possible regional differences. This study was supported by grants from the Conselho Nacional de Pesquisa (CNPq) and Fundacao de Apoio a Pesquisa na Bahia (FAPESB).

Recrudescent Kaposi's Sarcoma After Initiation of HAART: A Manifestation of Immune Reconstitution Syndrome

The objective of this case series and literature review is to characterize the clinical course and prognosis of HIV-infected patients with Kaposi's sarcoma (KS) flare during immune reconstitution inflammatory syndrome (IRIS), a heterogeneous and sometimes fatal disorder of immune perturbation after initiation of highly active antiretroviral therapy (HAART). Medical records of 9 HIV-infected patients with KS flare after virologic and immunologic response to HAART were reviewed from a single institution. An additional 10 cases were abstracted by computerized search of the medical literature. In our single institution series, mean time to onset of KS flare was 5 weeks. Pretreatment mean CD4+ count was 190 cells/mm(3) and mean HIV viral load was 153,934 copies per milliliter. During flare, mean CD4+ count was 256 cells/mm(3) and mean HIV viral load was 1156 copies per milliliter. Similar aggregate results are represented in the literature. Six fatalities are reported, 4 from pulmonary KS and 2 from unrelated causes. Systemic chemotherapy universally led to tumor regression, but was administered in only 10 of 19 cases. In no instance was HAART discontinued. Onset of IRIS-associated KS flare is observed as early as 3 weeks, with most cases diagnosed within 2 months after immunologic and virologic response to HAART. Such a flare does not necessarily portend a poor prognosis. Even for those patients with rapidly symptomatic KS, early systemic chemotherapy is effective in suppressing IRIS-associated flare. Close clinical supervision is warranted for the KS patient initiating, changing, or resuming HAART. Particular vigilance is recommended for pulmonary involvement.

Thalidomide in the concurrent management of recurrent aphthous ulcerations and Kaposi sarcoma in HIV patients with severe immunosuppression

Thalidomide is a complex immunomodulatory and antiangiogenic agent whose role in oncology practice is as yet not fully clear. We present an unusual case documenting the use of thalidomide in the concurrent management of recurrent aphthous ulceration and kaposi sarcoma in a patient with severe immmunosuppression.

Human Herpesvirus 8 Serological Markers and Viral Load in Patients with AIDS-Associated Kaposi's Sarcoma in Central African Republic

Epidemic Kaposi's sarcoma (KS) is one of the most frequent types of cancer in several African countries; however, very few data are available on human herpesvirus 8 (HHV-8) markers in KS patients from Central Africa. In a series of 36 AIDS-KS cases from Central African Republic, we showed, using a real-time PCR quantitative assay, the high frequency (82%) of detectable HHV-8 DNA in peripheral blood mononuclear cells (PBMCs). We also found that the level of antibodies directed against lytic or latent HHV-8 antigens is not correlated to the amount of HHV-8 viral load in the PBMCs, and finally, we demonstrated a much higher viral load in tumoral skin lesions (6.07 log copies/mug DNA) than in unaffected skin (2.93 log copies/mug DNA) or in PBMCs (2.55 log copies/mug DNA).

Epidemic and endemic Kaposi's sarcoma: A comparison of outcomes and survival after radiotherapy

We retrospectively studied the outcomes of 80 Epidemic and African-Endemic Kaposi's Sarcoma (EKS and AKS) patients treated with radiotherapy doses of 8.0 Gy. The objective response for EKS at one month was 74 and 58% for AKS while 5-year survival for EKS was 27 and 46% for AKS.

Cytomegalovirus and human herpesvirus 8 DNA detection in peripheral blood monocytic cells of AIDS patients: Correlations with the presence of Kaposi's sarcoma and CMV disease

To establish the effect of the presence in blood cells of cytomegalovirus (CMV) and human herpesvirus 8 (HHV8) DNA, two herpesviruses that are activated frequently in AIDS patients, were selected from the Amsterdam Cohort Studies on HIV/AIDS 181 PBMC samples from patients with and without Kaposi's sarcoma (KS), and with and without CMV-related disease. The viral loads of both HHV8 and CMV were determined by real-time PCR at the time of diagnosis of AIDS. There was no significant difference in prevalence and load for CMV between the KS and non-KS patients. The variable related most strongly to KS was the presence of HHV8 DNA in PBMCs, whilst CMV DNA was related to the development of CMV disease and shortened survival. The frequency of detection of HHV8 increased when the patient presented with more severe KS symptoms at diagnosis, but detection of HHV8 DNA did not influence survival. Therefore, HHV8 and CMV DNA measured in the blood of AIDS patients, are each related mainly to the associated disease, and have no additional predictive value in these patients.

Gastrointestinal and cutaneous AIDS-related Kaposi's sarcoma: different activity of liposomal doxorubicin according to location of lesions

Kaposi's sarcoma (KS) continues to be a frequent neoplasm in third world AIDS patients. We carried out a prospective study to evaluate the effectiveness of liposomal doxorubicin (LD) in gastrointestinal KS patients as well as its differential clinical activity depending on the location of the lesions. The study included 15 male AIDS patients aged between 25 and 35 years (mean: 27 years) with more than 25 cutaneous lesions and extensive gastrointestinal KS. They were treated with LD, 20 mg/m(2) every 21 days, for six cycles. Eleven (73%) of the patients obtained a complete response of the gastrointestinal KS lesions and four (27%) a partial response. Regarding cutaneous lesions, only two (13%) of the patients reached a complete response, six (40%) a partial response and seven (47%) stabilized their disease. By applying Fisher's test we found a significant difference (P < 0.00035) when comparing the effectiveness of LD in gastrointestinal lesions in relation to cutaneous lesions. We conclude that LD is more effective in gastrointestinal KS and can be recommended in patients in third world countries with extensive gastrointestinal lesions.

Gamma secretase inhibitor blocks Notch activation and induces apoptosis in Kaposi's sarcoma tumor cells

Kaposi's sarcoma (KS) is a common neoplasm in HIV-1-infected individuals causing significant morbidity and mortality. Despite recent advances, the pathogenesis of this potentially life-threatening neoplasm remains unclear, and there is currently no cure for KS. Notch proteins are known to play a fundamental role in cell fate decisions including proliferation, differentiation, and apoptosis. It is, therefore, not surprising that Notch proteins have been implicated in tumorigenesis and appear to function as either oncogenes or tumor suppressor proteins depending on cellular context. In this report, we demonstrate elevated levels of activated Notch-1, -2, and -4 in KS tumor cells in vivo and in vitro compared to endothelial cells, the precursor of the KS cell. Notch activation was confirmed through luciferase reporter assays and localization of Hes (Hairy/Enhancer of Split)-1 and Hey (Hairy/Enhancer of Split related with YRPW)1 (primary targets of the Notch pathway) in KS cell nuclei. Studies using gamma-secretase inhibitors (GSI and LY-411,575), which block Notch activation, resulted in apoptosis in primary and immortalized KS cells. Similar studies injecting GSI into established KS cell tumors on mice demonstrated growth inhibition or tumor regression that was characterized by apoptosis in treated, but not control tumors. The results indicate that KS cells overexpress activated Notch and interruption of Notch signaling inhibits KS cell growth. Thus, targeting Notch signaling may be of therapeutic value in KS patients.

Molecular epidemiology of Kaposi's sarcoma herpesvirus (KSHV) in Cuban and German patients with Kaposi's sarcoma (KS) and asymptomatic sexual contacts

Kaposi's sarcoma (KS) shows a distinct geographical and ethnic distribution. The variable K1 gene serves to differentiate the KSHV subtypes A–E, M, N, and Q. Phylogenetic characterization of 19 classical and epidemic German KS specimens revealed the Eurasian KSHV subtypes C ( n = 13, including 6 classical KS) and A ( n = 6), while 27 Cuban specimens showed a variety of different subtypes (A: n = 16, 4 being A5; C: n = 8; B: n = 2; and the new subtype E: n = 1). Three pairs of isolates from KS patients and peripheral blood mononuclear cells (PBMC) of their sexual partners without KS were studied for the first time and found identical, strongly arguing for sexual transmission of KSHV in this unique cohort. The unique ethnic background of the Cuban population may explain the variety of different KSHV strains.

Highly Active Antiretroviral Therapy in AIDS-Associated Kaposi's Sarcoma (KS): Implications for the Design of Therapeutic Trials in Patients With Advanced Symptomatic KS

TO THE EDITOR: The article by Dr Krown provides very appropriate and timely considerations with regard to the management of patients with advanced, symptomatic, AIDS-related Kaposi’s sarcoma (AIDS-KS) in the era of highly active antiretroviral therapy (HAART) and suggests, on the basis of a comprehensive review of the literature, that in T1 (according to the AIDS Clinical Trials Group [ACTG] staging classification) symptomatic KS patients, concomitant chemotherapy should be added to HAART without awaiting a response to HAART. Moreover, the author, referencing our study, states that “T1 and T0 groupings have been associated with distinct survival distribution.” In response, we would like to clarify our data as reported by Dr Krown. We believe that our data may help to better define which group of patients within the T1 category need a timely institution of chemotherapy concomitantly to HAART, and for which group it is too risky to await a possible response to HAART. In our study, we collected clinical and survival data from 211 patients with AIDS-KS enrolled in two prospective cohort studies beginning in 1996, the time when HAART became available in Italy, with the aim of validating the ACTG staging system for AIDS-KS in the HAART era. All patients received HAART. Our analysis identified two different risk categories: a good-risk group (T0S0, T1S0, and T0S1) and a poor-risk group (T1S1). The 3-year survival rate of patients with T1S1 was 53%, significantly lower than the 3-year survival rates of patients with T0S0, T1S0, and T0S1, which were 88%, 80%, and 81%, respectively (P .0001). Therefore, the T category alone does not provide an appropriate survival discrimination, as occurred in the pre-HAART period. When we considered only patients with pulmonary involvement (namely,Tp1) as compared with T1 patients without pulmonary disease (namely,Tp0), the 3-year survival rate was 46% for Tp1 and 77% for Tp0 patients (P .0002), indicating that patients with pulmonary involvement identify the group of patients with the poorest prognosis, independent of the other ACTG variables. Therefore, we believe that we were able to identify, within the T1 category, a specific subgroup of KS patients (ie, T1S1, Tp1) with an unfavorable survival rate in whom HAART and concomitant chemotherapy should be used.