Kaposi's Sarcoma Patients Research Articles

Manipulating Host Signaling for Pathogenic Purposes: Hijacking of the Transcriptional Activity of the Host Protein Nrf2 by Kaposi’s Sarcoma-Associated Herpesvirus

Kaposi’s sarcoma-associated herpesvirus (KSHV) is the etiological agent of two highly aggressive AIDS-related malignancies, endothelial Kaposi’s sarcoma (KS) and B cell primary effusion lymphoma (PEL). Although current antiretroviral therapy (ART) methods have decreased the overall morbidity and mortality in immunocompromised and AIDS patients, KS and PEL remain difficult to treat. Thus, novel therapeutic methods are essential to significantly improve the life expectancy and quality of life of PEL and KS patients, respectively. One of the signaling pathways that is highly modulated during KSHV infection is oxidative stress, which is a well-known inducer of the transcription factor Nrf2. Because Nrf2 plays an important role in the biology of several viral infections, and is an important agent in cancer progression and chemotherapeutic resistance, we recently undertook a study to investigate its role in KSHV infection of endothelial cells. Here, we provide important highlights of our recent findings, including the importance of oxidative stress and PKCζ in Nrf2 activation, a newly discovered feed-forward loop between Nrf2 and COX-2, and the impact of Nrf2 activation on host and KSHV gene expression and pathogenesis. Lastly, we provide insights on the potential therapeutic implications of Nrf2 modulation in KSHV and other virus-associated pathologies.

Markers to differentiate between Kaposi's sarcoma and tuberculous pleural effusions in HIV-positive patients.

Kaposi's sarcoma (KS) and tuberculosis (TB) commonly cause pleural effusions in high human immunodeficiency virus (HIV) burden resource-limited countries. Differentiating between them is challenging, as pleural biopsy and TB culture are rarely available. To identify markers to differentiate between TB effusions and KS effusions in HIV-positive patients, and to compare liquid culture and Xpert MTB/RIF in pleural fluid. Fifty HIV-positive patients with pleural effusions recruited in Malawi underwent pleural ultrasound and aspiration. Fluid visual inspection, cell count, bacterial culture, glucose/protein, solid and liquid TB culture and Xpert were performed. The mean age of the patients was 32 years; 30/50 (60%) were male and 29 (58%) had cutaneous/oral KS. Thirteen (26%) pleural fluid samples were liquid culture-positive for TB, while 9/13 (69%) were Xpert-positive. Three (10.3%) KS patients had culture-positive TB effusions; 17 (58.6%) had KS effusions. The relative risk of TB in KS patients increased with limited KS, loculated fluid and low glucose. Eleven (52.3%) non-KS patients had culture-positive TB effusions associated with male sex, straw-coloured fluid and fibrin stranding on ultrasound. KS patients were most likely to have KS effusion, but TB should be considered. Most non-KS patients had TB, supporting the use of World Health Organization guidelines. Xpert identified two thirds of liquid culture-positive results.

Characteristics and survival for HIV-associated multicentric Castleman disease in Malawi.

IntroductionClinical reports of multicentric Castleman disease (MCD) from sub-Saharan Africa (SSA) are scarce despite high prevalence of HIV and Kaposi sarcoma-associated herpesvirus (KSHV). Our objective is to describe characteristics and survival for HIV-associated MCD patients in Malawi. To our knowledge, this is the first HIV-associated MCD case series from the region.MethodsWe describe HIV-positive patients with MCD in Lilongwe, and compare them to HIV-associated lymph node Kaposi sarcoma (KS) and non-Hodgkin lymphoma (NHL) patients treated at our centre. All patients were enrolled into a prospective longitudinal cohort study at a national teaching hospital and cancer referral centre serving half of Malawi's 16 million people. We included adult patients≥18 years of age with HIV-associated MCD (n=6), lymph node KS (n=5) or NHL (n=31) enrolled between 1 June 2013 and 31 January 2015.Results and discussionMCD patients had a median age of 42.4 years (range 37.2–51.8). All had diffuse lymphadenopathy and five had hepatosplenomegaly. Concurrent KS was present for one MCD patient, and four had performance status ≥3. MCD patients had lower median haemoglobin (6.4 g/dL, range 3.6–9.3) than KS (11.0 g/dL, range 9.1–12.0, p=0.011) or NHL (11.2 g/dL, range 4.5–15.1, p=0.0007). Median serum albumin was also lower for MCD (2.1 g/dL, range 1.7–3.2) than KS (3.7 g/dL, range 3.2–3.9, p=0.013) or NHL (3.4 g/dL, range 1.8–4.8, p=0.003). All six MCD patients were on antiretroviral therapy (ART) with median CD4 count 208 cells/µL (range 108–1146), and all with HIV RNA <400 copies/mL. Most KS and NHL patients were also on ART, although ART duration was longer for MCD (56.4 months, range 18.2–105.3) than KS (14.2 months, range 6.8–21.9, p=0.039) or NHL (13.8 months, range 0.2–98.8, p=0.017). Survival was poorer for MCD patients than lymph node KS or NHL.ConclusionsHIV-associated MCD occurs in Malawi, is diagnosed late and is associated with high mortality. Improvements in awareness, diagnostic facilities, treatment and supportive care are needed to address this likely under-recognized public health problem in SSA.

Genotypic analysis of Kaposi's sarcoma-associated herpesvirus from patients with Kaposi's sarcoma in Xinjiang, China.

Kaposi’s sarcoma-associated herpesvirus (KSHV) is the causal agent of all forms of Kaposi’s sarcoma (KS), including AIDS-KS, endemic KS, classic KS and iatrogenic KS. Based on Open reading frame (ORF) K1 sequence analysis, KSHV has been classified into seven major molecular subtypes (A, B, C, D, E, F and Z). The distribution of KSHV strains varies according to geography and ethnicity. Xinjiang is a unique region where the seroprevalence of KSHV is significantly higher than other parts of China. The genotyping of KSHV strains in this region has not been thoroughly studied. The present study aimed to evaluate the frequency of KSHV genotypes isolated from KS tissues in Classical KS and AIDS KS patients from Xinjiang, China. ORF-K1 of KSHV from tissue samples of 28 KS patients was amplified and sequenced. Two subtypes of KSHV were identified according to K1 genotyping. Twenty-three of them belonged to subtype A, while five of them were subtype C. More genotype A than genotype C strains were found in both Classical KS and AIDS KS. No significant difference was found in the prevalence of different genotype between Classical KS and AIDS KS.

Twenty years of KSHV.

Twenty years ago, Kaposi’s sarcoma (KS) was the oncologic counterpart to Winston Churchill’s Russia: a riddle, wrapped in a mystery, inside an enigma. First described by Moritz Kaposi in 1872, who reported it to be an aggressive skin tumor, KS became known over the next century as a slow-growing tumor of elderly men—in fact, most KS patients were expected to die with the tumor rather than from it. Nevertheless, the course and manifestations of the disease varied widely in different clinical contexts. The puzzle of KS came to the forefront as a harbinger of the AIDS epidemic. The articles in this issue of Viruses recount progress made in understanding Kaposi’s sarcoma herpesvirus (KSHV) since its initial description in 1994.

Abstract 3649: Significance of HIV viral load and CD4 count on Kaposi sarcoma in the era of highly active antiretroviral therapy

Abstract Background: Approximately 20% of patients with HIV will have Kaposi Sarcoma (KS) and about half will die within 3 months of diagnosis. Incidence and outcomes of KS have traditionally been linked to CD4 counts &amp;lt;350. More recently, KS has been increasingly described in higher CD4 counts and variable presentations in the era of Highly-Active-Antiretroviral-Therapy (HAART). No studies have established the role of Viral Load (VL) on KS. Objective: To determine the effect of CD4 count and HIV VL on KS presentation and outcomes. Methods: Retrospective review of KS patients with HIV admitted over 12 years (2000-2012). KS patients without HIV infection were excluded. Patients were divided into 4 groups based on CD4 count (≥200 or 100,000 or &amp;lt;100,000). Groups were analyzed with regards to KS severity (good vs poor risk), extent (soft tissue vs visceral), receipt of HAART and survival (6months). Statistical analysis was done via Chi-Square test. Results: 43 patients were included. KS affected predominantly young (30-40yrs), male (93%) HIV patients with VL &amp;gt;100,000 (85%) and CD4 counts 100,000 had a statistically significant increased incidence for visceral involvement (96%, p100,000 ((66.7% with good risk), increased survival (59.4% survived &amp;gt;6months) and less use of HAART (20%). Although, these differences were statistically insignificant. Conclusion: HIV VL of &amp;gt;100,000 is correlated with increased severity and extent of KS. Though statistically insignificant, CD4 counts &amp;lt;200 showed a trend for less severe disease and increased survival despite less use of HAART. Larger prospective studies are warranted to elucidate on these differences. Citation Format: Gentry T. King, Shivani Garg. Significance of HIV viral load and CD4 count on Kaposi sarcoma in the era of highly active antiretroviral therapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3649. doi:10.1158/1538-7445.AM2014-3649

Abstract 4932: Kaposi's sarcoma represents a dynamic pathogenic process involving ongoing macrophage replenishment with both tumor cells as well as macrophages expressing CD206, a target for the recently approved imaging agent, Tilmanocept

Abstract Introduction In patients with Kaposi's sarcoma (KS), plasma elevation of macrophage (MO)-produced growth factors such as EGF and bFGF suggests a role for tumor associated MOs (TAM) in KS pathogenesis. Goals of the current study were twofold: 1) To define MO subsets using M1 (MAC387), M2 (CD163, CD206) and pan macrophage CD68 antibodies in tissue microarray (TMA) analysis of all forms of KS including plaque, oral and visceral tumors. 2) To test whether CD206, the macrophage mannose receptor recognized by the recently approved imaging agent Tilmanocept (Navidea), is present on TAMs and KS tumor cells. If TAMs and KS tumor cells are CD206+, Tilmanocept could allow KS specific imaging for purposes of tumor staging, a procedure heretofore unapproachable. Methods A KS TMA with 66 KS cases and controls was obtained from the AIDS and Cancer Specimen Resource (ACSR). MO antigens were identified by IHC studies and results were standardized to the proportion of KSHV LANA+ cells (KS tumor specific marker). ACSR KS specimens from Kenya and South Africa (where KS is a common cause of death) were tested in a follow-up study. Results Most TAMs in KS tissues were identified with the M2 specific anti-CD163 antibody whereas the M1 anti-MAC387 antibody identified a smaller subset of cells. The CD68 antibody also identified a large number of TAMs in more than 90% of tumors. KS tumor spindle cells in general expressed macrophage antigens; however the most prevalent antigen for both KS tumor cells (LANA+) and TAMs was CD206 molecule. Expression of MO antigens and CD206 in relation to level of LANA within tumor tissues was similar across all tissue forms of KS (plaque, oral, visceral). In general, KS tissues from Africa contained higher relative levels of TAMs than tissues from US cases. Conclusions KS pathogenesis appears to involve an ongoing replenishment of TAMs from recent blood derived monocytes that express either M1 (MAC-387) or M2 (CD163) antigens. Both MO antigens identify cells that are turned over within days, suggesting that KS while appearing relatively indolent has a very dynamic MO migration component, apparently required for KS pathogenesis. This study also confirmed a preliminary study (Uccini et al. AJP 1997) that found both TAMs and KS tumor cells to express the CD206 macrophage mannose receptor. Tilmanocept, a technetium labeled ligand for CD206 recently approved by the FDA for human imaging use, may allow effective imaging of KS involved nodes and other visceral sites of disease. Considering the current inability of clinicians to determine the degree of KS spread beyond the presence of obvious skin lesions, the potential for using Tilmanocept to define tumor burden may allow earlier tumor specific treatment beyond the current use of anti-retroviral therapy alone which is proving ineffective in growing numbers of KS patients worldwide. Citation Format: Michael S. McGrath, Paige M. Bracci, Frederick O. Cope, Rongzhen Zhang. Kaposi's sarcoma represents a dynamic pathogenic process involving ongoing macrophage replenishment with both tumor cells as well as macrophages expressing CD206, a target for the recently approved imaging agent, Tilmanocept. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4932. doi:10.1158/1538-7445.AM2014-4932

Triple secondary neoplasms

Pegylated liposomal doxorubicin (PLD) is a first-line therapy for AIDS Kaposi's sarcoma [1]. Kaposi's sarcoma lesions contain dilated vascular spaces with extravasated erythrocytes; PLD uptake due to extravasation of liposomes was anticipated, offering advantage over conventional formulation. Skin Kaposi's sarcoma biopsies of patients under PLD reached 10–20 times doxorubicin concentrations to that of the normal skin [1]. Complete regression of Kaposi's sarcoma solely with highly active antiretroviral therapy (HAART) has been reported [2–5], questioning the need of chemotherapy for this angioproliferative disease produced by human herpes virus 8, as chemotherapy can increase immunosuppression. Worsening of Kaposi's sarcoma after HAART initiation is a manifestation of immune reconstitution syndrome [6,7], and without visceral involvement, it is a limited phenomenon; as immune function recovers, Kaposi's sarcoma regresses without further therapy. Secondary malignancy is a concern from chemotherapy use, but its role is difficult to demonstrate as other factors can contribute to its development. A substantial high incidence of secondary neoplasms – 9% among Kaposi's sarcoma patients treated with PLD – was recently reported [8], and oral cavity squamous cell carcinoma has also been reported in PLD-exposed patients [9–12], raising concerns of a possible contributing effect of PLD in the development of these neoplasms. Here, we present the case of a 37-year-old man with a 20-year history of cigarette smoking (average 5 cigarettes per day), who was diagnosed with AIDS on May 2011; he presented with wasting syndrome, oropharyngeal-candidiasis, disseminated-Mycobacterium avium Intracelulare and cutaneous Kaposi's sarcoma. His viral load was 631 471 copies/ml and CD4+ 144 cells/ml. The patient was started on Truvada + Kaletra and, 4 months later, the viral load was undetectable and the CD4+ had risen to 196 cells/ml. Following this, he received five monthly cycles with bleomycin 17 units, vincristine 2 mg and dexamethasone 16 mg, after which monthly PLD was started. On October 2012, after eight cycles of PLD, the patient noted multiple erythematous plaques in his penis; his HIV viral load remained undetectable, but he had 73 cells/ml CD4+. A penis biopsy revealed epidermoid carcinoma, which was successfully treated with topical 5% fluouracil. In November 2012, the patient complained of lip and oral mucosa lesions, for which the biopsies reported high-grade dysplasia. Several variants of HPV were identified: in the penis carcinoma and ureteral smear 16, in lips 33 and 35, in oral mucosa 35, in fresh oral mucosal smear 16 and 33, and in perianal condylomas 16 and 11. To our knowledge, there are no reports on adverse effects of PLD in HIV patients with concomitant mucosal HPV infections. However, since PLD concentrates for prolonged periods in mucous membranes, it is likely that it might alter local immunity since. PLD immunosuppression could also increase HPV replication [13], and decrease CD4+ cell counts [8] as for the case herein reported, in whom despite HIV viral suppression, CD4+ cells decrease with PDL administration (Fig. 1).Fig. 1: Temporal events of patient's case.Administration of chemotherapy*: (1) bleomycin 17 mg + vincristine 2 g + dexamethasone 16 mg (5 cycles); (2) pegylated liposomal doxorubicin (PLD) 60 mg + dexamethasone 16 mg (10 cycles). Red line, HIV viral load; blue diamonds, CD4+ cell count; pink bars, accumulated PLD. (a) Hematoxylin and eosin (HE) 40×. Penis mucosa with marked cytological atypia involving the entire epithelium. Note numerous atypical mitosis in the upper zones. *In-situ epidermoid penis carcinoma, human papillomavirus (HPV)16+. (b) HE 10×. Lip mucosa with acanthosis, cytologic atypia involving half epithelium. Note koilocytosis in the upper. High grade dysplasia (HGD) of the lip HPV 33 and 35+. (c) Oral mucosa. HE 4× and Ki67 immunostain. Oral mucosa with irregular acanthosis and cytologic atypia. Involving more than half of the epithelium. Note Ki67 positive in the entire epithelium, HGD of oral mucosa HPV35+.Although there has been an increasing incidence of non-AIDS-defining malignancies in the HAART era, the incidence of cancers of the oral cavity and penis in HIV patients is rare (<1%) [14]. Kaposi's sarcoma remission can be achieved solely with HAART and thus the use of PLD in AIDS Kaposi's sarcoma should be questioned since it can chronically affect the control of HPV infection and thus increase the risk of HPV-related neoplasms. Acknowledgements Conflicts of interest There are no conflicts of interest.

Elevation of soluble intercellular adhesion molecule-1 levels, but not angiopoietin 2, in the plasma of human immunodeficiency virus-infected African women with clinical Kaposi sarcoma.

Circulating levels of endothelial activation biomarkers are elevated in during infection with human immunodeficiency virus 1 (HIV-1) and may also be increased in Kaposi sarcoma (KS). We compared 23 HIV-1-seropositive women with clinically diagnosed KS with 46 randomly selected controls matched for visit year, CD4 count, and antiretroviral therapy status. Conditional logistic regression was used to identify differences between cases and controls. The odds of clinical KS increased with increasing plasma viral load and with intercellular adhesion molecule 1 (ICAM-1) levels above or equal to the median. There was a borderline association between increasing plasma angiopoietin 2 levels and KS. In multivariable modeling including plasma viral load, angiopoietin 2, and ICAM-1, plasma ICAM-1 levels above or equal to the median remained associated with clinical KS (odds ratio = 14.2, 95% confidence interval = 2.3-87.7). Circulating ICAM-1 levels should be evaluated as a potential biomarker for disease progression and treatment response among HIV-infected KS patients.

Claudin-2 downregulation by KSHV infection is involved in the regulation of endothelial barrier function.

Kaposi sarcoma (KS), caused by the infection of Kaposi sarcoma-associated herpesvirus (KSHV), is a disease manifested mainly by dark purple skin and mouth nodules. Cancer care studies showed that co-infection of KSHV and human immunodeficiency virus (HIV) was able to increase the patients' survival, but the underlying mechanisms are still elusive. To understand the mechanism underlying the prolonged survival in KSHV-HIV co-infected patients, we performed microarray analysis on RNA extracted from biopsies from KS tumors and adjacent healthy tissues in four KS patients. Subsequently, we performed hierarchical clustering, gene ontology (GO) and ingenuity pathway analysis. We then characterized the roles of tight junction protein claudin-2 in the endothelial barrier function. Three hundred and forty-three differentially expressed genes were identified, of which 246 genes exhibited significantly increased expression in the tumor compared to the adjacent healthy tissue and 97 genes showed downregulated expression, including claudin-2. Knockdown of claudin-2 in cultured endothelial cells enhances barrier function by altering the charge selectivity, but not the size selectivity. Claudin-2 expression is decreased in KS tumors from patients co-infected with KSHV and HIV. Decreased claudin-2 enhances endothelial barrier function and may play a role in the prolonged survival of patients with KSHV and HIV co-infection.

Prognosis and delay of diagnosis among Kaposi's sarcoma patients in Uganda: a cross-sectional study.

BackgroundIn low- and middle-income countries, the association between delay to treatment and prognosis for Kaposi’s sarcoma (KS) patients is yet to be studied.MethodsThis is a prospective study of HIV-infected adults with histologically-confirmed KS treated at the Uganda Cancer Institute (UCI). Standardized interviews were conducted in English or Luganda. Medical records were abstracted for KS stage at admission to UCI. Multivariable logistic regression assessed relationships between diagnostic delay and stage at diagnosis.ResultsOf 161 patients (90% response rate), 69% were men, and the mean age was 34.0 years (SD 7.7). 26% had been seen in an HIV clinic within 3 months, 72% were on antiretroviral therapy, and 26% had visited a traditional healer prior to diagnosis. 45% delayed seeking care at UCI for ≥3 months from symptom onset. Among those who delayed, 36% waited 6 months, and 25% waited 12 months. Common reasons for delay were lack of pain (48%), no money (32%), and distance to UCI (8%). In adjusted analysis patients who experienced diagnostic delay were more likely than those who did not delay to have poor-risk KS stage (OR 3.41, p = 0.002, 95% CI: 1.46-7.45). In adjusted analyses visiting a traditional healer was the only variable associated with greater likelihood of delay (OR 2.69, p = 0.020, 95% CI: 1.17-6.17).ConclusionsDiagnostic delay was associated with poor-risk stage at diagnosis, and visiting a traditional healer was associated with higher odds of delay. The relationship between traditional and Western medicine presents a critical intervention point to improve KS-related outcomes in Uganda.

Survival and its determinants of Kaposi sarcoma in Tanzania: Retrospective study.

e20607 Background: Kaposi Sarcoma is the most common sarcoma and second most prevalent cancer seen in Tanzania. Its affect all age groups and strongly associated with AIDS. Little is known about disease/patients characteristics and survivorship in our settings, therefore this study expected to determine patients survival and its associated factors in Tanzania. Methods: Retrospective descriptive study using structured questionnaires. Patients with Kaposi Sarcoma diagnosed and treated at Ocean Road Cancer Institute, the only cancer care center in Tanzania were followed-up retrospectively using their hospital records and mobile phone communication system, with 199 patients included in the study. Descriptive, Bi-variate Analysis, Ordinal Regression, Life Tables and Kaplan Meier survival analysis as well as SPSS 16.0 and Log rants validity test were used during data analysis. Results: Mean age at KS diagnosis was 40 ± 12.012 yrs, with male (42.60 ± 12.6 yrs) population older than female ( 35.1 ± 9.7 yrs) . Patients waited 30 ± 120 days after diagnosis before start of treatment. Male : Female ratio was 1.6:1, with radiotherapy (82%) found to be most preferred modality of treatment. Skin (87.3%) was most primary organ affected followed by oral cavity (12.2%). Median and average survival of KS patients were 8 ± 0.613 months and 15.863 ± 1.407 months respectively. Primary organ affected and patient residence found significantly to influence survival while age, sex, treatment modality, hemoglobin level, time taken waiting for treatments found to be insignificant survival predictors. Serum white cell and platelets counts have not shown to influence survival with HIV found to affect 90% of Kaposi Sarcoma patients. Conclusions: Social demographic features, overall and median survival of patients with Kaposi Sarcoma in Tanzania, is closely related to other countries with similar settings but the latter two were significantly low compared to developed countries; This might be caused by differences in disease profile, late presentation, poor diagnostic and treatment resources seen in Tanzania compared with other settings.

Kaposi's Sarcoma in HIV-infected patients in South Africa: Multicohort study in the antiretroviral therapy era.

The incidence of Kaposi's Sarcoma (KS) is high in South Africa but the impact of antiretroviral therapy (ART) is not well defined. We examined incidence and survival of KS in HIV-infected patients enrolled in South African ART programs. We analyzed data of three ART programs: Khayelitsha township and Tygerberg Hospital programs in Cape Town and Themba Lethu program in Johannesburg. We included patients aged >16 years. ART was defined as a regimen of at least three drugs. We estimated incidence rates of KS for patients on ART and not on ART. We calculated Cox models adjusted for age, sex and time-updated CD4 cell counts and HIV-1 RNA. A total of 18,254 patients (median age 34.5 years, 64% female, median CD4 cell count at enrolment 105 cells/μL) were included. During 37,488 person-years follow-up 162 patients developed KS. The incidence was 1,682/100,000 person-years (95% confidence interval [CI] 1,406-2,011) among patients not receiving ART and 138/100,000 person-years (95% CI 102-187) among patients on ART. The adjusted hazard ratio comparing time on ART with time not on ART was 0.19 (95% CI 0.13-0.28). Low CD4 cell counts (time-updated) and male sex were also associated with KS. Estimated survival of KS patients at one year was 72.2% (95% CI 64.9-80.2) and higher in men than in women. The incidence of KS is substantially lower on ART than not on ART. Timely initiation of ART is essential to prevent KS and KS-associated morbidity and mortality in South Africa and other regions in Africa with a high burden of HIV.

Short-Chain Fatty Acids from Periodontal Pathogens Suppress Histone Deacetylases, EZH2, and SUV39H1 To Promote Kaposi's Sarcoma-Associated Herpesvirus Replication

Periodontal pathogens such as Porphyromonas gingivalis and Fusobacterium nucleatum produce five different short-chain fatty acids (SCFAs) as metabolic by-products. We detect significantly higher levels of SCFAs in the saliva of patients with severe periodontal disease. The different SCFAs stimulate lytic gene expression of Kaposi's sarcoma-associated herpesvirus (KSHV) dose dependently and synergistically. SCFAs inhibit class-1/2 histone deacetylases (HDACs) and downregulate expression of silent information regulator-1 (SIRT1). SCFAs also downregulate expression of enhancer of zeste homolog2 (EZH2) and suppressor of variegation 3-9 homolog1 (SUV39H1), which are two histone N-lysine methyltransferases (HLMTs). By suppressing the different components of host epigenetic regulatory machinery, SCFAs increase histone acetylation and decrease repressive histone trimethylations to transactivate the viral chromatin. These new findings provide mechanistic support that SCFAs from periodontal pathogens stimulate KSHV replication and infection in the oral cavity and are potential risk factors for development of oral Kaposi's sarcoma (KS). About 20% of KS patients develop KS lesions first in the oral cavity, while other patients never develop oral KS. It is not known if the oral microenvironment plays a role in oral KS tumor development. In this work, we demonstrate that a group of metabolic by-products, namely, short-chain fatty acids, from bacteria that cause periodontal disease promote lytic replication of KSHV, the etiological agent associated with KS. These new findings provide mechanistic support that periodontal pathogens create a unique microenvironment in the oral cavity that contributes to KSHV replication and development of oral KS.

Treatment of Kaposi sarcoma in children with HIV-1 infection

Kaposi sarcoma (KS) remains the second most frequently diagnosed HIV-related malignancy (HRM) worldwide and most common HRM in sub-Saharan Africa where HIV is most prevalent and human herpesvirus 8 (HHV-8), the precipitating agent for the development of KS, is endemic. The majority of KS patients would likely benefit from systemic chemotherapy in addition to the initiation of antiretroviral therapy (ART). However, as paediatric staging and treatment criteria are not readily available, there are no uniform treatment criteria. To describe the efficacy and effectiveness of current treatment options for HIV-associated KS in ART-treated paediatric populations. We used standard Cochrane methods to search electronic databases and conference proceedings with relevant search terms without limits to language. Randomised controlled trials, cohort studies, and case-control studies of HIV-infected infants and children <18 years old treated with ART and diagnosed with KS. Abstracts of all studies identified by electronic or bibliographic scanning were examined independently by two authors. We initially identified 920 references and examined 15 in detail for study eligibility. Data were abstracted independently using a standardised abstraction form. After initially screening 920 titles, 15 full-text articles were closely examined by two authors. We identified four cohort studies that met our inclusion criteria for data extraction, coding, and potential meta-analysis.Using the Newcastle-Ottawa Scale and Cochrane risk of bias assessments, all observational studies had cohorts that were representative of average (treated and untreated) HIV-infected children with Kaposi sarcoma. For all outcomes of interest, no study adjusted for any other potential confounders. Two of four observational studies either explicitly described complete follow up of the study participants and/or described the characteristics of the participants lost to follow up.The use of ART together with a chemotherapeutic regimen versus ART alone appears to increase the likelihood of KS remission in HIV-infected children diagnosed with KS, although data are sparse and not adequately adjusted for staging of disease and comorbidities. Additionally, though data are sparse, the use of ART together with a chemotherapeutic regimen versus chemotherapy alone in some analyses appears to increase the likelihood of KS remission and reduce the risk of death in HIV-infected children diagnosed with KS.In this analysis, we found that the quality of evidence was very low due to small sample sizes and a paucity of paediatric literature. Data describing the efficacy of different treatment options for pediatric KS, to include chemotherapy and ART, are sparse. However, the use of ART together with a chemotherapy regimen may be superior to the use of ART alone or of chemotherapy alone.

One hundred and five Kaposi sarcoma patients: a clinical study in Xinjiang, Northwest of China

Kaposi's sarcoma (KS) is an unusual illness that may be associated with human herpes virus 8 (HHV-8) infections, and appears mainly in Jews, Italians and Greeks. There is a lack of patient data in Xinjiang regarding the clinical characteristics of KS. To review the clinical characteristics of a series of patients with KS in Xinjiang, Northwest China, over 16-year period. A retrospective analysis of patients referred to a Xinjiang hospital in Northwest China with classic KS (CKS) and AIDS-associated KS (AIDS-KS) between January 1997 and April 2013 was performed. Reviewed information included demographics, clinical features, histopathological traits, treatment and presence of HHV-8 infection. During the study period, 105 patients with a diagnosis of KS, including 77 CKS and 28 AIDS-KS, were referred to our hospital. Mean age at diagnosis was 55.8±16.8years (range: 25-85years). There were 70 (90.9%) males and 7 (9.1%) females (male-to-female ratio: 10:1) having CKS and 21 (75.0%) males and 7 (25.0%) females (male-to-female ratio: 3:1) with AIDS-KS. Most of the patients were Uyghur, including 67 CKS and 24 AIDS-KS. The rate of multifocal lesions at diagnosis was 98.1% (103/105). The most common area of lesions was between 1% and 5% of CKS and AIDS-KS. The main types of lesions were nodules, patches and plaques. The lower extremity and foot were the most common locations for CKS and AIDS-KS. In addition to skin damage, the penis, mouth, lymph nodes and interstitial lung tissues were involved in some cases. No second primary malignancy was diagnosed. Systemic chemotherapy and radiotherapy were effective treatments for CKS. The HHV-8 positivity rate was 98.98% in 98 KS cases. In Xinjiang, most CKS and AIDS-KS patients were older Uyghur men. AIDS-KS was found predominantly among 30-year-old Uyghur patients, compared with 60years for those having CKS. The latter exhibited certain characteristics such as disseminated skin disease; in some patients, the condition was accompanied by lymphedema, visceral or lymph node involvement, but no secondary malignancies. In addition, the HHV-8 positivity rate associated with KS was very high.

YGLF motif in the Kaposi sarcoma herpes virus G-protein-coupled receptor adjusts NF-κB activation and paracrine actions

Kaposi sarcoma (KS) and primary effusion lymphoma (PEL) are two pathologies associated with KS herpes virus (KSHV/HHV-8) infection. KSHV genome contains several oncogenes, among which, the viral G-protein-coupled receptor (vGPCR open reading frame 74) has emerged as a major factor in KS pathogenicity. Indeed, vGPCR is a constitutively active receptor, whose expression is sufficient to drive cell transformation in vitro and tumour development in mice. However, neither the role of vGPCR in KSHV-infected B-lymphocytes nor the molecular basis for its constitutive activation is well understood. Here, we show that vGPCR expression contributes to nuclear factor-κB (NF-κB)-dependent cellular survival in both PEL cells and primary B cells from HIV-negative KS patients. We further identified within vGPCR an AP2 consensus binding motif, Y326GLF, that directs its localization between the plasma membrane and clathrin-coated vesicles. The introduction of a mutation in this site (Y326A) increased NF-κB activity and proinflammatory cytokines production. This correlated with exacerbated morphological rearrangement, migration and proliferation of non-infected monocytes. Collectively, our work raises the possibility that KSHV-infected B-lymphocytes use vGPCR to impact ultimately the immune response and communication within the tumour microenvironment in KSHV-associated pathologies.

Higher Levels of Neutralizing Antibodies against KSHV in KS Patients Compared to Asymptomatic Individuals from Zambia

Kaposi sarcoma-associated herpesvirus (KSHV) is the etiologic agent for Kaposi Sarcoma (KS), the most common cancer diagnosed in HIV- infected patients. The role of neutralizing antibodies in KS pathogenesis and in KSHV infected individuals is not clearly understood. The goal of this study was to investigate and compare the prevalence and titers of neutralizing antibodies in plasma samples from KS patients and KSHV infected asymptomatic individuals from Zambia, a KS endemic region in sub-Saharan Africa. Plasma samples (N = 267) consisting of KS patients (group 1) and asymptomatic individuals (group 2) were collected from Lusaka, Zambia. A flow cytometry based quantitative neutralization assay utilizing recombinant KSHV expressing GFP was used to detect KSHV neutralizing antibodies. Our results show that the overall prevalence of neutralizing antibodies in KS patients (group 1) was 66.7% which was significantly higher than the prevalence of 6.5% present in KSHV infected asymptomatic individuals (group 2). Total antibody titers as well as neutralizing antibodies titers were found to be significantly higher among KS patients. It is likely that higher neutralizing antibodies prevalence and titers in KS patients result from higher levels of antigenic stimulation over time. This study is first to compare prevalence and titers of neutralizing antibodies in participants with and without disease from a KSHV endemic region.

Continuous exposure to Kaposi sarcoma-associated herpesvirus (KSHV) in healthcare workers does not result in KSHV infection

Kaposi sarcoma (KS)-associated herpesvirus (KSHV or HHV-8) infection routes and risk of occupational exposure are still ill-defined. We analysed the risk for occupational acquisition of KSHV infection in healthcare workers (HCWs) with prolonged professional exposure to patients with classic KS, comparing the results to those obtained in healthy relatives of KS patients. Serum and/or saliva KSHV-specific antibodies and DNA were detected in five out of 35 healthy relatives of KS patients but in none of the eight HCWs, suggesting that, outside strict family contacts, horizontal transmission of KSHV is highly inefficient even for HCWs with prolonged contact with KS patients.

Treatment Response and Mortality among Patients Starting Antiretroviral Therapy with and without Kaposi Sarcoma: A Cohort Study

BackgroundImproved survival among HIV-infected individuals on antiretroviral therapy (ART) has focused attention on AIDS-related cancers including Kaposi sarcoma (KS). However, the effect of KS on response to ART is not well-described in Southern Africa. We assessed the effect of KS on survival and immunologic and virologic treatment responses at 6- and 12-months after initiation of ART.MethodsWe analyzed prospectively collected data from a cohort of HIV-infected adults initiating ART in South Africa. Differences in mortality between those with and without KS at ART initiation were estimated with Cox proportional hazard models. Log-binomial models were used to assess differences in CD4 count response and HIV virologic suppression within a year of initiating treatment.ResultsBetween January 2001–January 2008, 13,847 HIV-infected adults initiated ART at the study clinics. Those with KS at ART initiation (n = 247, 2%) were similar to those without KS (n = 13600,98%) with respect to age (35 vs. 35yrs), presenting CD4 count (74 vs. 85cells/mm3) and proportion on TB treatment (37% vs. 30%). In models adjusted for sex, baseline CD4 count, age, treatment site, tuberculosis and year of ART initiation, KS patients were over three times more likely to have died at any time after ART initiation (hazard ratio[HR]: 3.62; 95% CI: 2.71–4.84) than those without KS. The increased risk was highest within the first year on ART (HR: 4.05; 95% CI: 2.95–5.55) and attenuated thereafter (HR: 2.30; 95% CI: 1.08–4.89). Those with KS also gained, on average, 29 fewer CD4 cells (95% CI: 7–52cells/mm3) and were less likely to increase their CD4 count by 50 cells from baseline (RR: 1.43; 95% CI: 0.99–2.06) within the first 6-months of treatment.ConclusionsHIV-infected adults presenting with KS have increased risk of mortality even after initiation of ART with the greatest risk in the first year. Among those who survive the first year on therapy, subjects with KS demonstrated a poorer immunologic response to ART than those without KS.