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Background: Kaposi sarcoma (KS) is a rare skin tumour caused by herpesvirus 8 infection and characterized by either indolence or an aggressive course necessitating systemic therapies. The genetic basis of this difference remains unknown. Objectives: To explore the tumour mutational burden in indolent and aggressive KS. Methods: We performed whole‐exome sequencing on a cohort of 21 KS patients. We compared genetic landscape including tumor mutational burden between the two forms of indolent and agressive KS. Results: Aggressive KS tumours had a significantly higher TMB and a larger cumulative number of deleterious mutations than indolent KS tumours. In addition, all aggressive tumours had at least three deleterious mutations, whereas most indolent tumours harboured only one or no predicted deleterious mutations. Deleterious mutations listed in the Cancer Gene Census were detected exclusively in patients with aggressive disease. An analysis of somatic copy‐number alterations (SCNA) revealed a tendency towards higher number of alterations in aggressive KS. Conclusions: These data suggest that SCNA alterations and an increase in mutational burden promote aggressive KS and that it might be more appropriate to consider indolent KS as an opportunistic skin disease rather than a cancer. [ABSTRACT FROM AUTHOR]

Background Classic Kaposi's sarcoma (CKS) occurs predominantly among elderly men and is associated with Kaposi's sarcoma-associated herpesvirus (KSHV). In low-endemic countries, KSHV infects predominantly men having sex with men (MSM). Objectives To describe a cohort of classic Kaposi sarcoma in a low-endemic area for KSHV, to highlight the features of CKS in MSM and identify prognostic factors. Methods Retrospective single-centre study of CKS cases. We compared MSM to heterosexual patients. Then, we divided the patients into two subgroups, those requiring a systemic treatment and the others, and we performed univariate and multivariate analyses to determine aggressiveness of CKS. Results Between 2006 and 2015, seventy-four patients were included. Mean age at diagnosis was 68.9 years; sex ratio (M/F) was 6.4, and 28% were MSM; MSM patients were younger (P = 0.02), less often originated from endemic areas (P < 0.0001). KS was less severe (P = 0.04), required more often a local treatment than a systemic one (P = 0.03). On multivariate analysis, CD4 T-cell count > 500/mm3 at baseline was associated with a reduced risk of severe evolution. Conclusion First CKS cohort in low-endemic zone. We describe a fifth subtype of KS: KS in MSM. The CD4 T-cell count was found to correlate with prognosis. [ABSTRACT FROM AUTHOR]

Background Recent studies have independently implicated the chemokine CXCL12 and its receptors, CXCR4 and CXCR7, in the pathophysiology of Kaposi sarcoma ( KS). Objectives We investigated whether the CXCL12/ CXCR4- CXCR7 protein trio could constitute KS biomarkers. Methods Endothelial and spindle cells positive for CXCL12/ CXCR4- CXCR7, human herpesvirus-8 latency-associated nuclear antigen ( LANA), Ki67 antigen (proliferation) and vascular endothelial growth factor ( VEGF) were quantitated in skin lesions from patients with AIDS-associated KS, patients with classic KS and patients with angiomas, using immunohistochemistry and quantitative image analysis (16, 21 and 20 skin lesions, respectively). Plasma CXCL12 concentrations were measured by enzyme-linked immunosorbent assay from 20 patients with AIDS- KS, 12 HIV-infected patients without KS and 13 healthy donors' samples. Results Cells positive for CXCL12, CXCR4, CXCR7, LANA, Ki67 and VEGF were significantly enriched in patients with AIDS-associated KS and classic KS vs. angiomas ( P < 0·001), and in nodular vs. macular/papular KS lesions ( P < 0·05). CXCL12, CXCR4 and CXCR7 detection correlated with LANA, Ki67 and VEGF detection ( r > 0·4; P < 0·05). However, plasma CXCL12 concentrations did not differ between patients with AIDS-associated KS, HIV-infected patients without KS, and healthy donors. Conclusions The CXCL12/ CXCR4- CXCR7 trio is upregulated in KS and correlates with KS pathophysiological markers and the severity of skin lesions. Histological assessment of the CXCL12 axis could serve as a valuable biomarker for KS diagnosis and progression. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented concerning first-line treatment with paclitaxel for non- HIV-related Kaposi sarcoma.

The article discusses research which investigated the potential of everolimus, a mammalian target of rapamycin (mTOR) inhibitor approved in transplantation and oncology, as alternative treatment in Kaposi sarcoma (KS). Topics include a 6-month daily treatment with everolimus resulting in a clinical response and no correlation between clinical response and whole blood everolimus concentrations.

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. [ABSTRACT FROM AUTHOR]

We report the observation of cutaneous Kaposi's sarcoma (KS) worsening during the second trimester of pregnancy in 2 African women. Both patients were tested seronegative for HIV. They had no complication during their pregnancy, and no evidence of extracutaneous disease was found, allowing therapeutic abstention. They gave birth to healthy children showing no clinical evidence of human herpesvirus 8 (HHV-8) infection. Based on these observations and on the review of the literature, we discuss the risk of vertical transmission of HHV-8 as well as the impact of pregnancy on KS. © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Kaposi Sarcoma (KS) are opportunistic tumors, associated with human herpes virus 8 (HHV8) infection. KS development is highly favored by immune-depression and remains the second most frequent tumor in acquired immune deficiency syndrome patients. Although it has been shown that experimental expression of the HHV8 G-protein-coupled receptor (vGPCR) in the endothelial compartment is alone sufficient to recapitulate the formation and progression of KS-like lesions, its functional effects on endothelial homeostasis are not fully understood. Here we show that vGPCR expression in endothelial cells induces an increase in paracellular permeability both in vivo and in vitro. By using pharmacological inhibitors and small interference RNA-based knockdown, we demonstrate an essential role for the PI(3)Kinase-γ/Rac nexus in vGPCR-mediated permeability. This was further accompanied by dramatic remodeling of VE-cadherin-dependent cell-cell junctions. Importantly, this in vitro vGPCR-initiated signaling signature was observed in a large panel of human KS. Altogether, our results support the hypothesis that endothelial vGPCR signaling is co-opted in KS, and unveil new key cellular targets for therapeutic intervention. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented that discusses development of classical Kaposi sarcoma through anti-hypertensive renin-angiotensin system inhibitors.

Background Among heterosexuals, the sexual transmission of human herpesvirus 8 (HHV8) has not been established. Objectives To assess HHV8 seroprevalence in spouses of patients with classic and endemic Kaposi sarcoma (KS) and to suggest possible routes of transmission. Methods A case–control study was carried out in a teaching hospital among spouses of human immunodeficiency virus-negative patients with KS (cases – exposed subjects) and controls who did not have KS nor were related to patients with KS (nonexposed subjects). HHV8 seroprevalence in spouses of patients with KS was compared with HHV8 seroprevalence in controls matched for age, gender and place of birth. Other serology tests were compared between cases and controls. Among heterosexual couples, HHV8-seropositive and HHV8-seronegative spouses were compared for possible risk factors for virus transmission. Results HHV8 seroprevalence was significantly higher among spouses of patients with KS (13 of 22; 59%) than among matched controls (19 of 58; 33%; P = 0·043). Among heterosexual couples, five of five (100%) male spouses were HHV8 positive vs. six of 15 (40%) female spouses ( P = 0·04). There was no significant difference between HHV8-seropositive and HHV8-seronegative spouses for all other factors screened for among heterosexual couples. Conclusions Being a spouse of a patient with KS is a risk factor for HHV8 seropositivity. Our results suggest that female-to-male HHV8 transmission could be more efficient than male-to-female transmission among couples including a patient with KS. Transmission could involve distinctive behaviours, or currently unknown biological properties of HHV8. [ABSTRACT FROM AUTHOR]

Highly active antiretroviral therapy (HAART) reduces the incidence and improves the prognosis of Kaposi's sarcoma (KS). This study was designed to identify factors associated with KS clinical responses in HIV-infected patients during HAART. We reviewed the files of 138 HIV-1-infected patients with KS. Epidemiologic and HIV-related clinical and biological parameters were recorded at KS diagnosis (baseline) and every 6 months thereafter. In a subset of 73 antiretroviral-naive patients, we compared the clinical outcome of KS according to the use or nonuse of protease inhibitors (PI). After 6 months of follow-up, KS remission was more frequent in patients who were naive of HAART and who were at ACTG stage S0 at baseline (P=0.03 and 0.02). Undetectable HIV viral load was strongly associated with KS remission (P0.004 at all time points), while CD4 cell count was not. Among the 73 antiretroviral-naive patients at baseline, and who were studied for 24 months, KS outcome did not differ between patients who were prescribed PI-containing and PI-sparing regimens. Intercurrent multicentric Castleman's disease was associated with poor outcome after 60 months of follow-up (P0.0001). Fourteen deaths occurred after a median follow-up of 37.5 months, eight of which were KS related. Suppression of HIV replication appears to be crucial to control KS. Non-PI-based regimens were equivalent to PI-based regimens as regards the clinical and virological outcome of antiretroviral-naive HIV-infected patients with KS.British Journal of Cancer (2006) 94, 1000–1006. doi:10.1038/sj.bjc.6603056 www.bjcancer.com Published online 28 March 2006 [ABSTRACT FROM AUTHOR]

To assess the clinical and biological benefit of highly active antiretroviral therapy on AIDS-associated Kaposi's sarcoma (KS), 13 patients with AIDS-associated Kaposi's sarcoma (five pulmonary KS and eight cutaneous KS) were prospectively followed for a mean duration of 12 months. Six patients were treated with specific anti-KS chemotherapy before or simultaneously with the introduction of antiretroviral therapy. Clinical response was assessed according to the AIDS Clinical Trial Group (ACTG) criteria. CD4 cell counts, plasma HIV-1 RNA and human herpesvirus 8 (HHV-8) viraemia were measured at baseline and at different points. Among patients with pulmonary KS, we observed three complete responses (CR), one partial response (PR) and one progression. The median survival time after the diagnosis of pulmonary KS was 15 months with a median duration of the response after the discontinuation of specific chemotherapy for KS of 8 months. Among patients with cutaneous KS, we observed four CR, three PR and one stable response. A complete response was significantly associated with a reversal in HHV-8 viraemia (five of six vs. one of six; P = 0.02, Mann–Whitney test). [ABSTRACT FROM AUTHOR]

The article relates the author's perspective on the study by L. Martin-Carbonero and colleagues concerning the treatment of Kaposi sarcoma (KS) with pegylated liposomal doxorubicin in patients with AIDS. He remarks that the high incidence of non-Hodgkin lymphoma reported in the study should be the importance of avoiding excessive exposure to chemotherapeutic drugs. He notes that in these group of patients highly active antiretroviral therapy should be associated with adjuvant therapy.

Studies herpesvirus-like DNA sequences found in Kaposi's sarcoma lesions and normal adjacent skin in patients with Mediterranean Kaposi's sarcoma. Absence of major polymerase chain reaction (PCR) inhibitors in DNA samples from tissue biopsy specimens; Beta-globin gene amplification results; Involvement of herpesvirus-like agent in the pathogenesis of Kaposi's sarcoma.