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12 pages, 302 KiB

Open AccessArticle

Molecular Mechanisms of Kaposi Sarcoma Development

by Andy Karabajakian, Isabelle Ray-Coquard and Jean-Yves Blay

Cancers 2022, 14(8), 1869; https://doi.org/10.3390/cancers14081869 - 07 Apr 2022

Cited by 9 | Viewed by 2189

Abstract

Kaposi’s sarcoma (KS) is a heterogeneous angioproliferative tumor that generally arises in the skin. At least four forms of this disease have been described, with the ‘HIV’-related form being the most aggressive and can involve mucosae or visceral organs. Three quarters of KS [...] Read more.

Kaposi’s sarcoma (KS) is a heterogeneous angioproliferative tumor that generally arises in the skin. At least four forms of this disease have been described, with the ‘HIV’-related form being the most aggressive and can involve mucosae or visceral organs. Three quarters of KS cases occur in sub-Saharan Africa (SSA) as geographic variation is explained by the disparate prevalence of KS-associated herpes virus (KSHV), which is the underlying cause of this disease. It can infect endothelial and/or mesenchymal cells that consequently transdifferentiate to an intermediate state. KSHV establishes a latent phase in host cells in which latency proteins and various non-coding RNAs (ncRNAs) play a complex role in proliferation and angiogenesis. It also undergoes periods of sporadic lytic reactivation triggered by various biological signals in which lytic stage proteins modulate host cell signaling pathways and are key in KS progression. Complex interactions with the microenvironment with production of inflammatory cytokines with paracrine signaling is a standout feature of KS development and maintenance. KSHV impairs the immune response by various mechanisms such as the degradation of a variety of proteins involved in immune response or binding to cellular chemokines. Treatment options include classical chemotherapy, but other novel therapies are being investigated. Full article

(This article belongs to the Special Issue Perspectives on Kaposi's Sarcoma)

21 pages, 6746 KiB

Open AccessArticle

Valganciclovir as Add-On Therapy Modifies the Frequency of NK and NKT Cell Subpopulations in Disseminated Kaposi Sarcoma Patients

by Julio Flores-Gonzalez, Lucero A. Ramon-Luing, Ranferi Ocaña-Guzman, Ivette Buendia-Roldan, Beda Islas-Muñoz, Patricia Volkow-Fernández and Leslie Chavez-Galan

Cancers 2022, 14(2), 412; https://doi.org/10.3390/cancers14020412 - 14 Jan 2022

Cited by 1 | Viewed by 4369

Abstract

Human herpesvirus-8 infection (HHV-8) is the causative agent of Kaposi sarcoma (KS) and is highly prevalent among people living with HIV (KS/HIV). It has been reported that valganciclovir (VGC) reduces HHV-8 replication in KS/HIV patients. However, currently it is unclear if VGC modifies [...] Read more.

Human herpesvirus-8 infection (HHV-8) is the causative agent of Kaposi sarcoma (KS) and is highly prevalent among people living with HIV (KS/HIV). It has been reported that valganciclovir (VGC) reduces HHV-8 replication in KS/HIV patients. However, currently it is unclear if VGC modifies the frequency and induces changes in markers of immune regulation of immune cells necessary to eliminate HHV8-infected cells, such as Natural Killer (NK) and NK T cells (NKT). This study evaluated the effect of VGC used as antiviral HHV8 therapy in KS patients on the frequency of NK and NKT subpopulations based on the CD27 and CD57 expression, and the immunosenescence markers, PD-1 and KLRG1. Twenty KS/HIV patients were followed-up at baseline (W₀), 4 (W₄), and 12 weeks (W₁₂) of the study protocol. Among them, 10 patients received a conventional treatment scheme (CT), solely antiretroviral therapy (ART), and 10 patients received a modified treatment regime (MT), including VGC plus ART. In both groups, bleomycin/vincristine was administrated according to the treating physician’s decision. The soluble levels of IL-15, PD-L1, PD-L2, and E-cadherin were quantified across the follow-up. Our results showed that the higher IL-15 levels and lower NK frequencies cells in KS/HIV patients reach almost normal values with both treatments regimes at W₁₂. CD27+ NK and NKT cell frequencies increased since W₄ on KS/HIV patients with MT. Furthermore, PD-1 expression decreased while KLRG1 increased on NK and NKT subpopulations at W₁₂, and it is accompanied by increased PD-L1 plasma level since W₄. Our study highlights the disruption of NK and NKT subpopulations in patients with KS/HIV and explores VGC treatment’s contribution to immune reconstitution during the first weeks of treatment. Full article

(This article belongs to the Special Issue Perspectives on Kaposi's Sarcoma)

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Review

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17 pages, 1489 KiB

Open AccessReview

Endemic Kaposi’s Sarcoma

by Perla El Zeinaty, Céleste Lebbé and Julie Delyon

Cancers 2023, 15(3), 872; https://doi.org/10.3390/cancers15030872 - 31 Jan 2023

Cited by 2 | Viewed by 4803

Abstract

Kaposi’s sarcoma (KS) is a common neoplasm in Eastern and central Africa reflecting the spread of human gammaherpesvirus-8 (HHV-8), now considered a necessary causal agent for the development of KS. The endemic KS subtype can follow an aggressive clinical course with ulcerative [...] Read more.

Kaposi’s sarcoma (KS) is a common neoplasm in Eastern and central Africa reflecting the spread of human gammaherpesvirus-8 (HHV-8), now considered a necessary causal agent for the development of KS. The endemic KS subtype can follow an aggressive clinical course with ulcerative skin lesions with soft tissue invasion or even bone or visceral involvement. In the latter cases, a thorough imaging work-up and better follow-up schedules are warranted. As KS is a chronic disease, the therapeutic goal is to obtain sustainable remission in cutaneous and visceral lesions and a good quality of life. Watchful monitoring may be sufficient in localized cutaneous forms. Potential therapeutic modalities for symptomatic advanced KS include systemic chemotherapies, immunomodulators, immune checkpoint inhibitors, and antiangiogenic drugs. Full article

(This article belongs to the Special Issue Perspectives on Kaposi's Sarcoma)

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7 pages, 242 KiB

Open AccessReview

The Role of Radiotherapy in Treating Kaposi’s Sarcoma in HIV Infected Patients

by Laurent Quéro, Romain Palich, Marc-Antoine Valantin and on behalf of CANCERVIH Working Group

Cancers 2022, 14(8), 1915; https://doi.org/10.3390/cancers14081915 - 10 Apr 2022

Cited by 4 | Viewed by 1773

Abstract

Kaposi’s sarcoma (KS) is a radiosensitive cancer regardless of its form (classical, endemic, AIDS-related, and immunosuppressant therapy-related). Radiotherapy (RT) is an integral part of the therapeutic management of KS. RT may be used as the main treatment, in the case of solitary lesions, [...] Read more.

Kaposi’s sarcoma (KS) is a radiosensitive cancer regardless of its form (classical, endemic, AIDS-related, and immunosuppressant therapy-related). Radiotherapy (RT) is an integral part of the therapeutic management of KS. RT may be used as the main treatment, in the case of solitary lesions, or as palliative therapy in the disseminated forms. The dose of RT to be delivered is 20–30 Gy by low-energy photons or by electrons. The complete response rate after RT is high, around 80–90%. This treatment is well tolerated. However, patients should be informed of the possible risk of the development of late skin sequelae and the possibility of recurrence. With the advent of highly active antiretroviral therapy (HAART), the indications for RT treatment in HIV-positive patients have decreased. Full article

(This article belongs to the Special Issue Perspectives on Kaposi's Sarcoma)

15 pages, 359 KiB

Open AccessReview

Immune Reconstitution Inflammatory Syndrome Associated Kaposi Sarcoma

by Isabelle Poizot-Martin, Sylvie Brégigeon, Romain Palich, Anne-Geneviève Marcelin, Marc-Antoine Valantin, Caroline Solas, Marianne Veyri, Jean-Philippe Spano and Alain Makinson

Cancers 2022, 14(4), 986; https://doi.org/10.3390/cancers14040986 - 16 Feb 2022

Cited by 7 | Viewed by 3121

Abstract

People living with HIV (PLWH) with advanced immunosuppression who initiate antiretroviral therapy (ART) are susceptible to the occurrence of an immune reconstitution inflammatory syndrome (IRIS). Although ART is responsible for AIDS- associated Kaposi sarcoma (KS) improvement and resolution, new onset (unmasking KS-IRIS) or [...] Read more.

People living with HIV (PLWH) with advanced immunosuppression who initiate antiretroviral therapy (ART) are susceptible to the occurrence of an immune reconstitution inflammatory syndrome (IRIS). Although ART is responsible for AIDS- associated Kaposi sarcoma (KS) improvement and resolution, new onset (unmasking KS-IRIS) or sudden progression of preexisting KS (paradoxical KS-IRIS) can occur after a time delay of between a few days and 6 months after the initiation or resumption of ART, even in patients with a low degree of immunocompromise. KS-IRIS incidence varies from 2.4% to 39%, depending on study design, populations, and geographic regions. Risk factors for developing KS-IRIS include advanced KS tumor stage (T1), pre-treatment HIV viral load >5 log₁₀ copies/mL, detectable pre-treatment plasma-KSHV, and initiation of ART alone without concurrent chemotherapy. Both paradoxical and unmasking KS-IRIS have been associated with significant morbidity and mortality, and thrombocytopenia (<100,000 platelets/mm³ at 12 weeks) has been associated with death. KS-IRIS is not to be considered as ART failure, and an ART regimen must be pursued. Systemic chemotherapy for KS in conjunction with ART is recommended and, in contrast with management of IRIS for other opportunistic infections, glucocorticoids are contra-indicated. Despite our preliminary results, the place of targeted therapies in the prevention or treatment of KS-IRIS needs further assessment. Full article

(This article belongs to the Special Issue Perspectives on Kaposi's Sarcoma)

17 pages, 367 KiB

Open AccessReview

Therapeutic Perspectives in the Systemic Treatment of Kaposi’s Sarcoma

by Marc-Antoine Valantin, Léna Royston, Maxime Hentzien, Aude Jary, Alain Makinson, Marianne Veyri, Sylvie Ronot-Bregigeon, Stéphane Isnard, Romain Palich and Jean-Pierre Routy

Cancers 2022, 14(3), 484; https://doi.org/10.3390/cancers14030484 - 18 Jan 2022

Cited by 5 | Viewed by 2724

Abstract

In patients with Kaposi’s sarcoma (KS), the therapeutic goal is to achieve a durable remission in the size and number of skin and visceral lesions. Although most patients show tumor regression in response to standard systemic chemotherapy regimens, alternative systemic treatments are needed [...] Read more.

In patients with Kaposi’s sarcoma (KS), the therapeutic goal is to achieve a durable remission in the size and number of skin and visceral lesions. Although most patients show tumor regression in response to standard systemic chemotherapy regimens, alternative systemic treatments are needed for patients who develop refractory KS. Anti-angiogenic therapies represent attractive therapeutic targets in this context, due to the central role of angiogenesis in KS pathogenesis. Pomalidomide, which exhibits such anti-angiogenic activity through inhibition of VEGF, currently constitutes the most promising agent of this class and has been recently approved by the FDA. In addition, immune checkpoint blockade also represents an interesting alternative therapeutic approach through the restoration of immunity against HHV-8, the causative agent of KS, and improvement of tumor control. Although small series of cases treated successfully with these drugs have been reported, there is no marketing approval for anti-immune checkpoint antibodies for KS to date. In the present review, we will discuss potential therapeutic options for patients with recurrent or refractory KS, including systemic chemotherapies, immune checkpoint inhibitors, anti-herpesvirus agents, and anti-angiogenic drugs. Well-conducted clinical trials in this population are urgently needed to correctly address the efficacy of targeted agents and immunomodulators, while monitoring for adverse effects. Full article

(This article belongs to the Special Issue Perspectives on Kaposi's Sarcoma)

23 pages, 2505 KiB

Open AccessReview

Kaposi’s Sarcoma-Associated Herpesvirus, the Etiological Agent of All Epidemiological Forms of Kaposi’s Sarcoma

by Aude Jary, Marianne Veyri, Adélie Gothland, Valentin Leducq, Vincent Calvez and Anne-Geneviève Marcelin

Cancers 2021, 13(24), 6208; https://doi.org/10.3390/cancers13246208 - 09 Dec 2021

Cited by 9 | Viewed by 3728

Abstract

Kaposi’s sarcoma-associated herpesvirus (KSHV), also called human herpesvirus 8 (HHV-8), is an oncogenic virus belonging to the Herpesviridae family. The viral particle is composed of a double-stranded DNA harboring 90 open reading frames, incorporated in an icosahedral capsid and enveloped. The viral cycle [...] Read more.

Kaposi’s sarcoma-associated herpesvirus (KSHV), also called human herpesvirus 8 (HHV-8), is an oncogenic virus belonging to the Herpesviridae family. The viral particle is composed of a double-stranded DNA harboring 90 open reading frames, incorporated in an icosahedral capsid and enveloped. The viral cycle is divided in the following two states: a short lytic phase, and a latency phase that leads to a persistent infection in target cells and the expression of a small number of genes, including LANA-1, v-FLIP and v-cyclin. The seroprevalence and risk factors of infection differ around the world, and saliva seems to play a major role in viral transmission. KSHV is found in all epidemiological forms of Kaposi’s sarcoma including classic, endemic, iatrogenic, epidemic and non-epidemic forms. In a Kaposi’s sarcoma lesion, KSHV is mainly in a latent state; however, a small proportion of viral particles (<5%) are in a replicative state and are reported to be potentially involved in the proliferation of neighboring cells, suggesting they have crucial roles in the process of tumorigenesis. KSHV encodes oncogenic proteins (LANA-1, v-FLIP, v-cyclin, v-GPCR, v-IL6, v-CCL, v-MIP, v-IRF, etc.) that can modulate cellular pathways in order to induce the characteristics found in all cancer, including the inhibition of apoptosis, cells’ proliferation stimulation, angiogenesis, inflammation and immune escape, and, therefore, are involved in the development of Kaposi’s sarcoma. Full article

(This article belongs to the Special Issue Perspectives on Kaposi's Sarcoma)

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19 pages, 8138 KiB

Open AccessReview

Current and Future Tools for Diagnosis of Kaposi’s Sarcoma

by Nicolas Dupin, Aude Jary, Samia Boussouar, Charlotte Syrykh, Amir Gandjbakhche, Sébastien Bergeret and Romain Palich

Cancers 2021, 13(23), 5927; https://doi.org/10.3390/cancers13235927 - 25 Nov 2021

Cited by 10 | Viewed by 2578

Abstract

Kaposi’s sarcoma (KS) is a rare, atypical malignancy associated with immunosuppression and can be qualified as an opportunistic tumor, which responds to immune modulation or restoration. Four different epidemiological forms have been individualized (AIDS-related, iatrogenic, endemic or classic KS). Although clinical examination is [...] Read more.

Kaposi’s sarcoma (KS) is a rare, atypical malignancy associated with immunosuppression and can be qualified as an opportunistic tumor, which responds to immune modulation or restoration. Four different epidemiological forms have been individualized (AIDS-related, iatrogenic, endemic or classic KS). Although clinical examination is sufficient to diagnose cutaneous lesions of KS, additional explorations are necessary in order to detect lesions involving other organs. New histological markers have been developed in recent years concerning the detection of HHV-8 latent or lytic proteins in the lesions, helping to confirm the diagnosis when it is clinically doubtful. More recently, the evaluation of the local immune response has also been shown to provide some guidance in choosing the appropriate therapeutic option when necessary. We also review the indication and the results of conventional radiological imaging and of non-invasive imaging tools such as ¹⁸F-fluoro-deoxy-glucose positron emission tomography, thermography and laser Doppler imaging for the diagnosis of KS and for the follow-up of therapeutic response in patients requiring systemic treatment. Full article

(This article belongs to the Special Issue Perspectives on Kaposi's Sarcoma)

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13 pages, 311 KiB

Open AccessReview

Kaposi’s Sarcoma in Virally Suppressed People Living with HIV: An Emerging Condition

by Romain Palich, Alain Makinson, Marianne Veyri, Amélie Guihot, Marc-Antoine Valantin, Sylvie Brégigeon-Ronot, Isabelle Poizot-Martin, Caroline Solas, Sophie Grabar, Guillaume Martin-Blondel and Jean-Philippe Spano

Cancers 2021, 13(22), 5702; https://doi.org/10.3390/cancers13225702 - 15 Nov 2021

Cited by 6 | Viewed by 2060

Abstract

Since the advent of highly effective combined antiretroviral treatment (cART), and with the implementation of large HIV testing programs and universal access to cART, the burden of AIDS-related comorbidities has dramatically decreased over time. The incidence of Kaposi’s sarcoma (SK), strongly associated with [...] Read more.

Since the advent of highly effective combined antiretroviral treatment (cART), and with the implementation of large HIV testing programs and universal access to cART, the burden of AIDS-related comorbidities has dramatically decreased over time. The incidence of Kaposi’s sarcoma (SK), strongly associated with HIV replication and CD4 immunosuppression, was greatly reduced. However, KS remains the most common cancer in patients living with HIV (PLHIV). HIV physicians are increasingly faced with KS in virally suppressed HIV-patients, as reflected by increasing description of case series. Though SK seem less aggressive than those in PLHIV with uncontrolled HIV-disease, some may require systemic chemotherapy. Persistent lack of specific anti-HHV-8 cellular immunity could be involved in the physiopathology of these KS. These clinical forms are a real therapeutic challenge without possible short-term improvement of anti-HHV-8 immunity, and no active replication of HIV to control. The cumulative toxicity of chemotherapies repeatedly leads to a therapeutic dead end. The introduction or maintenance of protease inhibitors in cART does not seem to have an impact on the evolution of these KS. Research programs in this emerging condition are important to consider new strategies. Full article

(This article belongs to the Special Issue Perspectives on Kaposi's Sarcoma)

11 pages, 841 KiB

Open AccessReview

Epidemiology of Kaposi’s Sarcoma

by Sophie Grabar and Dominique Costagliola

Cancers 2021, 13(22), 5692; https://doi.org/10.3390/cancers13225692 - 14 Nov 2021

Cited by 21 | Viewed by 3331

Abstract

Kaposi’s sarcoma is an angioproliferative tumor caused by human herpesvirus 8 in the context of immunodeficiency, such as that induced by HIV infection or immunosuppressive therapy. Its incidence has dramatically fallen in patients living with HIV (PLHIV) since the introduction of potent antiretroviral [...] Read more.

Kaposi’s sarcoma is an angioproliferative tumor caused by human herpesvirus 8 in the context of immunodeficiency, such as that induced by HIV infection or immunosuppressive therapy. Its incidence has dramatically fallen in patients living with HIV (PLHIV) since the introduction of potent antiretroviral combinations 25 years ago due to the restoration of immunity and better control of HIV replication. However, KS is still one of the most frequently occurring cancers in PLHIV, in particular in men who have sex with men and in sub-Saharan Africa, where it is still endemic. Even in the context of restored immunity, the risk of KS is still more than 30 times higher in PLHIV than in the general population. Recent evidence indicates that early initiation of antiretroviral treatment, which is recommended by current guidelines, may reduce the risk of KS but it needs to be accompanied by early access to care. This review mainly focuses on the recent epidemiological features of KS in the context of HIV infection. Full article

(This article belongs to the Special Issue Perspectives on Kaposi's Sarcoma)

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