mTOR inhibitors block Kaposi sarcoma growth by inhibiting essential autocrine growth factors and tumor angiogenesis.

Feb 2013

Roy D, Sin SH, Lucas AS, Venkataramanan R, Wang L, Eason A, Chavakula V, Tamburro KM, Hilton IB, Damania B,Dittmer DP.

Source

Lineberger Comprehensive Cancer Center, UNC Chapel Hill.

Abstract

Kaposi's Sarcoma (KS) originates from endothelial cells and it is one of the most overt angiogenic tumors. In Sub-Saharan Africa, where HIV and the Kaposi Sarcoma-associated Herpes Virus (KSHV) are endemic, KS is the most common cancer overall, but model systems for disease study are insufficient. Here we report the development of a novel mouse model of KS where KSHV is retained stably and tumors are elicited rapidly. Tumor growth was sensitive to specific allosteric inhibitors (rapamycin, CCI-779, RAD001) of the pivotal cell growth regulator mTOR. Inhibition of tumor growth was durable up to 130 days and reversible. mTOR blockade reduced VEGF secretion and formation of tumor vasculature. Together, the results demonstrated that mTOR inhibitors exert a direct anti-KS effect by inhibiting angiogenesis and paracrine effectors, suggesting their application as a new treatment modality for KS and other cancers of endothelial origin.

Full Text

Cancer Research

Nationwide registry-based analysis of cancer clustering detects strong familial occurrence of kaposi sarcoma.

2013

Kaasinen E, Aavikko M, Vahteristo P, Patama T, Li Y, Saarinen S, Kilpivaara O, Pitkänen E, Knekt P, Laaksonen M, Artama M, Lehtonen R, Aaltonen LA, Pukkala E.

Source

Genome-Scale Biology Research Program, and Department of Medical Genetics, Faculty of Medicine, University of Helsinki, Helsinki, Finland ; Haartman Institute, University of Helsinki, Helsinki, Finland.

Abstract

Many cancer predisposition syndromes are rare or have incomplete penetrance, and traditional epidemiological tools are not well suited for their detection. Here we have used an approach that employs the entire population based data in the Finnish Cancer Registry (FCR) for analyzing familial aggregation of all types of cancer, in order to find evidence for previously unrecognized cancer susceptibility conditions. We performed a systematic clustering of 878,593 patients in FCR based on family name at birth, municipality of birth, and tumor type, diagnosed between years 1952 and 2011. We also estimated the familial occurrence of the tumor types using cluster score that reflects the proportion of patients belonging to the most significant clusters compared to all patients in Finland. The clustering effort identified 25,910 birth name-municipality based clusters representing 183 different tumor types characterized by topography and morphology. We produced information about familial occurrence of hundreds of tumor types, and many of the tumor types with high cluster score represented known cancer syndromes. Unexpectedly, Kaposi sarcoma (KS) also produced a very high score. We verified from population records that many of the KS patients forming the clusters were indeed close relatives, and identified one family with five affected individuals in two generations and several families with two first degree relatives. Our approach is unique in enabling systematic examination of a national epidemiological database to derive evidence of aberrant familial aggregation of all tumor types, both common and rare. It allowed effortless identification of families displaying features of both known as well as potentially novel cancer predisposition conditions, including striking familial aggregation of KS. Further work with high-throughput methods should elucidate the molecular basis of the potentially novel predisposition conditions found in this study. 

PubMed

Late post transplant HIV infection with BK viremia and allograft tuberculosis in a renal transplant recipient with Kaposi sarcoma.

Sep 2012

Viswanathan V, Kandasamy V, Reddy YN, Reddy YN, Kurien A, Mathew M, Abraham G.

Source

Department of Medicine and Tanker Foundation, Madras Medical Mission, Chennai, India.

Abstract

In this report, we discuss a case of a 51-year-old African renal transplant who presented with metastatic Kaposi sarcoma1 year after transplant. The Kaposi sarcoma was treated with a switch of immunosuppressants and chemotherapy. Six years after transplant, he presented with chronic allograft nephropathy, allograft tuberculosis, BK viremia, and was diagnosed to have contracted HIV infection.

Full text with images now available

PubMedCentral - Indian Journal of Nephrology

Simultaneous lymph node involvement by Castleman disease and Kaposi sarcoma.

2011

Pinto LW, Nunes EP.

Source

Instituto de Pesquisa Clínica Evandro Chagas (IPE), Fiocruz Rio de Janeiro (RJ), Brazil.

Abstract

Both multicentric Castleman disease and Kaposi sarcoma are more frequently observed in HIV infected patients. The coexistence of these Human herpes virus 8 related lesions, in the same tissue, has been observed, but literature reports are scant. On the other hand, the expression of HHV-8-LANA-1 is easily demonstrable by immunohistochemistry. This has been shown to be a powerful tool for the diagnosis of these entities. The aim of this report is to communicate our experience with a case of multicentric Castleman disease occurring in the setting of HIV infection, which demonstrated microscopic Kaposi sarcoma in the same lymph node during the pathological work-up.

PubMed

Cannabidiol inhibits growth and induces programmed cell death in kaposi sarcoma-associated herpesvirus-infected endothelium.

Jul 2012

Maor Y, Yu J, Kuzontkoski PM, Dezube BJ, Zhang X, Groopman JE.

Source

Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.

Abstract

Kaposi sarcoma is the most common neoplasm caused by Kaposi sarcoma-associated herpesvirus (KSHV). It is prevalent among the elderly in the Mediterranean, inhabitants of sub-Saharan Africa, and immunocompromised individuals such as organ transplant recipients and AIDS patients. Current treatments for Kaposi sarcoma can inhibit tumor growth but are not able to eliminate KSHV from the host. When the host's immune system weakens, KSHV begins to replicate again, and active tumor growth ensues. New therapeutic approaches are needed. Cannabidiol (CBD), a plant-derived cannabinoid, exhibits promising antitumor effects without inducing psychoactive side effects. CBD is emerging as a novel therapeutic for various disorders, including cancer. In this study, we investigated the effects of CBD both on the infection of endothelial cells (ECs) by KSHV and on the growth and apoptosis of KSHV-infected ECs, an in vitro model for the transformation of normal endothelium to Kaposi sarcoma. While CBD did not affect the efficiency with which KSHV infected ECs, it reduced proliferation and induced apoptosis in those infected by the virus. CBD inhibited the expression of KSHV viral G protein-coupled receptor (vGPCR), its agonist, the chemokine growth-regulated protein α (GRO-α), vascular endothelial growth factor receptor 3 (VEGFR-3), and the VEGFR-3 ligand, vascular endothelial growth factor C (VEGF-C). This suggests a potential mechanism by which CBD exerts its effects on KSHV-infected endothelium and supports the further examination of CBD as a novel targeted agent for the treatment of Kaposi sarcoma.

Complete Text:

NIH / Genes and Cancer

Human Herpesvirus 8 (HHV8) Sequentially Shapes the NK Cell Repertoire during the Course of Asymptomatic Infection and Kaposi Sarcoma

Jan 2012

Stéphanie Dupuy, Marion Lambert, David Zucman, Siméon-Pierre Choukem,^3,¤ Sara Tognarelli,¹ Cécile Pages, Céleste Lebbé, and Sophie Caillat-Zucma

Abstract

The contribution of innate immunity to immunosurveillance of the oncogenic Human Herpes Virus 8 (HHV8) has not been studied in depth. We investigated NK cell phenotype and function in 70 HHV8-infected subjects, either asymptomatic carriers or having developed Kaposi's sarcoma (KS). Our results revealed substantial alterations of the NK cell receptor repertoire in healthy HHV8 carriers, with reduced expression of NKp30, NKp46 and CD161 receptors. In addition, down-modulation of the activating NKG2D receptor, associated with impaired NK-cell lytic capacity, was observed in patients with active KS. Resolution of KS after treatment was accompanied with restoration of NKG2D levels and NK cell activity. HHV8-latently infected endothelial cells overexpressed ligands of several NK cell receptors, including NKG2D ligands. The strong expression of NKG2D ligands by tumor cells was confirmed in situ by immunohistochemical staining of KS biopsies. However, no tumor-infiltrating NK cells were detected, suggesting a defect in NK cell homing or survival in the KS microenvironment. Among the known KS-derived immunoregulatory factors, we identified prostaglandin E2 (PGE2) as a critical element responsible for the down-modulation of NKG2D expression on resting NK cells. Moreover, PGE2 prevented up-regulation of the NKG2D and NKp30 receptors on IL-15-activated NK cells, and inhibited the IL-15-induced proliferation and survival of NK cells. Altogether, our observations are consistent with distinct immunoevasion mechanisms that allow HHV8 to escape NK cell responses stepwise, first at early stages of infection to facilitate the maintenance of viral latency, and later to promote tumor cell growth through suppression of NKG2D-mediated functions. Importantly, our results provide additional support to the use of PGE2 inhibitors as an attractive approach to treat aggressive KS, as they could restore activation and survival of tumoricidal NK cells.

Complete Text:

NIH/PLOS

Variable clinical presentations of Classic Kaposi Sarcoma in Turkish patients

March 2012

Ilknur Altunay, Asli Kucukunal,^* Gulsen Tukenmez Demirci, and Bilge Ates

Abstract

Key Words: HHV-8, HIV, Kaposi sarcoma, skin cancer

Background

Kaposi sarcoma (KS) is a vascular neoplasm with multicentric cutanenous and extracutaneous involvements, which was first described by Moriz Kaposi in 1872. Since then, different epidemiological clinical and histopathological variants of this neoplasm have been identified. Classic Kaposi sarcoma (CKS) is one of four main clinico-epidemiologiologic variants. characteristics of the disease.

Materials and Methods

Four Turkish inpatients with CKS were evaluated in the study. All medical history and clinical data were noted. A screening immunodeficiency workup were performed for all patients. HHV-8 immunofluorescence testing on the specimens and ELISA test for human immunodeficiency virus (HIV 1 and 2) were performed. Pulmonary X ray graphies and computurized tomography (CT) scan were applied. Stage of the tumor was determined, in each case, according to the classification system proposed by Brambilla et al in 2003.

Results

All patients are positive for HHV-8. They were all immunocompetent and negative for HIV1 and HIV2. The first patient was unusual for morphological presentation of several verrucoid lesions that was evaluated as verrucoid KS. He was considered stage IB CKS. The patient 2 was a young man and the course of KS seemed unexpectedly aggressive for CKS. His clinical appearence seemed us to be a patient with AIDSassociated KS. The patient was evaluated as stage IVB CKS. Our third patient had also prominent lymphedema associated with bluish discoloration on the toes and fingers, suggesting a diagnosis of peripheral vascular disorder. He was diagnosed as stage IIIB CKS. The fourth case was interesting for very extensive lesions involving big sized plaques and also the existence of mucosal lesion. The patient was diagnosed as stage IVB CKS.

Conclusions

It seems that the reports of exceptional cases of KS are accumulating. Data from various cases should be collected and perhaps, novel clinical classifications should be considered. 

Full Text Article

NIH - Journal of Dermatological Case Reports

Classic kaposi sarcoma with pulmonary involvement mimicking endobronchial tuberculosis in a child.

July 2012

Cakir FB, Cakir E, Tuzuner N, Kut A.

Source

Department of Pediatric Hematology-Oncology, Bezmialem Vakif University, Istanbul, Turkey.

Abstract

Key Words: Kaposi' sarcoma; child, endobronchial lesion, pulmonary

Kaposi' sarcoma (KS) is a low-grade vascular neoplasm and classic KS, a subtype of KS, is extremely rare in children. Childhood pulmonary involvement in classic KS has not been reported in the literature. We describe an HIV-seronegative pediatric case with a fulminant course of classic KS with pulmonary involvement mimicking endobronchial tuberculosis. 

Wiley OnLine

Disseminated bone lesions in AIDS-associated Kaposi sarcoma, a bad prognosis? About four cases.

Nov 2012

Wassilew N, Ciaffi L, Vu D, Calmy A, Toutous Trellu L.

Source

University Hospital Geneva, Infectious Diseases, Geneva, Switzerland.

Abstract

Kaposi sarcoma (KS) can present with a wide range of clinical features ranging from minimal cutaneous disease to a rapidly progressing neoplasm. Bone lesions are most often discovered accidently in the context of radiological investigations done for the screening of KS-visceral involvement [1]. Little is known on clinical outcome and response to antiretroviral therapy (ART) and/or chemotherapy of these lytic osseous lesions. We report four cases with bone involvement in the context of systemic KS and aim at describing the long-term clinical outcome in two of these patients. Cases of AIDS-associated KS with disseminated bone lesions were collected in the HIV Unit, University Hospital Geneva, Switzerland. 

Patients were compared on clinical, biological and radiological features and therapeutic responses. Between 2002 and 2012, four HIV1-infected patients with T1 stage of KS presented disseminated osseous lesions (Table 1). Mean age was 43 years (range 39 - 47 years), mean time of follow up until our analysis was 48.5 months (SD 53.8), and mean CD4 count at KS diagnosis was 190.5 c/mL (SD 202.8). All patients showed hypodense bone lesions predominating the axial skeleton (Figure 1), but no radiological imaging was performed to search for peripheral bone lesions.No patient reported pain or experienced pathological fractures. In one patient a dual-energy X-ray absorptiometry (DXA) showed a bone mineral density within normal range after 10 years of KS diagnosis with disseminated bone lesions. No radiological change was observed in that patient despite stable KS disease after 13 cycles of liposomal doxorubicin and ART (Figure 1). 

We describe a well-documented long-term follow up of disseminated osseous AIDS-associated KS disease. In our four cases, lytic bone lesions were asymptomatic and were not associated with bone fragility. We even could confirm the KS nature of the lesions by bone biopsy in patient B (3 months after KS diagnosis), as the differential diagnosis is wide, and include bacillary angiomatosis, cancers or metastasis. Chemotherapy and antiretroviral treatment did not affect bone lesions using CT scan despite a good response on other KS-affected sites. Prognostic factors are well established in AIDS-associated KS [2]; however disseminated bone disease does not seem to have an impact on disease evolution. A larger sample size is needed to confirm this hypothesis.

PubMed

Risk of Kaposi sarcoma during the first months on combination antiretroviral therapy.

Nov 2012

Lacombe JM, Boue F, Grabar S, Viget N, Gazaignes S, Lascaux-Cametz AS, Pacanowski J, Partisani M, Launay O,Matheron S, Rosenthal E, Rouveix E, Tattevin P, de Truchis P, Costagliola D, Goedert JJ.

Source

aInserm UMR-S 943; UPMC Univ Paris 06 UMR-S 943; INSERM-TRANSFERT; Paris, France bAP-HP, Hôpital Antoine Béclère, Service de médecine interne et d'immunologie clinique; Université Paris-Sud, Clamart, France cINSERM UMR-S 943; AP-HP, Groupe Hospitalier Cochin Hôtel-Dieu, Unité de biostatistique et épidémiologie; Université Paris Descartes, Paris, France dCentre Hospitalier de Tourcoing, Service universitaire des maladies infectieuses et du voyage, Tourcoing, France eAP-HP, Hôpital Saint Louis, Service des maladies infectieuses et tropicales, Paris, France fAP-HP, Hôpital Henri-Mondor, Service d'immunologie clinique, Créteil, France gAP-HP, Hôpital Saint Antoine, Service des maladies infectieuses et tropicales, Paris, France hHôpitaux Universitaires de Strasbourg, Le Trait d'Union - Centre de soins de l'infection par le VIH, Strasbourg, France iUniversité Paris Descartes; AP-HP, Hôpital Cochin, Paris, France jUniversité Denis Diderot Paris 7; AP-HP Hôpital Bichat-Claude Bernard, Service de Maladies infectieuses et Tropicales, Paris, France kHôpital l'Archet, Département de médecine interne; Université de Nice-Sophia Antipolis, Nice, France lHôpital Ambroise Paré, Service de médecine interne, Boulogne, France mCHU Pontchaillou, Service des Maladies Infectieuses et de Réanimation Médicale, Rennes, France nAP-HP, Hôpital Raymond Poincaré, Service de médecine aigue spécialisée, Garches, France oINSERM UMR-S 943; UPMC Univ Paris 06 UMR-S 943, Paris, France pDivision of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD USA.

Abstract

OBJECTIVE: Determine if incident AIDS-defining Kaposi sarcoma (KS) or Pneumocystis jiroveci pneumonia (PJP) is associated with combination antiretroviral therapy (cART) initiation. 

DESIGN: Compare risk for KS and PJP by time on cART and CD4 reconstitution. 

METHODS: In the FHDH-ANRS CO4 cohort (N = 66,369), KS (N = 1811) and PJP (N = 1718) incidence rates were computed by demographic and HIV strata. Crude and adjusted relative risk (RR) with 95% confidence intervals (CI) following cART initiation were calculated by Poisson regression with untreated patients during 1996-2009 as reference. CD4 counts were compared by Wilcoxon rank sum tests. 

RESULTS: KS risk was very high during months 1-3 on cART (N = 160, RRCrude 3.94, CI 3.26-4.76), which was incompletely attenuated by adjustment for demographics and contemporaneous CD4 count (RRAdj 1.25, CI 1.02-1.53). Corresponding PJP risk was minimally elevated (N = 84, RRCrude 1.80, CI 1.42-2.30) and markedly reduced with adjustment on the same variables and PJP prophylaxis (RRAdj 0.52, CI 0.41-0.67). HIV load had no added effect. Median CD4 cell count at cART initiation was much lower in patients with incident KS (82/mm) or PJP (61/mm) within 3 months compared with those without (>250/mm). Notably, median CD4 change was +44 cells/month with incident KS within 3 months of cART initiation versus 0 cells/month with incident PJP . 

CONCLUSIONS: Failure of CD4 reconstitution during months 1-3 on cART fully accounted for incident PJP. In contrast, there were 1.6 additional KS cases per 1000 person-years during months 1-3 on cART, suggesting that immune reconstitution may contribute to the risk for AIDS-defining KS.

Lippincott Williams Wilkins

Sirolimus for the treatment of kaposi sarcoma after renal transplantation: a series of 10 cases.

Nov 2012

Yaich S, Charfeddine K, Zaghdane S, El Aoud N, Jarraya F, Kharrat M, Hachicha J.

Source

Department of Nephrology, Hedi Chaker Hospital, Sfax, Tunisia.

Abstract

The incidence of Kaposi sarcoma (KS) has substantially increased among immunocompromised patients, suggesting a role for immunosuppressive drugs. The aim of this study was to evaluate the incidence, features, and outcome of KS among 307 kidney transplantation patients at our center between January 1994 and June 2010. During the study period, the 10 patients who developed KS (3.25%) showed a mean age at transplantation of 35.8 ± 8.7 years (range, 22 to 49 years). The mean interval between transplantation and occurrence of KS was 24.7 ± 21.36 months (range, 6 to 64 months). The mean time of antithymocyte globulin induction was 9.5 days (range, 6 to 13 days). KS was restricted to the skin in 7 cases, among which, one presented with associated Hodgkin lymphoma. Visceral involvement (one lung and one colon) was observed in two cases. One patient presented with a gastric KS without skin lesions. Immunosuppressive treatment was reduced, then withdrawn in three cases, resulting in regression of KS a few weeks later, but with graft loss requiring hemodialysis at 1, 3 and 4 months. Among the remaining 7 cases, we stopped mycophenalate mofetil (MMF) and switched from calcineurin inhibitors to sirolimus. Allograft function remained stable after the switch. Only one patient who already had allograft dysfunction due to biopsy-proven chronic allograft nephropathy. Deteriorated progressively, undergoing hemodialysis at 2 years after KS diagnosis. In conclusion, we observed a relatively high incidence of KS among our cases. The introduction of sirolimus resulted in complete regression of KS lesions with preserved graft function.

Transplantation Proceedings

AIDS-related Gastrointestinal Kaposi Sarcoma in Korea: A Case Report and Review of the Literature.

Sept 2012

Chung CY, Park SW, Myung E, Cho DK, Song YA, Park KJ, Jang HC, Joo YE.

Source

Department of Internal Medicine, Chonnam National University Medical School, 8 Hak-dong, Dong-ku, Gwangju 501-757, Korea.

Abstract

Kaposi sarcoma (KS) is a vascular neoplasm, which is fairly prevalent in acquired immunodeficiency syndrome (AIDS) patients. Mucocutaneous and lymph node involvements are characteristic features of KS in AIDS patients. The involvement of gastrointestinal tract occurs in 40% of KS patients and leads to significant morbidity and mortality. In the highly active antiretroviral therapy (HAART) era, the rate of AIDS related KS has fallen with control of human immunodeficiency virus (HIV) viremia. However, it is still recognized as the primary AIDS-defining illness, and the proportion of AIDS diagnoses made due to KS ranged from 4.1% to 7.5%. In Korea, AIDS-related KS has been report in low rate incidence. Its gastrointestinal involvements are rarely reported. To date, five cases have been recorded in Korea. Herein, we present an additional case of gastrointestinal KS as the AIDS-defining illness and review of the Korean medical literature. (Korean J Gastroenterol 2012;60:166-171).

KJG

Oral HIV-Associated Kaposi Sarcoma: A Clinical Study from the Ga-Rankuwa Area, South Africa.

2012

Khammissa RA, Pantanowitz L, Feller L.

Source

Department of Periodontology and Oral Medicine, University of Limpopo, Medunsa Campus, Pretoria 0204, South Africa.

Abstract

Background. Kaposi sarcoma (KS) is one of the most common neoplasms diagnosed in HIV-seropositive subjects. Oral involvement is frequent and is associated with a poor prognosis. The aim of this study was to characterize the features of oral HIV-KS in patients from Ga-Rankuwa, South Africa. 

Methods. All cases with confirmed oral HIV-KS treated at the oral medicine clinic in Ga-Rankuwa from 2004 to 2010 were included in this retrospective study. Differences between males and females with oral HIV-KS in relation to HIV infection status, to oral KS presentation and to survival rates were statistically analysed. 

Results. Twenty (54%) of the 37 patients in the study were females and 17 (46%) were males. In 21 patients (57%), the initial presentation of HIV-KS was in the mouth. Other than the fact that females presented with larger (≥10 mm) oral KS lesions (P = 0.0004), there were no statistically significant gender differences. Significantly more patients presented with multiple oral HIV-KS lesions than with single lesions (P = 0.0003). Nine patients (24%) developed concomitant facial lymphoedema, and these patients had a significantly lower CD4+ T-cell count (28 cells/mm(3)) compared to the rest of the group (130 cells/mm(3)) (P = 0.01). The average CD4+ T-cell count of the patients who died (64 cells/mm(3)) was significantly lower (P = 0.0004), there were no statistically significant gender differences. Significantly more patients presented with multiple oral HIV-KS lesions than with single lesions (P = 0.016) at the time of oral-KS presentation than of those who survived (166  cells/mm(3)). 

CONCLUSIONS: In Ga-Rankuwa, South Africa where HIV-KS is prevalent, oral KS affects similarly males and females. A low CD4+ T-cell count at the time of oral HIV-KS diagnosis and the development of facial lymphoedema during the course of HIV-KS disease portends a poor prognosis.

NIH

Sézary syndrome, Kaposi sarcoma and generalized dermatophytosis 15 years after sulfur mustard gas exposure.

Sept 2012

Emadi SN, Babamahmoodi F, Poursaleh Z, Sayad-Noori SS, Soroush MR, Maleki AR, Izadi M, Khodaei-Ardakan MR, Emadi SE.

Source

Chemical Injuries Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran ; Skin Research Center, Mazandaran University of Medical Sciences, Sari, Iran ; Tehran University of Medical Sciences, Tehran, Iran.

Abstract

BACKGROUND:

The relationship between compromised immune system and the development of malignancy, generalized dermatitis, and infection after sulfur mustard gas exposure has been established.

MAIN OBSERVATION:

We introduce a 58-year-old man with an abrupt, de novo and erythrodermic eruption in 2002 that was previously exposed to sulfur mustard during the Iran - Iraq war in 1987. Six weeks after the onset of diffuse eruption, he developed papules on the glans penis and generalized dermatophytosis. A biopsy of his eruption was consistent with cutaneous T-cell lymphoma/Sézary syndrome. A complete blood count demonstrated leukocytosis, eosinophilia and atypical lymphocytosis. Subsequently, Sézary syndrome was confirmed and T-cell count with increased CD4/CD8 in flow cytometry. The biopsy of his penile papules was consistent with Kaposi's sarcoma.

CONCLUSION:

These findings suggest a causative relationship between sulfur mustard gas exposure, cutaneous T cell lymphoma and immune compromised state with opportunistic infections.

PubMed - Journal of Dermatological Case Reports