Other Languages

2007
German

2006
Portuguese
Vietnamese

2005
Russian
Spanisch

2003
Persian (Farsi)

Helmut Schöfer and Dana Sachs

Kaposi's sarcoma (KS) is a malignant, multifocal systemic disease that originates from the vascular endothelium and has a variable clinical course. The most frequently involved site is the skin , but mucous membranes, the lymphatic system and viscera - in particular the lung and gastrointestinal tract - can be involved. Five clinical forms are described: classic KS, KS secondary to immunosuppression; endemic African KS; epidemic HIV-associated KS and IRIS*-associated KS.

*In association with the immunologic and viral immune reconstitution (see special chapter: Immune reconstitution inflammatory syndrome, IRIS) an aggressive type of Kaposi`s sarcoma was reported recently (Bower 2005, Leidner 2005). IRIS-associated KS can occur spontaneously or progress from a mild or stable disease within the first three months of immune reconstitution. The initiation of effective HAART with increasing CD4-cell count and a reduced HIV viral load, is a precondition. Cutaneous, mucosal, lymphatic and pulmonary KS, which in most cases of efficient HAART have a tendency to stabilise or regress completely, show a paradoxical reaction and grow rapidlyPulmonary lesions can be especially threatening.. Early systemic chemotherapy is used to halt disease progression. It is not necessary to discontinue HAART while treating IRIS-associated KS.

More? HIV Medicine 2007, Chapter 13: Download

HIV Medicine
15th edition
818 pages
PDF, 3.7 MB

All types of KS are due to infection with human herpes virus-8 (HHV-8), which is transmitted sexually or via blood or saliva. In men having sex with men (MSM) the number of life-time sex partners is the highest risk factor for HHV-8 infection, however, KS is significantly linked to low CD4-cell counts (Martró 2007). Months before manifestation of the tumors, HHV-8 viremia leads to development of specific antibodies. A cutaneous eruption has been described in association with HHV-8 seroconversion (Andreoni 2002). In HIV-infected patients, KS is an AIDS-defining illness. Aggressive courses of disease, with lethal outcomes, have been observed in HIV patients with severe and untreated immunodeficiency. In such cases, the average survival time following diagnosis is less than one year. Since the introduction of HAART in 1996, the frequency of KS in HIV-infected patients has decreased sharply (by as much as 90% in the Department of Dermatovenereology at Frankfurt University Hospital), and the clinical course of disease has improved significantly. In many cases, stabilization or complete remission of tumors is possible with immune reconstitution and reduction of the HIV viral load. Of the available therapies, HAART is first line treatment. It can be used in combination with local treatments such as cryotherapy, retinoids, and radiation. Therapy with interferon-alpha, paclitaxel or chemotherapy with liposomal anthracyclines is only necessary if there is visceral progression of the disease whilst on HAART. New developments in KS therapies are phase clinical trials with matrix metalloproteinases inhibitors (e.g. COL-3; Dezube 2006), chemotherapy with irinotecan (Vaccher 2005). inhibition of the c-kit and PDGF receptors with imatinib etc.). Signs, symptoms and diagnosis In contrast to the classical KS found in older men, in whom the tumors usually occur on the lower legs and feet, HIV-associated KS does not have a preferential pattern of localization. It can begin on any area of the skin, but may also appear on oral, genital, or ocular mucous membranes. Typical findings are initially solitary, or a few asymptomatic purple macules or nodules, which have a predilection for distribution along relaxed skin tension lines. Disease progression is variable: the macules or tumors can remain unchanged for months to years, or grow rapidly within a few weeks and disseminate. Rapid growth can lead to localized pain and a yellow-green discoloration of the area around the tumor as a result of hemorrhage. Further progression of the tumor can lead to central necrosis and ulceration. The tumors may bleed easily. Plaque-like and nodular KS lesions, often become confluent and can be accompanied by massive edema. In the oral cavity, the hard palate is frequently affected. Lesions begin with purplish erythema and progress to plaques and nodules that ulcerate easily. KS lesions may also involve the external genitalia including the foreskin and glans penis. The diagnosis of KS in the skin and mucous membranes can usually be made based on the following clinical features: 1. Purple macules or nodules 2. Distribution along skin tension lines 3. Green-yellow discoloration around the tumors corresponding to hemorrhage 4. Surrounding edema 5. Dissemination of lesions, possibly with mucocutaneous involvement This is particularly characteristic for patients in whom HIV infection or another form of immunodeficiency is known. If there is clinical doubt, the lesions should be biopsied to confirm the diagnosis histologically. The clinical presentation may pose a challenge, especially with the telangiectatic, ecchymotic, keloidal and hyperkeratotic variants. The important features of KS on routine histology include: 1. Epidermis is usually intact. 2. Slit-like spaces formed by new, thin-walled and partly aberrant blood vessels running alongside normal dermal vessels and adnexal structures. 3. Extravasated erythrocytes around the new vessels. 4. Hemosiderin deposits. 5. Lymphocytic inflammatory infiltrate. 6. An infiltrate of oval- or spindle-shaped cells (spindle cell KS). When KS resolves, either spontaneously or following therapy, it often leaves gray-brown to light brown hyperpigmentation for months to years (post-inflammatory hyperpigmentation), caused by hemosiderin deposits from extravasated erythrocytes. The accompanying lymphedema can also persist for a similar length of time, particularly on the lower legs. HHV-8, which contributes to the development of the tumor, can be detected in tumor tissue by PCR. This can be a helpful diagnostic tool in cases where the histopathological diagnosis of Kaposi's sarcoma is uncertain. HHV-8 antibodies are often detected months before the clinical manifestation of the tumor. Neutralizing antibodies seem to control the HHV-8 infection and thus protect against the clinical manifestation of Kaposi's sarcoma (Kimball 2004). In patients with Kaposi's sarcoma the titres of neutralizing antibodies are low. In contrast,, high titres of antibodies against HHV-8 latent and lytic antigens are strongly associated with the risk of subsequent development of KS (Newton 2006). The HIV tat-protein is able to promote the HHV-8 transmission directly, which could be an explanation for the high rate of KS in patients coinfected with HHV-8 and HIV (Aoki 2004, Chandra 2003). Epidemiological studies have shown that a high regional incidence of KS (e.g. in Southern Italy, as well as in Central Africa) correlates with an increased regional HHV-8 seroprevalence. HHV-8 seems to mainly be transmitted sexually. The KS frequently seen in African children is presumably transmitted via saliva (Pauk et al. 2000). A saliva reservoir of HHV-8 was also found in adult HIV patients (Triantos 2004). On initial diagnosis of KS, the following investigations help to stage the disease: 1. Complete cutaneous inspection of the patient (including oral and genital mucous membranes) 2. Lymph node ultrasound 3. Abdominal ultrasound 4. Upper GI endoscopy (optional, but always required with mucocutaneous tumors) 5. Lower GI endoscopy (optional, but always required with mucocutaneous tumors) 6. Chest radiography 7. Determination of CD4+ T-cell count and HIV viral load (is initiation or optimization of antiretroviral therapy necessary?) Prognosis and staging HIV-associated KS ranges from indolent skin lesions to aggressive, disseminated disease with lymph node and visceral involvement. Left untreated, rapid tumor growth can lead to death of the patient within weeks. Malignant clonal tumor growth has been shown to occur in pulmonary KS. Whole body (99m)Tc-MIBI scans seem to be an effective tool, to demonstrate cutaneous and lymphnote KS and to monitor therapy (Peer 2007). The introduction of HAART has significantly improved the prognosis for patients with KS. Patients with extensive visceral involvement often achieve complete remission. Table 1. Staging of HIV-associated epidemic KS (from ACTG, Krown 1997) Early stage Late stage If all the following criteria are met: 1. Tumor (T): 0 KS limited to skin and/or lymph nodes; minimal oral disease (non-nodular KS confined to hard palate) 2. Immune system* (I): 0 CD4+ T-cells > 200/µl 3. Systemic illness (S): 0 No history of OI or thrush, no B symptoms* of HIV infection If one of the following applies: 1.Tumor (T): 1 Pulmonary or gastrointestinal KS; extensive oral KS; tumor-associated edema or ulceration 2. Immune system* (I): 1 CD4+ T-cells < 200/µl 3. Systemic illness (S): 1 History of opportunistic infections, thrush, malignant lymphoma or HIV-associated neurological disease, B** symptoms of HIV infection *CD4 cell count is not of any prognostic relevance in KS patients on HAART (Nasti 2003) ** unexplained fever, night sweats or diarrhea persisting for more than two weeks, involuntary weight loss of >10% The classification system for HIV-associated KS, published in 1993 and reviewed in 1997 by the AIDS Clinical Trials Group (ACTG, Krown 1997, table 1), was adapted by an Italian working group to address KS in the HAART era. However, the changes proposed by Nasti et al (2003) have not yet been validated and accepted on an international level. Of particular concern is the suggested omission of the CD4+ T-cell count as a prognostic factor, which results in the classification of KS patients into those with a good (T0S0, T1S0, T0S1) and those with a bad prognosis (T1S1). Treatment If KS is diagnosed in HIV-infected patients who have not yet been treated, or who are no longer being treated with antiretroviral drugs, it is essential to start HAART (see HAART chapter). If the HIV viral load can be reduced (ideally below the level of detection) and immune reconstitution is achieved with an increase in the CD4 T cell count, KS stabilizes or even resolves completely in many patients. Long-term remissions (<60 months) have been demonstrated in an Italian study (Cattelan 2005). One exception, however, is KS with severe pulmonary involvement which can progress rapidly during the first three months of HAART (see IRIS associated KS). The clinical observation that KS may resolve with protease inhibitors, even in the absence of a significant improvement in the immunological status, has been confirmed with the discovery of the direct anti-proliferative effects of the PIs indinavir and saquinavir (Sgadari 2002). The PI ritonavir has also been shown to have a direct anti-tumor effect (Pati 2002) In addition, the following treatment methods are available depending on the clinical stage of KS (table 1): § Early stage (ACTG): Local treatment (see below). With progression: primary treatment with interferon-a combined with HAART or with with liposomal anthracyclines. § Late stage (ACTG): Primary treatment for stage T 0, I 0, S 1 with interferon-a in combination with HAART or with liposomal anthracyclines. Should these therapies fail, paclitaxel or combination chemotherapy (ABV regimen) can be used. Immunosuppressed transplant recipients with KS may benefit from a change from calcineurin inhibitors to sirolimus (Stallone 2005, Lebbé 2006). Local therapy Local therapy has the advantages of being (1) provided in the ambulatory care setting, (2) well-tolerated, and (3) less costly than in-patient therapy. The following methods are used depending on the size and location of tumors: cryosurgery, vinca alkaloids, intralesional bleomycin or intralesional interferons, soft x-ray radiation, electron beam therapy, cobalt radiation (fractionated), retinoids: 9-cis-retinoic acid, alitretinoin (Bodsworth 2001, Duvic 2000), and cosmetic camouflage. In addition to intralesional vinblastine, tumors of the buccal mucosa can be injected with 3 % sodium tetradecyl sulphate (which has comparable efficacy rates) (Ramirez-Amador 2002). As Kaposi's sarcoma is a multifocal systemic disease, surgical treatment is limited to excisional biopsies for diagnosis and palliative removal of small tumors in cosmetically disturbing areas. Since tumors often extend further into the surroundings than is clinically visible and local trauma can lead to new tumors (Koebner phenomenon), local and regional recurrences can be expected. These can be prevented by radiation therapy: in order to reach the tumor cells spreading along the vascular channels, the field of radiation should be extended 0.5-1.0 cm beyond the edges of the tumor. KS is a strikingly radiosensitive tumor. Superficial macular or plaque-like KS lesions respond well to daily doses of 4-5 Gy (total dose 20-30 Gy, fractionated 3x/week) of soft x-ray radiation. To palliate fast growing tumors, a single dose of 8 Gy is recommended (Harrison 1998). For the treatment of extensive KS with edematous swelling and/or lymph node involvement, soft x-ray radiation, originating from 50-kV beryllium-windowed units, as used in dermatology, is not sufficient. Such tumors should be treated with electron beam therapy with conventional fractionation (5x2 Gy per week) to a target volume total dose of 40 Gy. Patients with KS of the lower extremities, frequently associated with lymphedema, may benefit from compression therapy with elastic stockings (Brambilla 2006). Local chemo- and immunotherapy have the advantage of less or no systemic side effects compared to systemic treatments. Within the tumor, high concentrations of drugs with direct antiproliferative efficacy can be reached. Chemotherapy Theoretically, aggressive chemotherapy harbors particular risks for HIV-infected patients. Bone marrow suppression, , can lead to deterioration of existing, HIV-associated cellular immunodeficiency and occurrence of acute, life-threatening opportunistic infections. To maintain a high quality of life HIV-associated KS should preferably be treated by chemotherapy in the presence of clinical symptoms (e.g. pain), rapid tumor progression and/or visceral involvement. In such cases, even patients with a good immune status should receive PCP and toxoplasmosis prophylaxis with cotrimoxazole (480 mg/day or 960 mg 3x/week). The myelotoxic effects of several chemotherapeutic drugs on a hematopoetic system that has already been impaired by HIV infection may require further treatment with erythropoetin or blood transfusions. The chemotherapeutics that achieve the highest remission rates for KS are anthracyclines. Compared to aggressive chemotherapy regimens (like ABV) pegylated, liposomal anthracyclines have a mild profile of bone marrow toxicity and other side effects . Treatment with intravenous pegylated liposomal doxorubicin (PLD) at a dose of 20 mg/m2 body surface area every 2-3 weeks leads to partial remission in up to 80 % of treated patients and is well tolerated in combination with HAART (Lichterfeld 2005). Treatment with intravenous liposomal daunorubicin 40 mg/m2 body surface area every 2 weeks has slightly lower remission rates (Krown 2004, Rosenthal 2002, Osoba 2001, Cheung 1999). In comparative studies, liposomal daunorubicin showed the same and doxorubicin a higher efficiency than the previous gold standard of KS treatment, which consisted of combination therapy with adriamycin, bleomycin and vincristine (ABV regimen). In a comparative study on patients with moderate to advanced KS, the combination of pegylated liposomal doxorubicin with HAART was substantially more effective than HAART alone (response rate 76 % versus 20 %) (Martin-Carbonero 2004). A German multicentre study demonstrated superiority of PLD treatment over recombinant interferon alfa-2a in 18 patients with classic KS, but the number of patients treated with interferon was low (n=6), and mean follow-up was only 6,3 months, so further comparative studies should be performed. Both therapies were well tolerated (Kreuter 2005). Cooley et al. (2007) confirmed a clinical benefit of pegylated liposomal doxorubicin in 80% of all patients treated and a tumour response rate in 55%. The most important side effects of anthracyclines are neutropenia (30%), nausea, asthenia and anemia. This usually occurs after 8-10 cycles. The cardiotoxicity associated with anthracyclines should also be considered. However, usually it only occurs with long-term administration (cumulative doses of 450 mg doxorubicin and higher). Macular and painful erythema of the palms and soles (palmoplantar erythrodysesthesia) is another notable side effect which can limit treatment. Paclitaxel is also a very effective drug for the treatment of KS (Tulpule 2002). The recommended dose is 100 mg/m2 body surface area administered intravenously over 3-4 hours every 2 weeks. Partial remission is achieved in up to 60 % of all treated patients. Paclitaxel is myelotoxic and almost always leads to alopecia, often after just one dose. Whether paclitaxel has important interactions with HAART therapy such as increasing the toxicity of paclitaxel is still under investigation (Bundow 2004). For this reason, patients on HAART and paclitaxel need very careful monitoring. Paclitaxel acts by disrupting the structural reorganization of intracellular microtubuli. This leads to mitotic arrest and programmed cell death (apoptosis) (Blagosklonny 2002). Paclitaxel can also be used successfully in those patients with tumor progression under anthracycline therapy. Docitaxel (taxotere) seems to be an interesting alternative from the taxane group. It is FDA approved for the treatment of breast cancer, but very recently a phase II clinical trial showed that taxotere is effective and safe for the treatment of KS (Lim 2005). Relapses (following anthracycline or paclitaxel therapy) may also be treated with low dose oral etoposide (Evans 2002). Table 2: Treatment recommendations for systemic therapy of Kaposi's sarcoma (evaluation of individual drugs in text) Therapeutic agent Dose Requirement Remission rate Side effects IFN-a (2a,b) 1-3 mil. I.U. sc daily until remission, followed by 3 x weekly >200 CD4+ T-cells/µl Endogenous IFN-a < 3 U/ml, HAART Approx. 40% Fever, myalgia, depression Pegylated IFN-a 2b* 50 µg sc 1 x weekly As for IFN-a (2a,b) ? As for IFN-a (2a,b) Pegylated liposomal Doxorubicin 20 mg/m2 iv at biweekly intervals KS stage T1, S0-1 (see Table 1, staging of KS) Approx. 80% Neutropenia, anemia Rarely: Flushing, dyspnea, back pain, palmo-plantar erythrodysesthesia Liposomal Daunorubicin 40 mg/m2 iv at biweekly intervals T1, S0-1 (see Table 1, staging of KS) Approx. 60% Neutropenia, anemia Rarely: Flushing, dyspnea, back pain, palmo-plantar erythrodysesthesia Paclitaxel 100 mg/m² iv at biweekly intervals T1, S0-1 (see Table 1, staging of KS) Approx. 60% Neutropenia, thrombocytopenia, anemia, alopecia Rarely: Hypotension, ECG-changes *Pegylated IFN-a 2b has only been licensed for treatment of chronic hepatitis C Immunotherapy Interferons (IFN-a 2a, IFN-a 2b, IFN-ß) are used successfully for classic, as well as sporadic and HIV-associated, epidemic Kaposi's sarcoma. Remission rates of 45-70% can be achieved. In addition to their well-known immunomodulatory activity, interferons induce apoptosis in tumor cells and lead to reduced ß-FGF expression by inhibiting angiogenesis and therefore proliferation. There are currently no standardized treatment regimens.. Daily doses of 3-6 million IU sc are usually given. After remission (tumor growth stopped, tumors flattened, loss of purple color, change to brownish color), interferon dosing can be reduced to 3x/week. Complete remission can, at the earliest, be expected after 6-8 weeks of treatment, but can occur significantly later.. An initial study showed that interferon doses can be reduced even further when given with HAART, thereby decreasing interferon side effects (Krown 2002). Depression with suicidal tendencies does not seem to be a dose-related side effect of interferons. There is almost no data on the use of the new, pegylated IFN-a 2b for KS. It is depegylated to IFN-a 2b, the active substance, following subcutaneous application. It has been used successfully for the treatment of classical Kaposi's sarcoma (Thoma-Greber 2002) in a dose of 50µg/week subcutaneously. Whether higher doses or shorter treatment intervals are necessary for HIV-associated KS still remains to be investigated. Such studies have become more difficult to perform as a result of the significant decrease in both the incidence and prevalence of KS since the introduction of HAART. In principle, this new formulation should lead to a further improvement in the efficacy of interferon. We have personal experience in the treatment of minor KS with 100µg pegylated IFN-a 2b weekly in two patients, which led to a satisfying remission with residual hyperpigmentation in both cases (Schöfer, unpublished data). The efficacy of interferon treatment is dependent on the cellular immune status of the patient. In patients with more than 400 CD4+ T-cells/µl, remission rates are > 45%; with less than 200 CD4+ T-cells/µl they stand at only 7 %. The endogenous interferon levels are important prognostic indicators and are significantly elevated in the advanced stages of HIV infection which leads to reduced responses to exogenous interferon. The criteria for treatment with interferon in epidemic KS therefore include an early stage of HIV disease (CD4+ T-cells > 200/µl) and endogenous interferon levels < 3 U/ml. In the late stage of HIV disease, interferons should only be given in combination with an efficient HAART regimen. IFN-? leads to tumor progression and is contraindicated. Monitoring and follow-up care In cases with isolated cutaneous and slowly progressive KS, HIV disease and HAART usually determine the necessary intervals for monitoring. However, even with a functional cellular immunity (CD4+ T-cells > 400/µl) and low viral load, tumor progression may be rapid with organ involvement in individual cases. Clinical examination of the skin, mucous membranes and lymph nodes is recommended at three-month intervals. The lungs and gastrointestinal tract should be monitored at 6-12 month intervals with appropriate diagnostic testing if indicated. However, evidence-based data that tumor follow-up leads to improvement in the remission rates as a result of close monitoring is not yet available for Kaposi's sarcoma. References 1. Aboulafia DM, Norris D, Henry D, et al. 9-cis-retinoic acid capsules in the treatment of AIDS-related Kaposi sarcoma: results of a phase 2 multicenter clinical trial. Arch Dermatol 2003; 139: 178-86. http://amedeo.com/lit.php?id=12588223 2. Aldenhoven M, Barlo NP, Sanders CJ. Therapeutic strategies for epidemic KaposiŽs sarcoma. Int J STD AIDS 2006; 17: 571-8. Abstract: http://amedeo.com/lit.php?id=16942647 3. Andreoni M, Sarmati L, Nicastri E, et al. Primary human herpesvirus 8 infection in immunocompetent children. JAMA 2002, 287:1295-300. http://amedeo.com/lit.php?id=11886321 4. Aoki Y, Tosato G. HIV-1 Tat enhances KSHV infectivity. Blood 2004; 104: 810-4http://amedeo.com/lit.php?id=15073028 5. Becker G, Bottke D. Radiotherapy in the management of KaposiŽs sarcoma. Onkologie 2006; 29: 329-33. Epub 2006 Jul 3. Abstract: http://amedeo.com/lit.php?id=16874018 6. 7. Blagosklonny MV, Robey R, Sheikh MS, Fojo T. Paclitaxel-induced FasL-independent apoptosis and slow non-apoptotic cell death. Cancer Biol Ther 2002, 1:113-7. http://amedeo.com/lit.php?id=12170770 8. Bodsworth NJ, Bloch M, Bower M, et al. Phase III vehicle-controlled, multi-centered study of topical alitretinoin gel 0.1% in cutaneous AIDS-related Kaposi's sarcoma. Am J Clin Dermatol. 2001; 2: 77-87. http://amedeo.com/lit.php?id=11705307 9. Bower M, Nelson M, Young AM, et al. Immune reconstitution inflammatory syndrome associated with KaposiŽs sarcoma. J Clin Oncol 2005; 23: 5224-8. http://amedeo.com/lit.php?id=16051964 10. Brambilla L, Tourlaki A, Ferrucci S, Brambati M, Boneschi V. Treatment of classic KaposiŽs sarcoma-associated lymphedema with elastic stockings. J Dermatol 2006; 33: 451-6. Abstract: http://amedeo.com/lit.php?id=16848816 11. Bundow D, Aboulafia DM. Potential drug interaction with paclitaxel and highly active antiretroviral therapy in two patients with AIDS-associated Kaposi sarcoma. Am J Clin Oncol 2004, 27: 81-4. http://amedeo.com/lit.php?id=14758138 12. Bower M, Fox P, Fife K, Gill J, Nelson M, Gazzard B. HAART prolongs time to treatment failure in Kaposi's sarcoma. AIDS 1999, 13: 2105-2111. http://amedeo.com/lit.php?id=10546864 13. Casper C. Defining a role for antiviral drugs in the treatment of persons with HHV-8 infection. Herpes 2006; 13: 42-7. Abstract: http://amedeo.com/lit.php?id=16895654 14. Cattelan AM, Calabro ML, De Rossi A, et al. Long-term clinical outcome of AIDS-related KaposiŽs sarcoma during highly active antiretroviral therapy. Int J Oncol 2005; 27: 779-85. http://amedeo.com/lit.php?id=16077928 15. Cheuk W, Wong KO, Wong CS, Dinkel JE, Ben-Dor D, Chan JK. Immunostaining for human herpesvirus 8 latent nuclear antigen-1 helps distinguish Kaposi sarcoma from its mimickers. Am J Clin Pathol 2004, 121: 335-42. http://amedeo.com/lit.php?id=15023037 16. Cooley T, Henry D, Tonda M, Sun S, OŽConnell M, Rackoff W. A randomized, double-blind study of pegylated liposomal doxorubicin for the treatment of AIDS-related KaposiŽs sarcoma. Oncologist 2007;12:114-23. Abstract: http://amedeo.com/lit.php?id=17227906 17. Cohen A, Wolf DG, Guttman-Yassky E, Sarid R. KaposiŽs sarcoma-associated herpesvirus: clinical, diagnostic, and epidemiological aspects. Crit Rev Clin Lab Sci 2005; 42: 101-53. http://amedeo.com/lit.php?id=15941082 18. Crane HM, Deubner H, Huang JC, Swanson PE, Harrington RD. Fatal Kaposi's sarcoma-associated immune reconstitution following HAART initiation.Int J STD AIDS 2005; 16:80-3. 19. Dagna L, Broccolo F, Paties CT, et al. A relapsing inflammatory syndrome and active human herpesvirus 8 infection. N Engl J Med 2005; 353: 156-63. http://amedeo.com/lit.php?id=16014885 20. Dezube BJ, Krown SE, Lee JY, Bauer KS, Aboulafia DM. Randomized phase II trial of matrix metalloproteinase inhibitor COL-3 in AIDS-related KaposiŽs sarcoma: an AIDS Malignancy Consortium Study. J Clin Oncol 2006; 24: 1389-94. http://amedeo.com/lit.php?id=16549833 21. Di Trolio R, Di Lorenzo G, Delfino M, De Placido S. Role of pegylated lyposomal doxorubicin (PLD) in systemic KaposiŽs sarcoma: a systematic review. Int J Immunopathol Pharmacol 2006; 19: 253-63. http://amedeo.com/lit.php?id=16831292 22. Dupont C, Vasseur E, Beauchet A, et al. Long-term efficacy on Kaposi's sarcoma of highly active antiretroviral therapy in a cohort of HIV-positive patients. AIDS 2000, 14:987-993. http://amedeo.com/lit.php?id=10853980 23. Duvic M, Friedman-Kien AE, Looney DJ, et al. Topical treatment of cutaneous lesions of acquired immunodeficiency syndrome-related Kaposi sarcoma using alitretinoin gel: results of phase 1 and 2 trials. Arch Dermatol 2000; 136: 1461-9. http://amedeo.com/lit.php?id=11115156 24. Evans SR, Krown SE, Testa MA, Cooley TP, Von Roenn JH. Phase II evaluation of low-dose oral etoposide for the treatment of relapsed or progressive AIDS-related KaposiŽs sarcoma: an AIDS Clinical Trials Group clinical study. J Clin Oncol 2002; 20: 3236-41. http://amedeo.com/lit.php?id=12149296 25. Harrison M, Harrington KJ, Tomlinson DR, Stewart JS. Response and cosmetic outcome of two fractionation regimens for AIDS-related Kaposi's sarcoma. Radiother Oncol 1998; 46: 23-8. http://amedeo.com/lit.php?id=9488123 26. Kimball LE, Casper C, Koelle DM, Morrow R, Corey L, Vieira J. Reduced levels of neutralizing antibodies to kaposi sarcoma-associated herpesvirus in persons with a history of kaposi sarcoma. J Infect Dis 2004; 189: 2016-22. http://amedeo.com/lit.php?id=15143468 27. Evans SR, Krown SE, Testa MA, Cooley TP, Von Roenn JH. Phase II evaluation of low-dose oral etoposide for the treatment of relapsed or progressive AIDS-related Kaposi's sarcoma: an AIDS Clinical Trials Group clinical study. J Clin Oncol 2002, 20:3236-41. http://amedeo.com/lit.php?id=12149296 28. Gessain A, Duprez R. Spindle cells and their role in KaposiŽs sarcoma. Int J Biochem Cell Biol 2005; 37: 2457-2465. Epub 2005 Aug 1. http://amedeo.com/lit.php?id=16188485 29. Grabar S, Abraham B, Mahamat A, Del Giudice P, Rosenthal E, Costagliola D. Differential impact of combination antiretroviral therapy in preventing KaposiŽs sarcoma with and without visceral involvement. J Clin Oncol 2006; 24: 3408-14. Abstract: http://amedeo.com/lit.php?id=16849755 30. Hernandez-Morales DE, Hernandez-Zaccaro AE. Gastrointestinal and cutaneous AIDS-related KaposiŽs sarcoma: different activity of liposomal doxorubicin according to location of lesions. Eur J Cancer Care Engl 2005; 14: 264-6. http://amedeo.com/lit.php?id=15952971 31. Jabr FI. Acquired immunodeficiency syndrome-related KaposiŽs sarcoma of the axilla and breast after percutaneous intravenous catheter insertion. Int J Dermatol 2005; 44: 611-2. http://amedeo.com/lit.php?id=15985038 32. Jarviluoma A, Ojala PM. Cell signaling pathways engaged by KSHV. Biochim Biophys Acta 2006; 1766: 140-58. Epub 2006 May 19. Abstract: http://amedeo.com/lit.php?id=16828973 33. Johnson AS, Maronian N, Vieira J. Activation of KaposiŽs sarcoma-associated herpesvirus lytic gene expression during epithelial differentiation. J Virol 2005; 79: 13769-77. http://amedeo.com/lit.php?id=16227296 34. Koon HB, Bubley GJ, Pantanowitz L, et al. Imatinib-induced regression of AIDS-related KaposiŽs sarcoma. J Clin Oncol 2005; 23: 982-9. http://amedeo.com/lit.php?id=15572730 35. Korman DB, Mikaelian SG, Boronovskaia LE, Maslova IA. [Results of a phase I-II clinical trial of Emoxyl, a novel antineoplastic anthracycline] Vopr Onkol 2004; 50: 202-7. http://amedeo.com/lit.php?id=15176224 36. Kreuter A, Rasokat H, Klouche M, et al. Liposomal pegylated doxorubicin versus low-dose recombinant interferon Alfa-2a in the treatment of advanced classic KaposiŽs sarcoma; retrospective analysis of three German centers. Cancer Invest 2005;23:653-9. http://amedeo.com/lit.php?id=16377582 37. Krown SE, Li P, Von Roenn JH, Paredes J, Huang J, Testa MA. Efficacy of low-dose interferon with antiretroviral therapy in Kaposi's sarcoma: a randomized phase II AIDS clinical trials group study. J Interferon Cytokine Res 2002, 22:295-303. http://amedeo.com/lit.php?id=12034036 38. Krown SE, Testa MA, Huang J. AIDS-related Kaposi's sarcoma prospective validation of the AIDS Clinical Trials Group staging classification. J Clin Oncol 1997, 15: 3085-3092. http://amedeo.com/lit.php?id=9294471 39. Lebbe C, Euvrard S, Barrou B, et al. Sirolimus conversion for patients with posttransplant KaposiŽs sarcoma. Am J Transplant 2006;6:2164-8. Epub 2006 Jun 19. http://amedeo.com/lit.php?id=16780549 40. Leidner RS, Aboulafia DM. Recrudescent KaposiŽs Sarcoma After Initiation of HAART: A Manifestation of Immune Reconstitution Syndrome. AIDS Patient Care STDS 2005; 19: 635-44. http://amedeo.com/lit.php?id=16232048 41. Lichterfeld M, Qurishi N, Hoffmann C, et al. Treatment of HIV-1-associated KaposiŽs sarcoma with pegylated liposomal doxorubicin and HAART simultaneously induces effective tumor remission and CD4+ T cell recovery. Infection 2005; 33: 140-7. http://amedeo.com/lit.php?id=15940415 42. Lim ST, Tupule A, Espina BM, Levine AM. Weekly docetaxel is safe and effective in the treatment of advanced-stage acquired immunodeficiency syndrome-related Kaposi sarcoma. Cancer 2005; 103: 417-21. http://amedeo.com/lit.php?id=15578686 43. Little RF, Wyvill KM, Pluda JM, et al. Activity of thalidomide in AIDS-related KaposiŽs sarcoma. J Clin Oncol 2000; 18: 2593-602. http://amedeo.com/lit.php?id=10893291 44. Lospalluti M, Mastrolonardo M, Loconsole F, Conte A, Rantuccio F. Classical Kaposi's sarcoma: a survey of 163 cases observed in Bari, South Italy. Dermatology 1995, 191:104-108. http://amedeo.com/lit.php?id=8520054 45. Martin-Carbonero L, Barrios A, Saballs P, et al. Pegylated liposomal doxorubicin plus highly active antiretroviral therapy versus highly active antiretroviral therapy alone in HIV patients with KaposiŽs sarcoma. AIDS 2004; 18: 1737-40. http://amedeo.com/lit.php?id=15280789 46. Martinez V, Caumes E, Gambotti L, et al. Remission from KaposiŽs sarcoma on HAART is associated with suppression of HIV replication and is independent of protease inhibitor therapy. Br J Cancer 2006; 94: 1000-6. Abstract: http://amedeo.com/lit.php?id=16570046 47. Martro E, Esteve A, Schulz TF, et al. Risk factors for human Herpesvirus 8 infection and AIDS-associated KaposiŽs sarcoma among men who have sex with men in a European multicentre study. Int J Cancer 2007;120:1129-35. http://amedeo.com/lit.php?id=17154170 48. McCormick C, Ganem D. The kaposin B protein of KSHV activates the p38/MK2 pathway and stabilizes cytokine mRNAs. Science 2005; 307: 739-41. http://amedeo.com/lit.php?id=15692053 49. Nasti G, Talamini R, Antinori A, Martellotta F, et al. AIDS-related Kaposi's Sarcoma: evaluation of potential new prognostic factors and assessment of the AIDS Clinical Trial Group Staging System in the Haart Era--the Italian Cooperative Group on AIDS and Tumors and the Italian Cohort of Patients Naive From Antiretrovirals. J Clin Oncol 2003, 21: 2876-82. http://amedeo.com/lit.php?id=12885804 50. Nasti G, Errante D, Talamini R, et al. Vinorelbine is an effective and safe drug for AIDS-related KaposiŽs sarcoma: results of a phase II study. J Clin Oncol 2000; 18: 1550-7. http://amedeo.com/lit.php?id=10735904 51. Newton R, Carpenter L, Casabonne D, et al. A prospective study of KaposiŽs sarcoma-associated herpesvirus and Epstein-Barr virus in adults with human immunodeficiency virus-1. Br J Cancer 2006;94:1504-9. http://amedeo.com/lit.php?id=16705315 52. Olweny CL, Borok M, Gudza I, et al. Treatment of AIDS-associated KaposiŽs sarcoma in Zimbabwe: results of a randomized quality of life focused clinical trial. Int J Cancer 2005; 113: 632-9. http://amedeo.com/lit.php?id=15472910 53. Osoba D, Northfelt DW, Budd DW, Himmelberger D. Effect of treatment on health-related quality of life in acquired immunodeficiency syndrome AIDS-related Kaposi's sarcoma: a randomized trial of pegylated-liposomal doxorubicin versus doxorubicin, bleomycin, and vincristine. Cancer Invest 2001, 19: 573-80. http://amedeo.com/lit.php?id=11486699 54. Pauk J, Huang ML, Brodie SJ, et al. Mucosal shedding of human herpesvirus 8 in men. N Engl J Med 2000, 343:1369-77. http://amedeo.com/lit.php?id=11070101 55. Peer FI, Pui MH, Mosam A, Rae WI. 99mTc-MIBI imaging of cutaneous AIDS-associated KaposiŽs sarcoma. Int J Dermatol 2007;46:166-71. http://amedeo.com/lit.php?id=17269969 56. Pfeffer U, Bisacchi D, Morini M, et al. Human chorionic gonadotropin inhibits KaposiŽs sarcoma associated angiogenesis, matrix metalloprotease activity, and tumor growth. Endocrinology 2002; 143: 3114-21. http://amedeo.com/lit.php?id=12130577 57. Ramirez-Amador V, Esquivel-Pedraza L, Lozada-Nur F, et al. Intralesional vinblastine vs. 3% sodium tetradecyl sulfate for the treatment of oral Kaposi's sarcoma. A double blind, randomized clinical trial. Oral Oncol 2002, 38:460-7. http://amedeo.com/lit.php?id=12110340 58. Rosen T. Limited extent AIDS-related cutaneous KaposiŽs sarcoma responsive to imiquimod 5% cream. Int J Dermatol 2006; 45: 854-6. http://amedeo.com/lit.php?id=16863526 59. Rosenthal E, Poizot-Martin I, Saint-Marc T, Spano JP, Cacoub P; DNX Study Group. Phase IV study of liposomal daunorubicin DaunoXome in AIDS-related Kaposi sarcoma. Am J Clin Oncol. 2002; 25: 57-9. http://amedeo.com/lit.php?id=11823698 60. Schöfer H. Kaposi-Sarkom. Hautarzt 1998, 48 Suppl 1: S39-45 61. Schöfer H, Brockmeyer N. Kaposi-Sarkom. In: Korting HC, Callies R, Reusch M, Schlaeger M, Sterry W Hrsg. Dermatologische Qualitätssicherung. Leitlinien und Empfehlungen, 4. Aufl. 2005, S241-54. 62. Sgadari C, Barillari G, Toschi E, et al. HIV protease inhibitors are potent anti-angiogenic molecules and promote regression of Kaposi sarcoma. Nat Med 2002, 8: 225-32. http://amedeo.com/lit.php?id=11875492 63. Stallone G, Schena A, Infante B, et al. Sirolimus for KaposiŽs sarcoma in renal-transplant recipients. N Engl J Med 2005;352:1317-23. http://amedeo.com/lit.php?id=15800227 64. Stebbing J, Wildfire A, Portsmouth S, et al. Paclitaxel for anthracycline-resistant AIDS-related KaposiŽs sarcoma: clinical and angiogenic correlations. Ann Oncol 2003; 14: 1660-6. http://amedeo.com/lit.php?id=14581275 65. Stebbing J, Sanitt A, Nelson M, Powles T, Gazzard B, Bower M. A prognostic index for AIDS-associated KaposiŽs sarcoma in the era of highly active antiretroviral therapy. Lancet 2006; 367: 1495-502. Abstract: http://amedeo.com/lit.php?id=16679162 66. Tappero JW, Conant MA, Wolfe SF, et al. Kaposi's sarcoma: epidemiology, pathogenesis, histology, clinical spectrum, staging criteria and therapy. J Am Acad Dermatol 1993, 28: 371-395. http://amedeo.com/lit.php?id=8445054 67. Thoma-Greber E, Sander CA, Messer G, Röcken M. Pegyliertes Interferon-a2b: Neue Therapie bei klassischem Kaposi-Sarkom. Diaklinik Münchner Fortbildungswoche für Dermatologen 2002, 52-54. 68. Triantos D, Horefti E, Paximadi E, et al. Presence of human herpes virus-8 in saliva and non-lesional oral mucosa in HIV-infected and oncologic immunocompromised patients. Oral Microbiol Immunol 2004; 19: 201-4. http://amedeo.com/lit.php?id=15107073 69. Tulpule A, Groopman J, Saville MW, et al. Multicenter trial of low-dose paclitaxel in patients with advanced AIDS-related Kaposi sarcoma. Cancer 2002, 95:147-54. http://amedeo.com/lit.php?id=12115328 70. Vaccher E, di Gennaro G, Simonelli C, Schioppa O, Tirelli U. Evidence of activity of Irinotecan in patients with advanced AIDS-related KaposiŽs sarcoma. AIDS 2005;19:1915-6. http://amedeo.com/lit.php?id=16227802 71. Vanni T, Sprinz E, Machado MW, Santana Rde C, Fonseca BA, Schwartsmann G. Systemic treatment of AIDS-related Kaposi sarcoma: current status and perspectives. Cancer Treat Rev 2006; 32: 445-55. Epub 2006 Jul 24. Abstract: http://amedeo.com/lit.php?id=16860939 72. Viejo-Borbolla A, Ottinger M, Schulz TF. Human herpesvirus 8: biology and role in the pathogenesis of KaposiŽs sarcoma and other AIDS-related malignancies. Curr HIV/AIDS Rep 2004; 1: 5-11. http://amedeo.com/lit.php?id=16091217 73. Wang L, Dittmer DP, Tomlinson CC, Fakhari FD, Damania B. Immortalization of primary endothelial cells by the K1 protein of KaposiŽs sarcoma-associated herpesvirus. Cancer Res 2006; 66: 3658-66. Abstract: http://amedeo.com/lit.php?id=16585191 74. Yarchoan R, Tosato G, Little RF. Therapy insight: AIDS-related malignancies--the influence of antiviral therapy on pathogenesis and management. Nat Clin Pract Oncol 2005; 2: 406-15 http://amedeo.com/lit.php?id=16130937