Kaposi’s sarcoma is an angioproliferative neoplasm which has undergone considerable epidemiologic change since the original description by Moritz Kaposi in the late 1800s. This opportunistic neoplasm gained widespread notoriety within the US during the height of the AIDS epidemic, where it was frequently found co-occurring with opportunistic infections. With the advent of modern antiretroviral therapies, as well as an increasing number of individuals on immunosuppression for autoimmune disease or organ transplantation, the landscape of the immunocompromised individual has changed. It is now important for clinicians to be mindful of Kaposi’s sarcoma manifesting in a growing variety of clinical contexts.

International Journal of DermatologyVolume 52, Issue 11 p. 1401-1403 Correspondence Postoperative pathergic pyoderma gangrenosum after aortic aneurysm repair Jonathan S. Leventhal BA (HONS), Jonathan S. Leventhal BA (HONS) Department of Dermatology, New York University School of Medicine, New York, NY, USASearch for more papers by this authorBrook E. Tlougan MD, Brook E. Tlougan MD Department of Dermatology, New York University School of Medicine, New York, NY, USASearch for more papers by this authorJenny A. Mandell MD, Jenny A. Mandell MD Department of Dermatology, New York University School of Medicine, New York, NY, USASearch for more papers by this authorAlvin E. Friedman-Kien MD, Alvin E. Friedman-Kien MD Departments of Dermatology and Microbiology, New York University School of Medicine, New York, NY, USASearch for more papers by this authorShane A. Meehan MD, Shane A. Meehan MD Departments of Dermatology and Dermatopathology, New York University School of Medicine, New York, NY, USASearch for more papers by this author Jonathan S. Leventhal BA (HONS), Jonathan S. Leventhal BA (HONS) Department of Dermatology, New York University School of Medicine, New York, NY, USASearch for more papers by this authorBrook E. Tlougan MD, Brook E. Tlougan MD Department of Dermatology, New York University School of Medicine, New York, NY, USASearch for more papers by this authorJenny A. Mandell MD, Jenny A. Mandell MD Department of Dermatology, New York University School of Medicine, New York, NY, USASearch for more papers by this authorAlvin E. Friedman-Kien MD, Alvin E. Friedman-Kien MD Departments of Dermatology and Microbiology, New York University School of Medicine, New York, NY, USASearch for more papers by this authorShane A. Meehan MD, Shane A. Meehan MD Departments of Dermatology and Dermatopathology, New York University School of Medicine, New York, NY, USASearch for more papers by this author First published: 25 October 2013 https://doi.org/10.1111/j.1365-4632.2011.05198.xCitations: 3 E-mail: brook.tlougan@gmail.com Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume52, Issue11November 2013Pages 1401-1403 RelatedInformation

Specific antibodies to human immunodeficiency virus type 1 (HIV-1) were detected in 200-fold concentrated urine samples, but none were detected in unconcentrated urine specimens, from 100 randomly selected HIV-1--seropositive individuals by enzyme-linked immunosorbent assay (ELISA) and Western blot techniques using the manufacturer's recommended procedures. Using modified methods for both the ELISA and Western blot tests, antibodies to HIV-1 have also been detected in the unconcentrated urine specimens from the same HIV-1--seropositive individuals. No difference in the frequency of antibodies to HIV-1 were found between unconcentrated and 200-fold concentrated urine samples when tested by the modified methods. HIV-1 core antigen (p24) was not detected in either the concentrated or the unconcentrated HIV-1--seropositive adult urine samples; none of these individuals showed overt clinical or laboratory evidence of renal dysfunction. The titer of the antibodies to HIV-1 found in the urine specimens was found to be parallel with the titer of antibodies to HIV-1 in the corresponding individual's serum. Further elucidation of the pathophysiology and the nature of the specific antibodies to HIV-1 observed in the urine of HIV-1--seropositive individuals is under investigation in our laboratories.

The skin is quite commonly involved in patients with HIV infection and the resulting diseases may serve as presenting signs of AIDS or ARC. The most common infectious and non-infectious inflammatory disorders as well as common neoplasms that are seen in this patient population are reviewed and depicted in detail.

Objective To assess the efficacy, safety and tolerance of oral 9-cis- retinoic acid in HIV-infected patients with Kaposi's sarcoma. Methods Sixty-six patients with AIDS-related Kaposi's sarcoma were enrolled at 14 centers; 60 received the study medication and were analyzed and, of these, 45 (75%) had received prior therapy for Kaposi's sarcoma. Once daily oral 9-cis-retinoic acid (alitretinoin, Panretin) was administered at doses up to 140 mg/m2. Most patients (72%) received a maximum dose of 100 mg/m2. Response was assessed using AIDS Clinical Trials Group (ACTG) criteria. Results The median age was 38 years and the median absolute CD4 cell count was 194 × 106 cells/l (range 6–784 × 106). Despite the use of three- and four-drug antiviral regimens (83%), the median HIV RNA at baseline was 8701 copies/ml [range < 500 (lower limit of detection) to 4.24 × 106]. The tumor response rate was 37% (95% confidence interval 25–49). Tumor response was associated with improved quality-of-life measures. There was a significant increase in interleukin 6 (IL-6) levels from baseline to week 4. Responders had significantly lower baseline soluble IL-6 receptor levels (P = 0.029) than non-responders. The median time to response was 9 weeks (mean, 13 weeks; range, 4–36). HIV RNA levels did not change significantly during therapy nor did they correlate with tumor responses. Study drug was discontinued by 28 patients for adverse events, which included headache (13) and skin toxicity (10). Conclusion Oral 9-cis-retinoic acid is an active antitumor drug for AIDS-related Kaposi's sarcoma. Treatment is associated with skin and constitutional toxicity and further studies are needed to improve its long-term tolerance.

BACKGROUND. Treatment options are limited for patients with advanced acquired immunodeficieny syndrome (AIDS)-related Kaposi sarcoma (AIDS-KS) whose disease has progressed after receiving therapy with liposomal anthracyclines or combination chemotherapy with doxorubicin (Adriamycin), bleomycin, and vincristine (ABV). This study was performed to assess the safety and efficacy of a novel dose and schedule of paclitaxel in patients with AIDS-KS who failed to respond to previous systemic chemotherapy.METHODS. This was an open-label, multicenter Phase II study. Eligible patients had advanced AIDS-KS consisting of at least 25 mucocutaneous lesions, visceral disease, or lymphedema, and had failed to respond to at least one previous systemic chemotherapy regimen. Patients were treated with paclitaxel at a dose of 100 mg/m(2) given intravenously over 3 hours, every 2 weeks. Primary efficacy end points were tumor response, time to progression, time to treatment failure, and survival. Quality of life and adverse events were evaluated using the Symptom Distress Scale (SDS) and the World Health Organization Toxicity Criteria, respectively.RESULTS. One hundred and seven male patients with advanced AIDS-KS were enrolled from nine participating sites. The median entry CD4+ lymphocyte count was 41/mm(3) (range 0-1139). Previous treatment regimens included A13V in 52, liposomal daunorubicin in 49, and liposomal doxorubicin in 40 patients. Forty-one patients (38%) received two or more previous chemotherapy regimens. Protease inhibitor use during the study was reported by 82 (77%) patients overall; 47 patients (44%) were receiving a protease inhibitor before study entry. Complete or partial response was documented in 60 patients (56%) The median duration of response was 8.9 months. Major response rate was similar when comparing patients not on a protease inhibitor at the time of response (59%) with patients on a protease inhibitor at time of response (54%). However, protease inhibitor use had a significant impact on survival (P = 0.04). Grade 4 neutropenia was reported in 35% of patients; other life-threatening side effects were uncommon. Significant improvements were seen in the total quality of life scores measured by the SDS, including significant improvement in KS-related symptoms such as faciat disease, tumor-associated edema, and pulmonary involvement.CONCLUSION. Paclitaxel given every 2 weeks induces major tumor regression in the majority of patients with advanced KS who failed to respond to previous systemic chemotherapy. Paclitaxel is associated with significant improvement in quality of life with acceptable toxicity and should be considered as an effective treatment option for patients with advanced KS. (C) 2002 American Cancer Society.

Kaposi's sarcoma-associated herpesvirus is a novel herpesvirus linked to AIDS-related neoplasms. Currently it is difficult to evaluate the number of virions in viral preparation or in samples obtained from patients with Kaposi's sarcoma (KS), since no protocol for determining the plaque forming units of KSHV exists. We constructed a fragment of a different size than the target viral DNA to carry out a competitive-quantitative PCR. Both fragment and viral DNA were added to a single PCR reaction to compete for the same set of primers. By knowing the amount of the competitor added to the reaction, we could determine the number of viral DNA molecules. We used this assay successfully to detect and quantify KSHV genomes from KS skin biopsies and pleural effusion lymphoma, and from different viral preparations. To date, this is the most convenient and economic method that allows an accurate and fast viral detection/quantitation with a single PCR.

ABSTRACT Kaposi's sarcoma-associated herpesvirus (KSHV) encodes a cellular dihydrofolate reductase (DHFR) homologue. Methotrexate (MTX), a potent anti-inflammatory agent, inhibits cellular DHFR activity. We investigated the effect of noncytotoxic doses of MTX on latency and lytic KSHV replication in two KSHV-infected primary effusion lymphoma cell lines (BC-3 and BC-1) and in MTX-resistant BC-3 cells (MTX-R-BC-3 cells). Treatment with MTX completely prevented tetradecanoyl phorbol acetate-induced viral DNA replication and strongly decreased viral lytic transcript levels, even in MTX-resistant cells. However, the same treatment had no effect on transcription of cellular genes and KSHV latent genes. One of the lytic transcripts inhibited by MTX, ORF50/Rta (open reading frame), is an immediate-early gene encoding a replication-transcription activator required for expression of other viral lytic genes. Therefore, transcription of genes downstream of ORF50/Rta was inhibited, including those encoding the viral G-protein-coupled receptor (GPCR), viral interleukin-6, and K12/kaposin, which have been shown to be transforming in vitro and oncogenic in mice. Resistance to MTX has been documented in cultured cells and also in patients treated with this drug. However, MTX showed an inhibitory activity even in MTX-R-BC-3 cells. Two currently available antiherpesvirus drugs, cidofovir and foscarnet, had no effect on the transcription of these viral oncogenes and ORF50/Rta. MTX is the first example of a compound shown to downregulate the expression of ORF50/Rta and therefore prevent viral transforming gene transcription. Given that the expression of these genes may be important for tumor development, MTX could play a role in the future management of KSHV-associated malignancies.

OBJECTIVE:To evaluate the efficacy and safety of topical alitretinoin gel (9-cis-retinoic acid [LGD1057], Panretin gel; Ligand Pharmaceuticals, Inc, San Diego, Calif) in cutaneous Kaposi sarcoma (KS).DESIGN:Open-label, within-patient, controlled, dose-escalating phase 1 and 2 clinical trials. In all patients, 1 or more cutaneous KS lesions were treated with alitretinoin gel, and at least 2 other lesions served as untreated controls for up to 16 weeks. Alitretinoin (0.05% or 0.1% gel) was applied twice daily for the first 2 weeks and up to 4 times daily thereafter, if tolerated.SETTING:Nine academic clinical centers.PATIENTS:One hundred fifteen patients with biopsy-proven acquired immunodeficiency syndrome (AIDS)-related KS.MAIN OUTCOME MEASURES:AIDS Clinical Trials Group response criteria.RESULTS:Statistically significant clinical responses were observed in 31 (27%) of 115 patients for the group of treated index lesions compared with 13 (11%) for the group of untreated control lesions (P<.001). Responses occurred with low CD4(+) lymphocyte counts (<200 cells/microL) and in some patients with refractory response to previous systemic anti-KS therapy. The incidence of disease progression was significantly lower for treated index lesions compared with untreated control lesions (39/115 [34%] vs 53/115 [46%]; P =.02). Alitretinoin gel generally was well tolerated, with 90% of treatment-related adverse events confined to the application site and only mild or moderate in severity.CONCLUSIONS:Alitretinoin gel has significant antitumor activity as a topical treatment for AIDS-related KS lesions, substantially reduces the incidence of disease progression in treated lesions, and is generally well tolerated.

51 Background: Topical retinoids are active in cutaneous Kaposi's sarcoma. But for patients with extensive disease, this is an impractical treatment. We sought to improve on the therapeutic range of retinoids with the use of oral 9-cis-retinoic acid (LGD 1057). We determined the safety, tolerance and efficacy of oral LGD1057 tablets in patients with AIDS-Kaposi's sarcoma. Methods: Phase II, open label clinical trial conducted in a multi-center network using a modified Simon two-stage enrollment method. Patients received 60 mg/M2 of LGD1057 each afternoon up to a maximum of 100 mg/M2 as tolerated. Patients were seen biweekly and evaluated at 16 weeks for tumor response using ACTG criteria. Laboratory parameters including CD4 cell counts and HIV RNA, adverse events, and quality of life data were analyzed for safety and tolerance. Results: An interim analysis of 66 patients was completed. Patients who met the study criteria for response, developed toxicity requiring drug discontinuation; or who had received at least 16 weeks of therapy were included. Of the 38 evaluable patients, 79% were white males; median age was 40; and median CD4 count was 229 (range 18-784). The majority (71%) were receiving at least 3 antiretroviral agents at study entry. Most patients (74%) had received prior therapy including 20 patients with local treatment and 16 patients with systemic chemotherapy or immunotherapy. Partial responses were seen in 37% (14), stable disease in 39% (15) and progressive disease in 11% (4) patients. Responses were seen in patients with large tumor burden, low CD4 counts and/or prior treatment with systemic chemotherapy. Eleven (11) patients withdrew for adverse events and 13 had dose reductions or interruptions because of toxicity. Ten patients remained on a dose of 100 mg/M2 for up to 38 weeks. Grade 3 or 4 toxicities included headache (n=8, 21%), elevated triglycerides (n=5, 13%) and skin (alopecia, desquamation, nail changes). Triglyceride (baseline, mean ± s.d., 240 ± 170, week 8, 788 ± 675) and cholesterol levels (baseline, 187 ± 71, week 8, 277 ± 98) rose significantly. Skin toxicity increased over time despite topical vitamin E therapy. Conclusion: Oral LGD1057 is an active agent in AIDS related Kaposi's sarcoma with a response rate of greater than 30% (C.I. 22-55%).

A human herpesvirus-8 (HHV-8) enzyme-linked immunosorbent assay (ELISA) with a whole virus lysate as antigen was developed and used to measure the seroprevalence rate and levels of IgG antibodies to HHV-8 in sera/plasma of various patient groups and blood donors. The virus antigen was prepared from the KS-1 cell line, which produces lytic virus, and therefore contains a broad array of viral proteins. Seroprevalence studies using this ELISA showed the following: 10 of 91 blood donors (11%) had an average HHV-8 antibody titer of 118; 67 of 72 (93%) classic Kaposi's sarcoma (KS) patients were positive with an average titer of 14,111; and 57 of 62 (92%) KS/human immunodeficiency virus (HIV) patients were positive with an average titer of 4,000. A study on a very limited number of serial serum samples from patients before and after diagnosis with KS showed highly elevated antibody titers to HHV-8 virus after KS lesions developed. Preliminary data show that 50% of the sera from HIV-1(+) homosexual patients contain IgG antibodies to HHV-8 suggesting that this population is at high risk for developing KS. Antibody results correlated well with the confirmatory immunofluorescent assays (IFA) using KS-1 cells as the substrate. This HHV-8 IgG antibody detection ELISA is sensitive and specific and does not cross-react with Epstein-Barr virus (EBV) or other human herpesviruses. The results of this HHV-8 antibody survey suggest that this rapid ELISA assay can be used to screen large numbers of sera to find those at risk for developing KS.

PURPOSE:Kaposi's sarcoma (KS), the most common neoplasm in patients with AIDS, is a significant clinical problem for which current therapies are frequently unsatisfactory. We conducted a randomized phase III clinical trial to compare the efficacy and toxicities of a new form of therapy, pegylated-liposomal doxorubicin, with standard combination chemotherapy in patients with advanced AIDS-related KS (AIDS-KS).PATIENTS AND METHODS:Two hundred fifty-eight patients with advanced AIDS-KS were randomly assigned to receive either pegylated-liposomal doxorubicin (20 mg/m2) or the combination of doxorubicin (20 mg/m2), bleomycin (10 mg/m2) and vincristine (1 mg) (ABV) every 14 days for six cycles. Standard response criteria, toxicity criteria, and predefined indicators of clinical benefit were examined to evaluate outcomes.RESULTS:Among 133 patients randomized to receive pegylated-liposomal doxorubicin, one achieved a complete clinical response and 60 achieved a partial response for an overall response rate of 45.9% (95% confidence interval [CI], 37% to 54%). Among 125 patients randomized to receive ABV, 31 achieved a partial response (24.8%; 95% confidence interval [CI], 17% to 32%). This difference was statistically significant (P < .001). In addition to objective responses, prospectively defined clinical benefits and toxicity outcomes also favored pegylated-liposomal doxorubicin.CONCLUSION:Pegylated-liposomal doxorubicin is more effective and less toxic than the standard combination chemotherapy regimen ABV for treatment of AIDS-KS.

Recently, the expression of fibroblast growth factor 3 (FGF3) was found in 55% of human Kaposi's sarcoma (KS) tumor tissues examined, while almost no expression of FGF3 was found in normal skin. To further these studies, human FGF3 cDNA were constructed by the overlap-extension method. The proteins translated from two FGF3 cDNA, which differ only in the sequences preceding the AUG presumed to be the initiation codon, were shown to have the same molecular mass. This result suggests that translation of human FGF3 , which is different from mouse FGF3, begins only at the AUG site. The human FGF cDNA was transfected into NIH3T3 cells. The NIH 3T3 cells transformed by FGF3 were then injected subcutaneously into athymic nude mice. Nodular lesions developed at the injection sites in all seven mice injected with the F3-1 cell clone, which showed high expression of FGF3, and in two out of six mice injected with the F3-2 cell clone, which expressed a low level of FGF3. Histopathological features of these tumors contained fascicles of spindle-shaped cells surrounding irregular endothelial lined vascular clefts, similar to those observed in human KS lesions. Immunohistochemical staining for factor V111 antigen revealed reactivity in multiple areas, especially in abundant vascular structures of the tumor sections examined. The expression of FGF3 together with the FGF receptors FGFR1, FGFR2, and FGFR3, was detected in the mouse tumors by Northern blot analysis. Our results indicate that tumors induced by FGF3 -transformed NIH3T3 cells show some similarities to human KS tumors. In conclusion, our results demonstrate the potential tumorigenic and angiogenic role of human FGF3.

BACKGROUND:Molluscum contagiosum is usually a self-limited benign viral disease in children and young adults. In patients with acquired immunodeficiency syndrome (AIDS), however, the infection is often widespread, disfiguring, and recalcitrant to conventional therapy.OBJECTIVE:A treatment modality for widespread, recurrent molluscum contagiosum is necessary that is effective, safe, and simple.METHODS:Widespread molluscum contagiosum recalcitrant to conventional therapy in a patient with AIDS was treated with the 585-nm pulsed dye laser.RESULTS:There was a significant reduction in the number of molluscum contagiosum lesions following a single treatment with the pulsed dye laser. Treated-areas remained disease-free after 4 months. No complications were associated with the procedure.CONCLUSION:Pulsed dye laser treatment may offer another therapeutic modality that is effective and safe in the treatment of widespread and recurrent molluscum contagiosum.

Background: Human herpesvirus 8 (HHV-8) is the first known agent that belongs to the genus Rhadinovirus (y2-herpesvirus). It is regularly found by PCR in all forms of Kaposi's sarcoma (KS), in certain types of Castleman's disease, and in body cavity based B-cell lymphoma. Other members of this virus group occur in non-human primates, ungulates, rabbits, and in mice, causing in part fulminant lymphomas and other neoplastic disorders of the hematopoetic system. Rhadinoviruses share a typical genome structure; most characteristically, they contain numerous sequences that appear to be sequestered from cellular DNA, including the coding sequences (1) for enzmes of the nucleotide metabolism, (2) for antagonists of the complement system, and (3) for proteins that may be involved in growth stimulation of persistently infected cells, such as interleukins and interleukin receptor analogues. Methods and Results: A genomic library from a KS biopsy was completely sequenced. It revealed collinear organization and extensive homologies with the open reading frames of H. saimiri. We found at least 12 viral genes in the HHV-8 genome with homology to cellular DNA; among them the genes for cellular interleukin-6 and the CC chemokines MIP 1 α and MIP 1 β. Conclusions: This lends support to a pathogenesis model according to which virus-encoded cytokine analogues contribute to autocrine and/or paracrine growth stimulation of KS spindle and lymphoma cells. It complements recent serology and PCR-based epidemiology, rendering it likely that HHV-8 is the essential factor, besides preexisting immunosuppression, that determines lymphomagenesis and the multifocal generation of Kaposi's Sarcoma.

The etiology of large granular lymphocyte (LGL) leukemia is uncertain. Recently, a Kaposi's sarcoma-associated herpes virus, denoted as human herpes virus 8 (HHV-8), has been identified. Some data suggest that HHV-8 and Epstein-Barr virus (EBV) may interact to induce malignant transformation. Infection with EBV has been implicated in the pathogenesis of some cases of LGL leukemia. Therefore, we performed PCR analyses for HHV-8 detection in samples from nineteen patients with LGL leukemia; three of these samples contained the EBV genome. We could not detect HHV-8 sequences in any of these patients. Therefore, HHV-8 infection is not involved in the pathogenesis of T-LGL leukemia.