AIDS-related Kaposi Research Articles

LGD-1057 gel effective in AIDS-related Kaposi??s sarcoma

LGD-1057 gel effective in AIDS-related Kaposi??s sarcoma

Thiol redox modulation of tumor necrosis factor-alpha responsiveness in cultured AIDS-related Kaposi's sarcoma cells.

Both clinical and experimental evidence indicates that AIDS-related Kaposi's sarcoma (AIDS-KS) has a multifactorial pathogenesis with factors such as HIV viral load, latent virus induction, and opportunistic infections contributing to disease progression. However, a consistent feature that unites these apparently diverse putative etiologic agents is sustained serum elevations of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha). While virtually every cell responds to TNF-alpha with gene activation, the extent of TNF-alpha-mediated cellular signaling is regulated by a delicate balance between signal activation and signal arresting events. Reactive oxygen intermediates (ROI), which are generated as a consequence of TNF-alpha membrane interaction, are part of this TNF-alpha-initiated cellular activation cascade. Previous studies in our laboratory have shown that AIDS-KS cells possess impaired oxygen intermediate scavenging capacities, thereby establishing conditions permissive for the intracellular retention of ROI. In this study, we used cellular capacity to upregulate the cytoprotective enzyme superoxide dismutase (SOD) to address the extent of cellular response to TNF-alpha. Concurrent with the SOD analyses, nucleotide profiles were obtained to assess cellular bioenergetic responses during TNF-alpha challenge. Proliferative growth levels of mitochondrial (Mn)SOD activities showed an activity spectrum ranging from lowest activity in AIDS-KS cells, to intermediate levels in matched, nonlesional cells from the AIDS-KS donors, to highest activities in HIV normal fibroblasts. In contrast, following TNF-alpha challenge, the AIDS-KS and KS donor nonlesional cells showed a 11.89- and 5.86-fold respective increase in MnSOD activity, while the normal fibroblasts demonstrated a 1.35-fold decrease. Subsequent thiol redox modulation studies showed that only the normal fibroblast cultures showed a potentiation of TNF-alpha-mediated MnSOD upregulation following GSH depletion. In addition, provision of the GSH precursor, N-acetylcysteine during TNF-alpha challenge only diminished MnSOD activity and mitochondrial compartmentalization in the AIDS-KS cells, a finding that likely reflects the lower levels of reduced thiols in this cellular population. Our data, which show that a perturbation in their cellular thiol redox status accentuates AIDS-KS cellular responsiveness to TNF-alpha, suggest a biochemical rationale for the recognized TNF-alpha AIDS-KS clinical correlation.

Classic Kaposi’s Sarcoma: Low-Dose Interferon Alfa Treatment

Background: Classic Kaposi’s sarcoma, a rare form of cancer, has no definitive cure. A beneficial effect of low-dose interferon (IFN) alfa was indicated by some case reports. In the present report, we summarize the results of our experience with subcutaneous low-dose IFN alfa treatment of 11 patients with extensive classic Kaposi’s sarcoma and review the literature. Design: Eleven patients, 56–96 years old, were treated: 10 men, 1 woman, 3 of whom had an associated malignancy. Subcutaneous injections of IFN alfa were given, starting with 3 million units 5 times a week, and modified according to side effects and response after 2 weeks (2–6 million units, 3–6 times a week). This treatment was continued for 6 months, except for 1 patient who died after 4 months and another who stopped treatment at 4 months due to surgery but was treated again after recurrence. Treatment was continued after 6 months when a partial response was noted, but further improvement was desired (1 patient). Results: In 9 out of the 11 patients, initial response was noted after 3–13 weeks of treatment. This was manifested by a reduction of lesion size and fading of color, leading to a partial resolution. Maximum response was achieved after 4–6 months. Remission lasted 4–72 months. Recurrences were retreated, with additional remissions after only 5–8 weeks of treatment. Side effects included fever and fatigue, which were overcome by dose reduction. Conclusion: Whereas in AIDS-related Kaposi’s sarcoma patients become refractory to IFN, this was not observed in our patients with classic Kaposi’s sarcoma. Moreover, unlike AIDS-related Kaposi’s sarcoma, continuous treatment was not needed in classic Kaposi’s sarcoma, and recurrences were responsive to retreatment.

Raynaud's phenomenon and acral necrosis after chemotherapy for AIDS-related Kaposi's sarcoma

Raynaud's phenomenon is a common vascular side effect of chemotherapy drug regimens. Chemotherapy-induced Raynaud's phenomenon leading to acral gangrene has rarely been reported. In this report, one patient who developed gangrene after bleomycin and vincristine/vinblastine chemotherapy for AIDS-related Kaposi's sarcoma and another HIV-infected patient who exhibited symptoms of severe Raynaud's phenomenon related to the same regimen are presented. Because the combination of bleomycin and vinca alkaloids is commonly used for the treatment of AIDS-related Kaposi's sarcoma, clinicians should be aware of the risk of provoking acral necrosis in patients who develop Raynaud's phenomenon under chemotherapy. The literature is reviewed, and clinical symptoms, pathophysiology, and treatment options are discussed.

Response and cosmetic outcome of two fractionation regimens for AIDS-related Kaposi's sarcoma

Purpose: A prospective study of the response and cosmetic effect of two short duration radiotherapy regimens in the treatment of epidemic cutaneous Kaposi's sarcoma. Materials and methods: Between June 1990 and May 1994, 57 patients were recruited into a prospective study of radiotherapy for cutaneous epidemic Kaposi's sarcoma. Patients were offered treatment of either 16 Gy in four fractions over 4 days or 8 Gy as a single fraction. In total 596 lesions were treated in a prospective fashion. Response was assessed in 590 and pigmentation in 573 lesions. A reproducible scale for assessing response and normal cutaneous damage was developed and used to grade the results of treatment. Results: There was an overall response rate of 78.8% (465/590) for complete responses and pigmented complete responses. Patients receiving 8 Gy as a single fraction had an overall response rate of 77.6% (305/393) and those treated with 16 Gy in four fractions had a response rate of 80.8% (160/198). There was no statistical difference in terms of response between the two groups. There appeared to be a significant variation in response and normal skin pigmentation according to the site irradiated with facial lesions responding best. Conclusions: Radiotherapy is a quick and effective treatment for cutaneous epidemic Kaposi's sarcoma. A single fraction of 8 Gy is an appropriate treatment for acceptable response and normal skin pigmentation within a group of patients in whom the median life expectancy is limited.

Expression of Human Herpesvirus 8-Encoded Cyclin D in Kaposi's Sarcoma Spindle Cells

Human herpesvirus 8 (HHV-8) DNA sequences have been detected in Kaposi's sarcoma, in primary effusion lymphoma (an unusual high-grade non-Hodgkin's lymphoma seen primarily in patients with acquired immunodeficiency syndrome [AIDS]), and in Castleman's disease (a rare lymphoproliferative disorder); however, proof that HHV-8 is involved in the pathogenesis of these diseases remains to be established. HHV-8 contains a gene, i.e., v-cyclin D, that is a homologue of the cellular cyclin D2 gene, which encodes a protein that promotes passage through G1 phase of the cell cycle. Previous studies have identified v-cyclin D messenger RNA (mRNA) in biopsy specimens of Kaposi's sarcoma. In this study, we isolated a full-length v-cyclin D complementary DNA and characterized the pattern of v-cyclin D mRNA expression in Kaposi's sarcoma. Standard methods were used to construct and to screen HHV-8 genomic and complementary DNA libraries. Reverse transcription-polymerase chain reaction (RT-PCR) methods and in situ hybridization with RNA probes were used to examine v-cyclin D mRNA expression. RT-PCR demonstrated the presence of v-cyclin D mRNA in biopsy specimens of AIDS-related Kaposi's sarcoma, in early-passage spindle cells from classical (i.e., not AIDS-related) Kaposi's sarcoma, and in spindle cells isolated from the peripheral blood of patients with AIDS-related Kaposi's sarcoma. In situ hybridization indicated that mRNAs for v-cyclin D and kaposin, an HHV-8 latency-associated gene, were present in approximately 1% of the spindle cells in early patch lesions and approximately 60% of the spindle cells in late nodular lesions of Kaposi's sarcoma. Spindle cells of Kaposi's sarcoma, which have been regarded as the tumor cells of this cancer, contain v-cyclin D mRNA. Expression of v-cyclin D protein may be involved in the pathogenesis of Kaposi's sarcoma by promoting cell proliferation.

IL-4R expression in AIDS-KS cells and response to rhIL-4 and IL-4 toxin (DAB389-IL-4).

Interleukin-4 (IL-4) is a pleiotropic cytokine affecting growth and differentiation of various cell types as well as regulating other cytokines. To study the effect of IL-4 on AIDS-related Kaposi's sarcoma (AIDS-KS) cells, we first examined the tumor cells for IL-4 receptor (IL-4R) expression. KS cells express a single 4 kB IL-4R-specific mRNA and 1828 +/- 408 high affinity IL-4 binding sites per cell with a dissociation constant (Kd) of 154 +/- 37 pM. Addition of recombinant human IL-4 (rIL-4) minimally inhibited AIDS-KS cell growth and expression of IL-6. We then studied the effects of a chimeric fusion toxin DAB389-IL-4 which exerts cellular toxicity only on cells expressing IL-4R. DAB389-IL-4 inhibited protein synthesis in AIDS-KS cells at low concentrations (IC50 of 5 x 10(-11) M). This effect was abrogated by neutralizing antibody to IL-4 (25D2). We conclude that KS cells express a functional IL-4R and this receptor could serve as a target for novel therapy with agents such as DAB389-IL-4.

P53 protein overexpression is a common but late event in the pathogenesis of iatrogenic and AIDS-related Kaposi's sarcoma.

p53 protein overexpression is a common but late event in the pathogenesis of iatrogenic and AIDS-related Kaposi's sarcoma.

Surface applicators for high dose rate brachytherapy in aids-related Kaposi's sarcoma

The development of commercially available surface applicators using high dose rate remote afterloading devices has enabled radiotherapy centers to treat selected superficial lesions using a remote afterloading brachytherapy unit. The dosimetric parameters of these applicators, the clinical implementation of this technique, and a review of the initial patient treatment regimes are presented. A set of six fixed-diameter (1, 2, and 3 cm), tungsten/steel surface applicators is available for use with a single stepping-source (Ir-192, 370 GBq) high dose rate afterloader. The source can be positioned either in a parallel or perpendicular orientation to the treatment plane at the center of a conical aperture that sits at an SSD of approximately 15 mm and is used with a 1-mm thick removable plastic cap. The surface dose rates, percent depth dose, and off-axis ratios were measured. A custom-built, ceiling-mounted immobilization device secures the applicator on the surface of the patient's lesion during treatment. Between November 1994, and September 1996, 16 AIDS-related Kaposi's sarcoma patients having a total of 120 lesions have been treated with palliative intent. Treatment sites were distributed between the head and neck, extremity, and torso. Doses ranged from 8 to 20 Gy, with a median dose of 10 Gy delivered in a single fraction. Treatments were well tolerated with minimal skin reaction, except for patients with lesions treated to 20 Gy who developed moderate/severe desquamation. Radiotherapy centers equipped with a high dose rate remote afterloading unit may treat small selected surface lesions with commercially available surface applicators. These surface applicators must be used with a protective cap to eliminate electron contamination. The optimal surface dose appears to be either 10 or 15 Gy depending upon the height of the lesion.

AIDS-related Kaposi's sarcoma: prospective validation of the AIDS Clinical Trials Group staging classification. AIDS Clinical Trials Group Oncology Committee.

To prospectively validate the AIDS Clinical Trials Group (ACTG) staging classification for AIDS-associated Kaposi's sarcoma (KS). Two hundred ninety-four consecutive patients enrolled in eight ACTG therapeutic trials for AIDS-associated KS were staged prospectively according to tumor extent (T), severity of immunosuppression (I), and other systemic human immunodeficiency virus type 1 (HIV-1)-associated illness (S) and were observed for survival. Patients were classified as good risk (subscript 0) or poor risk (subscript 1) for each variable according to published ACTG criteria. Univariate and multivariate analyses were used to evaluate the associations between TIS variables and survival; additional analyses were conducted to improve the predictive value of the staging system. Survival was significantly shorter for patients in the poor-risk category for each of the TIS variables. Respective median survivals for patients in the good- and poor-risk categories were 27 and 15 months for T (P < .001); 40 and 13 months for I (P < .001) when I0 included CD4 counts > or = 200/microL and 22 and 16 months for S (P = .04). Multivariate analysis indicated that severity of immunosuppression gave the most predictive information but also showed that T provided significant additional predictive information in patients whose immune function was least impaired. Refined Cox models using a CD4 count of 150/microL rather than 200/microL to distinguish I0 and I1 yielded a simplified model with better fit to the observed data. The ACTG TIS classification predicts survival in patients with AIDS-associated KS; CD4 count and tumor stage provide the most predictive information. However, a lower CD4 count than the one originally proposed provides better discrimination between prognostic groups.

ALRT-1057 effective in AIDS-related Kaposi??s sarcoma ???

ALRT-1057 effective in AIDS-related Kaposi??s sarcoma ???

Treatment of epidemic (AIDS-related) Kaposi's sarcoma.

Kaposi's sarcoma (KS) is the most common tumor seen in patients with HIV-1 infection. KS causes significant morbidity and mortality through involvement of the skin and visceral organs. The optimal treatment for KS depends on the extent of the disease and immunologic status. However, with knowledge gained on the pathogenesis of disease, newer therapies and compounds are being developed. Early disease patients are best treated with either local therapy or agents that have low toxicity and can be delivered long term. Advanced disease, such as in patients with widespread mucocutaneous disease, lymphedema, and visceral disease, are treated most effectively with cytotoxic agents such as liposomal anthracyclines, vinca alkaloids, or paclitaxel. Future treatment developments are focusing on the role of effective anti-HIV therapy and anti-human herpesvirus (HHV)-8 therapy in an effort to interfere with key steps in the etiology of KS to control the disease. Secondly, agents that focus on the interruption of autocrine and paracrine growth factors such as vascular endothelial cell growth factor and basic fibroblast growth factor, interleukin-6, and interleukin-8 are of therapeutic interest. Some of these compounds currently under evaluation include antiangiogenesis inhibitors and retinoids.

Prevalence of human herpesvirus-8 in skin lesions.

A putative new herpesvirus, designated Kaposi's sarcoma-associated herpesvirus (KSHV) or human herpesvirus-8 (HHV-8) was recently identified in AIDS-related Kaposi's sarcoma. The DNA sequence of the virus is homologous to the gamma-herpesviruses such as herpesvirus Saimiri or Epstein-Barr virus, both of which are tumorigenic, suggesting that this new virus may also be oncogenic. Thus, we determined whether the virus is present in other skin lesions. DNA samples from 118 skin specimens were tested for the HHV-8 sequence by polymerase chain reaction (PCR) and Southern hybridization. The sequences were detected in 13 of 21 samples from Bowen's disease, three of 11 squamous cell carcinomas, three of 11 actinic keratoses, three of seven leucoplakia, one of six from Paget's disease, one of 12 malignant melanoma, one of seven neurofibromas, two of seven chronic dermatites and one of 14 normal skin samples. On sequencing the PCR products, new mutation points were detected. These results suggest that the virus is associated with lesions other than Kaposi's sarcoma and may be more widespread than expected (with a latent level too low to be detected), like the other herpesviruses. Some lesions. e.g. in Bowen's disease or squamous cell carcinoma, may be locally immunosuppressed, allowing the virus to replicate until the copy number is sufficient for detection.

Systemic treatment modalities in the management of AIDS-related Kaposi's sarcoma

Abstract Background Kaposi's sarcoma (KS) is the most common neoplasm in patients with AIDS: in some cohorts of homosexual men with AIDS, the lifetime risk of KS approaches 50%. Prognosis is either ‘good risk’ or ‘poor risk’ according to recommended staging criteria. Objective In the present study we treated a good risk AIDS-KS group of patients with low dose of alpha-2 interferon (alpha-2IFN) plus AZT, and a poor risk AIDS-KS group of patients with chemotherapy. Study design Prospective, non-randomized trial. Subjects Forty-four homosexual or bisexual male patients between 21 and 45 years old with positive ELISA for HIV, and KS, were included in the study. Intervention Ten patients received alpha-2 IFN plus AZT, 12 bleomycin, 12 doxorubicin-bleomycin-vincristine (ABV), and ten patients did not receive treatment. Results One patient achieved complete remission, two partial remission (PR), six stable disease (SD) and one progression (P) during alpha-2 IFN plus AZT treatment. Seven patients showed SD and five P during bleomycin treatment; and four patients achieved PR and eight SD during ABV treatment. Outcome Despite the fact that the different systemic treatment modalities employed allowed us to achieve clinical responses, there was no significant improvement in survival.

Liposomal doxorubicin is active against AIDS-related Kaposi??s sarcoma

Liposomal doxorubicin is active against AIDS-related Kaposi??s sarcoma

The Effects of Preparations of Human Chorionic Gonadotropin on AIDS-Related Kaposi's Sarcoma

The Effects of Preparations of Human Chorionic Gonadotropin on AIDS-Related Kaposi's Sarcoma

Infection with AIDS-related herpesviruses in human immunodeficiency virus-negative infants and endemic childhood Kaposi's sarcoma in Africa.

Novel herpesviruses have been described recently. These include human herpesviruses 6, 7 and 8 (HHV-6, -7, -8). HHV-6 has at least two strain groups, variants A and B. The B strains are predominant in the West and can account for over 97% of infections in infants. In contrast, the A strains are rare and the few well-characterized isolates have been from adult African AIDS patients. It is not clear whether the HHV-6 variant A strains are AIDS-related and/or whether they can also be acquired as childhood infections and may reactivate later during adulthood. What contribution geographical variation plays has yet to be assessed. HHV-8 has been associated with AIDS-related epidemic Kaposi's sarcoma (KS), but has also been identified in endemic KS. In regions of Africa where KS is endemic, the onset of AIDS has led to increased prevalence of KS. In this report, we examine in Zambia, an AIDS epidemic and KS endemic region, infection with these novel herpesviruses during infancy. In blood samples from human immunodeficiency virus-negative infants with first febrile episode, both semi-quantitative PCR and sequence analyses were used to identify HHV-8 in 8% and HHV-6 in 30%, with 44% of these variant A; in childhood endemic KS biopsies HHV-8 was detected in 100% and HHV-6 in none. The high viral-DNA loads in the infant blood samples were consistent with viraemia. This is the first demonstration that HHV-6 variant A and HHV-8 may be acquired as common childhood infections.

Stealth liposomal doxorubicin or bleomycin/vincristine for the treatment of AIDS-related Kaposi's sarcoma

Stealth liposomal doxorubicin or bleomycin/vincristine for the treatment of AIDS-related Kaposi's sarcoma

A PHASE II STUDY OF THALIDOMIDE FOR KAPOSI'S SARCOMA

BACKGROUND: Thalidomide may have three possible mechanisms of action against Kaposi's sarcoma (KS). It is a selective inhibitor of synthesis of TNFα (an autocrine growth factor in KS), has anti-angiogenic activity in vivo and reduces HIV-1 activation in peripheral blood mononuclear cells (PBMC) in vitro. There is one case report of activity of thalidomide in AIDS KS (Soler et al., 1996). The detection of KSHV (Kaposi's sarcoma herpes virus) in the PBMCs of HIV-seropositive patients by polymerase chain reaction (PCR) has been shown to correlate with the presence of KS and to predict for its development. METHODS: A single institution open label phase II study was designed to establish the activity and toxicity of thalidomide in the treatment of AIDS KS. KSHV DNA levels in PBMCs were determined by PCR quantification and correlated with clinical response. Response evaluation was performed using the AIDS Clinical Trials Group (ACTG) criteria. Only male patients were eligible in view of the teratogenicity of thalidomide. The treatment schedule was thalidomide 100mg orally once at night for an initial study period of two months. RESULTS: Seventeen patients median age 40 years (range 30-48) were enrolled and 11 are evaluable for response. The median CD4 cell count was 36 cells/µl(range 4-552) and 8/17 had prior AIDS defining opportunistic infections. Four patients developed a rash and one Raynaud's syndrome. Six patients were unevaluable due to early withdrawal (toxicity in four patients, progressive disease in one and poor compliance in one). Five of the 11 evaluable patients achieved a partial response. Thus the overall response rate is 45% (95% confidence interval 10-81%). A further two patients had stable disease (18%: 95% confidence interval 0-45%). Results of the PCR quantification for KSHV DNA will be presented. CONCLUSIONS: Although the number of patients in this study is small and therefore the confidence intervals wide, thalidomide appears to have activity in the treatment of AIDS related KS and deserves further investigation. Reference: Soler R, Howard M, Brink N, Gibb D, Tedder R & Nadal D. Regression of AIDS-related Kaposi's sarcoma during therapy with thalidomide. Clin. Infect. Dis 1996:23, 501-503. Acknowledgement: MB and KF are supported by a grant from the Crusaid and Star Foundation.

Polyethylene glycol-liposomal doxorubicin. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in the management of AIDS-related Kaposi's sarcoma.

Doxorubicin is an antineoplastic drug which has in vitro and in vivo activity against a number of malignancies including Kaposi's sarcoma. Incorporation of doxorubicin into polyethylene glycol-coated (pegylated) liposomes alters the pharmacokinetics of the drug. Liposomal doxorubicin has a smaller volume of distribution and slower plasma clearance than standard free doxorubicin. The liposomal formulation achieves higher concentrations in the highly vascularised lesions of Kaposi's sarcoma than in normal tissue. Liposomal doxorubicin monotherapy in patients with AIDS-related Kaposi's sarcoma produced overall response rates (complete plus partial) of 43 and 59% in large comparative studies and 67 to 100% in noncomparative studies which included > or = 20 patients. In comparative studies, liposomal doxorubicin was significantly more effective than the combination of standard doxorubicin, bleomycin and vincristine (overall response rates of 43 and 25%, respectively) and bleomycin and vincristine (BV) [overall response rates of 59 and 23%, respectively]. In addition, overall response rates to the liposomal drug were higher in both treatment arms of 2 smaller comparative studies which compared liposomal doxorubicin with BV, but significant between-treatment differences were not detected. Patient numbers in these 2 studies, however, may have been too small to detect significant differences. Liposomal doxorubicin is generally well tolerated. Myelosuppression is the most common dose-limiting adverse effect in patients with AIDS and Kaposi's sarcoma. Neutropenia occurs most often; anaemia and thrombocytopenia occur less frequently, as do nausea and vomiting and stomatitis. Palmar-plantar erythrodysaesthesia occurs in some patients, most commonly after 6 to 8 weeks of chemotherapy. Although symptoms may occasionally be severe, the syndrome usually does not require dosage reduction or treatment delay. Limited data suggest that the incidence of cardiotoxicity may be lower after liposomal doxorubicin than after equivalent doses of standard doxorubicin. Overall, liposomal doxorubicin appears to be one of the most active single agents available for treating patients with AIDS-related Kaposi's sarcoma. The therapeutic potential of liposomal doxorubicin administered in combination with other active agents to patients with Kaposi's sarcoma is, as yet, unknown. However, administered alone, the drug seems to be more effective than the best available combination chemotherapy regimens.