AIDS-related Kaposi Research Articles

Changing incidence of AIDS-related Kaposi sarcoma and non-Hodgkin lymphoma in Ontario, Canada

To examine the influence of the AIDS epidemic on the incidence of Kaposi sarcoma (KS) and non-Hodgkin lymphoma (NHL) in Ontario. Age-standardized incidence rates for KS and NHL from 1981 to 2000 were calculated from the population-based Ontario Cancer Registry. AIDS cases were extracted from Ontario Ministry of Health and Long-Term Care reports. HIV death data were obtained from the Ontario Cancer Registry. KS was a rare cancer before the 1980s; however, incidence increased sharply between 1985 and 1995 by 13.8% per year. Thereafter, incidence rates fell close to those in the early 1980s. NHL incidence in males increased steadily during the 1980s at 3.2% per year and then slowed beyond 1990. In males aged 30-44, NHL incidence rose from 1981 to 1990 (8.8% per year) and then fell (-2.5%) thereafter. NHL and KS cases represented one-third of HIV deaths. The AIDS epidemic, the introduction of antiretroviral therapies, and the decrease in HIV infection rates explain the rise and decline of KS incidence in Ontario. NHL incidence trends are more complex, although the AIDS epidemic explains the trends observed in younger men (in whom AIDS is more common), and for the AIDS-related subtypes.

British HIV Association guidelines for HIV‐associated malignancies 2008

British HIV Association guidelines for HIV‐associated malignancies 2008

Gemcitabine for previously treated AIDS-related Kaposi’s sarcoma: The Western Kenya experience

10566 Background: The Academic Model for the Prevention and Treatment of HIV (AMPATH) Oncology Program in collaboration with Moi Teaching and Referral Hospital provides treatment for patients (pts) with AIDS-related Kaposi’s sarcoma (AR-KS) and other AIDS- related malignancies in Western Kenya. The objectives of this study are to evaluate the activity of gemcitabine (GEM) in previously treated pts with AR-KS and assess the feasibility of chemotherapy administration in a developing country. Methods: A retrospective chart review was conducted for 23 consecutive pts receiving GEM from Aug 2006 to Oct 2007. All pts were on HAART and failed prior doxorubicin, bleomycin, and vincristine-based therapy. Responses were evaluated 4 wks after the last dose of GEM and at the last follow-up visit. Pts free of all lesions were considered to have a complete response (CR). A partial response (PR) was defined as a >50% reduction in lesions. Clinical benefit response (CBR) was defined as ≥50% reduction in pain intensity, ≥ 50% reduction in analgesic consumption, ≥20 point increase in KPS, and/or a weight gain of ≥7%. Results: The population consisted of 19 males (82.6%) and 4 females (17.4%); the mean age was 38 yrs (range: 20–57). Average BSA was 1.73 m2 (range: 1.5–2.1). Pts were on HAART for an average of 13.4 mos (range: 4 - 41) before starting GEM. According to the AIDS Clinical Trials Group Oncology Committee classification of AR- KS, all pts were poor-risk based on tumor extent, CD4 cell count < 200 cells/mm3, systemic illness or KPS <70%. GEM dosing was: 1 g (n=19), 1 g/m2 (n=3), or both (n=1). Pts received a mean of 7.4 doses (range: 3–15). Average time between doses was 18.6 days. Objective response was seen in 11 pts (CR-3, PR-8; CR+PR= 48%); 11 were classified with stable disease (SD) and 1 with progressive disease (PD). CBR occurred in 15 pts (65%). Mean progression-free survival was 3.8 mos. With a median follow-up of 5.1 mos, 2 pts were still receiving chemotherapy, 3 were lost to follow-up, and 18 completed chemotherapy; 5 pts progressed and one died from hepatoma. Conclusions: Despite modest dosages, GEM may have activity in previously treated AR-KS. While barriers to treatment exist in Kenya, it is feasible to successfully administer GEM on a modified schedule. Further studies are warranted to confirm activity. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Eli Lilly

Persistent Kaposi sarcoma in the era of highly active antiretroviral therapy: characterizing the predictors of clinical response

Objectives: To evaluate the role of highly active antiretroviral therapy and chemotherapy on tumor response among persons with AIDS-related Kaposi sarcoma and identify factors associated with response in a clinic setting. Design: Retrospective cohort. Methods: One hundred and fourteen patients from two HIV clinics with a diagnosis of Kaposi sarcoma were identified via a clinical database. Records were reviewed to confirm Kaposi sarcoma diagnosis and abstract clinical and chemotherapy information. Demographics, laboratory values, and highly active antiretroviral therapy use were abstracted electronically. Cox's proportional hazards models identified predictors of Kaposi sarcoma improvement and resolution. Results: Thirty-six months following Kaposi sarcoma diagnosis, the rate of improvement among 64 patients with confirmed Kaposi sarcoma was 77% and that of complete resolution was 51%. In univariate analyses, recent chemotherapy was associated with Kaposi sarcoma improvement, and recent HIV viral load and highly active antiretroviral therapy were associated with both improvement and resolution. No measured baseline characteristics (tumor stage, diagnosis year, CD4 T-cell count, HIV viral load, or prior highly active antiretroviral therapy history) or recent CD4 T-cell counts predicted improvement or resolution. In multivariate analyses, recent chemotherapy (hazard ratio 5.5, 95% confidence interval: 2.7–11.2, P < 0.001) and highly active antiretroviral therapy (hazard ratio 4.1, 95% confidence interval: 1.4–12.6, P = 0.01) were predictors of improvement; only recent highly active antiretroviral therapy was associated with resolution (hazard ratio 6.2, 95% confidence interval: 1.5–26.4, P = 0.01). Response was not associated with type of highly active antiretroviral therapy regimen (non nucleoside reverse transcriptase inhibitor based, protease inhibitor based, or ritonavir-boosted protease inhibitor based). Conclusion: Highly active antiretroviral therapy and chemotherapy are important in clinical Kaposi sarcoma response. Despite widespread availability of these therapies, Kaposi sarcoma continues to be a clinical problem; only half the patients achieved complete resolution of disease. New therapeutic approaches are needed.

Classic Kaposi Sarcoma in the United States over the last two decades: A clinicopathologic and molecular study of 438 non-HIV-related Kaposi Sarcoma patients with comparison to HIV-related Kaposi Sarcoma

Classic Kaposi sarcoma is rare and occurs predominantly in Mediterranean and Middle Eastern men. Since the emergence of acquired immune deficiency syndrome (AIDS)-related Kaposi sarcoma, the incidence, clinicopathologic features, and molecular human herpesvirus 8 (HHV-8) association of American Classic Kaposi Sarcoma has not been fully explored. This study compares Classic Kaposi Sarcoma to AIDS-related Kaposi Sarcoma over the same two decade time period. There were 438 histologically and clinically confirmed Classic Kaposi Sarcoma patients. The ethnic/racial distribution included Caucasian/American (56%), Mediterranean (22%), South American Hispanic (18%), Black (10%), western European (4%), Middle East (4%), Scandinavian (2%), and other (2%). Classic Kaposi Sarcoma was more common in men, 7:1, with a mean age of 74 years. The lesions presented in the lower extremity (69%), in the nodular stage (83%), and HHV-8 was detected by PCR in 4 0/41 randomly selected cases. A second, non-Classic Kaposi Sarcoma, malignancy was present in 42% (n=45) of the 108 Classic Kaposi Sarcoma patients with complete clinical information, 73% (33 patients) with a higher incidence over the general population. Follow-up of <1–19 years (mean=4.8 years) revealed that 24% of patients died of second malignancy, 22% died of other medical conditions, 2% died of treatment-related complications, and 2% patients died of widespread disease. Thirty-five percent are alive with no evidence of disease and 15% with persistent disease. Human immunodeficiency virus-related Kaposi Sarcoma was observed in 354 cases. There was a male predominance and more aggressive behavior, with higher rates of visceral and disseminated disease. While Classic Kaposi Sarcoma in the United States is an indolent disease and rarely accounts for patient demise, predominantly affecting Caucasian/American males on the lower extremity in the nodular phase, it more importantly may denote an underlying other malignancy. Current PCR probes detect HHV-8 in 98% of Classic Kaposi Sarcoma cases. In comparison, AIDS-related Kaposi Sarcoma is predominately multicentric, visceral, and disseminated, with more aggressive behavior.

AIDS-related Kaposi Sarcoma of the Lung Presenting With a “Crazy-paving” Pattern on High-resolution CT

Kaposi sarcoma (KS) is a fulminate and disseminated form of acquired immunodeficiency syndrome (AIDS)-defining neoplasm, usually presenting pulmonary involvement. We report a 40-year-old woman with AIDS and biopsy-proven KS showing unusual high-resolution computed tomography (HRCT) findings. HRCT showed areas of ground-glass attenuation with superimposed septal thickening ("crazy-paving" pattern). CT-pathologic correlation revealed that crazy-paving pattern in this case was due to accompanying pulmonary edema and hemorrhage in addition to tumor cell infiltration into the peribronchovascular interstitium, interlobular and alveolar septa. The authors suggest the inclusion of KS in the differential diagnosis of lung diseases in patients with AIDS presenting with crazy-paving pattern on the HRCT.

Weekly paclitaxel for advanced aggressive classic Kaposi sarcoma: experience in 17 cases

Paclitaxel has proved to be highly effective in the treatment of severe AIDS-related Kaposi sarcoma (KS), for which it is now considered as a second-line monotherapy. Taxanes were recently shown to be active also in classic, endemic and post-transplantation KS. To evaluate the clinical efficacy and tolerability of standardized paclitaxel treatment (100 mg weekly, intravenously) in a homogeneous group of 17 patients with advanced aggressive and refractory classic KS (cKS). Seventeen patients with aggressive refractory cKS (stage IIIBc-IVBcv) were treated with intravenous paclitaxel 100 mg weekly. The response to the therapy was evaluated after 12 weeks. A maintenance treatment every 2 weeks was introduced for most of the patients and a final evaluation was made. A partial/complete response was achieved in 14 of 17 patients. Two patients had allergic reactions, for which treatment was discontinued. One patient had progression of disease despite initial improvement. Patients received a mean of 16.8 courses. The treatment was generally well tolerated. Mean time to recurrence was 4.5 months from the end of the therapy and 7.35 months from the 12th course. In four of 10 patients who relapsed at follow-up, the recurrence was mild and responsive to local treatment, while the other six relapsing patients repeated paclitaxel with good response in five of them. This study shows that low-dose paclitaxel proved to be effective and well tolerated in patients with aggressive refractory cKS, controlling the aggressiveness of the disease. The treatment can be repeated with good response.

Liposomal doxorubicin in combination with interleukin-12 (IL-12) appears to be an effective and rapid treatment for AIDS-related Kaposi's sarcoma,

Liposomal doxorubicin in combination with interleukin-12 (IL-12) appears to be an effective and rapid treatment for AIDS-related Kaposi's sarcoma,

Human herpesvirus 8 load and progression of AIDS-related Kaposi sarcoma lesions

IntroductionHuman herpesvirus 8 (HHV8) is necessary for Kaposi sarcoma (KS) to develop, but whether peripheral blood viral load is a marker of KS burden (total number of KS lesions), KS progression (the rate of eruption of new KS lesions), or both is unclear. We investigated these relationships in persons with AIDS. MethodsNewly diagnosed patients with AIDS-related KS attending Mulago Hospital, in Kampala, Uganda, were assessed for KS burden and progression by questionnaire and medical examination. Venous blood samples were taken for HHV8 load measurements by PCR. Associations were examined with odds ratio (OR) and 95% confidence intervals (CI) from logistic regression models and with t-tests. ResultsAmong 74 patients (59% men), median age was 34.5 years (interquartile range [IQR], 28.5–41). HHV8 DNA was detected in 93% and quantified in 77% patients. Median virus load was 3.8 logs10/106 peripheral blood cells (IQR 3.4–5.0) and was higher in men than women (4.4 vs. 3.8 logs; p=0.04), in patients with faster (>20 lesions per year) than slower rate of KS lesion eruption (4.5 vs. 3.6 logs; p<0.001), and higher, but not significantly, among patients with more (>median 20 KS lesions) than fewer KS lesions (4.4 vs. 4.0 logs; p=0.16). HHV8 load was unrelated to CD4 lymphocyte count (p=0.23). ConclusionsWe show significant association of HHV8 load in peripheral blood with rate of eruption of KS lesions, but not with total lesion count. Our results suggest that viral load increases concurrently with development of new KS lesions.

Selective Prostate Cancer Thermal Ablation With Laser Activated Gold Nanoshells

Laser activated gold nanoshell thermal ablation represents a new, minimally invasive technology that offers benign tissue sparing thermal ablation of malignant tumors. We evaluated the efficacy of this technology for eradicating prostate cancer in a subcutaneous tumor model. The 110 nm gold nanoshells with a 10 nm gold shell are designed to act as intense near infrared absorbers. PC-3 cells were injected on the dorsum of nude mice in 3 groups, including 1-gold nanoshell plus near infrared laser, 2-saline alone and 3-near infrared laser alone. Animals received 7.0 ml/gm body weight (low dose) or 8.5 ml/gm body weight (high dose) nanoshells via tail vein injection. Control animals received saline. A 810 nm near infrared laser with a 200 mu laser fiber and an energy setting of 4 W/cm(2) was aimed at the tumor bed for 3 minutes. Tumors were measured at days 0, 7, 14 and 21. Tissue temperature was monitored during laser activation. Tumors were harvested at day 21 and stained with hematoxylin and eosin, and for nicotinamide adenine dinucleotide diaphorase activity. We observed 93% tumor necrosis and regression in the high dose treated group. Nicotinamide adenine dinucleotide staining corroborated this finding. The ablation zone was sharply limited to the laser spot size. There was no difference in the size or tumor histology in control groups, indicating a benign course for near infrared laser treatment alone. Temperatures up to 65.4C were attained in the treated group. Laser activated gold nanoshell ablation is an effective and selective technique for prostate cancer ablation in an ectopic murine tumor model.

Phase 2 study of pegylated liposomal doxorubicin in combination with interleukin-12 for AIDS-related Kaposi sarcoma

Thirty-six patients with AIDS-associated Kaposi sarcoma (KS) requiring chemotherapy were treated for six 3-week cycles of pegylated liposomal doxorubicin (20 mg/m(2)) plus interleukin-12 (IL-12; 300 ng/kg subcutaneously twice weekly), followed by 500 ng/kg subcutaneous IL-12 twice weekly for up to 3 years. All received highly active antiretroviral therapy (HAART). Twenty-two had poor-prognosis KS (T(1)S(1)). Thirty patients had a major response, including 9 with complete response, yielding an 83.3% major response rate (95% confidence interval: 67.2%-93.6%). Median time to first response was 2 cycles. Median progression was not reached at median potential follow-up of 46.9 months. Of 27 patients with residual disease when starting maintenance IL-12, 15 had a new major response compared with this new baseline. The regimen was overall well tolerated; principal toxicities were neutropenia, anemia, transaminitis, and neuropsychiatric toxicity. Patients had increases in serum IL-12, interferon gamma, and inducible protein-10 (IP-10), and these remained increased at weeks 18 and 34. The regimen of IL-12 plus liposomal doxorubicin yielded rapid tumor responses and a high response rate in patients with AIDS-KS receiving HAART, and responses were sustained on IL-12 maintenance therapy. A randomized trial of IL-12 in this setting may be warranted. This study is registered at (http://www.clinicaltrials.gov) as no. NCT00020449.

HIV‐associated Kaposi sarcoma: pathogenesis and therapy

While classical Kaposi sarcoma is a slowly progressing tumor, AIDS-related Kaposi sarcoma is much more aggressive. After introduction of antiretroviral therapy and with the use of well- tolerated chemotherapeutic agents, complete remission of the tumor can be achieved. Local therapeutic options include excision, cryosurgery, radiation and alitretinoin gel. In 45 % of patients with more than 400/microl CD4+ lymphocytes, interferon-alpha induces complete remission. New concepts of pathogenesis lead to therapeutic targets, such as inhibition of angiogenesis.

A Retrospective Analysis of Thalidomide Therapy in Non-HIV-Related Kaposi’s Sarcoma

Background: Thalidomide has antiangiogenic and immunomodulatory properties and has recently been used in the management of human malignancies. Several studies have suggested its interest for treating AIDS-related Kaposi’s sarcoma. Objectives: This study aimed to assess the efficacy and toxicity of thalidomide, an antiangiogenic agent, for the treatment of non-HIV-related Kaposi’s sarcoma. Methods: Eleven patients were included in this retrospective study conducted in the Department of Dermatology of Saint Louis, Paris, between 2000 and 2003. Among them, 2 were immunosuppressed (1 renal transplant recipient and 1 patient with microscopic polyangiitis treated by oral steroids) with stable immunosuppressive regimens during the past 6 months. The median daily thalidomide dosage was 100 mg and the median duration of drug treatment was 16 weeks. Results: Three patients achieved a partial response and 4 had a stable disease. Although no grade 3 or 4 was observed, 3 (27%) out of 11 patients prematurely discontinued thalidomide because of grade 1 sensory neuropathy (paresthesia) and vertigo. Conclusions: Our results show a true although modest interest of thalidomide in non-HIV-related Kaposi’s sarcoma and prompt us to evaluate less toxic thalidomide analogues for this indication.

Kaposi’s sarcoma herpesvirus load in biopsies of cutaneous and oral Kaposi’s sarcoma lesions

Objectives To evaluate human herpesvirus 8/Kaposi’s sarcoma associated herpesvirus (HHV-8/KSHV) viral load in diagnostic, (formalin fixed, paraffinised) biopsies and patient serum during tumour progression of oral and cutaneous AIDS-related Kaposi’s sarcoma (AKS), and endemic Kaposi’s sarcoma (EKS) by a sensitive and specific quantitative real time polymerase chain reaction (qRT-PCR) assay. Study design Eighty six biopsies of both AKS (oral and cutaneous AKS, 68) and EKS (cutaneous EKS, 18) were evaluated by qRT-PCR and immunohistochemistry (IHC). The viral load in human tumour tissue and serum of some individual patients were compared. Results Higher viral load as well as frequency of latency-associated nuclear antigen (LANA)+ tumour spindle cells (SC) and number of LANA granules per SC was found in oral AKS compared to cutaneous AKS. Although few cases were available, serum viral load appeared to decrease compared to tumour tissue during KS progression. Conclusions The higher viral load in oral rather than cutaneous AKS is consistent with the well recognised reservoir function of the oral mucosa. Decrease of serum HHV-8 load during KS progression may indicate decreased virus release and/or increased virus clearance.

Non–AIDS-Related Kaposi Sarcoma Involving the Tarsal Conjunctiva and Eyelid Margin

Non–AIDS-Related Kaposi Sarcoma Involving the Tarsal Conjunctiva and Eyelid Margin

Investigational agents for treatment of AIDS-related Kaposi’s sarcoma

AIDS-related Kaposi’s sarcoma (KS) is a neoplasm that results from the co-infection of HIV and KS herpesvirus/human herpesvirus-8 (KSHV/HHV8). Targeting HIV with highly active antiretroviral therapy has attenuated the natural history of this disease. Recent discoveries have elucidated the role of multiple signaling pathways in the pathogenesis of AIDS-related KS. In particular, KSHV/HHV8-specific gene products, including a G-protein-coupled receptor (vGPCR) and a homolog of human IL-6 (vIL-6), have been implicated in the development of tumorigenesis and angiogenesis. In addition, KSHV/HHV8 can modulate cellular growth and angiogenic pathways to augment malignant transformation and potentiate growth. This article discusses the main signaling pathways that are implicated in the pathogenesis of AIDS-related KS, reviews recently completed clinical trials and anticipates the future direction of molecularly targeted agents in this disease.

Gender Differences in AIDS-Associated Kaposi Sarcoma in Harare, Zimbabwe

Reasons for gender-related differences in the risk of AIDS-related Kaposi sarcoma (AIDS-KS) are unknown. Four hundred thirty-eight male and 166 female AIDS-KS patients were evaluated in Harare, Zimbabwe. Female patients were younger than male patients in this study (median of 33 vs. 38 years; P < 0.001), mirroring the epidemiology of AIDS in Zimbabwe. In a multivariate model adjusted for CD4 T-cell count, age, prior radiation treatment, and chemotherapy, women were more likely to report fever, diaphoresis, or weight loss (odds ratio = 1.7, 95% confidence interval: 1.1 to 2.7; P = 0.009). These findings suggest an increased severity of KS or other unidentified infections among women with AIDS-KS in Zimbabwe.

Sialoadhesin (CD169) Expression in CD14+ Cells Is Upregulated Early after HIV-1 Infection and Increases during Disease Progression

BackgroundSialoadhesin (CD169, siglec-1 or Sn) is an activation marker seen on macrophages in chronic inflammatory diseases and in tumours, and on subsets of tissue macrophages. CD169 is highly expressed by macrophages present in AIDS-related Kaposi's sarcoma lesions. It is also increased on blood monocytes of HIV-1 infected patients with a high viral load despite antiretroviral treatment.Methodology/Principal FindingsWe investigated expression of sialoadhesin in untreated HIV-1 and HHV-8 infected patients, by real-time PCR and FACS analysis to establish its expression in relation to infection and disease progression. Patients analysed were either HIV-1 seroconverters (n = 7), in the chronic phase of HIV-1 infection (n = 21), or in the AIDS stage (n = 58). Controls were HHV-8 infected, but otherwise healthy individuals (n = 20), and uninfected men having sex with men (n = 24). Sialoadhesin mRNA was significantly elevated after HIV-1, but not HHV-8 infection, and a further increase was seen in AIDS patients. Samples obtained around HIV-1 seroconversion indicated that sialoadhesin levels go up early in infection. FACS analysis of PBMCs showed that sialoadhesin protein was expressed at high levels by approximately 90% of CD14+ and CD14+CD16+cells of HIV-1+ patients with a concomitant 10-fold increase in sialoadhesin protein/cell compared with uninfected controls.Conclusions/SignificanceWe have shown that sialoadhesin is induced to high levels on CD14+ cells early after HIV-1 infection in vivo. The phenotype of the cells is maintained during disease progression, suggesting that it could serve as a marker for infection and probably contributes to the severe dysregulation of the immune system seen in AIDS.

Management of AIDS-related Kaposi's sarcoma

The advent of highly active antiretroviral therapy (HAART) has lead to a substantial reduction in the prevalence, morbidity, and mortality associated with AIDS-related Kaposi's sarcoma. Similarly, concomitant advances in chemotherapy and supportive-care protocols have allowed for Kaposi's sarcoma to be managed more effectively in comparison with the pre-HAART era. Furthermore, developments in our understanding of the pathogenesis of Kaposi's sarcoma have identified several molecular targets that can potentially provide new therapeutic strategies. This Review discusses the role of conventional chemotherapeutic and immunomodulatory agents in the treatment of Kaposi's sarcoma and summarises the current status and future prospects of novel molecularly targeted agents in the treatment of this disease.

Tumours of the hand

Hand tumours of soft-tissue and bony origin are frequently encountered, and clinicians must be able to distinguish typical benign entities from life-threatening or limb-threatening malignant diseases. In this Review, we present a diagnostic approach to hand tumours and describe selected cancers and their treatments. Soft-tissue tumours include ganglion cysts, giant-cell cancers and fibromas of the tendon sheath, epidermal inclusion cysts, lipomas, vascular lesions, peripheral-nerve tumours, skin cancers, and soft-tissue sarcomas. Bony tumours encompass enchondromas, aneurysmal bone cysts, osteoid osteomas, giant-cell lesions of bone, bone sarcomas, and metastases. We look at rates of recurrence and 5-year survival, and recommendations for adjunct chemotherapy and radiotherapy for malignant lesions.