AIDS-related Kaposi Research Articles

Use of pegilated liposomal anthracycline (PLD) in clinical practice: Results and toxicity

5180 Background: Pegilated liposomal doxorubicin (PLD) is considered a less toxic drugs as compared to conventional doxorubicin. The drug has the following indications: AIDS related Kaposi sarcoma, pretreated ovarian carcinoma and breast cancer patients (pts) at risk of cardiotoxicity. Methods: We have reviewed all the cases treated with PLD in our Institute in the last 3 years, out of clinical studies, in order to define the results and toxicity of these very expensive drug in daily clinical practice. Results: From Jan 2001 to Dec 2003 we have treated 108 pts with the following characteristics: 103 women and 5 men, median age 63 yr (range 38–82), 51 ovarian, 37 breast, 5 sarcoma, 4 endometrial, 4 NHL, 3 Kaposi, 2 biliary tract, 1 thyroid and 1 mesothelioma. With regard to ovarian cancer series, 36 pts have been treated with PLD as single agent, 11 in combination with oxaliplatin, 3 with paraplatin and 1 with gemcitabine, respectively. Responses were observed in 7 pts (3 CR + 4 PR) out of 51 pts (14%) and SD was observed in 12 (23%) of pts. With regard to breast cancer pts, 6/37 (16%) PR and 11/37 (29%) SD were observed in this series of heavily pretreated patients. In fact, all breast cancer pts had previously received anthracyclines and most of them also taxanes. Of the 4 NHL patients, 3 responded, whereas no one of the other tumor types responded. With regard to the toxicity, 28 out of 108 (26%) pts showed either palmo-plantar erytrodisestesia (PPD) at various degree or any form of cutaneous toxicity or first dose reaction which prevented drug continuation in 11 (10%) pts. Moreover, mucositis was observed in 24% of pts treated with doses over 40 mg/mq every 3 weeks, whereas neutropenia and alopecia were rarely complained. Cardiac toxicity was observed in 3/108 (3%) pts who were heavily pretreated with conventional anthracyclines at dosage of 755, 875 and 1234 mg/mq PLD respectively. Conclusions: From our retrospective study we learnt that the cost-effectiveness of PLD is high, and that toxicity, other than cardiac hematologic and alopecia, is also severe in heavily pretreated pts. On the other hand, the low incidence of cardiovascular events should advice to a better selection of pts to submit to PLD and to an earlier use in the course of the neoplastic disease. No significant financial relationships to disclose.

Docetaxel in anthracycline-pretreated AIDS-related Kaposi's sarcoma: a retrospective study

Kaposi's sarcoma (KS) is a potentially life-threatening multifocal neoplasm. Despite the significant decline in the incidence of acquired immune deficiency syndrome (AIDS)-related KS with the use of highly active antiretroviral therapy (HAART), some patients, even those with a good immune restoration, still have aggressive disease. Liposomal anthracyclines or combination chemotherapy are widely used but adverse effects limit their utilization. We studied the efficacy and tolerance of docetaxel in the treatment of AIDS-related KS after pretreatment with anthracycline. PATIENTS/METHODS AND MAIN OUTCOME MEASURE: A retrospective cohort study was done. Nine human immunodeficiency virus (HIV)-infected patients were treated from 1997 to 2002 with docetaxel. Tumour response was evaluated using the AIDS Clinical Trial Group (ACTG) staging criteria. Clinical and biological toxicity was evaluated. AIDS status with HIV viral load and CD4 T-cell count were measured at the beginning and at the end of the treatment. A major (complete or partial) response and a stabilization of the disease were demonstrated in seven and two patients, respectively. Grade 4 neutropenia and thrombocytopenia were observed in four of nine and one of nine patients, respectively. One patient died after sepsis. Docetaxel has a good and rapid efficacy in anthracycline-pretreated patients with severe AIDS-related KS. Phase II/III trials should be done to compare docetaxel with liposomal anthracyclines as a first-line treatment.

Reversal of some viral IL‐6 electrostatic properties compared to IL‐6 contributes to a loss of alpha receptor component recruitment

Human interleukin-6 (hIL-6) is a pleiotropic mediator of activation and proliferation across a large number of different cell types. Human herpesvirus-8 (HHV-8) has been associated with classical and AIDS-related Kaposi's sarcoma (KS). HHV-8 encodes viral IL-6 (vIL-6), a functional homolog of human interleukin-6, that promotes the growth of KS and of some lymphoma cells. Signaling induced by human IL-6 requires recruitment of the glycoprotein gp130, which acts as the signal transducing chain, and of IL-6Ralpha, which is necessary for cognate recognition and high affinity receptor complex formation. In contrast, the formation of a functional complex between vIL-6 and gp130 does not require the presence of IL-6Ralpha. The physico-chemical properties of vIL-6 have been analyzed and compared to those of hIL-6 and of the receptor chains, gp130 and IL-6Ralpha. Interaction sites on vIL-6 involve more hydrophobic residues than those of hIL-6. The electrostatic fields induced by vIL-6 and IL-6Ralpha are repulsive and prevent interaction between vIL-6 and IL-6Ralpha, whereas the electrostatic field induced by hIL-6 steers the complex formation with IL-6Ralpha. Subsequently, electrostatic binding free energy in the vIL-6/IL-6Ralpha complex is destabilizing, whereas it is stabilizing in the complex comprising hIL-6. These properties result from charge reversals between viral and human IL-6, an unusual phenomenon of amino acid substitutions within a homologous protein family. This suggests a selection pressure for vIL-6 to by-pass the IL-6Ralpha control of host defense against virus infection. This selection pressure has yielded the reversal of electrostatic properties of vIL-6 when compared to hIL-6.

Highly Active Antiretroviral Therapy in AIDS-Associated Kaposi's Sarcoma (KS): Implications for the Design of Therapeutic Trials in Patients With Advanced Symptomatic KS

TO THE EDITOR: The article by Dr Krown provides very appropriate and timely considerations with regard to the management of patients with advanced, symptomatic, AIDS-related Kaposi’s sarcoma (AIDS-KS) in the era of highly active antiretroviral therapy (HAART) and suggests, on the basis of a comprehensive review of the literature, that in T1 (according to the AIDS Clinical Trials Group [ACTG] staging classification) symptomatic KS patients, concomitant chemotherapy should be added to HAART without awaiting a response to HAART. Moreover, the author, referencing our study, states that “T1 and T0 groupings have been associated with distinct survival distribution.” In response, we would like to clarify our data as reported by Dr Krown. We believe that our data may help to better define which group of patients within the T1 category need a timely institution of chemotherapy concomitantly to HAART, and for which group it is too risky to await a possible response to HAART. In our study, we collected clinical and survival data from 211 patients with AIDS-KS enrolled in two prospective cohort studies beginning in 1996, the time when HAART became available in Italy, with the aim of validating the ACTG staging system for AIDS-KS in the HAART era. All patients received HAART. Our analysis identified two different risk categories: a good-risk group (T0S0, T1S0, and T0S1) and a poor-risk group (T1S1). The 3-year survival rate of patients with T1S1 was 53%, significantly lower than the 3-year survival rates of patients with T0S0, T1S0, and T0S1, which were 88%, 80%, and 81%, respectively (P .0001). Therefore, the T category alone does not provide an appropriate survival discrimination, as occurred in the pre-HAART period. When we considered only patients with pulmonary involvement (namely,Tp1) as compared with T1 patients without pulmonary disease (namely,Tp0), the 3-year survival rate was 46% for Tp1 and 77% for Tp0 patients (P .0002), indicating that patients with pulmonary involvement identify the group of patients with the poorest prognosis, independent of the other ACTG variables. Therefore, we believe that we were able to identify, within the T1 category, a specific subgroup of KS patients (ie, T1S1, Tp1) with an unfavorable survival rate in whom HAART and concomitant chemotherapy should be used.

Pharmacokinetics of low-dose doxorubicin and metabolites in patients with AIDS-related Kaposi sarcoma

Systemic chemotherapy is the treatment of choice for AIDS-related advanced Kaposi sarcoma. One principal schedule combines adriamycin (doxorubicin), bleomycin, and vincristine (ABV). We analysed the plasma concentrations of low-dose doxorubicin (Dx) and its metabolites doxorubicinol, 7-deoxydoxorubicinone, doxorubicinone, doxorubicinolone, and 7-deoxydoxorubicinolone in AIDS-patients to define patient-group and dose-specific pharmacokinetic parameters. A previously described high-performance liquid chromatographic (HPLC) method and a population approach with non-linear mixed effects modelling (NONMEM) were used for analysis and subsequent modelling of the time-concentration data of low-dose Dx and metabolites in seven patients with AIDS-related advanced Kaposi sarcoma. Patients received Dx 20 mg m(-2), bleomycin 15 U m(-2) and vincristine 2 mg as a 30-min intravenous infusion each. Blood samples were collected up to 72 h after the start of Dx treatment. WinNonlin software version 4.1 was used for non-compartmental analysis and NONMEM software version V for compartmental analysis. Covariate analysis was performed for various clinical and laboratory parameters. Non-compartmental analysis yielded an area under the plasma concentration-time curve (AUC) for Dx of 566 mug h L(-1), a maximum plasma concentration (c(max)) of 599 mug L(-1) and an elimination half-life (t(1/2)) of 30.8 h. Compartmental analysis resulted in a two-compartment model with first-order elimination, which best fitted the concentration-time data. Model estimate for Dx clearance was 61.8 L h(-1), for intercompartmental clearance (Q) 112 L h(-1), for the volume of the central compartment (V(1)) 23.3 L, and for the volume of the peripheral compartment (V(2)) 1,130 L. Metabolite data could adequately be estimated by NONMEM using single-compartment models. Graphical plots of residuals versus time for all metabolites yielded no evidence of non-linear pharmacokinetic behaviour. Laboratory parameters of liver and renal function were all in the normal range and their inclusion in the pharmacokinetic model did not improve data fit. A final jack-knife analysis was performed. Concentration-time data for low-dose Dx and metabolites in the ABV-regimen are best described by a two-compartment model with first-order elimination. The results confirm that the aglycones doxorubicinone, 7-deoxydoxorubicinone, and doxorubicinolone can be reliably detected in the studied patient group and implemented into a common metabolic model. Model estimates suggest that pharmacokinetic parameters are similar for low-dose Dx and higher-dosed Dx. As the role of the aglycones is still poorly understood, despite their potential clinical relevance, their analysis should be implemented in future pharmacokinetic and pharmacodynamic studies of Dx.

HHV‐8/KSHV during the development of Kaposi's sarcoma: evaluation by polymerase chain reaction and immunohistochemistry

The human gamma-herpes virus-8 (HHV-8) was first described in AIDS-related Kaposi's sarcoma (KS) tumour samples. In this study, we report comparative studies on paraffin-embedded biopsies of AIDS-related KS (AKS) and endemic KS (EKS) with regard to HHV-8 content as evaluated using polymerase chain reaction (PCR) and immunohistochemistry. DNA was extracted either using Chelex-100 or using Qia-gene kit and was evaluated with the help of a semiquantitative PCR assay. The PCR detection of HHV-8 was more sensitive to the Chelex method than to Qia-gene. The threshold for PCR test sensitivity with the help of serial dilution of DNA was at the level of five plasmid ORF-26 regions, and DNA from 25 body cavity-based lymphoma-1 cells. The results expressed as virus load/actin unit showed progressively higher HHV-8 levels in late (nodular) cases, compared to those in early (patch/plaque) stages. Evaluation of HHV-8 DNA levels in tumour tissues, thus, indicates a correlation between virus load and KS stage. Double immunostaining of spindle cells (SC) in KS biopsies for CD34 and HHV-8/latency-associated nuclear antigen (LANA) showed an increase in double-positive SC in the lesions of nodular AKS and EKS cases, compared to that in plaque and patch stages. However, 10-15% of CD34+/LANA- SC cells were observed during the development from patch to nodular cases of AKS and EKS. Our results indicate that PCR analysis is a simple and sensitive diagnostic method for HHV-8 evaluation in KS tissues, processed for conventional histopathology.

Imatinib-Induced Regression of AIDS-Related Kaposi's Sarcoma

Activation of the platelet-derived growth factor (PDGF) and c-kit receptors has been proposed as important in mediating the growth of AIDS-related Kaposi's sarcoma (KS). We investigated the response of KS to the PDGF receptor (PDGFR)/c-kit inhibitor, imatinib mesylate, and investigated the effect of this therapy on critical signal transduction intermediates. Ten male patients with AIDS-related cutaneous KS, which progressed despite chemotherapy and/or highly active antiretroviral therapy, received imatinib mesylate administered orally, 300 mg twice daily. Clinical response was determined by serial tumor measurements. To determine biologic and histologic response, skin lesion biopsies were obtained at baseline and following 4 weeks of therapy. Five of 10 participants had a partial response by tumor measurements. Biopsies after 4 weeks of therapy demonstrated histologic regression in four of six patients. Four patients' tumor biopsies were assessable for immunohistochemistry end points pre- and post-therapy. These demonstrated inhibition of PDGFR and its downstream effector, extracellular receptor kinase, which is a member of the mitogen-activated protein kinase family. The most common adverse event was diarrhea, which led to dose reduction in six patients. Imatinib mesylate administered orally twice daily for AIDS-related KS results in clinical and histologic regression of cutaneous KS lesions within 4 weeks. These promising results demonstrate that inhibition of the c-kit and/or PDGF receptors may represent an effective strategy for treating KS.

Epidemiological characteristics of human herpesvirus‐8 infection in a large population of antenatal women in Zambia

Comprehensive data describing epidemiological characteristics of the human herpesvirus-8 or Kaposi's sarcoma-associated herpesvirus (HHV-8 or KSHV) infection among pregnant women in a central sub-Saharan Africa are not available. This study determined virus prevalence estimates and the risk factors associated with HHV-8 infection. Cross-sectional, enrollment visit data were analyzed from a prospective cohort study of perinatal transmission of HHV-8 in Lusaka, Zambia. Exposure data were obtained via structured interview, physical examination, medical chart review, and laboratory testing. Among 3,160 antenatal women serologically screened for HHV-8 between September 1998 and October 2000, 40.2% were seropositive. The HHV-8 positive women were more likely to be co-infected with HIV-1 than those who were HHV-8 negative (34% vs. 26%; P < 0.0001). Of 154 variables evaluated by logistic regression analyses, only three risk factors, have emerged as independent predictors of HHV-8 positive serology: diagnosis of genital warts, HIV-1 co-infection and primary education. The association of HHV-8 infection with genital warts and HIV-1 co-infection suggests heterosexual transmission of HHV-8. HIV-1 infection may also act as a marker for particular behaviors, which could be sexual in nature, that are associated with both HIV-1 and HHV-8 transmission. Since HHV-8 facilitates development of AIDS-related Kaposi's sarcoma (KS), the results of this study could be utilized to identify specific population groups of pregnant women who are at increased risk for this disease.

Effect of intravenous heparin on serum levels of endostatin, VEGF and HGF: author's reply.

We thank Dr Bhatia, Dr Clesham and Dr Turner for their interest in our paper [1], and we agree with them that the studies on the serum levels of endostatin, VEGF and HGF under administration of heparin should be interpreted very carefully, and there is an important limitation in our study. However, we disagree with them on some points as follows. We think that the significant decrease in serum VEGF levels after reperfusion may be due to down-regulation of VEGF production (although we did not state in our paper) as well as internalization of VEGF after binding to its receptor (which may be facilitated by heparin [2]). VEGF was shown to be internalized in HUVECs (human umbilical vein endothelial cells) [3]. In fact, we found that VEGF concentrations in culture supernatants of cardiac myocytes increased rapidly and then decreased in response to acute hypoxia in vitro without addition of any drugs including heparin (Y. Seko, unpublished work). This is also the case for endostatin. Recently, it has been reported that AIDS-related Kaposi's sarcoma cells rapidly internalize endostatin [4]. We also found that concentrations of endostatin in culture supernatants of cardiac myocytes subjected to hypoxia in vitro increased a little later than those of VEGF, suggesting that VEGF and endostatin are similarly released into culture supernatants in response to hypoxia (Y. Seko, unpublished work).Kawamoto et al. [5] reported that the serum concentration of VEGF in patients with acute myocardial infarction was reduced by up to 93% 1 h after administration of intravenous heparin. However, it is strange that the authors [5] did not report the serum VEGF levels at the time of admission before the start of heparin administration, and that heparin administration markedly decreased the serum VEGF level, but had no effects on the serum bFGF (basic fibroblast growth factor) level, although both growth factors are heparin-binding proteins. Moreover, we analysed the same serum samples with an ELISA kit from R&D Systems and that from Immuno-Biological Laboratories (as used by Kawamoto et al. [5]), but the data were quite different between the two kits. As we stated in our paper [1], marked elevation of serum levels of HGF after reperfusion was thought to be at least in part (but not entirely) due to heparin administration. However, we could not exclude a possibility that HGF may be released into the circulation in response to reperfusion and play a protective role against the reperfusion-induced oxidative stress [6].In conclusion, to know the precise effects of myocardial ischaemia/reperfusion on the serum levels of endostatin, VEGF and HGF, further studies using animal models without administration of any drugs, including heparin, are needed.

Retrospective, longitudinal analysis of serum human herpesvirus-8 viral DNA load in AIDS-related Kaposi's sarcoma patients before and after diagnosis.

Human herpesvirus 8 (HHV-8) is detected more often in patients progressing towards Kaposi's sarcoma (KS) than in patients who do not develop the disease, suggesting that the level of viremia might be associated with Kaposi's sarcoma disease and progression. Longitudinal serum samples from 19 AIDS-Kaposi's sarcoma patients, ranging from 2 years before KS till 2 years after KS diagnosis were tested. No correlation was found between viral load and progression to KS, or disease stage.

Development and characterization of a novel Cremophor ® EL free liposome-based paclitaxel (LEP-ETU) formulation

Taxol ® is a marketed product for the treatment of ovarian, breast, non-small cell lung cancer and AIDS-related Kaposi's Sarcoma. It is thus far one of the most effective anticancer drugs available on the market. However, paclitaxel is only sparingly soluble in water and therefore, intravenous administration depends on the use of the non-ionic surfactant Cremophor ® EL (polyethoxylated castor oil) to achieve a clinically relevant concentrated solution. Unfortunately, Cremophor ® EL increases toxicity and leads to hypersensitivity reactions in certain individuals. We have developed a well characterized novel lyophilized liposome-based paclitaxel (LEP-ETU) formulation that is sterile, stable and easy-to-use. The mean particle size of the liposomes is about 150 nm before and after lyophilization, and the drug entrapment efficiency is greater than 90%. Stability data indicated that the lyophilized LEP-ETU was physically and chemically stable for at least 12 months at 2–8 and 25 °C. Moreover, the formulation can be diluted to about 0.25 mg/ml without drug precipitation or change in particle size. In vitro drug release study in phosphate-buffered saline (PBS, pH 7.4) showed that less than 6% of the entrapped paclitaxel was released after 120 h, indicating that the drug is highly stable in an entrapped form at physiologic temperature.

Advances in the pathobiology and treatment of Kaposi sarcoma.

Kaposi sarcoma, which has reached epidemic proportions in parts of Africa and in the Western world, continues to pose a problem in patients with AIDS receiving highly active antiretroviral therapy (HAART). This article reviews the new and important information regarding the epidemiology, biology, and management of Kaposi sarcoma that was published in the last year. Worldwide Kaposi sarcoma herpesvirus/human herpesvirus 8 (HHV8) seropositivity has been found to exceed the incidence of Kaposi sarcoma. Therefore, investigators have justifiably implicated other cofactors (eg, blood-sucking arthropods, angiotensin converting enzyme inhibitors, hemodialysis, and iron) in the development of Kaposi sarcoma. In the transplant setting, Kaposi sarcoma lesions have been shown to originate from the engraftment of donor tumor cells. The detection of HHV8 in Kaposi sarcoma lesions has provided a new diagnostic tool to help differentiate Kaposi sarcoma from its mimics. Kaposi sarcoma lesional cells, now confirmed to be of lymphatic origin, have been shown to express several chemokine receptors, some of which may help explain the predilection for skin. Regression of Kaposi sarcoma has been characterized histologically for the first time. The finding that some tumor cells can remain in an atrophic state even in completely regressed lesions suggests that they have the potential to recur. Protease inhibitor-based and nonnucleoside reverse transcriptase inhibitor-based HAART regimens have been verified to be similarly effective. Although antiretrovirals have been noted to favorably alter the clinical characteristics of Kaposi sarcoma favorably, they seem not to alter the natural history of this disease. In the HAART era, because CD4 cell count was shown no longer to provide prognostic information about AIDS-related Kaposi sarcoma, the traditional classification system for staging AIDS-related Kaposi sarcoma has been refined. Also, a new staging system for classic Kaposi sarcoma has been proposed. Numerous advances have emerged regarding Kaposi sarcoma during the last year, many of which still need to be translated into clinically useful information. The results of new clinical trials involving antivirals purposely directed against HHV8 and antiretrovirals for HIV-uninfected people are anticipated. Finally, although investigators during this period did provide us with additional potential therapeutic targets, more novel approaches such as RNA interference and gene therapy have been also proposed as options in the future management of Kaposi sarcoma.

Phase I trial of anti-sense oligonucleotide vascular endothelial growth factor (VEGF-AS, Veglin) in patients with relapsed and refractory malignancies

3008 Background: Vascular endothelial growth factor (VEGF) is critical for tumor angiogenesis and is an autocrine growth factor in some cancers. Elevated tumor/serum VEGF levels predict poor survival in cancer patients (pts). A novel VEGF-antisense coumpound (VEGF-AS, Veglin) has been developed, targeting VEGF-A,-C and -D. In vitro and in vivo studies with Veglin show inhibition of VEGF receptor binding and expression, resulting in tumor growth inhibition. Methods: For the first 4 levels of this phase I dose escalation trial, pts received a single course of Veglin given IV over 2 hours for 5 consecutive days at 15, 22.5, 30, and 37.5 mg/m2. Subsequent pts were given repeat cycles of Veglin for 5 days every 2 weeks (8 cycles, max) at doses of 47, 59, 74, and 85 mg/m2. 3 pts were accrued to each dose level. Results: To date, 19 males and 7 females, median age 57 years, (range 19–83) were accrued. All failed standard therapy including systemic chemotherapy in 24 (92%), biologics/ immunotherapy in 13 (50%), and radiation in 9 (35%). The most common tumor types accrued were lymphoma (NHL) in 5; sarcoma in 4; renal and AIDS-related Kaposi's sarcoma in 3 each; colon and lung in 2 each. All pts completed the initial 5 days of Veglin. Plasma VEGF levels declined in 56% of pts.Veglin infusions were well tolerated with no dose limiting toxicities observed at doses up to 85 mg/m2. One case of grade 3 anemia has occurred; there was no grade 3 or 4 neutropenia or thrombocytopenia. No perturbation in coagulation or complement profiles have been seen. Non-hematologic side effects were grade 1 or 2 and included fatigue, hypotension, and perioral numbness (all <20% of pts). The maximum tolerated dose has not been reached. \(\underline{\mathrm{Response\ data}}\): There has been anti-tumor activity in 2 patients with AIDS-related KS (one biopsy-proven CR at level 1), in 1 pt with renal cell (PR), and 1 pt with tumor cutaneous T-cell NHL (PR). Conclusions: Veglin is well tolerated at doses up to 85 mg/m2with no dose limiting toxicities. Veglin has shown evidence of anti-tumor activity, even at the lowest dose studied. Updated clinical and pharmacokinetic information will be presented. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Vasgene Corporation; The Whittier Foundation

Phase I trial of anti-sense oligonucleotide vascular endothelial growth factor (VEGF-AS, Veglin) in patients with relapsed and refractory malignancies

3008 Background: Vascular endothelial growth factor (VEGF) is critical for tumor angiogenesis and is an autocrine growth factor in some cancers. Elevated tumor/serum VEGF levels predict poor survival in cancer patients (pts). A novel VEGF-antisense coumpound (VEGF-AS, Veglin) has been developed, targeting VEGF-A,-C and -D. In vitro and in vivo studies with Veglin show inhibition of VEGF receptor binding and expression, resulting in tumor growth inhibition. Methods: For the first 4 levels of this phase I dose escalation trial, pts received a single course of Veglin given IV over 2 hours for 5 consecutive days at 15, 22.5, 30, and 37.5 mg/m2. Subsequent pts were given repeat cycles of Veglin for 5 days every 2 weeks (8 cycles, max) at doses of 47, 59, 74, and 85 mg/m2. 3 pts were accrued to each dose level. Results: To date, 19 males and 7 females, median age 57 years, (range 19–83) were accrued. All failed standard therapy including systemic chemotherapy in 24 (92%), biologics/ immunotherapy in 13 (50%), and radiation in 9 (35%). The most common tumor types accrued were lymphoma (NHL) in 5; sarcoma in 4; renal and AIDS-related Kaposi's sarcoma in 3 each; colon and lung in 2 each. All pts completed the initial 5 days of Veglin. Plasma VEGF levels declined in 56% of pts.Veglin infusions were well tolerated with no dose limiting toxicities observed at doses up to 85 mg/m2. One case of grade 3 anemia has occurred; there was no grade 3 or 4 neutropenia or thrombocytopenia. No perturbation in coagulation or complement profiles have been seen. Non-hematologic side effects were grade 1 or 2 and included fatigue, hypotension, and perioral numbness (all <20% of pts). The maximum tolerated dose has not been reached. \(\underline{\mathrm{Response\ data}}\): There has been anti-tumor activity in 2 patients with AIDS-related KS (one biopsy-proven CR at level 1), in 1 pt with renal cell (PR), and 1 pt with tumor cutaneous T-cell NHL (PR). Conclusions: Veglin is well tolerated at doses up to 85 mg/m2with no dose limiting toxicities. Veglin has shown evidence of anti-tumor activity, even at the lowest dose studied. Updated clinical and pharmacokinetic information will be presented. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Vasgene Corporation; The Whittier Foundation

Gastrointestinal and cutaneous AIDS-related Kaposi's sarcoma: Different activity of liposomal doxorubicin according to location of lesions

9030 Background: Kaposi's sarcoma (KS) continuous being a frequent neoplasm in third world AIDS patients. Liposomal doxorubicin (LD) is the drug of choice for advanced KS; nevertheless, it is very ...

Gastrointestinal and cutaneous AIDS-related Kaposi's sarcoma: Different activity of liposomal doxorubicin according to location of lesions

9030 Background: Kaposi's sarcoma (KS) continuous being a frequent neoplasm in third world AIDS patients. Liposomal doxorubicin (LD) is the drug of choice for advanced KS; nevertheless, it is very expensive for third world countries. In addition, we believe that the greatest usefulness of LD is in patients with visceral KS and that there is a different activity of the drug according to the location of the lesions. Due to this, we carried out a prospective study to evaluate the effectiveness of LD in gastrointestinal KS patients as well as its differential clinical activity, depending on the location of the lesions. Methods: The study included thirteen AIDS male patients with ages between 25 and 35 years (mean: 27 years), a performance status > 70, with more than 25 cutaneous lesions and extensive gastrointestinal KS. They were treated with LD, 20 mg/m2 every 21 days, during 6 cycles, and half of them were under highly active antiretroviral therapy. Results: Ten patients (77%) were able to obtain a complete response of the gastrointestinal KS lesions and three (23%) a partial response. Regarding the cutaneous lesions, there was only one patient (8%) who showed a complete response, five (38%) showed partial responses and seven (54%) stabilized their disease. By applying Fisher's test we found a significant difference (p< 0.00035) when comparing the effectiveness of LD in gastrointestinal lesions in relation to cutaneous ones. Conclusions: It can be concluded that LD has a different activity in KS lesions, being more effective in gastrointestinal KS, which is very relevant since gastrointestinal KS can compromise the life of patients due to the massive bleeding risk. Due to this, we can recommend LD in patients from third world countries with extensive gastrointestinal KS. No significant financial relationships to disclose.

An IL-8 gene promoter polymorphism is associated with the risk of the development of AIDS-related Kaposi's sarcoma: a case-control study.

In a case-control study, we studied the effect of a single nucleotide polymorphism in the IL-8 promoter on the risk of the development of AIDS-related Kaposi's sarcoma (KS). KS developed in 46% of individuals with the TT genotype and in 66% of AA/AT genotypes (P=0.038). Patients with TT genotype were rarely affected with visceral KS (7% versus 36%; P=0.06), which suggests that carriers of the TT genotype are protected from (severe) KS development.

Cyclin D1 overexpression in AIDS-related and classic Kaposi sarcoma.

The anatomic distribution and rate of progression vary significantly between acquired immunodeficiency syndrome (AIDS)-related Kaposi sarcoma (KS) and classic KS. The reasons are unclear, but cyclin D1 overexpression is associated with tumor progression in other malignancies. Cyclin D has an important regulatory role in the progression of cell cycle at the G1-S phase due to its effect in phosphorylating the retinoblastoma gene product. Forty-one paraffin-embedded surgical specimens (31 AIDS-related, 10 classic) were examined using streptavidin-biotin-peroxidase immunohistochemistry with monoclonal antibody to cyclin D1. A scoring system based on the intensity and extent of staining was used. The correlations among cyclin D1 expression and clinicopathologic parameters were statistically analyzed. Cyclin D1 overexpression was found in 29% (12/41) of all KS cases. There was a strong correlation between cyclin D1 overexpression and pathologic stage (0% in patch stage, 13% in plaque stage, 50% in nodular stage; P = 0.0017). Classic KS lesions had a higher incidence of cyclin D1 overexpression than AIDS-related lesions (70% vs 16%, P = 0.001). Cyclin D1 overexpression was detected in 78% of the classic nodular lesions and 31% of the AIDS-related nodular lesions (P = 0.03). On multivariate analysis, negative human immunodeficiency virus status (P = 0.001) and nodular lesions (P = 0.007) were strong predictors of cyclin D1 overexpression. Age, gender, recurrence of the tumor, multiplicity, and site of the lesions hold no statistically significant association with cyclin D1 expression on multivariate analysis. In summary, cyclin D1 overexpression was more prevalent in classic lesions and more advanced nodular stage. These findings raise the possibility of a different pathogenetic mechanism in the progression of AIDS-related KS and classic KS.

Highly active antiretroviral therapy in AIDS-associated Kaposi's sarcoma: implications for the design of therapeutic trials in patients with advanced, symptomatic Kaposi's sarcoma.

TO THE EDITOR: The article by Dr Krown provides very appropriate and timely considerations with regard to the management of patients with advanced, symptomatic, AIDS-related Kaposi’s sarcoma (AIDS-KS) in the era of highly active antiretroviral therapy (HAART) and suggests, on the basis of a comprehensive review of the literature, that in T1 (according to the AIDS Clinical Trials Group [ACTG] staging classification) symptomatic KS patients, concomitant chemotherapy should be added to HAART without awaiting a response to HAART. Moreover, the author, referencing our study, states that “T1 and T0 groupings have been associated with distinct survival distribution.” In response, we would like to clarify our data as reported by Dr Krown. We believe that our data may help to better define which group of patients within the T1 category need a timely institution of chemotherapy concomitantly to HAART, and for which group it is too risky to await a possible response to HAART. In our study, we collected clinical and survival data from 211 patients with AIDS-KS enrolled in two prospective cohort studies beginning in 1996, the time when HAART became available in Italy, with the aim of validating the ACTG staging system for AIDS-KS in the HAART era. All patients received HAART. Our analysis identified two different risk categories: a good-risk group (T0S0, T1S0, and T0S1) and a poor-risk group (T1S1). The 3-year survival rate of patients with T1S1 was 53%, significantly lower than the 3-year survival rates of patients with T0S0, T1S0, and T0S1, which were 88%, 80%, and 81%, respectively (P .0001). Therefore, the T category alone does not provide an appropriate survival discrimination, as occurred in the pre-HAART period. When we considered only patients with pulmonary involvement (namely,Tp1) as compared with T1 patients without pulmonary disease (namely,Tp0), the 3-year survival rate was 46% for Tp1 and 77% for Tp0 patients (P .0002), indicating that patients with pulmonary involvement identify the group of patients with the poorest prognosis, independent of the other ACTG variables. Therefore, we believe that we were able to identify, within the T1 category, a specific subgroup of KS patients (ie, T1S1, Tp1) with an unfavorable survival rate in whom HAART and concomitant chemotherapy should be used.

Treatment of AIDS-Related Kaposi’s Sarcoma: Response to Highly Active Antiretroviral Therapy and Chemotherapy

Treatment of AIDS-Related Kaposi’s Sarcoma: Response to Highly Active Antiretroviral Therapy and Chemotherapy