Topical treatment of cutaneous Kaposi sarcoma with imiquimod 5% in renal-transplant recipients: a clinicopathological observation

Kaposi sarcoma (KS) is a vascular neoplasm pathogenetically linked to human herpesvirus 8. Transplant recipients, in particular renal-transplant recipients (RTRs) are at higher risk for post-transplant (P)-KS which affects 0.2-11% of RTRs. The course of P-KS is influenced by the post-transplantation immunosuppressive treatment. Reduction of immunosuppressive drugs can result in tumour regression, and is the treatment of choice for P-KS, but is associated with the risk for transplant rejection. Imiquimod is a topically applied immunomodulator without relevant systemic absorption, and may thus represent a promising treatment for cutaneous KS in RTRs. The aim of this study was to investigate the clinical and histological effects of imiquimod in two RTRs with cutaneous KS. Imiquimod resulted in complete clinical and histologically proven remission in one patient, but in the second patient, although there was clinical remission, histological persistence of KS was found. Imiquimod may represent an effective treatment for RTRs with cutaneous P-KS. However, clinical remission does not necessarily indicate complete tumour regression, as shown in one of our patients, who had a persisting tumour, as shown by biopsy examination. Thus, histological confirmation is crucial to confirm complete response.     

Granulomas in acquired immunodeficiency syndrome‐associated cutaneous Kaposi sarcoma: evidence for a role for Mycobacterium tuberculosis

Background: Co‐lesional acquired immunodeficiency syndrome‐associated cutaneous Kaposi sarcoma (AIDS‐KS) and Mycobacterium tuberculosis‐associated granulomatous inflammation are undocumented. Method: Retrospective appraisal of skin biopsies with co‐lesional AIDS‐KS and microscopic tuberculosis (TB). Results: Sixteen biopsies from nine males and seven females form the study cohort. Histological assessment confirmed nodular and plaque KS in 12 and 4 cases each, respectively. Necrotizing, non‐necrotizing and a combination of necrotizing and non‐necrotizing granulomatous inflammation were present in nine, two and five biopsies each, respectively. The identification of acid fast bacilli on Ziehl‐Neelsen staining and M. tuberculosis on polymerase chain reaction confirmed co‐lesional TB in 15/16 biopsies. Co‐lesional AIDS‐KS and lichen scrofulosorum, hitherto undocumented, were confirmed in one biopsy. The histopathological findings served as a marker of human immunodeficiency virus (HIV) infection, visceral TB, therapeutic noncompliance and multidrug resistant pulmonary TB in nine, eight, five and one patient, respectively. M. tuberculosis was cultured from sputum or nodal tissue of all patients. Conclusion: Granulomatous inflammation in KS requires optimal histopathological and molecular investigation to confirm an M. tuberculosis origin. The cutaneous co‐lesional occurrence of AIDS‐KS and microscopic TB may serve as the sentinel clue to HIV infection, systemic TB, therapeutic noncompliance or multidrug resistant TB. Ramdial PK, Sing Y, Subrayan S, Calonje E, Aboobaker J, Sydney C, Sookdeo D, Ramburan A, Madiba TE. Granulomas in acquired immunodeficiency syndrome‐associated cutaneous Kaposi sarcoma: evidence for a role for Mycobacterium tuberculosis.     

9-cis-retinoic acid capsules in the treatment of AIDS-related Kaposi sarcoma: results of a phase 2 multicenter clinical trial

OBJECTIVE: To evaluate the safety, dose tolerance, and anti-tumor effects of 9-cis-retinoic acid in the treatment of Kaposi sarcoma (KS) related to acquired immunodeficiency syndrome (AIDS). DESIGN: Phase 2, open-label clinical trial of oral doses of 9-cis-retinoic acid increasing in 40-mg increments every 2 weeks from 60 mg/m(2) per day to a maximum of 140 mg/m( 2) per day. SETTING: Five hospital or health maintenance organization outpatient clinics. PATIENTS: Fifty-seven adult male patients with human immunodeficiency virus and biopsy-proven KS. MAIN OUTCOMES MEASURES: Safety was evaluated by adverse events, physical examination, laboratory test abnormalities, treatment-limiting toxic effects, and reasons for early withdrawal. Response (>/=50% improvement) was evaluated by an overall KS response and by the area and height from 6 index lesions selected at baseline. RESULTS: Patients tolerated 60 and 100 mg/m(2) per day. Most patients found 140 mg/m(2) per day intolerable owing to headache. Common treatment-related adverse events were headache, xerosis, rash, alopecia, and hyperlipemia. The patient response rate for the overall KS disease was 19% (11/57), including 1 patient with clinically complete response. The response rate assessed by measuring 6 index lesions during treatment was 39% (22/57). Sixteen responding patients (73%) were refractory to at least 1 previous anti-KS therapy. Patients with CD4( +) counts of 150 cells/ micro L or lower were as likely to respond as patients with counts of higher than 150 cells/ micro L. The median time to response was 8.5 weeks (range, 4.0-21.1 weeks). The median duration of treatment was 15.1 weeks (range, 0.14 to >/=62 weeks). CONCLUSION: 9-cis-retinoic acid capsules have moderate activity and provide durable responses, but substantial toxic effects at higher doses limit its suitability as an anti-KS therapy.     

The effects of human herpesvirus 8 infection and interferon-gamma response in cutaneous lesions of Kaposi sarcoma differ among human immunodeficiency virus-infected and uninfected individuals

Background Kaposi sarcoma (KS) is associated with human herpesvirus 8 (HHV‐8). The cutaneous immune response in this tumour is not well established and a better understanding is necessary. Objectives To evaluate the HHV‐8 expression and immune response in cutaneous lesions of classic KS (CKS) and AIDS‐associated KS (AIDS‐KS). Methods We performed a quantitative immunohistochemical study of cells expressing HHV‐8 latency‐associated nuclear antigen (LANA), CD4, CD8 and interferon (IFN)‐γ in skin lesions from patients with CKS and AIDS‐KS (with or without highly active antiretroviral therapy, HAART). Results CKS showed higher LANA expression compared with AIDS‐KS, regardless of HAART. We also found higher LANA expression in nodules compared with patch/plaque lesions. The tissue CD4+ cell proportion was lower in AIDS‐KS patients without HAART than in patients with CKS. In CKS lesions, CD4+ and CD8+ cells expressed IFN‐γ, as shown by double immunostaining. AIDS‐KS presented low numbers of IFN‐γ‐expressing cells. CD8+ cell numbers were similar in all groups, which appeared unrelated to the clinical or epidemiological type of KS. Conclusions Our quantitative data on the pattern of KS lesions in selected groups of patients, as shown by in situ immune response, demonstrated a CD4+ T‐cell involvement associated with IFN‐γ, an environment of immune response‐modified human immunodeficiency virus (HIV) infection. In our sample, the promotion of KS in patients without HIV appears to be related to higher HHV‐8 load or virulence than in those with AIDS. This higher resistance may be explained by a sustained immune response against this herpesvirus, that is only partially restored but effective after HAART.     

Radiotherapy of classic and human immunodeficiency virus-related Kaposi's sarcoma: results in 1482 lesions

Background The lesions of the various forms of Kaposi's sarcoma (KS), which are relatively radiosensitive, have been treated with different modalities of radiotherapy, with heterogeneous aims and results. Objective To verify the effectiveness and safety of radiotherapy on a large number of lesions endowed (classic KS) with a prolonged follow‐up. Methods A retrospective study was done on 711 lesions of classic KS and 771 lesions of human immunodeficiency virus (HIV)‐related KS, treated with traditional X‐ray therapy. Results In classic KS, a cure rate of 98.7% resulted after 13.5 years from the end of radiotherapy. In three lesions (0.42%) in the same patient, an acute radiodermatitis occurred after traumatic action. In HIV‐related KS, a complete remission was obtained in 91.43% of the lesions, partial remission in 6.74% and non‐response in 0.51% at 1 to 46 months from the end of radiotherapy. Conclusion Radiotherapy showed to be a safe and effective method, with relevant importance in the therapeutic strategy of KS.     

Endemic Kaposi's sarcoma in human immunodeficiency virus type 1-seronegative persons: demonstration of retrovirus-like particles in cutaneous lesions

In 1984, Greek physicians reported on the clustering of cases of Kaposi's sarcoma (KS) on the Peloponnesus peninsula. To gain more insight into its pathogenesis, we studied the seroepidemiologic and clinicopathologic characteristics of 12 Greek KS patients (eight male/four female) five of whom were residents of an endemic area on the Peloponnesus. These patients were in good general health with ages ranging from 48 to 80 years, had no clinical signs of immunodeficiency, and combined the features of both classic and epidemic KS in that they displayed not only involvement of acral areas but also widespread mucocutaneous lesions. Routine laboratory data were within normal limits; no patient had HTLV-1 and HIV-1/2 antibodies, but all patients had antibodies to several herpesviruses. The histopathology was characteristic of KS with the peculiar feature of a dense infiltrate composed predominantly of CD4+ T lymphocytes. Immunoenzymatic/morphologic studies of the KS cells were consistent with their origin from lymphatic endothelium. Outstanding ultrastructural findings were tubuloreticular structures and cylindrical confronting cisternae, structures that are indicative of an ongoing viral infection. Indeed, extensive electronmicroscopic studies resulted in the detection of retrovirus-like particles in close association to KS cells in five of 12 patients. This in situ observation opens the possibility that this retro-virus contributes to KS development.     

Bexarotene capsules and gel for previously treated patients with cutaneous T-cell lymphoma: results of the Australian patients treated on phase II trials

Bexarotene (Targretin, LGD1069) is a novel synthetic retinoid analogue that binds selectively to retinoid X receptors. We describe eight previously treated patients who entered phase II international multicentre studies examining the role of bexarotene in cutaneous T-cell lymphoma. Patients received either the oral formulation (n = 7) or the topical gel (n = 1). Of the seven patients who received 300 mg/m2 per day capsules, five (71%) achieved a partial response, with mean time to onset of response of 27 days (range, 20-29) with responses persisting for a mean of 92 days (range, 57-115). The single patient receiving the topical preparation (stage IB) remains in partial response at 31 months. The major toxicity with oral administration was hypertriglyceridaemia requiring therapy. Bexarotene capsules and gel are active and generally well-tolerated agents in patients with cutaneous T-cell lymphoma and studies examining its role in previously untreated patients or as part of combination therapy are warranted.     

Phase 1 and 2 trial of bexarotene gel for skin-directed treatment of patients with cutaneous T-cell lymphoma

OBJECTIVE: To evaluate the safety, dose tolerance, and efficacy of topical bexarotene gel in patients with early-stage cutaneous T-cell lymphoma (CTCL). DESIGN: Phase 1 and 2, open-label, dose-escalation clinical trial of bexarotene gel. SETTING: Three university-based clinics. PARTICIPANTS: Sixty-seven adults with early-stage (TNM stages IA-IIA) CTCL. INTERVENTIONS: Bexarotene gel, 0.1%, 0.5%, and 1.0%, applied in incremental dose adjustments from 0.1% gel every day to 1.0% gel 4 times daily or the maximal tolerated dose. MAIN OUTCOME MEASURES: Patients were followed for efficacy and safety, and treatment continued as long as they benefited. Response (> or =50% improvement) was evaluated by the Physician's Global Assessment of cutaneous disease and by an overall severity assessment of cutaneous disease, including signs of CTCL and area involved. RESULTS: Most patients tolerated topical bexarotene at 1% gel twice daily for routine use. Adverse events were generally mild to moderate in severity and were confined to treatment sites. Treatment-limiting toxic effects were associated with skin irritation and increased with gel exposure. Patients achieved an overall response rate of 63% and a clinical complete response rate of 21%. Median projected time to onset of response was 20.1 weeks (range, 4.0-86.0 weeks), and the estimated median response duration from the start of therapy was 99 weeks. Patients with no previous therapy for mycosis fungoides responded at a higher rate (75%) than those who previously underwent topical therapies (67%). CONCLUSIONS: Bexarotene gel was well tolerated, was easily self-applied, and had a substantial response rate in treating patients with early-stage CTCL.     

Acquired immunodeficiency syndrome-related oral and/or cutaneous histoplasmosis: a descriptive and comparative study of 21 cases in French Guiana

BACKGROUND: Oral or cutaneous acquired immunodeficiency syndrome (AIDS)-related histoplasmosis is a rare presentation of disseminated histoplasmosis. OBJECTIVE: To describe this clinical presentation and to compare it with other forms of AIDS-related disseminated histoplasmosis. METHODS: A cross-sectional study of patients with AIDS-related disseminated histoplasmosis was performed. CD4 counts and survival were compared between patients with oral or cutaneous histoplasmosis and patients with nonmucocutaneous disseminated histoplasmosis. RESULTS: The mean CD4 lymphocyte count was lower in patients with mucocutaneous lesions than in patients with nonmucocutaneous disseminated histoplasmosis (29 vs. 72/mm3, P = 0.002). The proportion of survivors 1 month after diagnosis did not differ significantly between the two groups (13/21 vs. 32/45, P = 0.4). At 6 months, the proportion of survivors was significantly lower for patients with mucocutaneous lesions (6/21 vs. 22/39, P = 0.03). CONCLUSIONS: These results suggest that mucocutaneous lesions occur at a later stage of human immunodeficiency virus infection, but are not, in themselves, associated with a higher level of mortality. The excess mortality at 6 months reflects deaths from other complications of severe immunodepression. This study confirms the polymorphism of mucocutaneous lesions, emphasizing the need for systematic testing for Histoplasma in all cases of mucocutaneous lesions in AIDS patients.     

Topical bexarotene therapy for patients with refractory or persistent early-stage cutaneous T-cell lymphoma: results of the phase III clinical trial

OBJECTIVES: We sought to determine the safety and efficacy of topical bexarotene (Targretin; Ligand Pharmaceuticals, La Jolla, Calif) gel 1% in patients with refractory or persistent early-stage cutaneous T-cell lymphoma. METHODS: We conducted a multinational, open-label, phase III study of 50 patients with stage IA to IIA cutaneous T-cell lymphoma. The primary end point classification was the overall complete and partial response rate by the higher of 2 measures: the Physician's Global Assessment of Clinical Condition or the Composite Assessment of Index Lesion Disease Severity. RESULTS: The overall response rates for the Physician's Global Assessment of Clinical Condition, Composite Assessment of Index Lesion Disease Severity, and primary end point classification were 44%, 46%, and 54%, respectively. The most common adverse events possibly related to study medication were mild to moderate irritant dermatitis, pruritus, pain (ie, primarily burning at application site), and skin disorder (eg, skin inflammation, excoriation, and new lesions). There were no serious treatment-related adverse events. CONCLUSIONS: Topical bexarotene gel was generally well tolerated and demonstrated substantial efficacy in patients with refractory or persistent early-stage cutaneous T-cell lymphoma.     

Topical 5-aminolaevulinic acid photodynamic therapy for cutaneous lesions: outcome and comparison of light sources

BACKGROUND: Topical 5-aminolaevulinic acid (ALA) photodynamic therapy (PDT) is increasingly used for superficial non-melanoma skin cancers and their precursors. METHODS: We report our 3-year experience of topical ALA-PDT, with a preliminary comparison of the effects of broadband and laser light sources. RESULTS: We performed 688 treatments on 483 lesions in 207 patients. Complete clearance was achieved in 222/239 lesions of Bowen's disease (BD), superficial basal cell carcinoma (sBCC) and actinic keratosis (AK) (93%) - 117/129 BD (91%), 84/87 sBCC (97%) and 21/23 AK (91%), with a median follow up of 48 weeks. Broadband and laser light sources were of similar efficacy. Recurrences have occurred in 10.3% BD, 4.8% sBCC and 4.8% AK. Adverse effects from PDT were uncommon but included pigmentary change (2%) and minor scarring (2%). How-ever, severe pain was experienced in 16-21% of treatments using the high-output broadband and laser sources, but in only 2% with the low-output xenon arc source. CONCLUSION: Topical ALA-PDT is effective for BD, sBCC and AK and has been an invaluable addition to our dermatology service. Efficacy is similar for broadband and laser light sources, although treatment at higher surface irradiance may be painful, and excellent cosmetic results can be achieved.     

Topical methotrexate 1% gel for treatment of vitiligo: A case report and review of the literature

Vitiligo is quite a common hypopigmentary disorder, which may affect both children and adults with important psychological effects due to the well‐known leopard skin‐like appearance. Even if asymptomatic and not life threatening, vitiligo has to be increasingly studied and treated. Hitherto, the efficacy of topical methotrexate in treatment of vitiligo has not been reported. We herein reporting our preliminary observation on the promising efficacy of topical methotrexate in one patient with stable vitiligo. The patient applied topical methotrexate 1% gel twice daily for 12 weeks. Significant improvement of the lesion with no local or systemic side effects were noted during the course of therapy. We propose that this well‐tolerated drug can be used for vitiligo therapy; however, further investigations should be performed to ascertain the exact topically effective dose.