Nicholas Francis

A double-blind, randomized controlled trial of the use of imiquimod cream for the treatment of anal canal high-grade anal intraepithelial neoplasia in HIV-positive MSM on HAART, with long-term follow-up data including the use of open-label imiquimod.

Objective:To determine whether imiquimod was more effective than placebo for the treatment of high-grade anal canal intraepithelial neoplasia (HG-ACIN). Design:Double-blind, randomized placebo-controlled clinical trial. Methods:Sixty-four HIV-positive patients were randomized to self-application of imiquimod cream or matched placebo into the anal canal three times a week for 4 months. Response was assessed by cytology, high-resolution anoscopy and biopsy 2 months after therapy. All patients who failed to resolve were offered treatment with open-label imiquimod for a further 4 months. Results:Fifty-three patients completed the study, of which 28 patients were on active drug and 25 patients on placebo. In the imiquimod group, four patients resolved and eight patients downgraded to low-grade squamous intraepithelial lesion (LSIL) with a median follow-up of 33 months. In the placebo group, one patient resolved. Imiquimod was significantly associated with a positive outcome (P = 0.003). Only one patient discontinued owing to side effects. Twenty-one patients entered a second open-label phase of treatment. Five of these patients cleared their anal canal intraepithelial neoplasia (ACIN) and four patients downgraded to LSIL. The overall mean duration of follow-up was 36 months. During this extended follow-up period, 61% have exhibited sustained absence of high-grade squamous intraepithelial lesion (HSIL). Conclusion:This study demonstrates the effectiveness of imiquimod for the treatment of ACIN, and the benefit of prolonged or repeated treatments. This form of therapy is likely to be especially valuable for patients with widespread multifocal ACIN who are otherwise difficult to treat, and should be considered as an adjunct to ablative therapy.

Intestinal inflammation, ileal structure and function in HIV

Objectives:This study examines small intestinal absorption–permeability, intestinal inflammation and ileal structure and function in HIV-positive male homosexuals. Methods:Thirty HIV-seropositive male homosexuals at various stages of disease underwent intestinal absorption–permeability and 111indium leukocyte studies (for quantification of intestinal inflammation). Twenty-six men with AIDS had a dual radio-isotopic ileal function test (whole body retention of tauro 23-[75Se]-selena 25-homocholic acid and 58cobalt-labelled cyanocobalamine), and 17 underwent ileocolonoscopy with terminal ileal biopsy. Results:Well, HIV-infected, subjects had normal intestinal absorption–permeability, but both functions were impaired upon the development of AIDS. The median faecal excretion of 111 indium in well patients (0.66%) did not differ significantly (P > 0.5) from controls (0.46%), but subjects with AIDS who were well or who had diarrhoea had significant (P < 0.005) intestinal inflammation (1.33% and 2.18%, respectively). The median 7-day retention of tauro 23-[75Se]-selena 25-homocholic acid in well patients with AIDS (38.9%) did not differ significantly (P > 0.2) from controls (39.3%), whereas the absorption of 58cobalt-labelled cyanocobalamine was significantly (P < 0.05) lower than controls (32.1% and 59.4%). Patients with AIDS-diarrhoea had significant (P < 0.001) malabsorption of both the bile acid (7.7%) and vitamin B12 (8.9%) which was more severe than in Crohns ileitis (14.2% and 30.3%, respectively). Morphometric analyses of ileal biopsies were unremarkable in AIDS. Conclusions:These studies demonstrate a low-grade enteropathy in patients with AIDS, severe ileal malabsorption in patients with AIDS diarrhoea and relatively minor ileal morphologic changes. Malabsorption of bile acids may play a pathogenic role in patients with AIDS and diarrhoea.

The effect of HAART in 254 consecutive patients with AIDS-related Kaposi's sarcoma.

Objective:A prospective cohort study was performed to evaluate the clinical outcomes of patients with histologically confirmed AIDS-related Kaposis sarcoma diagnosed since the introduction of HAART. Methods:Two hundred and fifty-four consecutive patients (96% men) diagnosed with Kaposis sarcoma between 1996 and 2008 are included. Clinicopathological and treatment details were prospectively collected. The median follow-up is over 4 years and maximum 12 years. Results:The mean age at Kaposis sarcoma diagnosis was 39 years and average duration of known HIV seropositivity was 4 years. At Kaposis sarcoma diagnosis, only 19% patients were on HAART and only 7% patients had an undetectable plasma HIV viral load. Seventy-nine (31%) patients had AIDS clinical Trial Group stage T1 disease at Kaposis sarcoma diagnosis and 122 (48%) had AIDS clinical Trial Group stage I1 disease (CD4 cell count < 150 cells/μl). Nodular grade Kaposis sarcoma represented 28% of the tumours and was significantly associated with black African ethnicity and AIDS clinical Trial Group T1 stage disease. The overall 5-year survival is 89% (95% confidence interval 84–93). One hundred and sixty-three patients were treated with HAART alone for T0 stage Kaposis sarcoma; only one died of Kaposis sarcoma and only 37 (22%) required chemotherapy, giving a systemic treatment-free survival at 5 years of 74% (95% confidence interval 67–82) and the overall survival at 5 years is 91% (95% confidence interval 87–95). Conclusion:The high success rate of HAART in a large cohort of AIDS–Kaposis sarcoma patients over a prolonged period of follow-up will reassure patients and clinicians that this is a well tolerated and effective approach to stage T0 Kaposis sarcoma.

Cutaneous manifestations of mycobacterial infection in patients with AIDS

Summary We report three cases of mycobacterial infection of the skin in HIV‐positive individuals, in whom the diagnosis was not suspected until microbiological and histological investigations were performed.

Contribution of focal haemorrhage and microvascular fibrin deposition to fatal envenoming by Russell's viper (Vipera russelli siamensis) in Burma.

In Burma, clinicopathological studies were carried out in three young farmers who died 15, 52 and 36 h after being bitten by Russells vipers. Clinical features included local swelling, spontaneous systemic bleeding, defibrination, shock, cardiac arrhythmia, hypoglycaemia, coma and oliguria. On admission to hospital, 15, 48 and 21 h after the bites, serum venom antigen concentrations ranged from 50 to 130 ng/ml. Autopsies revealed widespread congestion and bleeding in the lungs, gastrointestinal and renal tracts, adrenals, heart, brain and anterior pituitary. There was histopathological evidence of focal haemorrhage and fibrin deposition at the site of the bite and in the pituitary, lungs and kidneys and acute tubular necrosis. Deposition of fibrin microthrombi results from the action of venom procoagulants. Shock was attributed to increased capillary permeability, revealed clinically by conjunctival oedema. Acute pituitary/adrenal failure in one case was explained by fibrin deposition and haemorrhage in the anterior pituitary--resembling Sheehans syndrome. Acute tubular necrosis resulted from ischaemia caused by fibrin deposition and to prerenal factors. An intractable cardiac tachyarrhythmia may have been caused by subendocardial and myocardial haemorrhages.

High-resolution anoscopy screening of HIV-positive MSM: longitudinal results from a pilot study.

Background:The ability to detect and treat pre-malignant anal lesions suggests screening may prevent anal cancer. The incidence of anal cancer in men who have sex with men (MSM) living with HIV exceeds that of cervical cancer before screening was introduced. Methods:High-resolution anoscopy (HRA) with intervention for high-grade squamous intraepithelial lesions (HSILs) was offered to asymptomatic HIV-positive MSM. Patients with HSILs were treated and follow-up HRA performed after 6 months, whilst patients with low-grade squamous intraepithelial lesions had a repeat HRA after 12 months. Results:Three hundred and sixty-eight asymptomatic MSM had a total of 1497 HRAs during a median follow-up of 4.2 years (maximum 13 years). At first HRA, 36% had normal appearances, 16% had no dysplasia, 15% anal intraepithelial neoplasia (AIN)-1, 19% AIN-2 and 13% AIN-3. During follow-up, five patients (1.4%) developed invasive anal cancer (incidence 2.7 per 1000 person-years). The 5-year cancer rate for the 368 patients was 0.3% [95% confidence interval (CI) 0–0.6%]. Progression to cancer was associated with higher age (P = 0.049) and AIN-3 (P = 0.024). Ninety patients had AIN-3 present at least at one HRA. The cumulative risk of cancer from first AIN-3 diagnosis was 3.2% (95% CI 0–7.8%) at 5 years. One hundred and seventy-one patients had HSILs (AIN-2 or 3) present at least once. The cumulative risk of cancer from first HSIL diagnosis was 0.6% (95% CI 0–1.8%) at 5 years. Conclusion:AIN-3 is a significant risk factor for subsequent anal cancer, although the tumours detected in screened patients were small localized, and generally the outcomes were favourable.

Gene expression profiling in male genital lichen sclerosus

Male genital lichen sclerosus (MGLSc) has a bimodal distribution in boys and men. It is associated with squamous cell carcinoma (SCC). The pathogenesis of MGLSc is unknown. HPV and autoimmune mechanisms have been mooted. Anti extracellular matrix protein (ECM)1 antibodies have been identified in women with GLSc. The gene expression pattern of LSc is unknown. Using DNA microarrays we studied differences in gene expression in healthy and diseased prepuces obtained at circumcision in adult males with MGLSc (n = 4), paediatric LSc (n = 2) and normal healthy paediatric foreskin (n = 4). In adult samples 51 genes with significantly increased expression and 87 genes with significantly reduced expression were identified; paediatric samples revealed 190 genes with significantly increased expression and 148 genes with significantly reduced expression. Concordance of expression profiles between adult and paediatric samples indicates the same disease process. Functional analysis revealed increased expression in the adult and child MGSLc samples in the immune response/cellular defence gene ontology (GO) category and reduced expression in other categories including genes related to squamous cancer. No specific HPV, autoimmune or squamous carcinogenesis‐associated gene expression patterns were found. ECM1 and CABLES1 expression were significantly reduced in paediatric and adult samples respectively.

Fatal toxic epidermal necrolysis due to lansoprazole

Toxic epidermal necrolysis (TEN) is a serious cutaneous reaction and is most commonly drug induced. It is associated with significant morbidity and mortality. We describe a patient who developed fatal TEN after re‐exposure to lansoprazole. Three years previously he presented with erythema multiforme due to the same drug. To our knowledge this is the first published report of TEN occurring with lansoprazole.

Elevated Mucosal Addressin Cell Adhesion Molecule-1 Expression in Acquired Immunodeficiency Syndrome Is Maintained during Antiretroviral Therapy by Intestinal Pathogens and Coincides with Increased Duodenal CD4 T Cell Densities

Reduced intestinal CD4 T cell numbers and gastrointestinal disease are common features of acquired immunodeficiency syndrome (AIDS). Duodenal lymphocyte densities and mucosal addressin cell adhesion molecule (MAdCAM)-1 expression were analyzed in patients with AIDS after highly active antiretroviral therapy (HAART). Compared with human immunodeficiency virus (HIV)-seronegative individuals, HAART-naive patients with AIDS displayed reduced duodenal CD4 T cell densities. After HAART, AIDS patients with opportunistic intestinal pathogens displayed greater increases in duodenal lamina propria (LP) CD4 T cell densities than patients without such infections. Duodenal MAdCAM-1 expression was elevated in all HAART-naive patients with AIDS but remained elevated only in the intestinal pathogen group after HAART. The data suggest that, in HIV-1 infection, lymphocyte migration to the intestine may be promoted by increased MAdCAM-1 expression. After HAART, opportunistic intestinal pathogens maintain elevated MAdCAM-1 expression, which results in prominent increases in LP CD4 T cell densities in the absence of HIV-mediated CD4 T cell destruction.

Clinico-pathological features of relapsing very thin melanoma.

In the UK the incidence of malignant melanoma is increasing and more patients with thinner primary lesions are diagnosed earlier. Most patients with very thin melanoma (< 0.76 mm Breslow thickness) are cured by surgical excision, however, 2–18% relapse over 0–11 years with local or distant metastatic disease and may die. There are still no recognized prognostic or predictive, clinical, serological or molecular markers that accurately determine which of these very thin melanoma will relapse: the Breslow thickness remains the single most important prognostic factor for melanoma in general. Improved prognostic indicators are therefore needed for this rare, but important, unusually aggressive group, to better direct new invasive and expensive investigations and treatment. This article reviews the clinical and histological aspects of relapsing very thin melanoma and discusses the findings of several recent studies, including our own. There is no clinical or biological evidence to support either wide surgical excision or sentinel node biopsy in these patients.