Erythroderma (exfoliative dermatitis). Part 1: underlying causes, clinical presentation and pathogenesis.

Erythroderma (exfoliative dermatitis), first described by Von Hebra in 1868, manifests as a cutaneous inflammatory state, with associated skin barrier and metabolic dysfunctions. The annual incidence of erythroderma is estimated to be 1-2 per 100 000 population in Europe with a male preponderance. Erythroderma may present at birth, or may develop acutely or insidiously (due to progression of an underlying primary pathology, including malignancy). Although there is a broad range of diseases that associate with erythroderma, the vast majority of cases result from pre-existing and chronic dermatoses. In the first part of this two-part concise review, we explore the underlying causes, clinical presentation, pathogenesis and investigation of erythroderma, and suggest potential treatment targets for erythroderma with unknown causes.

Propensity Score Analysis of an Enhanced Recovery Programme in Upper Gastrointestinal Cancer Surgery.

INTRODUCTION: The aim of this study was to examine the influence of an enhanced recovery programme (ERP) on outcomes of upper gastrointestinal (UGI) cancer surgery by means of propensity score-matched analysis. METHODS: Three hundred consecutive patients diagnosed with UGI cancer were studied prospectively before and after the introduction of an ERP. Multiple regression models, including propensity scores, were developed to assess confounding variables associated with undergoing surgery, and the risk adjusted association between treatment and length of hospital stay (LOHS). RESULTS: After regression for confounding factors, a cohort of 252 patients was available of whom 160 received ERP [median age 66 years (IQR 58-73), 119 male, 81 oesophageal, 79 gastric cancer] and 92 control [66 years (IQR 58-74), 74 male, 58 oesophageal, 34 gastric cancer]. ERP operative morbidity (Clavien-Dindo ≥3) and mortality were 13.8 and 3.1 % compared with 17.4 (p = 0.449) and 2.2 % (p = 0.658) in controls. Median ERP critical care and total LOS were 1 (IQR 0-1) and 13 (IQR 10-17) days, compared with 1 (IQR 1-2, p = 0.009) and 16 (IQR 13-26, p < 0.001) days. Multivariable analysis revealed ERP (HR 1.477, 95 % CI 1.084-2.013, p = 0.013), tumour location (HR 2.420, 95 % CI 1.624-3.606, p < 0.001), operative procedure (HR 1.143, 95 % CI 1.032-1.265, p = 0.010), and operative morbidity (HR 0.277, 95 % CI 0.179-0.429, p < 0.001) to be associated with LOHS. CONCLUSION: An ERP in UGI cancer surgery was feasible, safe, and effective.

Five-year recurrence rate of lentigo maligna after treatment with imiquimod.

BACKGROUND: The current recommended treatment for lentigo maligna (LM) is surgical resection, which can cause significant scarring. The reported recurrence rate after Mohs micrographic surgery is 0-6·25%. There is little published data on long-term outcome after imiquimod therapy. Several reports record progression to LM melanoma during treatment. Clinical assessment of clearance is difficult. Histological confirmation is preferred but risks sampling error and missing areas of invasion. Confocal microscopy can be used to assess entire lesions. OBJECTIVES: To assess the 5-year recurrence rate of LM after imiquimod treatment. METHODS: Forty patients with LM were treated with imiquimod between 2002 and 2007. Their previous treatments included cryotherapy, incomplete surgical excision and radiotherapy. All applied imiquimod three times per week for 6 weeks; 25 (62·5%) experienced inflammation. The other 15 (37·5%) then applied imiquimod five times per week for a further 4 weeks; all experienced inflammation. All patients were subsequently examined and biopsied. Clinical clearance did not always correlate with histological clearance. Eleven patients (27·5%) had residual LM on histology and underwent surgical excision. At the time of this study, three patients had died (deaths were unrelated to LM). Eighteen of the 27 patients (66·7%) who were clear on biopsy after imiquimod attended for the study and were assessed using confocal microscopy (Vivascope 1500 and 3000). RESULTS: The recurrence rate of LM in patients who were clear on histology after imiquimod treatment who attended for this follow-up study was 0% (n = 18). CONCLUSIONS: Imiquimod is an effective long-term treatment for LM. Its use avoids potentially disfiguring surgical resection.

Dermatofibrosarcoma protuberans: 35 patients treated with Mohs micrographic surgery using paraffin sections.

BACKGROUND: Dermatofibrosarcoma protuberans (DFSP) has conventionally been treated with wide local excision. More recently Mohs micrographic surgery (MMS) has been advocated. OBJECTIVES: To assess our departmental experience with DFSP in the context of a literature review relating to DFSP treated with MMS. METHODS: This was a case review of 35 patients with DFSP treated between 1998 and 2009 with MMS using paraffin-embedded sections. RESULTS: Seventeen patients required one horizontal layer to clear their tumour, 10 patients needed two and eight patients needed three layers or more. The median preoperative clinical size was 6 cm(2) (range 0·75-54·8) and the median postoperative wound size was 46·8 cm(2) (range 4-145·2). Tumour persistence has not been observed in any of our patients after a median follow-up duration of 29·5 months (range 6-146). CONCLUSIONS: We present 35 DFSP patients, none of whom showed persistent tumour after treatment with 'slow' MMS using paraffin sections. We advocate MMS as the treatment of choice for DFSP, especially for tumours over the head and neck region where tissue conservation is particularly important.

Pharmacokinetic mapping for lesion classification in dynamic breast MRI.

PURPOSE: To prospectively investigate whether a rapid dynamic MRI protocol, in conjunction with pharmacokinetic modeling, could provide diagnostically useful information for discriminating biopsy-proven benign lesions from malignancies. MATERIALS AND METHODS: Patients referred to breast biopsy based on suspicious screening findings were eligible. After anatomic imaging, patients were scanned using a dynamic protocol with complete bilateral breast coverage. Maps of pharmacokinetic parameters representing transfer constant (K(trans)), efflux rate constant (k(ep)), blood plasma volume fraction (v(p)), and extracellular extravascular volume fraction (v(e)) were averaged over lesions and used, with biopsy results, to generate receiver operating characteristic curves for linear classifiers using one, two, or three parameters. RESULTS: Biopsy and imaging results were obtained from 93 lesions in 74 of 78 study patients. Classification based on K(trans) and k(ep) gave the greatest accuracy, with an area under the receiver operating characteristic curve of 0.915, sensitivity of 91%, and specificity of 85%, compared with values of 88% and 68%, respectively, obtained in a recent study of clinical breast MRI in a similar patient population. CONCLUSION: Pharmacokinetic classification of breast lesions is practical on modern MRI hardware and provides significant accuracy for identification of malignancies. Sensitivity of a two-parameter linear classifier is comparable to that reported in a recent multicenter study of clinical breast MRI, while specificity is significantly higher.

Aberrant expression of CD19 in AML with t(8;21) involves a poised chromatin structure and PAX5.

Correct hematopoietic differentiation requires the tightly regulated execution of lineage-specific and stage-restricted gene expression programs. This process is disturbed in hematological malignancies that typically show incomplete differentiation but often also display a mixed lineage phenotype. Co-expression of lymphoid and myeloid molecules is a well-known feature of acute myeloblastic leukemia (AML) with t(8;21). These cells consistently express the B-cell-specific transcription factor PAX5, and the B-cell-specific cell surface protein CD19. However, the functional consequences of PAX5 expression are unknown. To address this question, we studied the chromatin features of CD19, which is a direct target of PAX5 in cells with and without the t(8;21) chromosomal translocation. We show that CD19 chromatin exists in a poised configuration in myeloid progenitors and that this poised chromatin structure facilitates PAX5-dependent CD19 activation. Our results also show a positive correlation between PAX5 and CD19 expression in t(8;21)-positive AML cells and demonstrate that PAX5 binds to the promoter and enhancer of CD19 gene and remodels chromatin structure at the promoter. This study shows that expression of PAX5 in leukemic cells has functional consequences and points to an important role of a progenitor-specific chromatin configuration in myeloid leukemia.

Self-complementary AAV-mediated gene therapy restores cone function and prevents cone degeneration in two models of Rpe65 deficiency.

To test whether fast-acting, self-complimentary (sc), adeno-associated virus-mediated RPE65 expression prevents cone degeneration and/or restores cone function, we studied two mouse lines: the Rpe65-deficient rd12 mouse and the Rpe65-deficient, rhodopsin null ('that is, cone function-only') Rpe65(-/-)::Rho(-/-) mouse. scAAV5 expressing RPE65 was injected subretinally into one eye of rd12 and Rpe65(-/-)::Rho(-/-) mice at postnatal day 14 (P14). Contralateral rd12 eyes were injected later, at P35. Rd12 behavioral testing revealed that rod vision loss was prevented with either P14 or P35 treatment, whereas cone vision was only detected after P14 treatment. Consistent with this observation, P35 treatment only restored rod electroretinogram (ERG) signals, a result likely due to reduced cone densities at this time point. For Rpe65(-/-)::Rho(-/-) mice in which there is no confounding rod contribution to the ERG signal, cone cells and cone-mediated ERGs were also maintained with treatment at P14. This work establishes that a self-complimentary AAV5 vector can restore substantial visual function in two genetically distinct models of Rpe65 deficiency within 4 days of treatment. In addition, this therapy prevents cone degeneration but only if administered before extensive cone degeneration, thus supporting continuation of current Leber's congenital amaurosis-2 clinical trials with an added emphasis on cone subtype analysis and early intervention.

Imiquimod and lentigo maligna: a search for prognostic features in a clinicopathological study with long-term follow-up.

BACKGROUND: Melanoma in situ/lentigo maligna (LM) is a potential precursor of LM melanoma. It occurs most commonly in elderly individuals on sun-exposed skin of the head and neck. Although surgical excision is the treatment of choice, this may not be desirable or feasible for large lesions at functionally or cosmetically important sites. Imiquimod is a topical immunomodulator which can generate a local cytotoxic response with potentially antiviral and antitumour effects. OBJECTIVES: To present our experience of LM treated with imiquimod. METHODS: A retrospective review was performed of all patients with facial LM treated in our unit with topical imiquimod between January 2001 and December 2006. Pretreatment diagnostic biopsies were also reviewed and histologically graded. RESULTS: Forty-eight patients were treated with imiquimod. There were 37 responders and 11 treatment failures (of whom two were 'partial responders'). Of the 37 responders, 31 showed a clinical inflammatory response to imiquimod. One patient in whom treatment failed subsequently developed invasive disease. The mean follow-up duration was 49 months. We could not identify histological features of prognostic significance. However, the ability to develop an inflammatory reaction to imiquimod was a strong predictor of therapeutic benefit. CONCLUSIONS: We consider imiquimod to have a role in the treatment of LM in patients in whom surgery may be contraindicated or for those in whom the cosmetic or functional consequences may be considerable. Until better characterized, its use should probably be confined to centres with experience in the detection and treatment of LM and melanoma.

Fatal peri-operative acute tumour lysis syndrome precipitated by dexamethasone.

A 3-year-old patient presented for elective adenotonsillectomy to treat symptomatic obstructive sleep apnoea. The patient had not been assessed at a pre-operative anaesthesia clinic but had undergone uneventful general anaesthesia twice in the previous two years. An uneventful operative course was complicated by the development of clinical instability over the first 6 h postoperatively culminating in cardiorespiratory arrest. Subsequent investigation demonstrated the acute development of tumour lysis syndrome in the setting of a new onset, undiagnosed acute leukaemia. The patient died on the third postoperative day. The use of dexamethasone for prophylaxis against postoperative nausea and vomiting was the likely aetiology of the acute tumour lysis syndrome in this case. This is the first documented peri-operative death due to tumour lysis syndrome after administration of dexamethasone. We discuss the various problems encountered with this case and review the recent literature and case reports on tumour lysis syndrome in the operating theatre.

Linear basal cell carcinoma: A distinct clinical entity.

The purpose of the study is to describe linear basal cell carcinoma (BCC) as a distinct clinical entity, and highlight its existence to the plastic surgery literature. A Medline and PubMed literature search was conducted, and 33 reported cases of linear BCC were analysed. Of these 33 cases, the most common site for linear BCC was the periocular region, accounting for 49% (n= 16). The most common histologic subtype, was nodular BCC, accounting for 50% (n= 17). Of the 33 reported cases the postoperative defect size was mentioned in five cases only. None of these would have been completely excised if a 2 mm margin was applied, and only one out of five if a 4 mm margin was applied. Linear BCC is a distinct clinical entity. Presence of the tumour along relaxing skin tension lines, increase in subclinical extension, and aggressive tumour behavior are reported observations. Because of these observations it is suggested that margin-controlled excision should be considered for linear BCC.

Laser remodelling of nodular nasal lupus pernio.

Disfiguring nodular nasal lupus pernio is a rare condition that responds poorly to medical management. We have treated three affected patients with carbon dioxide laser remodelling, and report their progress 6 years, 2 years and 16 months following treatment, respectively. Although the abnormal granulomatous tissue was debulked rather than completely excised, the wounds healed within 4 weeks in all patients. The cosmetic results are acceptable and have been maintained in two of the patients, perhaps a reflection of their overall systemic sarcoidosis control.

Topical imiquimod immunotherapy in the management of lentigo maligna.

Melanoma in situ of the lentigo maligna (LM) type is a precursor lesion of LM melanoma. It most commonly occurs in elderly individuals, on the head and neck. Although surgical excision is recommended, this may not be practical for large lesions at cosmetically sensitive sites. In addition, histological changes commonly extend beyond the clinical margins of the lesion. This study describes the use of imiquimod 5% cream as topical immunotherapy in the management of lentigo maligna. Twelve patients (average age 63 years, 10 female), of biopsy-proven facial LM were treated with topical imiquimod, three times a week for 6 weeks. In the absence of an inflammatory response, patients were asked to apply the treatment daily. Seven showed clearance of the LM clinically and histologically. A further three patients showed clearance histologically with persisting pigmentation due to dermal melanin and melanophages. Thus, 10 of 12 patients cleared with no relapse after a median follow-up of 6 months. Two patients failed to respond to imiquimod and their lesions were treated with surgical excision. Imiquimod was well tolerated, except in three patients who experienced an intense inflammatory response. Two of these also developed secondary infection. Imiquimod 5% cream appears to offer a potential noninvasive method for the treatment of lentigo maligna.

Treatment of Darier's disease with photodynamic therapy.

BACKGROUND: Photodynamic therapy (PDT) using topical 5-aminolaevulinic acid (5-ALA) as a photosensitizer has been reported in the treatment of both neoplastic and benign cutaneous disorders. OBJECTIVES: To evaluate the efficacy of photodynamic therapy in selected patients with Darier's disease (keratosis follicularis). METHODS: Six patients with Darier's disease were assessed before and after treatment with PDT using 5-ALA and mean fluence rates of 110-150 mW cm-2. RESULTS: Of the six patients, one was unable to tolerate the treatment. Of the remaining five, all experienced an initial inflammatory response that lasted two to three weeks. In four of the five patients, this was followed by sustained clearance or improvement over a followup period of six months to three years. Three of these four patients were on systemic retinoids and the fourth had discontinued acitretin prior to PDT. In the fifth patient partial improvement was followed by recurrence after etretinate therapy was discontinued. Biopsy specimens taken immediately after the procedure in two patients demonstrated a mild inflammatory cell infiltrate in the dermis. A biopsy obtained eighteen months after PDT from a successfully treated area showed no signs of Darier's disease and a subtle increase of collagen in the upper dermis. CONCLUSIONS: Photodynamic therapy can be viewed as a potential adjunctive modality for Darier's disease but should not be considered as a substitute for retinoids in patients who require systemic treatment.

Nonablative laser resurfacing: a systematic review of the literature.

'Nonablative laser resurfacing' is a new treatment for photoaged skin, the aim of which is to wound the upper dermis in order to induce dermal fibrosis and improve the clinical appearance. Unlike conventional laser resurfacing or dermabrasion, the epidermis is protected and retained to avoid the problems associated with open wounds and reepithelialization. A number of lasers and light sources have been developed or adapted for this purpose.