Jürg Hafner

Uremic small-artery disease with medial calcification and intimal hyperplasia (so-called calciphylaxis): A complication of chronic renal failure and benefit from parathyroidectomy

BACKGROUND Uremic small-artery disease with medial calcification and intimal hyperplasia can lead to life-threatening skin necrosis or acral gangrene. It is a distinct complication of chronic renal failure that must be differentiated from soft-tissue calcification. An increased calcium-phosphate product and secondary hyperparathyroidism are the main underlying conditions. The benefit of parathyroidectomy is controversial. OBJECTIVE This article is based on a literature search to determine prognostic factors and, in particular, the benefit of parathyroidectomy. METHODS The literature on uremic small-artery disease (so-called calciphylaxis) was reviewed (full data set: 104 cases, including five of our own). The therapeutic benefit of parathyroidectomy and the relation between prognostic predictors (localization, dialysis, and transplant) and outcome were analyzed. The relation between diabetes and acral gangrene was also examined. Further epidemiologic data on the reviewed group of patients were established. RESULTS Thirty-eight of 58 patients who underwent parathyroidectomy survived compared with 13 of 37 patients who did not undergo parathyroidectomy (p = 0.007, n = 95). Forty of 53 patients with distal localization of necrosis survived compared with 11 of 42 patients with proximal pattern (p < 0.00001; n = 95). Dialysis and kidney transplantation followed by immunosuppression showed no relation to disease outcome. No association was found between diabetes and acral gangrene (p = 0.50). CONCLUSION Uremic small-artery disease is a distinct complication of chronic renal failure. Its recognition and early diagnosis should allow more effective treatment. In our retrospective study parathyroidectomy was significantly related to survival. Only a randomized, controlled, prospective trial (parathyroidectomy vs conservative treatment of secondary hyperparathyroidism) can establish the value of parathyroidectomy in uremic small-artery disease.

Topical photodynamic therapy in the treatment of actinic keratoses and Bowen’s disease in transplant recipients

Background. Transplant recipients (TR) have a dramatically increased risk for widespread epithelial neoplasms of the skin. Thus, there is a need to treat initial stages of these neoplasms such as actinic keratoses (AK) and Bowen’s disease (BD) to prevent progression to invasive and potentially fatal squamous cell carcinoma. Topical photodynamic therapy (PDT) has been proven to be an effective treatment for AK and BD in immunocompetent patients, but no prospective trials in immunocompromised TR have been performed so far. Methods. Twenty TR and 20 controls with histologically confirmed AK or BD underwent either a single or two consecutive treatments of topical PDT in an open trial. The application of 20% 5-aminolevulinic acid (ALA) for 5 hours was followed by illumination with 75 J/cm2 of visible light delivered at 80 mW/cm2 by an incoherent light source. Results. The overall complete response rates in TR at 4, 12, and 48 weeks were 0.86, 0.68, and 0.48, respectively. The cure rates in both patient groups were comparable at 4 weeks but were significantly lower in TR than in controls at 12 and 48 weeks (P <0.05). Side effects included erythema, edema, and crust formation after illumination. Cosmetic results were excellent without scar formation or alterations in pigmentation. Conclusions. Topical PDT with 20% 5-ALA is an effective and safe treatment for AK and BD in immunosuppressed TR, with initial response rates comparable with those in immunocompetent patients. It is particularly useful in TR because of the possibility for repeated treatment of large lesional areas.

A randomized controlled clinical trial of topical photodynamic therapy with methyl aminolaevulinate in the treatment of actinic keratoses in transplant recipients.

Background  Transplant recipients have an increased propensity to develop multiple actinic keratoses, which demonstrate an increased transformation rate into invasive squamous cell carcinoma.

An autologous epidermal equivalent tissue-engineered from follicular outer root sheath keratinocytes is as effective as split-thickness skin autograft in recalcitrant vascular leg ulcers

The outer root sheath of hair follicles plays an important role in epidermal regeneration in vivo. Keratinocytes isolated by explantation of outer root sheath tissue have extensive proliferative capacity irrespective of donor age, which probably depends on pluripotent epithelial stem cells residing in the outer root sheath. These keratinocytes can be organotypically grown to epidermal equivalents in vitro. We report here that in a multicenter, randomized phase II study, EpiDex™, a tissue‐engineered, fully differentiated autologous epidermal equivalent derived from keratinocytes of the outer root sheath of plucked anagen hair follicles, is as effective as split‐thickness skin autografting in the promotion of healing and complete closure of recalcitrant vascular leg ulcers. (WOUND REP REG 2003;11:248–252)

Baseline staging in cutaneous malignant melanoma.

Background  Baseline staging in patients with primary cutaneous malignant melanoma (MM) is routine, but the diagnostic accuracy and the impact on clinical outcome are still unclear.

Squamous cell carcinoma of the skin shows a distinct microRNA profile modulated by UV radiation.

investigated CHR expression in mast cells just in vicinity of eccrine glands. Serial sections were alternatively stained with toluidine blue and with anti-CHRM3 antibody. Mast cells were identified by positive toluidine blue staining (Figure 2c, upper panel), and CHRM3 expression by mast cells was examined in the antibody-stained adjacent sections (Figure 2c, lower panel). In a normal control, mast cells expressed CHRM3 at high levels. Mast cells in conjunction with the secretory portion expressed CHRM3 in the hypohidrotic but not anhidrotic areas. There was no significant difference in the number of mast cells between the anhidrotic and hypohidrotic areas. Our study revealed that the skin of patients with CUAH is divided into the wheal-non-occuring anhidrotic and wheal-occuring hypohidrotic areas. Even in the hypohidrotic areas, the intradermal injection of autologous sweat did not yield wheal, suggesting the absence of sweat allergy (Tsuchiya et al., 2004). We found the lack of CHRM3 expression in the anhidrotic skin, which may lead to the lack of sensitivity to acetylcholine. Mast cells are responsible for wheal formation and present just in the vicinity of eccrine glands. Neither eccrine gland cells nor mast cells expressed CHRM3 in the anhidrotic area, and it is thus reasonable that sweating and wheal formation were absent in this area. CHR mediates wheal development (Tong et al., 1997), and acetylcholine can induce degranulation of mast cells (Fantozzi et al., 1978; Blandina et al., 1980). In the hypohidrotic area, we are tempting to speculate that acetylcholine released from nerves upon exercise cannot be completely trapped by CHR of eccrine glands and overflows to the adjacent mast cells. In this scenario, mast cells may be capable of producing histamine and resultant wheal in response to acetylcholine because of the expression of some degree of CHRM3.

Autologous cultured keratinocytes on porcine gelatin microbeads effectively heal chronic venous leg ulcers

We have established a specific bioreactor microcarrier cell culture system using porcine gelatin microbeads as carriers to produce autologous keratinocytes on a large scale. Moreover, we have shown that autologous keratinocytes can be cultured on porcine collagen pads, thereby forming a single cell layer. The objective of this study was to compare efficacy and safety of autologous cultured keratinocytes on microbeads and collagen pads in the treatment of chronic wounds. Fifteen patients with recalcitrant venous leg ulcers were assigned to three groups in a single‐center, prospective, uncontrolled study: five underwent a single treatment with keratinocyte monolayers on collagen pads (group 1); another five received a single grafting with keratinocyte‐microbeads (group 2); and the last five received multiple, consecutive applications of keratinocyte‐microbeads 3 days apart (group 3). All patients were followed for up to 12 weeks. By 12 weeks, there was a mean reduction in the initial wound area of 50, 83, and 97 percent in the three groups, respectively. The changes in wound size were statistically significant between the first and third groups (p= 0.0003). Keratinocyte‐microbeads proved to be more effective than keratinocyte monolayers on collagen pads when the former were applied every 3 days. Rapid availability within 10–13 days after skin biopsy and easy handling represent particular advantages.

Imiquimod Treatment Induces Expression of Opioid Growth Factor Receptor: A Novel Tumor Antigen Induced by Interferon-α?

Purpose: Imiquimod represents a synthetic local immune response modifier that has demonstrated efficacy in clearing basal cell carcinoma. Via interaction with Toll-like receptor 7 on immune cells, imiquimod induces local production of cytokines, such as interferon (IFN)-α. Experimental Design: To more closely define and elucidate mechanisms leading to basal cell carcinoma clearance in vivo, we examined gene expression profiles of skin basal cell carcinoma before and after treatment with 5% imiquimod cream (Aldara) by using high-density oligonucleotide arrays. Results: We show that imiquimod predominantly induces genes involved in different aspects of immune response. In addition to effects on immunity, imiquimod treatment modulates the expression of genes involved in the control of apoptosis and oncogenesis. Array data indicated that imiquimod treatment induces expression of opioid growth factor receptor, a molecule recently reported to be a target for antitumor antibody responses. Immunohistochemistry revealed in vivo up-regulation of opioid growth factor receptor protein on tumor and on infiltrating cells after treatment. By using basal cell carcinoma cell lines treated with IFN-α or imiquimod, we show that opioid growth factor receptor up-regulation is IFN-α-mediated, rather then directly imiquimod-mediated. By using tissue microarray containing 52 basal cell carcinomas, we demonstrate opioid growth factor receptor expression in almost half of the cases. Expression of opioid growth factor receptor correlated with a longer recurrence-free period in basal cell carcinoma that recurred after radiotherapy (Kaplan-Meier analysis, P = 0.041). Conclusions: In addition to its immunomodulatory and antiproliferative activity, opioid growth factor receptor seems to have a prognostic significance in basal cell carcinoma patients. Our data add to the growing list of basal cell carcinoma-associated tumor antigens.

Diagnostic delay in hidradenitis suppurativa is a global problem.

DEAR EDITOR, Hidradenitis suppurativa (HS) is clinically defined with recognized diagnostic criteria and recognizable physical characteristics. Untreated, the disease causes significant morbidity. The prevalence varies between 0 0003% and 4% depending on the study population. Estimates from insurance databases suggest a prevalence of < 0 1%. This variation strongly suggests a significant selection bias or misclassification, and it may be speculated that not all patients present for care. This is reinforced by clinical experience and published evidence indicating a significant delay in diagnosis. This study explores the delay in diagnosis for patients with HS on an international level. The study (survey) was conducted in 2013. Observational data were collected during routine visits or extracted from case records. Because of the simple and obvious symptomatology of recurrent painful lesions present in restricted welldefined areas of the body, patients’ self-reported history was considered valid regarding onset of symptoms. Consecutive patients with HS and psoriasis were included from each participating centre during a period of 4 months or less. The data were anonymized by removing any names, addresses and social security numbers, and included age, sex, age at disease onset, age at diagnosis, delay in diagnosis, time from onset of symptoms to first physician contact, age at first medical contact, number of physicians seen prior to the diagnosis, family history and disease severity. If the diagnosis was made by a primary care physician or by a specialist other than a dermatologist prior to seeing a dermatologist, this was recorded as the date of the diagnosis. Individual centres were responsible for and obtained any locally required permissions and signed informed consent forms, for example ethics committee approval, in accordance with national registry and data protection rules. Patients diagnosed with HS or psoriasis (and confirmed by the investigator) were included. The primary outcome was quantification of the delay in diagnosis. Additionally, documentation was made of both the delay in visiting a physician (and so gaining access to specialist treatment) and the relative delay in diagnosis of HS compared with psoriasis with/without a family history. The severity of HS was determined by Hurley’s staging criteria: stage I, mild; stage II, moderate and stage III, severe. In patients with psoriasis, severity was evaluated by the Psoriasis Area and Severity Index: score < 7, mild; 7–12, moderate and > 12, severe. The t-test, Wilcoxon rank sum test and v-test were used where appropriate. Univariate and multivariate logistic regression analyses were used to identify factors predictive of significant diagnostic delay. Diagnostic delay > 2 years was defined as significant. Diagnosis, sex, age of onset, family history and disease severity were selected as potentially important

Imiquimod in basal cell carcinoma: how does it work?

Imiquimod is a topical immune response modifier that binds to Toll‐like receptor‐7 and ‐8, inducing interferon‐α. We treated superficial basal cell carcinomas (BCC) with imiquimod 5% cream daily for 5–8 days. The BCC lesions were biopsied before treatment and following imiquimod treatment, when the lesion showed the signs of erosion. We applied histology, immunohistochemistry and gene array technology (AffymetrixTM) to gain further insight into the mode of action of imiquimod. Our findings demonstrate that imiquimod‐induced BCC regression is associated with a strong activity of the innate immune response, mediated by cells of macrophage–monocyte origin and is associated with the induction of apoptosis.