Which medical disciplines diagnose and treat melanoma in Europe in 2019? A survey of experts from melanoma centres in 27 European countries.

BACKGROUND AND OBJECTIVES: The incidence of melanoma is increasing. This places significant burden on societies to provide efficient cancer care. The European Cancer Organisation recently published the essential requirements for quality melanoma care. The present study is aimed for the first time to roughly estimate the extent to which these requirements have been met in Europe. MATERIALS AND METHODS: A web-based survey of experts from melanoma centres in 27 European countries was conducted from 1 February to 1 August 2019. Data on diagnostic techniques, surgical and medical treatment, organization of cancer care and education were collected and correlated with national health and economic indicators and mortality-to-incidence ratio (MIR) as a surrogate for survival. Univariate linear regression analysis was performed to evaluate the correlations. SPSS software was used. Statistical significance was set at P < 0.05. RESULTS: The MIR was lower in countries with a high health expenditure per capita and with a higher numbers of general practitioners (GPs) and surgeons (SURG) per million inhabitants. In these countries, GPs and dermatologists (DER) were involved in melanoma detection; high percentage of DER used dermatoscopy and were involved in the follow-up of all melanoma stages; both medical oncologists (ONC) and dermato-oncologists administered systemic treatments; and patients had better access to sentinel lymph node biopsy and were treated within multidisciplinary tumour boards. CONCLUSION: Based on these first estimates, the greater involvement of GPs in melanoma detection; the greater involvement of highly trained DER in dermatoscopy, dermatosurgery, follow-up and the systemic treatment of melanoma; and the provision of ongoing dermato-oncology training for pathologists, SURG, DER and ONC are necessary to provide an optimal melanoma care pathway. A comprehensive analysis of the melanoma care pathway based on clinical melanoma registries will be needed to more accurately evaluate these first insights.

Pili annulati: refinement of the locus on chromosome 12q24.33 to a 2.9-Mb interval and candidate gene analysis.

BACKGROUND: Pili annulati is an autosomal dominant hair shaft disorder characterized by alternating light and dark bands in hairs of affected individuals. Recently, a locus for pili annulati was mapped to chromosome 12q24.32-24.33 and recombination events defined a critical region of 9.2 cM (3.9 Mb). OBJECTIVES: The aim of the current study was to narrow the size of the candidate region and to identify the pathogenic mutation for pili annulati by analysing the candidate genes. METHODS: In three families with 90 individuals, including 40 affected subjects, linkage analysis was performed with 13 microsatellite markers in the candidate region on chromosome 12. Candidate genes were analysed for their expression in hair follicles and other tissues by reverse transcriptase-polymerase chain reaction (RT-PCR) and mutation analysis. RESULTS: Multipoint LOD score analysis for all three families confirmed the locus on the long arm of chromosome 12 with a maximum LOD score of 12.26 at marker D12S357. In two families, recombinations were identified which narrowed the region to 2.9 Mb containing 36 genes. We analysed the candidate genes in this region by RT-PCR and found that 24 were expressed in human hair follicles. Based on the result of the expression analysis, DNA sequencing of the coding region of the candidate genes was performed; this did not result in the discovery of a causal mutation. CONCLUSION: We reduced the critical interval of pili annulati to 2.9 Mb and excluded mutations in the coding region of all 36 possible candidate genes by sequence analysis.

Metallothionein-overexpression as a prognostic marker in melanoma.

Malignant melanoma is one of the most aggressive human neoplasms and its incidence is still increasing. Prognoses for melanoma patients are currently based on statistical parameters. For estimating the risk for a possible progression and for overall survival, Breslow tumour thickness and the invasion level (Clark level) are the most established markers for melanomas at the time of the primary diagnosis. In thicker melanomas (>1 mm) the additional information about the status of the sentinel lymph-node (SLN) might be helpful. Nevertheless new prognostic parameters are needed, that will allow us to formulate more precise prognoses for the individual cases. The metallo-thionein family is a class of intracellular low-molecular-weight, cysteine-rich proteins with a high affinity for heavy-metal ions. They are involved in many (patho-) physiological processes and presumably play an important role in the carcinogenesis. In the last decades overexpression of immunohistochemically labelled metallothioneins (MTs) on paraffin-embedded tissues turned out as a highly significant prognostic marker in different tumours. This review summarizes the results of those studies, in which MT-overexpression was able to show a very high significance for progression and survival in melanoma patients. In contrast to most other progression markers, MT-overexpression is independent from tumour-thickness, and is highly specific even in thin (low risk) melanoma patients. Nowadays, in high risk melanoma patients sentinel lymph-node (SLN-) biopsy is performed, a surgical technique with predictive value for progression, the benefit of this procedure for the individual overall survival still remains unclear. In a study comparing SLN and MT-overexpression the results corroborate the validity of MT-overexpression in primary melanoma as a useful additional prognostic marker, accuracy is comparable although to some degree supplementary to the results of SLN biopsy.

More than 5000 patients with metastatic melanoma in Europe per year do not have access to recommended first-line innovative treatments.

BACKGROUND: Despite the efficacy of innovative treatments for metastatic melanoma, their high costs has led to disparities in cancer care among different European countries. We analysed the availability of these innovative therapies in Europe and estimated the number of patients without access to first-line recommended treatment per current guidelines of professional entities such as the European Society for Medical Oncology (ESMO), the European Organisation for Research and Treatment of Cancer (EORTC), the European Association of Dermato-Oncology (EADO), and European Dermatology Forum (EDF). MATERIALS AND METHODS: Web-based online survey was conducted in 30 European countries with questions about the treatment schedules from 1st May 2015 to 1st May 2016: number of metastatic melanoma patients, registration and reimbursement of innovative medicines (updated data, as of 1st October 2016), percentage of patients treated and availability of clinical studies and compassionate-use programmes. RESULTS: The recommended BRAF inhibitor (BRAFi) + MEK inhibitor (MEKi) combination was both registered and fully reimbursed in 9/30 (30%) countries, and in 13/30 (43%) (all from Eastern Europe) not reimbursed. First-line immunotherapy with anti-PD1 antibodies was registered and fully reimbursed in 14/30 (47%) countries, while in 13/30 (43%) (all from Eastern Europe) not reimbursed. It was estimated that in Europe 19,600 patients with metastatic melanoma are treated, and 5238 (27%) do not have access to recommended first-line therapy. Significant correlation was found between human development index (HDI, UNDP report 2015), (r = 0.662; p < 0.001), health expenditure per capita (r = 0.695; p < 0.001) and the Mackenbach score of health policy performance (r = 0.765; p < 0.001) with the percentage of patients treated with innovative medicines and a number of reimbursed medicines. CONCLUSIONS: Great discrepancy exists in metastatic melanoma treatment across Europe. It is crucial to increase the awareness of national and European policymakers, oncological societies, melanoma patients' associations and pharma industry.

Entry into afferent lymphatics and maturation in situ of migrating murine cutaneous dendritic cells.

An important property of dendritic cells (DC), which contributes crucially to their strong immunogenic function, is their capacity to migrate from sites of antigen capture to the draining lymphoid organs. Here we studied in detail the migratory pathway and the differentiation of DC during migration in a skin organ culture model and, for comparison, in the conventional contact hypersensitivity system. We report several observations on the capacity of cutaneous DC to migrate in mouse ear skin. (i) Upon application of contact allergens in vivo the density of Langerhans cells in epidermal sheets decreased, as determined by immunostaining for major histocompatibility complex class II, ADPase, F4/80, CD11b, CD32, NLDC-145/DEC-205, and the cytoskeleton protein vimentin. Evaluation was performed by computer assisted morphometry. (ii) Chemically related nonsensitizing or tolerizing compounds left the density of Langerhans cells unchanged. (iii) Immunohistochemical double-staining of dermal sheets from skin organ cultures for major histocompatibility complex class II and CD54 excluded blood vessels as a cutaneous pathway of DC migration. (iv) Electron microscopy of organ cultures revealed dermal accumulations of DC (including Birbeck granule containing Langerhans cells) within typical lymphatic vessels. (v) Populations of migrating DC in organ cultures upregulated markers of maturity (the antigen recognized by monoclonal antibody 2A1, CD86), but retained indicators of immaturity (invariant chain, residual antigen processing function). These data provide additional evidence that during both the induction of contact hypersensitivity and in skin organ culture, Langerhans cells physically leave the epidermis. Both Langerhans cells and dermal DC enter lymphatic vessels. DC mature while they migrate through the skin.

Novel Hairless mutations in two kindreds with autosomal recessive papular atrichia.

Papular atrichia is an autosomal recessive disorder characterized clinically by the occurrence of universal congenital alopecia and disseminated papular lesions. Recently, mutations in the human hairless (HR) gene have been reported in Irish and Arab Palestinian families with papular atrichia. We have studied two further kindreds with this clinical phenotype from other ethnic backgrounds. For mutation detection the complete coding region as well as exon-intron boundaries of the HR gene were sequenced. The first family is a Mexican family with clinically typical papular atrichia. Sequencing identified a homozygous deletion of 4 bp in exon 7 (2001delCCAG) leading to a premature stop codon in exon 8. The second family is a South Tyrolian family with affected individuals showing papular atrichia and retardation of bone age during childhood. All affected individuals were identified as homozygous for an A-->G transition at nucleotide position 2909 (exon 14) leading to an amino acid change of asparagine to serine in codon 970 (Asn970Ser). These data provide further evidence for the involvement of hairless mutations in papular atrichia. In addition, these findings suggest that the hairless protein is not only involved in hair development but also in the process of ossification during development.

Dermal and subcutaneous variants of plexiform fibrohistiocytic tumor.

We report five cases of plexiform fibrohistiocytic tumors, three classic subcutaneous lesions and two dermal ones. Both variants had similar profiles and were clinically indistinguishable. The lesions affected the trunk more than the upper extremities and were found in children and young adults (18.4 +/- 12.8 years). They showed a marked female predominance (4:1, including both dermal variants). Clinically, they were skin-colored, hard nodules of 1-2-cm diameter that resulted in such differential diagnoses as fibroma, histiocytoma, pilomatricoma, or cyst. Interestingly, one subcutaneous case with a painful "worms in the sack" presentation was thought to represent a plexiform neurofibroma. Histology revealed well-circumscribed dermal or subcutaneous plexiform lesions with a characteristic biphasic appearance. Most of the tumor bulk consisted of spindle-shaped to stellate myofibroblasts with a variable admixture of collagen or loosening of stroma. In the center of the plexiform strands and nodules, a few osteoclast-like giant cells as well as epithelioid mononuclear cells (< 10%) were found. Myofibroblasts were positive with HHF35 and for smooth muscle actin in three of five cases. Osteoclast-like giant cells were positive with KP1 in all five cases. Both types of cells stained with the macrophage marker Ki-M1p. A broad panel of other markers was negative. This series expands the spectrum of plexiform fibrohistiocytic tumor, but it also broadens the differential diagnosis of (dermal) plexiform lesions, which at present includes spindle cell nevi, schwannomas, neurofibromas, granular cell tumors, nerve sheath myxomas (neurothekeomas), spindle cell lipomas, and tufted angiomas.

Permeability barrier function of skin exposed to ionizing radiation.

OBJECTIVE: To characterize the epidermal permeability barrier function of skin during exposure to ionizing radiation. DESIGN: A prospective cohort study. SETTING: University hospital medical center. PATIENTS: Fifteen women receiving local radiation therapy (5000-6000 rad [50-60 Gy]) following breast-conserving surgery for breast cancer. MAIN OUTCOME MEASURES: Clinical symptoms and transepidermal water loss (TEWL). RESULTS: Epidermal permeability barrier function is impaired in patients who exhibit clinical signs of radiation dermatitis. The functional damage to the stratum corneum induced by ionizing radiation occurs with a delayed course, starting within a mean period of 11 days and reaching maximal values after a mean period of 27 days (range, 13-75 days). The onset of TEWL increase precedes the onset of radiation dermatitis and the maximal TEWL measurements precede the peak of skin changes. Patients with an early onset of TEWL increase show a longer duration of skin symptoms. CONCLUSIONS: Skin changes caused by radiation dermatitis are associated with an increase in TEWL. The barrier impairment is comparable to the changes observed with UV radiation exposure but exhibits an even more delayed course. Our results suggest that preservation of the epidermal permeability barrier function by topical treatment may ameliorate radiation dermatitis.

Clear cells in acral melanoma.

Acral melanoma may present clinically and histologically with atypical features causing a delay in proper diagnosis. The aim of the present study was to assess the frequency of a histological variant with clear cell changes. Clinical information, hematoxylin & eosin stained paraffin sections and immunohistochemical staining profiles were reviewed in 49 cases of acral melanoma. Twenty-one (43%) specimens contained tumor cells with clear cell changes in focal areas, whereas in 7 (14%) specimens clear cells were the major tumor constituting cells. The tumor thickness ranged from melanoma in situ to 14 mm. Immunohistochemistry demonstrated weak staining for S100 and HMB45 as well as strong positivity for Melan A and NK1C3. Recognition of clear cell features is important since differential diagnosis includes a variety of other clear cell malignancies, among them metastasis from renal cell carcinoma, clear cell sarcoma and hidradenocarcinoma.

Comparison of metallothionein-overexpression with sentinel lymph node biopsy as prognostic factors in melanoma.

BACKGROUND: Metallothioneins (MT) are ubiquitous, intracellular small proteins with high affinity for heavy metal ions. Immunohistochemical MT overexpression in paraffin-embedded tissues of patients with primary melanoma is associated with poor prognosis. While sentinel lymph node (SLN) biopsy is an established surgical technique for high-risk melanoma patients with predictive value for progression, the benefit of this procedure for the individual patient's overall survival remains unclear. AIM AND METHODS: We examined the role of MT overexpression in comparison with SLN biopsy in melanoma patients as a prognostic marker for progression and survival. One hundred and fifty-eight (158) patients underwent SLN biopsy due to high-risk melanoma. Primary melanoma specimens were investigated by using a monoclonal antibody against MT on routinely fixed, paraffin-embedded tissues. The patients were followed up (median 37 months); the data of disease free survival and overall survival were calculated with a broad panel of statistical analyses. RESULTS: Twenty-eight (18%) out of 158 recruited melanoma patients developed metastases, 17 (11%) patients died due to widespread disease. Kaplan-Meier curves gave significant disadvantages for the MT-positive as well as the SLN-positive group for progression and survival. In the Fisher's exact test and Pearson's chi(2)-test MT overexpression was highly significant for progression, whereas SLN biopsy failed significance. In univariate as well as multivariate Cox regression analysis MT overexpression proved an excellent marker for progression (P=0.007 and P=0.009), although the P-values for survival were not significant. In contrast, while in the univariate analysis SLN biopsy did not show significant results for progression it did for survival, and in the multivariate analysis reached a P-value < 0.05 for both measured endpoints. CONCLUSION: Results corroborate the validity of MT overexpression in primary melanoma as a useful prognostic marker in melanoma patients. Accuracy is comparable and to some degree supplementary to the results of SLN biopsy.

Metallothionein - overexpression as a highly significant prognostic factor in melanoma: a prospective study on 1270 patients.

Metallothioneins (MT) are ubiquitous, intracellular small proteins with high affinity for heavy metal ions. In the last decades, it was shown that MT overexpression in a variety of cancers is associated with resistance to anticancer drugs and is combined with a poor prognosis. In this prospective study, we examined the role of MT overexpression in melanoma patients as a prognostic factor for progression and survival. Between 1993 and 2004, 3386 patients with primary cutaneous melanoma were investigated by using a monoclonal antibody against MT on routinely fixed, paraffin-embedded tissues. In all, 1270 patients could be followed up for further statistical analysis (Fisher's exact test, Mantel-Haenszel chi2 test, Kaplan-Meier curves). The MT data of disease-free interval and overall survival were compared univariately and multivariately in Cox regression analysis. Immunohistochemical overexpression of MT in tumour cells of patients with primary melanoma (310 of 1270; 24.4%) was associated with a higher risk for progression (117 of 167; 70.1%) and reduced survival (80 of 110; 72.7%) of the disease (P<0.0001). Similarly, Kaplan-Meier curves gave highly significant disadvantages for the MT-positive group. Univariate analysis (relative risk 7.4; 95% confidence interval (CI) 5.2-10.2; P<0.0001 for progression; relative risk 7.1; 95% CI 4.7-10.9; P<0.0001 for survival), as well as multivariate analysis with other prognostic markers resulted in MT overexpression as a highly significant and independent factor for prognosis in primary melanoma.

Perineuroma. A frequently unrecognized entity with emphasis on a plexiform variant.

AIMS: The present series describes six cases of perineurioma, a rare and frequently unrecognized entity, including one case with an unusual plexiform growth pattern. METHODS: Retrospective clinicopathologic study of six perineuriomas. RESULTS: All lesions occurred on the upper extremities or shoulders of adults, five in females. Histologically, all six cases of perineurioma had been initially unrecognized or misdiagnosed as dermatofibroma, fibroma of tendon sheath, neurofibroma, schwannoma, or naevus, respectively. Scanning magnification revealed well circumscribed, dermal to subcutaneous lesions without capsule formation. Besides characteristic onion bulbs", i.e. concentric whorls of epithelioid to spindle-shaped cells, there was great variation of histomorphologic features: single nodules or plexiform architecture; a few to many concentric whorls; five to several dozens of cell layers in concentric whorls; high to low cellularity; round/oval to spindle-shaped/wavy cells/nuclei; delicate to prominent collagen; variable mucin, sclerosis, and/or intralesional clefts. Immunohistochemically, all lesions were consistently positive for EMA, ultrastructurally (1 case) with evidence of perineurial differentiation such as slender and elongated, bipolar cytoplasmic processes with discontinuous basal lamina, prominent pinocytosis and desmosome-like junctions. CONCLUSION: Our series documents that cutaneous and subcutaneous perineurioma is frequently unrecognized or misinterpreted and may occasionally show a plexiform growth pattern. The differential diagnosis of plexiform variants includes a variety of plexiform lesions such as naevi, neurofibroma, schwannoma, etc. Historically, similar plexiform lesions seem to have been published as nerve sheath myxoma/neurothekeoma, Pacinian neurofibroma or perineurial myxoma. This terminology is imprecise and confusing and, thus, should be avoided in favour of the correct term of perineurioma.

Variegate porphyria with coexistent decrease in porphobilinogen deaminase activity.

Variegate porphyria is a rare disease caused by a deficiency of protoporphyrinogen oxidase. In most cases, the clinical findings are a combination of systemic symptoms similar to those occurring in acute intermittent porphyria and cutaneous lesions indistinguishable from those of porphyria cutanea tarda. We report on a 24-year-old woman with variegate porphyria who, after intake of lynestrenol, developed typical cutaneous lesions but no viscero-neurological symptoms. The diagnosis was based on the characteristic urinary coproporphyrin and faecal protoporphyrin excretion patterns, and the specific peak of plasma fluorescence at 626 nm in spectrofluorometry. Biochemical analysis revealed that most of the family members, though free of clinical symptoms, excrete porphyrin metabolites in urine and stool similar to variegate porphyria, accompanied by a significant decrease of porphobilinogen deaminase activity of a range which is ordinarily found in patients with acute intermittent porphyria only (approximately 50%). These data first led to the assumption of two separate and independently inherited genetic defects, similar to the dual porphyria of Chester. Molecular analysis, however, revealed only a missense mutation of the protoporphyrinogen oxidase gene, but not of the porphobilinogen deaminase gene. Thus, in the family presented, porphobilinogen deaminase deficiency is likely to be a phenomenon secondary to the genetic defect of protoporphyrinogen oxidase.

Anaphylaxis to camomile: clinical features and allergen cross-reactivity.

BACKGROUND: Medicinal remedies of plant origin became very popular in recent years, and allergic reactions to these are on the rise, accordingly. Camomile has been reported as a potential trigger of severe anaphylaxis. The allergens responsible for camomile allergy have not been characterized as yet. OBJECTIVE: The present study aims at reviewing the clinical symptomatology of immediate-type reactions in a series of patients sensitized to camomile and at characterizing the responsible allergens. METHODS: Fourteen patients with a history of allergy either to camomile or to spices or weeds, and a positive skin prick test/RAST to camomile were investigated for related allergic reactions to food, pollen and others. IgE-binding patterns were determined by immunoblotting, inhibition tests and deglycosylation experiments. RESULTS: Ten of 14 patients had a clinical history of immediate-type reactions to camomile, in some cases life threatening. Eleven subjects were also sensitized to mugwort in prick or RAST, eight to birch tree pollen. Using a polyclonal rabbit anti-Bet v 1 antibody, a homologue of the major birch pollen allergen Bet v 1 was detected in two camomile blots. In four cases a group of higher molecular weight allergens (23-50 kDa) showed IgE-binding to camomile. All allergens proved heat stable. Binding was inhibited in variable degrees by extracts from celery roots, anize seeds and pollen from mugwort, birch and timothy grass. Deglycosylation experiments proved the presence of carbohydrate determinants in camomile which were not responsible for IgE-binding, though. Profilins (Bet v 2) were not detected in our camomile extracts. CONCLUSION: Incidence and risk of type I allergy to camomile may be underestimated. Concurrent sensitization to mugwort and birch pollen is not infrequent. Bet v 1 and noncarbohydrate higher molecular weight proteins were found to be eliciting allergens and are responsible for cross-reactivity with other foods and pollen.

Metallothionein-overexpression as a prognostic factor for progression and survival in melanoma. A prospective study on 520 patients.

BACKGROUND: Metallothioneins (MTs) are ubiquitous proteins with high affinity for heavy metal ions, e.g. zinc, copper and cadmium. In the last decade it has been shown that MT overexpression in a variety of cancers is associated with resistance to anticancer drugs and radiotherapy, and with a poor prognosis. OBJECTIVES: To examine the role of MT overexpression in melanoma patients as a prognostic factor for progression and survival. METHODS: In a prospective cohort study 760 patients with primary cutaneous melanoma were investigated over 5 years (1993-98) by using a monoclonal antibody (E9) against MT on routinely fixed and paraffin-embedded tissues. In total, 520 patients were able to be followed up for progression of their disease or death due to melanoma and were included for statistical analysis (Fisher's exact test, Mantel-Haenszel chi2 test, Kaplan-Meier curves). MT data, progress-free interval and overall survival were compared univariately and multivariately with other prognostic factors, e.g. Breslow thickness, Clark level, ulceration, localization, age and gender (Cox regression analysis). RESULTS: The immunohistochemical overexpression of MT in tumour cells (cut-off level > 10% of all tumour cells) in patients with primary melanoma (156 of 520; 30%) was associated with a higher risk for progression of the disease (33 of 45; 73%) and reduced survival (24 of 30; 80%) than MT-negative lesions [364 of 520 (70%), 12 of 45 (27%) and six of 30 (20%), respectively (P < 0.0001)]. Similarly, Kaplan-Meier tumour-free survival and overall survival curves for the comparison of MT-positive and MT-negative tumours gave highly significant advantages for the MT-negative group. In a univariate analysis (comparison with Breslow thickness: relative risk 2.9, 95% confidence interval, CI 1.46-5.76, P = 0.0023 for progression; relative risk 4.19, 95% CI 1.73-10.19, P = 0.0015 for survival), as well as in a multivariate analysis with other prognostic markers, MT overexpression turned out to be a highly significant and independent factor for prognosis in primary melanoma. CONCLUSIONS: MT overexpression in primary melanoma is associated with an increased risk for disease progression. This marker is independent from Breslow thickness and helps to identify those thin melanomas (< 1.5 mm) that are at increased risk of progression. Moreover, the immunohistochemical staining of paraffin material is a cheap, easy and widely available technique to gain these results.

Leg ulcers associated with long-term hydroxyurea therapy.

Hydroxyurea is commonly used in the treatment of various hematologic disorders, e.g., chronic myelogenous leukemia (CML), polycythemia vera, and occasionally, at lower doses, for severe psoriasis vulgaris. Cutaneous side effects such as alopecia, diffuse hyperpigmentation, poikiloderma, atrophy of the skin, or nail changes occur, especially with long-term treatment. Painful leg ulcers in association with hydroxyurea have only rarely been reported. We describe 2 patients who developed spontaneous painful leg ulcers during long-term hydroxyurea therapy for a myeloproliferative disorder; these ulcers healed only after hydroxyurea was withdrawn.

Cutaneous lesions as the presenting sign of acute graft-versus-host disease following liver transplantation.

Acute graft-versus-host disease (GVHD) is a frequent complication of bone marrow transplantation but is only rarely observed after solid organ transplantation. We describe a 68-year-old man who developed a maculopapular eruption 7 days following orthotopic liver transplantation for cirrhosis with malignant transformation due to haemochromatosis. At day 20, the patient complained of nausea, vomiting, diarrhoea and fever. Skin biopsy revealed a lymphocytic infiltrate at the dermoepidermal interface, vacuolization of basal cells and epidermal dyskeratosis. Immunohistochemistry showed HLA-DR and intercellular adhesion molecule-1 expression of lesional keratinocytes. HLA-typing of peripheral blood lymphocytes demonstrated circulating lymphocytes of donor origin. Endoscopy revealed extensive erosions of the oesophagus, stomach and duodenum that on histology disclosed multifocal loss of crypts, lymphocytic infiltrates and epithelial cell death. A diagnosis of acute GVHD was made, and high-dose immunosuppressive therapy with azathioprine and methylprednisolone was instituted. The skin and gastrointestinal symptoms subsided within 4 weeks, but the patient died from severe infectious complications 105 days after transplantation. We conclude that acute GVHD is a rare but potentially fatal complication of liver transplantation. Skin lesions are an early sign of acute GVHD and thus represent an important tool for early diagnosis.

Intravenous immunoglobulin treatment in therapy-resistant epidermolysis bullosa acquisita.

Epidermolysis bullosa acquisita is an uncommon autoimmune bullous disease of the skin and mucous membranes. It is chronic, disabling, and difficult to treat. We describe a case of severe epidermolysis bullosa acquisita of 7 years' duration that had been treated with azathioprine, corticosteroids, chlorambucil, plasma exchanges, cyclophosphamide, cyclosporine, and colchicine without any lasting effect. Seven cycles of treatment were administered with immunoglobulin given intravenously at a low dose, 40 mg/kg body weight daily for 5 days. The patient was free of disease for 10 months after the initiation of therapy. We suggest that low-dose regimens of immunoglobulins may be as effective in this disease as the high-dose regimens suggested in the literature, and at much lower cost.

Topical corticosteroid therapy for acute radiation dermatitis: a prospective, randomized, double-blind study.

BACKGROUND: Radiation dermatitis is a common side-effect of radiation therapy, but there is no current consensus about its appropriate therapy. OBJECTIVES: To compare treatment with topical 0.1% methylprednisolone vs. 0.5% dexpanthenol in a cohort of patients undergoing fractionated radiation therapy for breast cancer. METHODS: In a randomized, double-blind design, treatment was initiated at the beginning of radiation therapy and continued for 2 weeks after termination of radiation. Outcomes were compared by three different measures: clinical (symptom score), functional (transepidermal water loss, TEWL) and subjective (quality of life, QOL). RESULTS: In a preliminary cohort of untreated patients undergoing radiation therapy, clinical signs and TEWL levels increased progressively during radiation therapy, reaching highest values at 5 and 4 weeks, respectively. Although neither topical treatment reduced the incidence of radiation dermatitis, both delayed the emergence of greatest clinical and TEWL scores until approximately 6 and 5 weeks, respectively. With topical corticosteroids, clinical symptoms and TEWL were less pronounced than with dexpanthenol. Whereas general QOL improved after completion of radiation therapy, skin-related QOL declined. However, the skin-related QOL decline could be at least in part reversed by use of topical corticosteroid vs. dexpanthenol-containing emollient. CONCLUSIONS: We provide evidence that prophylactic and ongoing use of topical therapy with either topical corticosteroid or a dexpanthenol-containing emollient ameliorates, but does not prevent radiation dermatitis. Our data suggest, but do not prove, a benefit of a topical corticosteroid vs. a dexpanthenol-containing emollient. Further controlled studies with larger cohorts will be needed to determine optimal forms of topical therapy for radiation dermatitis.