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Background The BOLT study for sonidegib, a Hedgehog pathway inhibitor (HHI) approved for patients with locally advanced basal cell carcinoma (laBCC) not amenable to curative surgery or radiotherapy, used modified Response Evaluation Criteria in Solid Tumors (mRECIST) for laBCC tumor evaluation. The ERIVANCE study for vismodegib, another HHI, used a composite RECIST endpoint of ≥30% reduction in externally visible tumor or radiographic dimension, or complete ulceration resolution. This preplanned sensitivity BOLT analysis evaluated efficacy outcomes using ERIVANCE-like criteria in patients with laBCC who received sonidegib 200 mg once daily. Methods This phase 2, double-blind study randomized patients 1:2 to sonidegib 200:800 mg daily, respectively. Key endpoints included objective response rate (ORR), duration of response (DOR), complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). laBCC tumors were assessed by both mRECIST and ERIVANCE-like criteria. Per mRECIST, an overall response of CR was based on negative histology; photographic assessment of CR, PR (scar/fibrosis only), SD (scar/fibrosis only), or not available (NA); and a magnetic resonance imaging response of CR or NA. An overall response of CR was primarily based on negative histology using ERIVANCE-like criteria. Results Per mRECIST criteria, ORR (95% confidence interval [CI]) by central and investigator review for patients with laBCC (n = 66) was 56.1% (43.3–68.3%) and 71.2% (58.7–81.7%), respectively. CR per central review was achieved in 3 (4.5%) patients and PR, SD, and PD occurred in 34 (51.5%), 23 (34.8%), and 1 (1.5%) patient, respectively. Median (95% CI) DOR was 26.1 months (not estimable [NE]). Using ERIVANCE-like criteria, efficacy outcomes per central and investigator review were higher, with an ORR (95% CI) of 60.6% (47.8–72.4%) and 74.2% (62.0–84.2%), respectively. CR per central review was reached in 14 (21.2%) patients and PR, SD, and PD occurred in 26 (39.4%), 20 (30.3%), and 1 (1.5%) patient, respectively. DOR was unchanged with a median (95% CI) of 26.1 months (NE). Conclusions Overall, applying ERIVANCE-like criteria to patients with laBCC receiving sonidegib 200 mg daily yielded higher response rates vs mRECIST criteria. Trial registration BOLT registration: ClinicalTrials.gov (NCT01327053) on March 30, 2011.

The chemokine CCL18 is produced in cells of the myelomonocytic lineage and represents one of the most highly expressed chemokines in lesional skin and serum of atopic dermatitis patients. We investigated the role of histamine in CCL18 production in human monocyte-derived M2 macrophages differentiated in the presence of M-CSF and activated with IL-4, IL-13 or with IL-10. Since expression and regulation of histamine H1 receptor (H1R), H2R and H4R by IL-4 and IL-13 on human M2 macrophages were described, we analyzed expression of the histamine receptors in response to IL-10 stimulation by quantitative RT-PCR. IL-10 upregulated H2R and downregulated H4R mRNA expression by trend in M2 macrophages. IL-10, but in a more pronounced manner, IL-4 and IL-13, also upregulated CCL18. Histamine increased the cytokine-induced upregulation of CCL18 mRNA expression by stimulating the H2R. This effect was stronger in IL-10-stimulated M2 macrophages where the upregulation of CCL18 was confirmed at the protein level by ELISA using selective histamine receptor agonist and antagonists. The histamine-induced CCL18 upregulation in IL-10-activated M2 macrophages was almost similar in cells obtained from atopic dermatitis patients compared to cells from healthy control persons. In summary, our data stress a new function of histamine showing upregulation of the Th2 cells attracting chemokine CCL18 in human, activated M2 macrophages. This may have an impact on the course of atopic dermatitis and for the development of new therapeutic interventions.

The phase III IMspire150 study (NCT02908672) demonstrated significantly improved progression-free survival (PFS) with atezolizumab, vemurafenib, and cobimetinib (atezolizumab group) versus placebo, vemurafenib, and cobimetinib (control group) in patients with BRAFFive hundred fourteen patients were randomized to atezolizumab (n = 256) or control (n = 258). Outcomes were evaluated in subgroups defined by key biomarkers, including programmed death-ligand 1 (PD-L1) expression, lactate dehydrogenase (LDH) level, tumor mutational burden (TMB), and interferon-γ (IFN-γ) gene signature. Exploratory recursive partitioning analysis was then used to model associations between PFS and baseline covariates, including key biomarkers.PFS benefit for atezolizumab versus control was greater in patients with high TMB [≥10 mutations/Mb; hazard ratio (HR) 0.73; 95% confidence interval (CI) 0.52-1.02; P = 0.067] versus low TMB (10 mutations/Mb; HR 0.92; 95% CI 0.65-1.30; P = 0.64) and similar between patients with strong IFN-γ (≥median; HR 0.76; 95% CI 0.54-1.06) versus weak IFN-γ (median; HR 0.79; 95% CI 0.58-1.08). In patients with elevated LDH, PFS benefit for atezolizumab versus control was greater in the PD-L1- subgroup (HR 0.53; 95% CI 0.29-0.95; P = 0.032) than in the PD-L1+ subgroup (HR 1.16; 95% CI 0.75-1.80; P = 0.51). Recursive partitioning analysis showed that IFN-γ discriminated PFS outcomes in patients with normal LDH, whereas TMB discriminated outcomes in patients with elevated LDH in the atezolizumab group. Neither IFN-γ nor TMB discriminated PFS outcomes in the control group.Treatment benefits in the atezolizumab group seemed to be most evident in patients with elevated LDH and PD-L1- tumors. LDH remains the primary predictor of outcomes regardless of treatment. IFN-γ and TMB further differentiate outcomes for patients treated with atezolizumab, vemurafenib, and cobimetinib.

Background Pembrolizumab demonstrated clinically meaningful and durable antitumor activity with a manageable safety profile in recurrent/metastatic (R/M) cutaneous squamous cell carcinoma (cSCC). Patients and methods KEYNOTE-629 was a global, open-label, nonrandomized, phase II trial of patients with locally advanced (LA) or R/M cSCC conducted at 59 centers. Eligible patients received intravenous pembrolizumab 200 mg every 3 weeks for up to 35 cycles. Primary endpoint was objective response rate (ORR), defined as the percentage of patients with a complete (CR) or partial response (PR), by blinded independent central review as per Response Evaluation Criteria in Solid Tumors 1.1. Secondary endpoints included duration of response (DOR), disease control rate, progression-free survival, overall survival, and safety and tolerability. Efficacy and safety were analyzed in patients who were treated with at least one dose of pembrolizumab. Results Between 29 November 2017 and 25 September 2019, 159 patients were enrolled and treated with pembrolizumab (LA cohort, n = 54; R/M cohort, n = 105). The median time from the first dose to data cut-off date (29 July 2020) was 14.9 [interquartile range (IQR), 12.6-17.2] months for the LA cohort and 27.2 (IQR, 25.6-29.2) months for the R/M cohort. In the LA cohort, ORR was 50.0% [95% confidence interval (CI), 36.1% to 63.9%], including 16.7% of patients with a CR and 33.3% with a PR. In the R/M cohort, ORR was 35.2% (95% CI, 26.2% to 45.2%), including 10.5% of patients with a CR and 24.8% with a PR. Median DOR was not reached in either cohort. Grade 3-5 treatment-related adverse events occurred in 11.9% of patients. Conclusions The robust antitumor activity of pembrolizumab in both LA and R/M cSCC was confirmed and demonstrated to be durable without unexpected safety signals. Our findings establish pembrolizumab as a promising treatment option for cSCC.

Treatment of patients with metastatic melanoma is hampered by drug-resistance and often requires combination with radiotherapy as last-resort option. However, also after radiotherapy, clinical relapses are common.Our preclinical models indicated a higher rate of tumour relapse when melanoma cells were first treated with BRAFThe level of cross-resistance between combined MAPK inhibition and radiotherapy is dependent on the treatment sequence. JARID1B may represent a novel therapy-overarching resistance marker.

The medical therapy of inoperable malignant melanoma has changed dramatically over the last few years.The purpose of this article is to summarize the current state of systemic medical treatment of malignant melanoma.Clinical studies and guidelines in the therapy of malignant melanoma are reviewed.Medical therapy of inoperable melanoma changed due to developments in immunotherapies (checkpoint inhibitors) and molecular-targeted therapies (BRAF and MEK inhibitors). Checkpoint inhibitors are antibodies administered as infusions every 2-3 weeks, blocking the checkpoints PD-1 or CTLA-4, thus, preventing downregulation of the immune system. BRAF and MEK inhibitors are small molecules, they are given orally and block a certain signaling pathway in tumor cells. The activation of this pathway has to be demonstrated by molecular analysis of tumor tissue first. This strategy is currently registered for 40-50 % of melanomas harboring a BRAF V600 mutation, while the combination of a BRAF plus MEK inhibitor has been proven more efficient than a BRAF inhibitor alone.A fascinating development has started in the melanoma field due to immunotherapeutic and molecular-targeted treatment strategies. The continuation of this development needs further clinical and translational studies. This includes particular clinical studies with the new substances in the adjuvant situation, and sequences and combinations in the metastatic setting. Translational studies are needed to develop biomarkers for response and side effects.

The retrospective evaluation of bone marrow biopsies of 569 patients with primary myelodysplastic syndrome--pMDS--revealed 256 refractory anemias--RA--, 52 refractory anemias with ringed sideroblasts--RARS--, 133 refractory anemias with excess of blasts--RAEB--, 52 refractory anemias with excess of blasts in transformation--RAEB-t--, and 53 chronic myelo-monocytic leukemias--CMMOL--according to FAB-criteria, 23 patients were not otherwise specified (myelodysplastic syndrome: not otherwise specified--MDS.NOS--). RARS-patients had the best prognosis (median survival 41.9 months, incidence of leukemia 3.8%), followed by RA-patients (26.5 months, 16.4%), MDS.NOS-patients (22.4 months, 21.7%), CMMOL-patients (12.5 months, 49.1%). RAEB- and RAEB-t-patients had the worst prognosis (median survival time 8.5 and 4.6 months, incidence of leukemia 42.1% and 57.7%, respectively). But the survival times showed a considerable range in each FAB-subgroup with 0-154 months in RA or 0-52 months in CMMOL. To forecast life expectancy more precisely, a scoring system was developed using nine histopathological parameters, among which the three most important ones were determined: quantity of myeloblasts, myelofibrosis and ALIP's. The scoring system allows a determination of three risk groups with significantly different survival times. It is valid also for patients without increase of myeloblasts (< 5% myeloblasts in the bone marrow) and identifies high-risk MDS patients in this group. By this proposed scoring system, a prognostic approval in primary MDS can be achieved applying histopathology without regarding further methods herewith presenting a system which could be considered independently from hematologic, cytological or laboratory data.

BACKGROUND: More than half of patients with melanoma that has spread to regional lymph nodes develop recurrent disease within the first 3 years after surgery. The aim of the study was to improve disease-free survival (DFS) and overall survival (OS) with interferon (IFN) alpha2a with or without dacarbazine (DTIC) compared with observation alone. PATIENTS AND METHODS: A total of 444 patients from 42 centers of the German Dermatologic Cooperative Oncology Group who had received a complete lymph node dissection for pathologically proven regional node involvement were randomized to receive either 3 MU s.c. of IFNalpha2a three times a week for 2 years (Arm A) or combined treatment with same doses of IFNalpha2a plus DTIC 850 mg/m(2) every 4-8 weeks for 2 years (Arm B) or to observation alone (Arm C). Treatment was discontinued at first sign of relapse. RESULTS: A total of 441 patients were eligible for intention-to-treat analysis. Kaplan-Meier 4-year OS rate of those who had received IFNalpha2a was 59%. For those with surgery alone, survival was 42% (A versus C, P = 0.0045). No improvement of survival was found for the combined treatment Arm B with 45% survival rate (B versus C, P = 0.76). Similarly, DFS rates showed significant benefit for Arm A, and not for Arm B. Multivariate Cox model confirmed that Arm A has an impact on OS (P = 0.005) but not Arm B (P = 0.34). CONCLUSIONS: 3 MU interferon alpha2a given s.c. three times a week for 2 years significantly improved OS and DFS in patients with melanoma that had spread to the regional lymph nodes. Interestingly, the addition of DTIC reversed the beneficial effect of adjuvant interferon alpha2a therapy.

Aims: The presence of micrometastases in the sentinel lymph node (SLN) is an important prognostic parameter for melanoma patients. The aim was to determine the prognostic relevance of histopathological characteristics of micrometastases in the SLN, which has not been adequately addressed thus far. Methods and results: In 169 melanoma patients with positive SLN, histopathological features of the SLN were correlated with overall survival (OS) and relapse-free survival (RFS). Tumour burden, expansion of melanoma cells in the periphery (infiltration of capsule) and towards the centre of the SLN [tumour penetrative depth (TPN)] were of prognostic significance for OS and RFS on univariate analysis. Multivariate analysis revealed three independent significant parameters which predict a poor prognosis: presence of infiltration of the SLN capsule, TPN ≥ 2 mm and size of the largest tumour deposit ≥ 30 cells. Conclusions: Histopathological analysis of SLN allows the identification of patients with a poor prognosis depending on the location of melanoma cells and tumour burden.

The colorectal cancer antigen GA733 (also termed CO17-1A, KSI-4, Ep-CAM, KSA) has proved to be a useful target in passive immunotherapy with monoclonal antibody and in active immunotherapy with antiidiotypic antibodies in cancer patients. The GA733 antigen was molecularly cloned and expressed in baculovirus (BV), adenovirus (AV), and vaccinia virus (VV). Recombinant BV-, VV-, and AV-GA733 induced antigen-specific cytotoxic antibodies and proliferative and delayed-type hypersensitive lymphocytes. However, only the AV recombinant induced antigen-specific cytolytic T lymphocytes and regression of established tumors. Cured mice were protected against challenge with antigen-negative tumors, indicating antigen spreading of immune responses. In a model of active immunotherapy against the murine homologue of the human GA733 antigen, murine epithelial glycoprotein (mEGP), BV-derived mEGP protein in various adjuvants did not protect mice against a challenge with mEGP-positive tumors. AV mEGP, only when combined with interleukin-2, significantly inhibited growth of established mEGP-positive tumors. This is in contrast to the same vaccine expressing the human antigen that was effective without interleukin-2. AV GA733, in combination with interleukin-2, is a candidate vaccine for colorectal cancer patients.

The incidence of non-melanoma skin cancer (NMSC) is increasing. Squamous cell carcinoma of the skin (SCC) is a tumor of the elderly. Due to the increasing life expectancy, SCC will become more and more frequent in the future. Generally SCC has a favorable prognosis. Standard therapy is microscopically- controlled excision. Therapy of advanced and metastatic SCC is still challenging. Patients with regional lymph node metastasis have ten-year survival rates less than 20%; patients with distant metastases less than 10%. Immunosuppression has been shown to be one of the key prognostic factors for metastasis. The article reviews SCC and focusses on patients being at risk for an unfavorable course.

BRAF and MEK inhibitors are new targeted therapies which are used in the treatment of malignancies, in particular of malignant melanoma.Cutaneous side effects are common during the treatment with both types of inhibitors. These side effects include inflammatory reactions such as maculopapular and papulopustular exanthema, hand-foot syndrome, panniculitis, paronychia, photo- and radio-sensitization. As a class effect, BRAF-inhibitors induce proliferative disorders of keratinocytes and melanocytes, such as palmoplantar hyperkeratosis (as part of the hand-foot syndrome), verruciform and acanthoma-like lesions, follicular and Grover disease-like hyperkeratoses, keratoacanthomas, squamous cell carcinomas and atypical melanocytic nevi with transition to secondary melanomas. Furthermore, hair alterations and xerosis are possible.Treatment with BRAF and MEK inhibitors requires close dermatologic monitoring of the patient. This manuscript summarizes the most frequent cutaneous side effects and their management.

Oral lichen planus is a mucosal inflammatory disease whose pathogenesis is unclear. The chronic inflammation leads to development of a squamous cell carcinoma in 1-2% of the patients; we present an exemplary case.

To compare the prognostic value of scoring systems in primary myelodysplastic syndromes (pMDS), four clinicohematological systems (Rennes, Bournemouth, Düsseldorf, Pavia) and the histopathological Hannover Scoring System were applied to 415 MDS patients from the Bone Marrow Registry of Hannover Medical School. According to the FAB classification, 180 patients (43%) were diagnosed as RA, 33 (8%) as RARS, 99 (24%) as RAEB, 36 (9%) as RAEBt, and 48 (12%) as CMMOL; 19 patients (4%) were not further classified (MDS.UC). All scoring systems revealed three or four groups of patients with significantly different survival times. The ranges and standard deviations in these groups were similar but high in all scoring systems. A good differentiation between short-term survivors (1 year survival time) and intermediate-term survivors (1-4 years) was possible with all tested scoring systems, but the differentiation between intermediate- and long-term survivors (4 years) was not distinctive enough. The problem of risk assessment in the single patient is furthermore elucidated by the values of specificity and sensitivity, which were relatively low in all scoring systems tested. Best results were yielded by the Bournemouth Score for long-term survivors and the Düsseldorf and Hannover Score for intermediate- and short-term survivors. Multivariate analysis of all parameters used in the scoring systems showed the highest negative impact on survival for increase of myeloblasts, anemia, myelofibrosis, high age of the patient, and abnormal localization of immature precursors (ALIPs). Therefore, the histopathological Hannover Scoring System is not only equal to clinicohematological risk assessment in pMDS, but also includes important independent prognostic parameters. Risk assessment for the individual low-risk MDS patient using only initial parameters may be rendered impossible due to the biological nature of pMDS. Therefore, sequential analysis is needed to elucidate random events which alter the prognosis.

Iatrogenic Kaposi sarcomas (KS) in organ transplant recipients are often treated by switching immunosuppressive therapy to an mTOR inhibitor, such as sirolimus or everolimus, as these have immunosuppressive as well as anti-tumor effects. We report on an 80-year-old male patient who developed a disseminated cutaneous KS during therapy with prednisone and azathioprine for myasthenia gravis. After discontinuation of azathioprine therapy and despite continuing therapy with cortisone, the KS progressed and autoantibody levels against the nicotinic acetylcholine receptor increased. During the administration of everolimus, a long-term near-complete remission of KS and a decrease in autoantibodies took place. This case study illustrates that even in non-organ transplant patients with iatrogenic KS, switching to immunosuppressive therapy using an mTOR inhibitor can be beneficial.

Radical lymphadenectomy for malignant melanoma continues to be controversial. In order to reduce morbidity but preserve prognostic informations, a minimally invasive technique for the iliac part of dissection was developed. We evaluated the practicability of this intervention under routine conditions as well as its prognostic impact. A total of 106 patients with tumor cell involvement of at least one inguinal lymph node underwent open inguinal dissection combined with a minimally invasive iliac dissection. Perioperative and postoperative data on morbidity, survival, and histopathological features of the primary and the dissected specimens were collected. Histopathological data were evaluated statistically for their prognostic relevance. Of the 106 patients, 38 showed evidence of additional metastases in the resected specimen, of which 11 cases were related to the iliac portion. Detection of lymph node metastases in the specimen was significantly correlated with a poorer prognosis, while out of all factors implicated, a new prognostic factor comprising iliac tumor involvement and primary tumor ulceration showed the strongest statistical correlation with prognosis. The median dissection time was 137 min, 58 min devoted to the iliac part. Complications necessitating reoperation (n = 7) related only to the inguinal wound area. Minimally invasive iliac lymph node dissection is ready for clinical routine. The additional information obtained by the iliac dissection—in particular, in combination with primary tumor ulceration—is of important prognostic relevance. Further development of this technique performing a completely minimally invasive ilioinguinal dissection may confer additional advantages.

Agents used in medical tumor therapies can cause peculiar cutaneous side effects. In particular the newly developed targeted therapies are associated with specific cutaneous side effects, such as a papulopustular exanthems associated with EGFR inhibitors and epithelial skin cancers associated with inhibitors of mutated BRAF. In this review the clinical pictures as well as pathogenetic and therapeutic aspects of the hand-foot-syndrome, papulopustular exanthems, epithelial skin cancers, paronychia and changes of hair and nails as side effects of medical tumor therapies are summarized. Knowledge of these side effects is important to avoid interruption or termination of the tumor therapy, in particular since some of the cutaneous reactions have been shown to correlate with the therapeutic benefit of the tumor therapy.

Histamine is an important mediator of allergic reactions, and recent studies indicated that the function of different types of antigen presenting cells (APC) can be modulated by histamine, in particular via the newly described histamine H(4) receptor (H(4)R). Therefore, we investigated possible interactions of histamine via the H(4)R on Langerhans cells (LC), which represent the professional APC in the skin and therefore have an important role in the initiation and maintenance of allergic skin diseases.The expression of the H(4)R was evaluated by real-time PCR, flow cytometry and immunofluorescence staining. The function of the H(4)R was determined by intracellular flow cytometric measurement of chemokine production and LC migration assays.Here, we show H(4)R expression on in vitro generated monocyte-derived LC (mRNA and protein) and on primary LC from murine and human skin samples (protein). The immunofluorescence staining in murine and human skin samples clearly proved that LC express the H(4)R in situ. Stimulation with histamine or a H(4)R agonist downregulated the chemokine (C-C motif) ligand 2 (CCL2) in human monocyte-derived LC and primary LC. Prestimulation with a selective H(4)R antagonist abolished this effect. Moreover, migration of LC from the epidermis was increased after H(4)R agonist stimulation in ex vivo migration assays using human epidermis and murine in vivo assays.Our findings show that LC express a functional H(4)R and point towards a possible pathogenic relevance of the H(4)R in inflammatory and allergic diseases.

Treatment of autoimmune bullous diseases, especially of the pemphigus diseases, regularly requires the use of immunosuppressive drugs, often with insufficient clinical benefit but considerable side effects. A variety of autoimmune diseases (such as rheumatoid arthritis, lupus erythematosus, pemphigus vulgaris) have been successfully treated with rituximab, a chimeric monoclonal antibody against CD20, leading to a transient depletion of B cells. We report on three patients with pemphigus foliaceus who responded to rituximab after failing multiple other immunosuppressive therapies. We also examine the controversial issue of continuation therapy with rituximab in detail.

A 47-year-old immunocompetent man presented with a nodule on the right side of the upper lip that appeared suddenly and grew rapidly. Histological examination was consistent with the diagnosis of keratoacanthoma which is often associated with immunosuppression. Low-risk HPV type 11 was detected in the PCR analysis. While formerly one often waited for spontaneous regression of keratoacanthomas, today one routinely treats them as a well-differentiated squamous cell carcinoma. Complete surgical excision was not possible in our patient because of the size of the tumor. Radiation with a cumulative dose of 30 Gray (15 sessions of 2 Gray) led to complete remission. In addition to ultraviolet exposure, trauma, genetic factors and chemical carcinogens, HPV should be considered as a possible cofactor in the etiology of keratoacanthoma.

Intravascular lymphoma (IVL) is a rare subtype of extranodal large-B-cell lymphoma, histologically characterized by accumulation of clonal lymphocytes in small vessels of different organs. Overall survival is usually poor. The clinical manifestations are highly variable, depending on the involved organs. Cutaneous and neurological involvement is frequent; the cutaneous symptoms are heterogeneous with erythema, erythematous papules and plaques, generalized telangiectases and lesions resembling panniculitis or Kaposi sarcoma. IVL may also be limited to the skin; this entity is included the current classifications. We present here two patients with two different variants of IVL. One showed only skin involvement with panniculitis-like induration and responded well to therapy with Rituximab-CHOP (Rituximab plus Cyclophosphamide, Doxorubicin, Vincristine, Prednisolone). The other patient had distinctive cutaneous and neurological symptoms which did not respond to therapy. By means of these two patients, we present the heterogeneity of IVL and discuss current aspects of diagnosis and treatment.

The receptor of the epidermal growth factor (EGF-receptor) plays a role in the pathogenesis of many human carcinomas. Recent strategies in anti-tumor therapy target the EGF-receptor, e.g., by the EGF-receptor blocking monoclonal antibody cetuximab or by small molecules inhibiting the tyrosine kinase activity of the EGF-receptor, such as gefitinib and erlotinib. The EGF-receptor is also expressed in normal human skin; in clinical trials with different EGF-receptor inhibitors, cutaneous side effects were common. We report on cutaneous side effects of EGF-receptor blockade, in particular acneiform lesions, xerosis and paronychia, and discuss their management.

A 65-year-old patient presented with grey-brownish maculae localized on the face. He had been treated with oral terbinafine due to onychomycosis, and the first spots manifested after 4 weeks of therapy. Other drugs were not taken by the patient, who was otherwise in a healthy condition. Histology showed melanin localized within macrophages in the upper and lower dermis. Cutaneous side effects are well described in patients treated with terbinafine and usually present as urticaria or eczema. Severe reactions may occur in rare cases. Hyperpigmentation has not yet been described as a consequence of oral terbinafine. Grey hyperpigmentation as it occurred in our patient has been described as a side effect of therapy with minocycline, amiodarone, tricyclic antidepressants, or heavy metals. This case report shows that drug-induced hyperpigmentation should also be considered if the patient takes drugs not known for this kind of side effect.

A 61-year old female patient with cutaneous sarcoidosis was treated with fumaric acid esters (Fumaderm). After 12 months of therapy, lesions were markedly improved and treatment was discontinued. 18 months later, the cutaneous lesions recurred, angiotensin converting enzyme (ACE) serum levels were increased and a chest X-ray demonstrated pulmonary involvement. Therapy with fumaric acid esters was again started. The skin showed improvement after 2 months and completely cleared within 17 months, within 4 months ACE levels normalized, and within 10 months radiologic changes markedly resolved. This case demonstrates a possible role for fumaric acid esters not only in the treatment of cutaneous but also systemic sarcoidosis.

A 56-year old female patient with cutaneous sarcoidosis in the face was treated with fumaric acid esters and doxycycline without any effect. Topical tacrolimus led clinically and histologically to a nearly complete remission within three months, which continued after 4 months of follow-up.

Sentinel lymph node biopsy is an increasingly established procedure in the primary staging of high-risk melanoma patients. However, the laboratory evaluation of sentinel lymph node biopsies is a matter of controversy. The aim of this study was to determine the specificity of polymerase chain reaction (PCR) techniques for the evaluation of lymph nodes with regard to melanoma metastases in comparison with histology and immunohistology.Sentinel lymph nodes (n = 41) from 29 melanoma patients and 29 lymph nodes from 27 patients without melanoma were analysed by histology (HE) and immunohistology (Melan A, HMB45). cDNA of these lymph nodes was subjected to LightCycler PCR amplification using primers specific for tyrosinase and HMB45. Two melanoma sentinel lymph nodes contained naevus cells by histology and immunohistology and were therefore excluded from further evaluation. Eight (20.5%) of the remaining 39 melanoma sentinel lymph nodes were positive by histology and immunohistology and tyrosinase PCR, 15.4% (6/39) were positive only by tyrosinase PCR, 2.6% (1/39) were positive only by histology and immunohistology. HMB45 PCR revealed positive results in 7.7% (3/39) sentinel lymph nodes, which were also positive by tyrosinase PCR and histology and immunohistology. Of non-melanoma lymph nodes 13.8% (4/29) and 14.8% (4/27) of non-melanoma patients were positive by tyrosinase PCR but negative by histology and immunohistology and HMB45 PCR. Thus, tyrosinase PCR had a specificity of only 85.2%.The specificity of tyrosinase PCR and the sensitivity of HMB45 PCR are too low to recommend these PCR examinations for the guidance of therapy, in particular complete regional lymph node dissection.

Granulomatous skin changes following herpes zoster are uncommon and their pathogenesis is unclear. We demonstrated varicella-zoster virus in the granuloma tissue of an immunocompromised patient with postherpetic granulomas and use this finding as basis for discussing the pathogenesis of these lesions.

During the last decade an unusual amicrobial intertriginous pustulosis has been described in association with autoimmune disease in sixteen female patients. The clinical hallmark is a sterile pustular dermatosis preferentially located in intertriginous regions that responds to local or systemic corticosteroids. Histologic features are subcorneal sometimes spongiform neutrophilic pustules. We report an additional patient suffering from this unusual dermatosis. An overview of the patients described to date and a review of the literature are given in an attempt to delineate this amicrobial intertriginous pustulosis from the known pustular dermatoses.

Bart syndrome was described first by Bart in 1966; it represents the combination of congenital epidermolysis bullosa, congenital localized absence of skin affecting the extremities and shedding or dystrophy of nails. This syndrome may be of clinical relevance because of its more favourable prognosis in comparison with other forms of epidermolysis bullosa. We report two patients with Bart syndrome and focus on the question, if this syndrome represents a distinct entity or a variant of epidermolysis bullosa.

We report three new cases of the SAPHO syndrome. This acronyme consists of synovitis, acne, pustulosis, hyperostosis and osteitis. Symptoms of this syndrome, which may not all be present, are pustulotic skin diseases (pustulosis palmoplantaris or severe acne) associated with osteoarticular lesions (mainly sternoclavicular hyperostosis, spondylarthropathies or chronic recurrent multifocal osteomyelitis). The dermatological aspects of this syndrome are discussed in detail.