Expression of Hedgehog signalling molecules in microcystic adnexal carcinoma.

BACKGROUND: Microcystic adnexal carcinoma (MAC) is a rare skin neoplasm that has not been characterized on a molecular basis. AIM: To assess expression profiles of Hedgehog (HH) signalling molecules in MAC and control tumours. METHODS: Immunohistochemistry was performed for Sonic Hedgehog (SHH), Indian Hedgehog (IHH), Patched 1 (PTCH1) and Smoothened (SMO) on patient MAC tissue (n = 26) and control tumour tissue, including syringoma (SyG; n = 11), trichoepithelioma (TE; n = 11) and basal cell carcinoma (BCC; n = 12) tissues. RESULTS: Patched 1 and SMO immunoreactivity was significantly higher in BCC than in SyG, TE or MAC (P < 0.001 and P < 0.03, respectively). The highest IHH expression was observed in BCC and TE compared with SyG and MAC (P < 0.04). Notably, the highest SHH protein expression was observed in SyG compared with MAC, TE and even BCC (P < 0.001). In patients with MAC, SMO immunoreactivity significantly (r = 0.51; P < 0.01) correlated with PTCH1 expression. Further correlation studies did not show significant associations between the HH expression markers assessed (P > 0.05). CONCLUSION: Our results indicate that alterations of the HH signalling are unlikely to play a major role in the pathogenesis of MAC, which is in contrast to the morphologically similar BCC and TE. Our observation provides additional information to the limited molecular pathology knowledge on this rare tumour.

Effectiveness, safety and utilization of vismodegib in locally advanced basal cell carcinoma under real-world conditions in Germany - The non-interventional study NIELS.

BACKGROUND: Basal cell carcinoma (BCC) can arise by the uncontrolled proliferation of cells from multiple epidermal compartments due to aberrant activation of the Hedgehog (Hh) signalling pathway. Vismodegib, a small-molecule inhibitor of this pathway, is approved for treatment of patients with locally advanced (la) BCC inappropriate for surgery or radiotherapy or patients with symptomatic metastatic (m) BCC. OBJECTIVES: The aim of this non-interventional study was to assess effectiveness with a special focus on duration of response (DOR), safety and utilization of vismodegib for treatment of laBCC in daily practice in Germany. METHODS: This non-interventional study (NIS) observed treatment of laBCC with vismodegib according to the German label in clinical practice. All available patients who had received at least one dose of vismodegib between commercial availability of vismodegib in Germany (02 August 2013) and 3 years before end of study (31 March 2016) could be included and were documented retrospectively and/or prospectively for up to 3 years. Primary effectiveness variable was DOR. Assessment of tumour response was carried out by the treating physicians. Exploratory variables included utilization of vismodegib, decision makers for therapy and method of tumour response evaluation. All statistical analyses were descriptive. RESULTS: Between September 2015 and March 2019, 66 patients were observed at 26 German centres. The objective response rate (ORR) was 74.2% and the disease control rate (DCR) was 90.9%. The median DOR was 15.9 months (95% CI: 9.2; 25.7; n = 49 patients with response). The median progression-free survival (PFS) was 19.1 months and the median time to response (TTR) 2.7 months. A total of 340 adverse events were reported in 63 (95.5%) patients; no new safety signals were identified. CONCLUSIONS: The NIS NIELS shows effectiveness and safety of vismodegib in patients with laBCC. It confirms the transferability of the results of the pivotal trial into routine clinical practice.

Long-term efficacy and safety of sonidegib in patients with advanced basal cell carcinoma: 42-month analysis of the phase II randomized, double-blind BOLT study.

BACKGROUND: Basal cell carcinomas (BCCs) exhibit aberrant activation of the hedgehog pathway. Sonidegib is a hedgehog pathway inhibitor approved for the treatment of locally advanced BCC (laBCC) and metastatic BCC (mBCC) based on primary results of the BOLT study [Basal Cell Carcinoma Outcomes with LDE225 (sonidegib) Treatment]. OBJECTIVES: This is the final 42-month analysis of the BOLT study, evaluating the efficacy and safety of sonidegib. METHODS: Adults with no prior hedgehog pathway inhibitor therapy were randomized in a 1 : 2 ratio to sonidegib 200 mg or 800 mg once daily. Treatment continued for up to 42 months or until disease progression, unacceptable toxicity, death, study termination or withdrawal of consent. The primary efficacy end point was the objective response rate (ORR) by central review, assessed at baseline; weeks 5, 9 and 17; then subsequently every 8 or 12 weeks during years 1 or 2, respectively. Safety end points included adverse event monitoring and reporting. RESULTS: The study enrolled 230 patients, 79 and 151 in the 200-mg and 800-mg groups, respectively, of whom 8% and 3.3% remained on treatment by the 42-month cutoff, respectively. The ORRs by central review were 56% [95% confidence interval (CI) 43-68] for laBCC and 8% (95% CI 0·2-36) for mBCC in the 200-mg group and 46·1% (95% CI 37·2-55·1) for laBCC and 17% (95% CI 5-39) for mBCC in the 800-mg group. No new safety concerns emerged. CONCLUSIONS: Sonidegib demonstrated sustained efficacy and a manageable safety profile. The final BOLT results support sonidegib as a viable treatment option for laBCC and mBCC. What's already known about this topic? Basal cell carcinoma (BCC) is usually treatable with surgery or radiation therapy, but there are limited treatment options for patients with advanced BCC. Sonidegib, a hedgehog pathway inhibitor approved for the treatment of advanced BCC, demonstrated clinically relevant efficacy and manageable safety in prior analyses of the phase II randomized, double-blind BOLT study [Basal Cell Carcinoma Outcomes with LDE225 (sonidegib) Treatment]. What does this study add? This final 42-month analysis of BOLT is the longest follow-up available for a hedgehog pathway inhibitor. Clinically relevant efficacy results were sustained from prior analyses, with objective response rates by central review of the approved 200-mg daily dose of 56% in locally advanced BCC and 8% in metastatic BCC. No new safety concerns were raised. The results confirmed sonidegib as a viable long-term treatment option for patients with advanced BCC.

Lysyl oxidase-like-2 mutations and reduced mRNA and protein expression in mid-dermal elastolysis.

BACKGROUND: Mid-dermal elastolysis (MDE) is a rare skin condition, characterized by selective loss of elastic fibres in the mid dermis. The pathogenesis of MDE is still unclear. AIM: To investigate expression of lysyl oxidase-like 2 (LOXL2) in a reasonable sample of patients with MDE and to search for mutations in LOXL2. METHODS: We investigated archived lesional tissue of 13 patients with MDE and skin tissue samples of 10 sex- and age-matched healthy controls (HCs). Gene and protein expression of LOXL2 was investigated using real-time reverse-transcription PCR and immunohistochemistry. Mutation analysis was performed using the Sanger method. RESULTS: We observed decreased LOXL2 mRNA expression in lesional skin of patients with MDE (0.48 ± 0.16) compared with healthy skin of the same patients (1.5 ± 0.51) and normal skin of HCs (1.9 ± 0.13). Compared with healthy patient skin (epidermis 2.38 ± 1.6, dermis 1.2 ± 1), LOXL2 protein expression in lesional patient skin (epidermis 1.1 ± 0.7, dermis 0.3 ± 0.45) was significantly decreased (P < 0.04 and P = 0.02, respectively). Mutation analysis of the entire LOXL2 gene could be performed for five patients, all of whom were found to have at least one mutation in the LOXL2 gene. Three of these had a mutation in the promoter region (c.967 G>C, c.1022 C>T, and c.1025 G>A, respectively), and one of them also had a mutation in the splice region of intron 11/exon 12 (IVS11-1 G>A). Of the remaining two patients, one had a mutation in exon 3 (T1391), and the other had a mutation in exon 11 (C663Y). CONCLUSIONS: Our present data suggest that decreased elastin renewal due to LOXL2 mutations and consecutive reduced LOXL2 expression contribute to the pathogenesis of MDE.

Is ultraviolet exposure acquired at work the most important risk factor for cutaneous squamous cell carcinoma? Results of the population-based case-control study FB-181.

BACKGROUND: Squamous cell carcinoma (SCC) is one of the most frequent types of cancer constituting a significant public health burden. Prevention strategies focus on limiting ultraviolet (UV) exposure during leisure time. However, the relative impact of occupational and nonoccupational UV exposure for SCC occurrence is unclear. OBJECTIVES: To investigate the association between occupational and nonoccupational UV exposure for SCC in a multicentre population-based case-control study hypothesizing that high occupational UV exposure increases the risk of SCC. METHODS: Consecutive patients with incident SCC (n = 632) were recruited from a German national dermatology network. Population-based controls (n = 996) without history of skin cancer were recruited from corresponding residents' registration offices and propensity score matched to cases. Lifetime UV exposure, sociodemographic and clinical characteristics were assessed by trained physicians. Occupational and nonoccupational UV exposure doses were estimated by masked investigators using established reference values. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were assessed using conditional logistic regression adjusting for relevant confounders. RESULTS: Total solar UV exposure was significantly associated with increased SCC. The OR for high (> 90th percentile) vs. low (< 40th percentile) and high vs, moderate (40-59th percentile) occupational UV exposure was 1·95 (95% CI 1·19-3·18) and 2·44 (95% CI 1·47-4·06) for SCC. Adjusting for occupational UV exposure, nonoccupational UV exposure was not significantly related to SCC incidence. Dose-response relationships were observed for occupational but not for nonoccupational solar UV exposure. CONCLUSIONS: Solar occupational UV exposure is a major determinant of incident SCC. Our findings indicate that prevention strategies should be further expanded to the occupational setting.

Erythrocyte sedimentation rate as an independent prognostic factor in mycosis fungoides.

BACKGROUND: Mycosis fungoides has a characteristically indolent clinical course, with a slow progression from patches over plaques to tumours. In advanced stages, with generalized skin involvement or tumours, the prognosis is poor. Well defined prognostic parameters for the individual risc stratifications are rare. OBJECTIVES: To determine prognostic factors for mycosis fungoides. METHODS: In a retrospective monocenter study, we reevaluated 97 consecutive cases of mycosis fungoides seen at our clinic. We correlated various routinely accessed parameters with survival data. The parameters were "sex", "age at time of diagnosis", "age-adjusted erythrocyte sedimentation rate"?(ESR), and "anemia". RESULTS: We identified ESR as a highly significant prognostic marker for MF that also affects overall survival and disease specific survival (P = 0·0014). The five-years disease specific survival was 100% for patients without elevation of ESR, and 52·83% for patients with elevated ESR above normal range (P < 0·001). It is of main interest that the ESR is a significant prognostic marker also in the T2 stage of MF. For the other parameters there was no significant impact on disease specific survival. CONCLUSIONS: ESR has turned out as independent prognostic factor in mycosis fungoides.

Can regional anaesthesia for lymph-node dissection improve the prognosis in malignant melanoma?

BACKGROUND: Optimized anaesthetic management might improve the outcome after cancer surgery. A retrospective analysis was performed to assess the association between spinal anaesthesia (SpA) or general anaesthesia (GA) and survival in patients undergoing surgery for malignant melanoma (MM). METHODS: Records for 275 patients who required SpA or GA for inguinal lymph-node dissection after primary MM in the lower extremity between 1998 and 2005 were reviewed. The follow-up ended in 2009. Survival was calculated as days from surgery to the date of death or last patient contact. The primary endpoint was mortality during a 10 yr observation period. RESULTS: Of 273 patients included, 52 received SpA and 221 GA, either as balanced anaesthesia (sevoflurane/sufentanil, n=118) or as total i.v. anaesthesia (propofol/remifentanil, n=103). The mean follow-up period was 52.2 (sd 35.69) months after operation. Significant effects on cumulative survival were observed for gender, ASA status, tumour size, and type of surgery (P=0.000). After matched-pairs adjustment, no differences in these variables were found between patients with SpA and GA. A trend towards a better cumulative survival rate for patients with SpA was demonstrated [mean survival (months), SpA: 95.9, 95% confidence interval (CI), 81.2-110.5; GA: 70.4, 95% CI, 53.6-87.1; P=0.087]. Further analysis comparing SpA with the subgroup of balanced volatile GA confirmed this trend [mean survival (months), SpA: 95.9, 95% CI, 81.2-110.5; volatile balanced anaesthesia: 68.5, 95% CI, 49.6-87.5, P=0.081]. CONCLUSIONS: These data suggest an association between anaesthetic technique and cancer outcome in MM patients after lymph-node dissection. Prospective controlled trials on this topic are warranted.

[Diffuse brown discoloration of skin, mucosa and urine]. / Diffuse Braunfärbung von Haut, Schleimhaut und Urin.

A 45-year-old woman presented with diffuse melanosis, icteric sclera and melanuria. Physical examination revealed a massive nodular melanoma with ulceration and satellite metastases on the back. Further investigation showed distant cutaneous and visceral metastasis. After palliative debulking along with postoperative multidrug chemotherapy, the patient has shown objective disease regression for more than 11 months. However, it remains to be seen if disease regression will translate into increased survival.

[Malignant lymphoma of the skin: update on diagnostics and therapy of primary cutaneous B-cell lymphoma]. / Maligne Lymphome der Haut : Update zu Diagnostik und Therapie primär kutaner B-Zell-Lymphome.

The diagnosis of primary cutaneous B-cell lymphoma is made based principally on the results of histological investigations and staging. For an exact staging abdominal sonography and chest X-ray examinations and for appropriate clinical symptoms special investigations as well as radiological imaging procedures including PET are indicated in addition to conventional laboratory investigations. For therapy rituximab is normally administered as monotherapy in order to avoid over therapy of indolent lymphoma. Further options are radiotherapy and new approaches with electrochemotherapy as well as pegylated doxorubicin.

The regulatory T-cell phenotype in progressive mycosis fungoides.

In early stages mycosis fungoides (MF) often runs an indolent course. Nevertheless a small but significant part of these patients develop an aggressive, life threatening course. These patients usually were immunocompromised. In most of those cases the lymphoma cells express CD25. This raised the question if those lymphomas may express a regulatory phenotype. Recently a couple of in vitro and in vivo studies analyzed this issue with different methods. This review discusses the recent developments in this highly topical area of research.

Chemoimmunotherapy for cutaneous melanoma with dacarbazine and epifocal contact sensitizers: results of a nationwide survey of the German Dermatologic Co-operative Oncology Group.

PURPOSE: To scrutinize published data from small mono-centric studies and case reports which implicated high response rates and promising survival times for a combination therapy consisting of epifocal dinitrochlorobenzene (DNCB) and dacarbazine (DTIC) for metastasized melanoma. This therapy merges the effects of an allergic contact dermatitis elicited at the site of a cutaneous metastasis, and systemic chemotherapy. METHODS: We performed a retrospective survey with nine German centers and evaluated 72 patients treated from 1993 to 2005. RESULTS: The objective response rate in stage III melanoma (n = 39) was 62%. In contrast, only 9% objective responses were observed in 33 stage IV patients. Interestingly, more than half of patients with objective remissions remained progression-free for more than 1 year irrespective of the stage of disease. CONCLUSIONS: Epifocal DNCB combined with DTIC is effective in patients with regionally metastasized melanoma not amenable to surgery or isolated limb perfusion, whereas in stage IV disease in spite of few durable remissions the addition of DNCB does not improve the therapeutic efficacy of DTIC.

Left-sided laterality of Merkel cell carcinoma in a German population: more than just sun exposure.

BACKGROUND: Lateral distribution of cancer has been observed previously. Most evident is this laterality in ultraviolet (UV)-induced skin cancer, based on an unequally distributed UV exposure. OBJECTIVES: The aim of this study was to explore whether patients from Germany also show asymmetrical lateral distribution of Merkel cell carcinoma (MCC). METHODS: In total, 115 patients with MCC were studied for laterality of the primary tumour. Correlation of clinical variables with lateral distribution of MCC was investigated as well. RESULTS: In 64/115 (55.7%) patients, primary tumours were present on the left side, in 37/115 (32.2%) on the right side, and in 14/115 (12.2%) in the midline (P < 0.0001). Excluding the latter localization occurrence of left-sided MCCs (64 of 101/63.4%) was significantly (P = 0.0072) more often observed (1.73-fold) when compared to right-sided tumours (37 of 101/36.6%). The excess of left-sided tumours was found on the head with a left-right ratio of 1.8, trunk of 8, arm of 1.2, and leg of 1.8. There was no significant association between laterality and gender, age, MCPyV status, and anatomic localization of primary tumours including the occurrence in sun-exposed sites. CONCLUSIONS: Occurrence of left-sided MCCs was significantly more often observed when compared to right-sided tumours. Laterality was not associated with tumour presentation at chronically ultraviolet-exposed sites. Hence, the reason for laterality in MCC remains obscure, but likely goes beyond UV exposure.

Prognostic relevance of high atonal homolog-1 expression in Merkel cell carcinoma.

BACKGROUND: It has recently been reported that atonal homolog 1 (ATOH1) gene is down-regulated in Merkel cell carcinoma (MCC) and thus may represent a tumor suppressor gene. OBJECTIVES: We aimed to test for ATOH1 gene mutations and expression levels in MCC tissues and cell lines. METHODS: Genomic DNA isolation and amplification via PCR was successfully performed in 33 MCCs on formalin-fixed paraffin-embedded tissue and three MCC cell lines, followed by Sanger sequencing of the whole ATOH1 gene to detect genomic aberrations. ATOH1 mRNA levels were determined by RT-PCR. Immunohistochemistry of ATOH1 was performed to quantify protein expression in tumor samples and cell lines. RESULTS: Neither in any of the 33 MCC tissue samples nor in the three cell lines ATOH1 mutations were present. ATOH1 was expressed in all lesions, albeit at different expression levels. Univariate analysis revealed that the total immunohistology score significantly correlated with the occurrence of tumor relapse (r = 0.57; P = 0.0008). This notion was confirmed in multivariate analysis suggesting that ATOH1 expression is a potential independent predictor for tumor relapse in MCC patients (P = 0.028). MCC-related death also correlated with ATOH1 expression (r = 0.4; P = 0.025); however, ATOH1 expression did not retain its predictive value in the regression model. CONCLUSIONS: In contrast to anecdotal reports ATOH1 expression is not lost by genetic alterations in MCC. However, protein expression of ATOH1 is increased in advanced MCC indicating that ATOH1 is involved in MCC progression.

Cutaneous Angiosarcoma of Head and Neck: A New Predictive Score for Locoregional Metastasis.

OBJECTIVES: Cutaneous angiosarcoma of head and neck (cAS-HN) is a malignant neoplasm with deficient data on prognostic factors. The aim of this study is to present our monocenter database on cAS-HN so far and a new predictive score for locoregional metastasis (LRM). METHODS: Retrospectively, tumor characteristics and outcome of 103 consecutive patients with cAS-HN were analyzed. The main predictors of LRM (identified by univariate and multivariate statistics) were combined to a LRM risk score. The prognostic values of stratification into high-, medium-, and low-risk groups concerning disease-specific survival (DSS), distant metastasis (DM), and progression-free survival (PFS) were evaluated. RESULTS: LRM (n = 29) and control (n = 74) groups differed significantly concerning several tumor characteristics and outcome (DM, PFS, and DSS). Patients developing LRM showed 3-, 5-, and 10-year survival rates of 32%, 16%, and 11% (mean DSS time of 36.7 months [95% confidence interval (CI) 20.5-52.8]) compared to 81%, 73%, and 69% (mean DSS time of 292.4 months [95% CI 208.4-376.5]) in controls without LRM (P < .001). The main predictors were American Joint Committee on Cancer (AJCC) stage, tumor extent, and origin of the primary tumor. The LRM risk score revealed significant higher values for the LRM group [7.14 (SD 1.46) vs 4.88 (SD 1.89), P < .001]. The high-risk group showed significantly higher risk for DM and more unfavorable DSS and PFS. CONCLUSION: The LRM risk score is a simple way to estimate the risk for LRM and DM, to stage patients, and to determine treatment options.

Strong hyperon-nucleon pairing in neutron stars.

We explore the possibilities of hyperon-nucleon pairing, involving lambda or sigma- hyperons, using different Nijmegen hyperon-nucleon potentials. We find possible very large nsigma- gaps and estimate their relevance for neutron star physics.

Order of Three-Phase (Solid-Liquid-Gas) Contact Line Tension Probed by Simulation of Three-Phase Contact Line Expansion on Small Hydrophobic Spheres

Expansion of the three-phase (solid-liquid-gas) contact line on the surface of silanated glass spheres was experimentally studied by means of a CCD high-speed video technique. The dependence of the central angle (measured at the particle center) of the contact line on time was determined. This dependence was theoretically simulated. Results of this simulation show a strong effect of line tension on the kinetics of the three-phase contact expansion. Order of the line tension (&mgr;J/m) is the same as that determined by A. W. Neumann and co-workers for similar hydrophobic surfaces by means of different techniques.