CHEK2*1100delC and risk of malignant melanoma: Danish and German studies and meta-analysis

It is possible that reduced function of DNA repair and cell-cycle control genes increases the individual susceptibility to malignant melanoma. As CHEK2 is a cell-cycle master controller, we tested the hypothesis that heterozygosity for the frameshift alteration CHEK2*1100delC is associated with increased risk of malignant melanoma. First, we performed case-control studies of 1,152 Danish and 752 German individuals with malignant melanoma compared with 9,142 Danish and 3,718 German controls. Second, we performed a meta-analysis of CHEK2*1100delC and malignant melanoma, involving 2,619 cases and 17,481 controls. Third, we examined the risk of malignant melanoma associated with CHEK2*1100delC heterozygosity in an analysis stratified for sun exposure, as well as for subtype and location on the body. The odds ratios for malignant melanoma for CHEK2(*)1100del heterozygotes compared with those for noncarriers were 2.01 (95% confidence interval (CI), 1.03-3.91) in Danes, 1.42 (95% CI, 0.46-4.31) in Germans, and 1.79 (95% CI, 1.02-3.17) in Danes and Germans combined. In a meta-analysis, the odds ratio of malignant melanoma for CHEK2*1100delC heterozygotes compared with that for noncarriers was 1.81 (95% CI, 1.07-3.05). Stratifications did not alter these results. CHEK2*1100delC heterozygotes have a twofold risk of malignant melanoma compared with noncarriers.     

Brodalumab and ixekizumab,anti‐interleukin‐17‐receptor antibodies for psoriasis: a critical appraisal

Aim Papp et al. (N Engl J Med 2012; 366: 1181–9) and Leonardi et al. (N Engl J Med 2012; 366: 1190–9) respectively assessed the efficacy and safety of brodalumab (AMG 827), a human monoclonal antibody directed against interleukin (IL)‐17RA, the receptor of IL‐17A and ixekizumab (LY2439821), a humanized anti‐IL‐17 monoclonal antibody for the treatment of moderate‐to‐severe plaque psoriasis. Setting and design In these phase II, multicentre, randomized, double‐blind, placebo‐controlled, dose‐ranging studies, 198 patients with severe chronic plaque‐type psoriasis [Psoriasis Area and Severity Index (PASI) ≥ 12, body surface area (BSA) ≥ 10] were enrolled in Papp et al. between December 2009 and April 2010 and 142 patients in Leonardi et al. between April 2010 and March 2011. Study exposure In Papp et al., patients with chronic plaque‐type psoriasis were randomly assigned to receive placebo or brodalumab at a dose of 70, 140 or 210 mg, administered subcutaneously on day 1 and at weeks 1, 2, 4, 6, 8 and 10, or at a dose of 280 mg administered subcutaneously on day 1 and at weeks 4 and 8. In Leonardi et al., patients were randomly assigned to receive subcutaneous injections of placebo or 10, 25, 75 or 150 mg of ixekizumab at 0, 2, 4, 8, 12 and 16 weeks, followed by a 4‐week follow‐up period. Outcomes In both studies the PASI, static Physician’s Global Assessment (sPGA), Dermatology Life Quality Index (DLQI), adverse events, and routine haematological and laboratory values were analysed. Additionally in Papp et al. the BSA and Medical Outcomes Study 36‐item short‐form health survey, and in Leonardi et al. the joint pain visual analogue scale (VAS), itch severity VAS, Nail Psoriasis Severity Index (NAPSI) and the Psoriasis Scalp Severity Index (PSSI) were also measured. Primary outcome measures At week 12, in Papp et al. and Leonardi et al.: (A) The percentage improvement in PASI. In Leonardi et al. (and in Papp et al. as one of the secondary outcomes): (B) The percentage of patients who achieved a reduction in the PASI by at least 75% (PASI 75) over baseline. Results Primary endpoints: (A) At week 12 in Papp et al., the mean improvements in PASI were significantly greater in the 140, 210 and 280 mg brodalumab groups than in the 70 mg brodalumab group (85·9%, 86·3% and 76·0%, respectively, vs. 45·0%; P < 0·001); in addition, the mean improvement in PASI was significantly greater in each brodalumab group than in the placebo group (16·0%; P < 0·001). (At week 16 lower but still significant percentages compared with placebo were seen). In Leonardi et al., the mean improvements in PASI of the 10, 25, 75 and 150 mg ixekizumab groups are not reported. Significant differences between the two highest dose groups and the placebo group were seen as early as 1 week in PASI. (B) At week 12 in Papp et al., the percentages of patients with PASI 75 were 33% in the 70 mg, 77% in the 140 mg, 82% in the 210 mg and 67% in the 280 mg brodalumab group. The percentages of patients with a 50%, 75%, 90% or 100% improvement in PASI at week 12 were significantly higher among patients who received brodalumab (taking into account all doses) than among patients who received placebo. The authors do not give an explanation for the lower improvements at week 16. In Leonardi et al., the PASI 75 occurred in significantly more patients in the 25 mg (76·7%), 75 mg (82·8%) and 150 mg (82·1%) ixekizumab groups vs. placebo (7·7%; P < 0·001). No significant difference was seen for the 10 mg group. Significant differences between the 150 mg group and the placebo group were seen as early as 2 weeks in PASI 75. Differences were sustained through 20 weeks for all clinical measures in the ixekizumab study. Secondary endpoints: At week 12, in Papp et al., significant decreases of BSA, sPGA and DLQI were also seen. In Leonardi et al., significantly higher percentages of patients in the three highest ixekizumab dose groups had an sPGA score of 0 (clear of disease) or of 0 or 1 (minimal disease) for each dose and score group vs. placebo (P < 0·05). Significant reductions in the mean ± SD DLQI scores were detected at 8 weeks in the 150 mg ixekizumab group (?7·8 ± 5·7), the 75 mg ixekizumab group (?8·5 ± 5·1) and the 25 mg ixekizumab group (?7·1 ± 6·5) as compared with placebo (?2·4 ± 4·4) for all comparisons (P < 0·001). In addition, at 16 weeks, significantly more patients had a DLQI score of 0 in the 150, 75 and 25 mg ixekizumab groups (39·3%, 37·9% and 31·0%, respectively) as compared with placebo (0%) for all comparisons (P < 0·05). In Leonardi et al., significant reductions were seen in the PSSI, in the NAPSI and in the itch severity (VAS scores). Significant reductions from baseline of the joint pain VAS were also observed in the 150 mg ixekizumab group at 12 weeks, and this reduction was sustained through 20 weeks. At week 16: with respect to the other secondary efficacy endpoints and patient‐reported outcomes, significant improvements in scores were seen compared with placebo, but some of these differences were lower than observed at week 12. Safety Papp et al. summarized that during the first 12 weeks of the trial, 68% of the patients in the 70 mg brodalumab group, 69% (140 mg), 82% (210 mg), 73% (280 mg) and 62% in the placebo group had at least one adverse event. Although the authors mentioned only three serious adverse events, four were reported during the study: renal colic (70 mg brodalumab group), two patients with grade 3 asymptomatic neutropenia (210 mg brodalumab group; Papp et al. clarified that only one of these episodes was a serious adverse event) and an ectopic pregnancy in one patient in the placebo group. Leonardi et al. reported that there were no serious adverse events in any group. The frequency of adverse events was similar between the combined ixekizumab groups and the placebo group. A few patients were withdrawn from the trial due to adverse events including hypertriglyceridaemia (placebo group), peripheral oedema (10 mg ixekizumab), hypersensitivity (10 mg ixekizumab) and urticaria (25 mg ixekizumab). Conclusions Papp et al. and Leonardi et al. concluded that brodalumab and ixekizumab, respectively, significantly improved plaque psoriasis in 12‐week, phase II studies. For difficult‐to‐treat areas such as the scalp and nails, significant differences from placebo were observed with ixekizumab treatment. These trials were not large enough or of long enough duration to ascertain uncommon adverse events or to assess the risk of infection or cardiovascular events.     

Evidence and interdisciplinary consensus-based German guidelines: surgical treatment and radiotherapy of melanoma

The primary treatment of a melanoma is surgical excision. An excisional biopsy is preferred, and safety margins of 1 cm for tumor thickness up to 2 mm and 2 cm for higher tumor thickness should be applied either at primary excision or in a two-step procedure. When dealing with facial, acral or anogenital melanomas, micrographic control of the surgical margins may be preferable to allow reduced safety margins and conservation of tissue. The sentinel lymph node biopsy should be performed in patients whose primary melanoma is thicker than 1.0 mm and this operation should be performed in centers where both the operative and nuclear medicine teams are experienced. In clinically identified lymph node metastases, radical lymph node dissection is considered standard therapy. If distant metastases involve just one internal organ and operative removal is feasible, then surgery should be seen as therapy of choice. Radiation therapy for the primary treatment of melanoma is indicated only in those cases in which surgery is impossible or not reasonable. In regional lymph nodes, radiation therapy is usually recommended when excision is not complete (R1 resection) or if the nodes are inoperable. In distant metastases, radiation therapy is particularly indicated in bone metastases, brain metastases and soft tissue metastases.     

Melanoma of the ear: prognostic factors and surgical strategies

BACKGROUND: The ear's specific anatomical and lymphatic characteristics impose special requirements on the treatment of melanoma of the ear. OBJECTIVES: The aim of this prospective study was to define prognostic factors for melanoma of the ear and to evaluate surgical strategies for excision margins, histological evaluation and sentinel lymph node biopsy (SLNB) in order to achieve better cosmetic and functional results. PATIENTS AND METHODS: One-hundred and sixty-one patients with stage I/II melanoma of the external ear were treated in the Department of Dermatology, University of Tuebingen, from March 1976 to March 2004 (median follow-up 62 months). Malignant melanoma of the external ear represented 3% of the stage I/II cutaneous melanomas and 20% of the stage I/II head and neck melanomas recorded in the Melanoma Registry of the Department of Dermatology at the University of Tuebingen. Twenty of 42 lentigo maligna melanomas (LMM) underwent conventional histological evaluation, 22 underwent complete three-dimensional histology of excision margins (3D histology) in a paraffin-technique, i.e. micrographic surgery. SLNB was performed in 28 patients with melanomas thicker than 1.0 mm. Clinical, histological and surgical risk factors were evaluated by univariate and multivariate analysis. RESULTS: The median thickness of the tumours in the present study was 1.08 mm (mean 1.51 mm; range 0.18-8.50 mm), and the median excision margins were 11.0 mm (mean 12.61 mm; range 2.0-31.0 mm). The 3-year disease-specific survival rate was 98%, and the 3-year recurrence-free survival rate was 83%. Tumour thickness and invasion level were the only risk factors significant for disease-specific survival. Tumour thickness, location of the tumour and extent of excision margins were independently significant risk factors for recurrence-free survival. LMMs removed surgically with accompanying 3D histology were thicker than those examined by conventional histology (median 0.93 mm vs. 0.83 mm). The use of surgery with 3D histology, i.e. micrographic surgery, made it possible to reduce the excision margins (median 5 mm vs. 10 mm) without an increased risk of recurrence. Two of 29 SLNBs were positive (6.9%). There were six preregional recurrences after negative SLNB and one after positive SLNB. None of the patients who underwent SLNB died of melanoma-related causes during the observation period. CONCLUSIONS: This is the largest series of ear melanomas reported so far. The overall survival depended only on the tumour thickness and Clark level of invasion. Local recurrence was more frequent with smaller excision margins, but this did not influence the overall survival. Smaller excision margins under 3D-histological control did not carry an increased risk of local recurrence. Our results do not permit conclusions regarding the prognostic impact of SLNB for patients with melanoma of the ear.     

Basal cell carcinoma: histological classification and body-site distribution

BACKGROUND: Basal cell carcinoma (BCC) is the most common cancer worldwide in white-skinned populations. Recent studies suggest that BCC is not a single entity and that different histological subtypes show different clinical behaviour and might have different aetiology. OBJECTIVES: To provide information on the incidence of BCC by histopathological subtype and body site. METHODS: A case series of BCC from a prospective population-based register study collecting information on all excised and histologically confirmed skin cancers in Townsville, north Australia between 1997 and 1999. RESULTS: Age-standardized incidence rates for nodular BCC were 727.1 per 100 000 inhabitants per year for males and 411.8 for females, while rates for superficial BCC were 336.5 for males and 251.4 for females. Incidence rates for 'high risk' BCC were 261.3 for males, 146.5 for females with infiltrative, and 156.7 for males and 100.2 for females with micronodular types. Superficial BCC occurred at a younger age, particularly in female patients. For all histological subtypes and both genders relative tumour density was highest for the face, followed by the neck. An exception was superficial BCC in males, where the posterior trunk was second, followed by the neck. CONCLUSIONS: The study found a higher rate of superficial BCC than previous studies from less sun-exposed countries, and a more equal distribution of superficial BCC on face, trunk and limbs. These results seem to blur the difference between intermittent and continuous sun exposure as the causative environmental agents. The clinical implications of 'high risk' BCC rates are discussed.     

Noggin blocks invasive growth of murine B16-F1 melanoma cells in the optic cup of the chick embryo

Melanoma cells originate from the neural crest and are characterized by high migratory potential and invasive growth. After transplantation into the neural tube of the chick embryo, melanoma cells spontaneously emigrate along the neural crest pathways without tumor formation or malignant growth. This emigration depends on the constitutive over-expression of bone morphogenetic protein-2 (BMP-2) and can be ablated by the BMP-antagonist noggin. When transplanted into the embryonic optic cup, melanoma cells invade the host tissue and form malignant tumors. Here, we asked if the invasive growth of melanoma cells in the optic cup could be influenced by BMP-2 or noggin. Mouse B16-F1 cells were grown as aggregates, treated with BMP-2 or noggin during aggregation and transplanted into the optic cup of 3-day chick embryos. After 3 days of subsequent incubation, embryos were evaluated for melanoma cell invasiveness. Immunohistochemical examination revealed that untreated and BMP-2-treated melanoma cells had grown malignantly into the host tissue. However, noggin pretreatment of the aggregates had blocked melanoma cell invasiveness and tumor formation. We conclude that invasive growth of melanoma cells in vivo is BMP-dependent and can be ablated by noggin, thus rendering noggin a promising agent for the treatment of BMP-over-expressing melanoma.     

Molecular genetics of cutaneous squamous cell carcinoma: perspective for treatment strategies

Cutaneous squamous cell carcinoma (cSCC) represents 20% of all skin cancers. Although primary cSCCs can be successfully treated with surgery, a subset of highly aggressive lesions may progress to advanced disease, representing a public healthcare problem with significant cancer-related morbidity and mortality. A complex network of genes (TP53, CDKN2A, NOTCH1 and NOTCH2, EGFR and TERT) and molecular pathways (RAS/RAF/MEK/ERK and PI3K/AKT/mTOR) have been shown to play an important role in the pathogenesis of cSCC. The epigenetic regulation of TP53 and CDKN2A is an attractive therapeutic target for the treatment of cSCC, as well as NOTCH-activating agents capable to restore its tumour-suppressor function. EGFR inhibitors including both monoclonal antibodies (cetuximab and panitumumab) and tyrosine kinase inhibitors (erlotinib, gefitinib and dasatinib) have been used in clinical trials for the treatment of advanced cSCC, achieving only partial clinical benefit. Recently, an immune-modulatory drug (cemiplimab) has been introduced for the treatment of advanced cSCC with good clinical results and a favourable safety profile, while other PD1/PD-L1 inhibitors, either as monotherapy or in combination with targeted therapies, are currently under investigation. This review focuses on molecular findings involved in the pathogenesis of cSCC and their implications for the future development of new treatment strategies. In addition, current and ongoing treatments on targeted therapies and/or immunotherapy are illustrated.