Nivolumab for locally advanced and metastatic cutaneous squamous cell carcinoma (NIVOSQUACS study)-Phase II data covering impact of concomitant haematological malignancies.

BACKGROUND: Monoclonal antibodies, such as cemiplimab and pembrolizumab, against the programmed death receptor (PD)-1 have become the current standard of care and first-line treatment of advanced cutaneous squamous cell carcinoma (cSCC), proving remarkable clinical benefit and acceptable safety. OBJECTIVES: To assess efficacy and safety of the anti-PD-1 antibody nivolumab in patients with locally advanced and metastatic cSCC. METHODS: Patients received open-label nivolumab 240 mg intravenously every 2 weeks for up to 24 months. Patients with concomitant haematological malignancies (CHMs), either non-progressing or stable under active therapy, were eligible for inclusion. RESULTS: Of 31 patients with a median age of 80 years, 22.6% of patients achieved an investigator assessed complete response, resulting in an objective response rate (ORR) of 61.3% and a disease control rate (DCR) of 64.5%. Progression-free survival (PFS) was 11.1 months, and the median overall survival (OS) was not reached after 24 weeks of therapy. Median follow-up was 23.82 months. Subgroup analysis of the CHM cohort (n = 11; 35%) revealed an ORR of 45.5%, a DCR of 54.5%, a median PFS of 10.9 months, and median OS of 20.7 months. Treatment related adverse events were reported in 58.1% of all patients (19.4% grade 3, the remaining grade 1 or 2). PD-L1 expression and CD-8+ T-cell infiltration did not significantly correlate with clinical response, although a trend towards a shorter PFS of 5.6 months was observed with PD-L1 negativity and low CD8+ intratumoral infiltration. CONCLUSION: This study demonstrated robust clinical efficacy of nivolumab in patients with locally advanced and metastatic cSCCs and a tolerability comparable to data of other anti-PD-1 antibodies. Favourable outcomes were obtained despite involving the oldest hitherto reported study cohort for anti-PD-1 antibodies and a significant proportion of CHM patients prone to high risk tumours and an aggressive course otherwise typically excluded from clinical trials.

Does the time interval between sentinel lymph node biopsy and completion lymph node dissection affect outcome in malignant melanoma? A retrospective cohort study.

Nodal clearance was recommended after positive sentinel lymph node biopsy (SLNB) despite further metastases to the regional lymph node basin being found in only 6-21% in the literature. This retrospective study was conducted to determine the role of the time interval between excision of primary melanoma and confirmed metastasis in the sentinel lymph node biopsy as well as the one between positive sentinel lymph node biopsy (SLNB-positive patients) and subsequent completion lymph node dissection (CLND) on the presence of metastases. The monocentric analysis included 121 patients with a history of completion lymph node dissection after positive SLNB from January 2005 to October 2013. Additional metastases in the regional lymph node basin (non-sentinels) were found in 14.05% (n = 17). Significant risk factors for the presence of metastases in CLND were the time between confirmed primary tumour to metastasis in sentinel lymph nodes (SLN) (p = 0.0034), N-category of TNM-classification (p = 0.0066) and independent of thickness of primary tumour (p = 0.11). If SLNB was performed up to forty-three days after confirmed primary melanoma, subsequent lymph node dissection was positive in less than 9.1%. When SLNB was performed with a delay of more than 80 days, all patients had metastases in the CLND specimens. Our data analysis suggests that delays in subsequent procedures of SLNB after diagnosis of primary melanoma may have a greater impact on positivity of non-sentinel lymph nodes than previously assumed. Our retrospective analysis may indicate the reconsideration of time schedule in the management of primary melanoma to potentially avoid local relapse in the draining lymph node region after positive SLNB.

Problems and challenges of predatory journals.

The companies publishing predatory journals are an emerging problem in the area of scientific literature as they only seek to drain money from authors without providing any customer service for the authors or their readership. These predatory journals try to attract new submissions by aggressive email advertising and high acceptance rates. But in turn, they do not provide proper peer review, and therefore, the scientific quality of submitted articles is questionable. This is important because more and more people, including patients, are reading such journals and rely on the information they provide. Consequently, predatory journals are a serious threat to the integrity of medical science, and it is crucial for scientists, physicians and even patients to be aware of this problem. In this review, we briefly summarize the history of the open access movement, as well as the rise of and roles played by predatory journals. In conclusion, young and inexperienced authors publishing in a predatory journal must be aware of the damage of their reputation, of inadequate peer review processes and that unprofitable journals might get closed and all published articles in that journal might be lost.

Beyond the BRAFV600E hotspot: biology and clinical implications of rare BRAF gene mutations in melanoma patients.

BRAF gene mutations can be found in approximately 50% of melanomas, but the most common BRAF mutation leads to substitution at residue 600 of the protein, from valine to glutamic acid. BRAFV600E occurs in up to 95% of all melanoma cases and can be successfully blocked by using a combination of BRAF- and MEK inhibitors. The wider availability of next-generation sequencing is revealing more non-V600 BRAF mutations, and the clinical implications of these mutations are widely unknown. In this review, we will discuss the biology of the MAPK pathway and the different types of BRAF mutations as well as their effect on MEK activation. Current literature will be reviewed including in vitro data, case reports and case series.

Pregnancy as a driver for melanoma.

Whether or not pregnancy favours the occurrence and growth of melanoma is a source of controversy in the literature. Several case reports have shown dramatic courses of diseases in pregnancy. We present a case of a 36-year-old woman with multiple naevi with one melanoma detected in 2009 in the first trimester and a second primary melanoma in 2010 in the third trimester of her pregnancy. Both lesions have been present for at least 5 years and have been interpreted as dysplastic naevi. Because of their growth during pregnancy they were removed. No metastatic disease has been found between 2010 and early 2017. This case shows the difficulty of detecting melanomas in pregnancy, particularly when they mimic dysplastic naevi in women with multiple naevi, who are at higher risk. Therefore, we suggest that pregnant women with numerous naevi should be precautious of any changes of their naevi in size, shape and colour. Every suspicious lesion should be either excised or documented/monitored carefully, for example with sequential digital dermoscopy imaging.

Adjuvant treatment with pegylated interferon α-2a versus low-dose interferon α-2a in patients with high-risk melanoma: a randomized phase III DeCOG trial.

BACKGROUND: Adjuvant treatment with interferon (IFN)-α-2a improved disease-free survival (DFS) and showed a trend for improving overall survival (OS) in melanoma. This trial was designed to examine whether PEG-IFN is superior to IFN with regard to distant metastasis-free survival (DMFS), DFS and OS. PATIENTS AND METHODS: In this multicenter, open-label, prospective randomized phase III trial, patients with resected cutaneous melanoma stage IIA(T3a)-IIIB (AJCC 2002) were randomized to receive PEG-IFN (180 µg subcutaneously 1×/week; 24 months) or IFN α-2a (3MIU subcutaneously 3×/week; 24 months). Randomization was stratified for stage, number of metastatic nodes, age and previous IFN treatment. The primary end point was DMFS; secondary end points were OS, DFS, quality of life (QoL) and tolerability. RESULTS: A total of 909 patients were enrolled (451 PEG-IFN versus 458 IFN). Neither 5-year DMFS [PEG-IFN 61.0% versus IFN 67.3%; hazard ratio (HR) 1.16, P = 0.21] nor 5-year OS (PEG-IFN 73.2% versus IFN 75.2%; HR 1.05, P = 0.70) nor 5-year DFS (PEG-IFN 57.3% versus IFN 60.9%; HR 1.09, P = 0.40) showed significant differences. Subgroup analyses in patients ± ulcerated primaries and of different tumor stages did not find differences in DMFS, OS or DFS between the treatment groups. One hundred and eighteen patients (26.2%) in the PEG-IFN and 61 patients (13.3%) in the IFN population did not receive the full dosage and length of treatment due to adverse events (P < 0.001). Leukopenia and elevation of liver enzymes were more common in the PEG-IFN arm (56% versus 23.5% LCP; 19.1% versus 9.4% AST; 33.0% versus 16.5% ALT). QoL was identical for nearly all domains. CONCLUSION: PEG-IFN did not improve the outcome over IFN. A higher percentage of patients under PEG-IFN discontinued treatment due to toxicity. CLINICAL TRIALSGOV IDENTIFIER: NCT00204529.

Characterization of patients at high risk of melanoma in Austria.

BACKGROUND: Risk of melanoma is determined by genetic and exogenous factors. Only a few studies have included both characteristics in a comprehensive multivariable analysis. OBJECTIVES: To find determinants of patients at high risk of melanoma in Austria, including phenotype, genotype and lifestyle characteristics in comprehensive analyses. METHODS: In total, 1668 patients with melanoma from the M3 case-control study were studied. Overall, 567 participants were sequenced for CDKN2A, 232 for CDK4, 123 for MITF encoding the variant E318K and 964 for MC1R. RESULTS: Patients with melanoma with a positive family history (n = 190, 11·6%), multiple primary melanomas (n = 261, 15·7%) and younger age (< 50 years, n = 675, 40·5%) were defined as being at high risk. All other patients with melanoma were defined as the reference group. We found significant differences between those two groups and between the high-risk subgroups (positive family history, multiple primary melanomas and younger age). Pigmentation phenotype was associated with the high-risk group in general (childhood freckling, odds ratio 1·46, P = 0·007; blond/reddish hair colour, odds ratio 1·43, P = 0·011). Patients with a positive family history and patients with early-onset disease were similar regarding both their phenotypic characteristics and external factors. Established high-risk mutations in CDKN2A were found in cases with a positive family history (n = 12) or multiple melanomas (n = 2). Moreover, we found three patients carrying the MITF p.E318K variant, two with a CDK4 variant and seven with nonsynonymous MC1R variants with undescribed biological significance, of which four were predicted as damaging. CONCLUSIONS: Austrian patients could represent a reservoir for novel genetic variants. Further investigation of populations in Central and Eastern Europe might reveal more novel and disease-relevant variants.

Erythema nodosum-like lesions during BRAF inhibitor therapy: Report on 16 new cases and review of the literature.

IMPORTANCE: BRAF inhibitors have been licensed for the therapy of BRAF-mutated melanoma. Recently, inflammatory skin lesions clinically resembling erythema nodosum have been reported as therapy side-effects that may lead to treatment discontinuation. OBJECTIVE: To identify and characterize cases with BRAF inhibitor-associated erythema nodosum-like inflammatory skin lesions and development of an algorithm for their management. DESIGN AND SETTING: Retrospective chart review of melanoma patients treated with BRAF inhibitors in 14 departments of Dermatology in Germany and Austria and PubMed search for cases in the literature. RESULTS: Sixteen patients were identified who developed erythema nodosum-like lesions under BRAF inhibitor therapy; 14 had received vemurafenib and two dabrafenib plus trametinib. The most frequently involved body sites were the legs. Histopathology was performed in five cases and revealed panniculitis in three and vasculitis in two patients respectively. Arthralgia and fever were associated symptoms in 44% and 31% of patients respectively. Inflammatory symptoms led to discontinuation of treatment in three patients, while in the majority of cases symptomatic management was sufficient. Skin lesions finally resolved despite continued BRAF inhibitor therapy in seven patients. In the literature, 19 additional patients with similar cutaneous appearance under BRAF inhibitors could be identified. An algorithm for the management of such lesions is proposed. CONCLUSION: Erythema nodosum-like skin lesions histologically correspond to panniculitis and/or vasculitis. Symptomatic treatment may be sufficient. However, additional work-up and interruption of BRAF inhibitor therapy may be necessary in severe cases which are commonly associated with systemic symptoms.

Assessment of changes in lentigo maligna during radiotherapy by in-vivo reflectance confocal microscopy: a pilot study.

BACKGROUND: Radiotherapy is an effective treatment for therapy of lentigo maligna (LM). OBJECTIVES: To investigate the usefulness of in-vivo reflectance confocal microscopy (RCM) in radiotherapy of LM and document the changes within the lesions during treatment. METHODS: A total of six lesions in six patients were investigated by RCM before, during and after radiotherapy. For diagnostic assessment three observers with experience in RCM diagnosis, blinded as to the stage of treatment, assessed the RCM images of each lesion and documented the findings by consensus. RESULTS: Epidermal disarray worsened in three patients during radiotherapy and superficial necrosis was observed in four patients. Large pagetoid round/dendritic cells decreased or even vanished during or after radiotherapy. Dilated vessels and apoptotic cells were seen in all patients during radiotherapy as well as an increase of inflammatory cells in the epidermis and dermis in most of the patients. Dendritic cells with small dendrites were observed during radiotherapy in all patients with an increase in number in three patients. Melanophages appeared in five patients at least once during the examination period. All RCM images were assessed correctly by the three observers. CONCLUSIONS: Reflectance confocal microscopy is a useful method to visualize changes during and after radiotherapy and might also be used for early detection of potential treatment failures. In addition, it might be helpful in planning radiotherapy.

Proposal for a clinical-dermoscopic classification of scalp naevi.

BACKGROUND: Recent research suggests that scalp naevi differ with respect to their epidemiology, patient characteristics and morphological patterns, but currently a classification of scalp naevi is lacking. OBJECTIVES: To investigate the prevalence, together with clinical and dermoscopic features, of scalp naevi detected in persons attending a skin cancer screening programme, and to elaborate a classification of scalp naevi based on their most common morphological patterns. METHODS: Participants were recruited during the melanoma prevention programme 'sun watch' of Austrian Cancer Aid in Styria. Each participant received a clinical and dermoscopic total-body skin examination including the scalp. For each participant, demographics and clinical characteristics including number of scalp naevi were recorded. Clinical and dermoscopic photographs of at least one scalp naevus per participant were taken and evaluated for specific clinical and dermoscopic features. RESULTS: In total 867 subjects, including 119 participants (13·7%) with scalp naevi, participated in the study. Compared with those without scalp naevi, subjects with scalp naevi were significantly younger, were more often men and more often exhibited congenital naevi on the body (P < 0·01 for all). Analysis of the clinical and dermoscopic variability of scalp naevi allowed for a proposal to classify scalp naevi into six main groups, namely common, papillomatous, eclipse, congenital, blue and atypical naevus. CONCLUSIONS: Scalp naevi can be classified into six morphological groups; scalp lesions deviating from these six main patterns should be carefully managed to rule out melanoma.

Analysis of clinical, dermoscopic and histopathological features of primary melanomas of patients with metastatic disease--a retrospective study at the Department of Dermatology, Medical University of Graz, 2000-2010.

BACKGROUND: Incidence rates of malignant melanoma have been increasing worldwide and metastatic melanoma is still a significant problem despite widespread prevention programmes. OBJECTIVES: We made a systemic review of all metastasized melanoma patients treated at the Department of Dermatology, Medical University of Graz in the years 2000-2010 and looked at the kind of melanoma type, e.g. if it has been slowly growing superficial spreading melanoma (SSM) or fast growing nodular melanoma (NM). METHODS: Histological slides and clinical images of patients treated at our department between 2000 and 2010, who received chemotherapy because of proven metastatic disease were analysed with regard to growth type of their primary tumours. RESULTS: A total of 88 patients met the inclusion criteria. Mean age of all patients was 57 years (median 59 years, SD ± 15 years). Of these 88 patients 51 patients (58%) (28 male patients and 23 female patients) had SSM; mean age 58 years (median 58 years, SD ± 14 years) and 37 patients (42%) (18 male patients and 19 female patients) had NM; mean age 56 years (median 61 years, SD ± 17 years). Mean Breslow thickness in the SSM group was 2.26 mm (median: 1.6 mm, SD ± 2.11 mm). In the NM group, mean Breslow thickness was 4.59 mm (median: 3.50 mm, SD ± 4.07 mm). When separated by gender, 46 melanomas were seen in the male group (28 SSM and 18 NM) and 42 melanomas in the female group (23 SSM and 19 NM). CONCLUSIONS: Our results showed that more than half of the patients with metastatic disease had SSMs and not, as suspected, NMs. As SSMs are growing over a longer period to become invasive and potentially metastatic, there might be a chance to focus primary and secondary prevention programmes not only on fast growing tumours but also on slowly changes of tumours.

Patient acceptance and diagnostic utility of automated digital image analysis of pigmented skin lesions.

BACKGROUND: Computerized analysis of pigmented skin lesions may help to increase diagnostic accuracy for melanoma, help to avoid unnecessary procedures and reduce health care costs. OBJECTIVES: We evaluated both the patient acceptance and diagnostic utility of such an analysis tool in a real clinical setting. METHODS: Two hundred nine consecutive patients (median age: 34 years, range: 2-73 years), who were concerned about a pigmented skin lesion, answered a questionnaire about their attitude towards computerized analysis and their confidence in the resulting findings. Using a dermoscopy analyser, their skin lesions (n = 219) were then grouped into the categories, benign, suspicious and malignant, and results were compared with those obtained by in-person examination of dermato-oncologic experts. RESULTS: More than half of the patients (n = 114) would accept the use of computer analysis for melanoma screening; although 16 (14.0%) patients would accept this method solely, 98 (86.0%) patients would prefer an additional in-person examination by a dermatologist. Of the 219 pigmented skin lesions, the dermoscopic experts rated 171 (78.1%) as benign, 36 (16.4%) as suspicious and 12 (5.5%) as malignant, whereas computer analysis revealed 102 (46.6%) benign, 78 (35.6%) suspicious and 39 (17.8%) malignant lesions. At the expense of specificity (48.8%), the sensitivity of computerized analysis was excellent (100%) and equal to that of in-person examination. CONCLUSIONS: Most patients would accept computer analysis for melanoma screening, some of them even without reservations. However, due to a high rate of false positive computer assessments, it cannot be recommended as a screening tool at this time.

In vivo reflectance confocal microscopy: automated diagnostic image analysis of melanocytic skin tumours.

BACKGROUND: In vivo reflectance confocal microscopy (RCM) has been shown to be a valuable imaging tool in the diagnosis of melanocytic skin tumours. However, diagnostic image analysis performed by automated systems is to date quite rare. OBJECTIVES: In this study, we investigated the applicability of an automated image analysis system using a machine learning algorithm on diagnostic discrimination of benign and malignant melanocytic skin tumours in RCM. METHODS: Overall, 16,269 RCM tumour images were evaluated. Image analysis was based on features of the wavelet transform. A learning set of 6147 images was used to establish a classification tree algorithm and an independent test set of 10, 122 images was applied to validate the tree model (grouping method 1). Additionally, randomly generated 'new' learning and test sets, tumour images only and different skin layers were evaluated (grouping method 2, 3 and 4). RESULTS: The classification tree analysis correctly classified 93.60% of the melanoma and 90.40% of the nevi images of the learning set. When the classification tree was applied to the independent test set 46.71 ± 19.97% (range 7.81-83.87%) of the tumour images in benign melanocytic skin lesions were classified as 'malignant', in contrast to 55.68 ± 14.58% (range 30.65-83.59%; t-test: P < 0.036) in malignant melanocytic skin lesions (grouping method 1). Further investigations could not improve the results significantly (grouping method 2, 3 and 4). CONCLUSIONS: The automated RCM image analysis procedure holds promise for further investigations. However, to date our system cannot be applied to routine skin tumour screening.