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Background: Sentinel lymph node biopsy (SLNB) is a critical staging tool for melanoma patients. The optimal number of lymph nodes removed in SLNB remains unclear. In this study, we retrospectively analysed and tested different criteria for selecting sentinel lymph nodes (SLNs) by radiotracer uptake and blue dye, and their impact on nodal staging. We also evaluated the association between SLN tumour burden and radiotracer uptake., Methods: The study population consisted of melanoma patients undergoing SLNB. During the operation all radioactive and blue nodes were removed and sent for histopathological analysis. The ex vivo radioactive count and presence of blue dye of each node were recorded, and these were correlated with presence and size of metastasis in each SLN., Results: Altogether 175 patients with clinically occult metastasis presented with one or more positive, i.e. metastatic, SLNs. The mean number of lymph nodes removed was 4.5, and the mean number of positive lymph nodes was 1.5 per patient. The most radioactive or hottest node was negative in 38 patients (22%). By removing the hottest node and all nodes with radioactivity >10% of the hottest node, 97% of patients would have been staged correctly. In five patients, metastasis was found solely in a SLN with radioactivity <10% of the hottest node. Of all 267 positive nodes removed, 125 (47%) contained blue dye. Patients with a negative hottest node were associated with lower SLN tumour burden., Conclusions: By removing the hottest node and all nodes with radioactivity >10% of the hottest node, 97% of patients with SLN metastases are correctly staged with or without using blue dye.

Introduction: Cutaneous squamous cell carcinoma (cSCC) shows malignant behaviour in 3-4% of patients with locoregional metastases and a poor prognosis, metastases that are difficult to predict clinically. Therefore, sentinel lymph node biopsy (SLNB) has been assessed, with contradictory findings thus far. We aimed to clarify the prognostic value of SLNB in high-risk cSCC patients., Patients and Methods: We completed a retrospective clinical study amongst 63 patients, preoperatively classified as N0 with a high-risk primary cSCC of the head and neck who underwent SLNB between 2001 and 2014 at Helsinki University Hospital (Finland). Considered high risk, the inclusion criteria comprised at least two of the following characteristics: tumour diameter ≥10 mm and/or thickness ≥4 mm and a specific tumour location, such as the lips, ear, scalp and central face. Patients were followed-up postoperatively for a median of 4.1 years (0.2-13.8 years)., Results: Only four (6.3%) patients had positive sentinel nodes. One of these patients died of cSCC, while the other three ultimately survived their disease. Five (7.9%) patients showed a negative SLNB, but developed recurrence within one year postoperatively. Recurrence appeared in the neck lymph nodes concurrently with locoregional soft-tissue invasion in all patients. Amongst these patients, three died for cSCC and the remaining two from other causes. Comparing the SLNB-positive and SLNB-negative groups with recurrence, we identified no significant differences in terms of patient or tumour characteristics., Conclusions: SLNB appears to carry no prognostic value for identifying recurrent disease amongst high-risk cSCC in the head and neck area., Competing Interests: Declaration of Competing Interest Each author declares no financial conflicts of interest with regard to the data presented in this manuscript., (Copyright © 2021 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)

Therapy options for patients with metastatic melanoma (MM) have considerably improved over the past decade. However, many patients still need effective therapy after unsuccessful immunotherapy, especially patients with BRAF-negative tumors who lack the option of targeted treatment second line. Therefore, the elucidation of efficient and personalized therapy options for these patients is required. In this study, three patient-derived cancer cells (PDCs) were established from NRAS Q61-positive MM patients. The response of PDCs and five established melanoma cell lines (two NRAS-positive, one wild type, and two BRAF V600-positive) was evaluated toward a panel of 527 oncology drugs using high-throughput drug sensitivity and resistance testing. The PDCs and cell lines displayed strong responses to MAPK inhibitors, as expected. Additionally, the PDCs and cell lines were responsive to PI3K/mTOR, mTOR, and PLK1 inhibitors among other effective drugs currently undergoing clinical trials. Combinations with a MEK inhibitor were tested with other targeted agents to identify effective synergies. MEK inhibitor showed synergy with multikinase inhibitor ponatinib, ABL inhibitor nilotinib, PI3K/mTOR inhibitor pictilisib, and pan-RAF inhibitor LY3009120. The application of the patients' cancer cells for functional drug testing ex vivo is one step further in the process of identifying potential agents and agent combinations to personalize treatment for patients with MM. Our preliminary study results suggest that this approach has the potential for larger-scale drug testing and personalized treatment applications in our expansion trial. Our results show that drug sensitivity and resistance testing may be implementable in the treatment planning of patients with MM., (Copyright © 2021. Published by Elsevier Inc.)

Background: Lower limb or trunk melanoma often presents with femoral and pelvic sentinel lymph nodes (SLNs). The benefits of harvesting pelvic lymph nodes remain controversial. In this retrospective study, the frequency and predictors of pelvic SLNs (PSLNs), and the impact of PSLNs on survival and staging was investigated., Methods: Altogether 285 patients with cutaneous melanoma located in the lower limb or trunk underwent sentinel lymph node biopsy of the inguinal/iliac lymph node basin at Helsinki University Hospital from 2009-2013. Patient characteristics, detailed pathology reports and follow-up data were retrieved from hospital files. Subgroups of patients categorized by presence of PSLNs were compared for outcome parameters including progression-free survival, melanoma-specific survival and groin recurrence., Results: Superficial femoral/inguinal SLNs were present in all patients and 199 (69.8 per cent) also had PSLNs removed. Median number of SLNs per patient was five and median number of PSLNs was two. Sixty-three patients (22.1 per cent) had metastases in their SLNs and seven (2.5 per cent) had metastases in PSLNs. A single patient had metastases solely in PSLNs, while superficial SLNs remained negative. Harvesting PSLNs or the number of PSLNs retrieved had no impact on progression-free survival or overall survival. The removal of PSLNs did not affect the risk of postoperative seroma or lymphoedema. The only predictor of positive PSLNs was radioactivity count equal to or more than that of the hottest superficial SLNs., Conclusion: Pelvic SLNs have minimal clinical impact on the outcome of melanoma patients especially in cases with negative superficial femoral/inguinal SLNs. Removal of PSLNs should be considered when they are the most radioactive nodes or equal to the hottest superficial femoral/inguinal SLNs in lymphoscintigraphy or during surgery.Preliminary results were presented in part at the International Sentinel Node Society Biennial Meeting, Tokyo, Japan, 11-13 October 2018., (© The Author(s) 2021. Published by Oxford University Press on behalf of BJS Society Ltd.)

Background: Sentinel node biopsy (SNB) is an important step in melanoma staging and prognostication. It is commonly performed for patients with intermediate thickness melanomas, based on clinicopathological features. However, only 20-25% of patients eventually demonstrate nodal involvement. The aim of this study was to evaluate whether tissue biomarkers with links to melanoma biology, together with clinicopathological parameters, could aid in the prediction of sentinel node involvement and improve selection of patients for SNB. In addition, we examined the role of these clinical or biological markers in disease outcome., Methods: We collected a case-control cohort of 140 intermediate thickness (Breslow 0,9-4,0mm) melanoma patients with or without SNB involvement matched for age, gender, Breslow thickness and location. From this cohort, we tested the predictive value of common clinicopathological parameters (ulceration, mitotic count and tumor regression) and FMNL-2, ezrin and BRAF V600E immunoreactivity, for sentinel node involvement and survival. We further analyzed the correlations in the superficial spreading melanoma subtype., Results: Based on our case control analysis, of the markers, BRAF V600E status (p = 0.010) and mitotic count (p = 0.036) correlated with SNB involvement. SNB status was a strong independent prognosticator for recurrence free survival (RFS p<0.001), melanoma specific survival (MSS p = 0.000) and overall survival (OS p = 0.029). In the superficially spreading melanoma subgroup, BRAF V600E positivity indicated poorer RFS (p = 0.039) and OS (p = 0.012). By combining the Breslow thickness, mitotic count and BRAF immunohistochemistry, we identified a group of superficially spreading melanomas with an excellent survival probability independent of SNB status., Conclusions: These results demonstrate that BRAF immunohistochemistry could serve as a useful addition to a marker panel for selecting intermediate thickness melanoma patients for SNB., Competing Interests: The authors have declared that no competing interests exist.

Skin biopsy due to a changed appearance of a skin mole is a common cause for visiting a doctor. Skin biopsy is a surgical procedure involving the usual surgical complications that can be avoided with careful planning. Histological microscopic examination is the indication for skin biopsy. The main principle should be that if the patient or the physician is concerned about the skin tumor, it should be removed and referred for further analysis and definitive diagnosis.

The aim of this study was to clarify the roles of the tumour proliferation marker Ki-67, the anti-apoptotic protein Bcl-2 and the cell cycle regulator p53 in primary cutaneous and metastatic melanoma. One hundred and seventeen primary melanomas and 18 metastatic tissue samples were analysed for immunohistochemical expression of Ki-67, Bcl-2 and p53. The staining results were correlated with disease progression and clinical outcome. The patient population comprised patients diagnosed with melanoma between 1988 and 1991. The clinical follow-up period for disease recurrence was 4.6 years (median; range, 0.2-7.5 years) and the follow-up period for overall survival was 10.0 years (median; range, 8.6-15.6 years). Ki-67 expression was not a prognostic factor in primary melanoma. High Bcl-2 expression was associated with such adverse prognostic factors as male gender, old age of the patient and tumour ulceration. High Bcl-2 expression was also associated with an adverse prognosis in intermediate-thickness (1.01-4.0 mm) melanomas (n=52) for disease-free (P=0.09) and overall (P=0.08) survival. In multivariate analysis, tumour thickness was the strongest prognostic factor for disease-free survival (P<0.01). High p53 expression indicated a poorer prognosis (P=0.05). In metastatic melanoma, the expression levels of Bcl-2 and p53 were lower than those in their primary counterparts (P=0.08 for each). Ki-67 expression showed no remarkable changes. It can be concluded that high p53 expression in tumour cells is associated with a poorer prognosis in primary melanoma, and high Bcl-2 expression in tumour cells is an adverse prognostic marker in intermediate-thickness primary melanoma.

Ezrin is a member of the ezrin-radixin-moesin family of proteins that link the actin-containing cytoskeleton to the plasma membrane. Ezrin is also connected to signaling molecules involved in the regulation of cell survival, proliferation and migration. Here, we examined the expression of ezrin in 95 primary cutaneous melanomas and correlated ezrin expression with conventional prognostic factors and biomarkers. From 12 patients metastatic tissue samples were also examined. In addition to ezrin staining, Mib-1 proliferation antigen, p53 and Bcl-2 were evaluated. Ezrin immunoreactivity was seen in most tumors; only 19 (20%) melanomas were negative. A total of 48 (51%) tumors had weak immunoreactivity and 28 (29%) strong immunoreactivity. The intensity of ezrin immunoreactivity was associated with tumor thickness (Breslow, P=0.0008) and with tumor invasion level (Clark, P=0.004), thicker tumors having stronger immunoreactivity. Also, there was a correlation between higher Mib-1 index in tumors and strong ezrin expression. All metastatic samples (n=12) showed positive ezrin immunoreactivity. In univariate analysis of survival, patients (n=76) with positive ezrin immunoreactivity had worse clinical disease behavior than those (n=19) without ezrin immunoreactivity, but the difference was not significant (P=0.19). In multivariate analysis of survival, the ezrin immunoreactivity was not a significant marker. The results indicate that ezrin is expressed in most primary melanomas of the skin and in all metastatic tumors. Ezrin expression correlates with tumor thickness and level of invasion suggesting an association between ezrin expression and tumor progression.

To investigate the prognostic value of tumour vascularity we studied 84 patients with primary melanomas ranging in tumour thickness (Breslow) from 0.37 to 7 mm and in depth of tumour infiltration (Clark) from II to V. Vascularization was assessed by immunohistochemistry with a CD-31 antibody recognizing endothelial cells. The CD-31-positive vessels were counted and the degree of vascularization was correlated with the survival of the patients. In addition, the relationship between blood vessel density and some histopathological data is discussed. In our study, the multivariate Cox model showed that the only independent variable in disease-free survival was tumour thickness (Breslow classification) and the only one in overall survival was depth of tumour infiltration (Clark classification). In disease-free survival, tumour thickness (Breslow classification) was a clear prognostic factor (P = 0.004) after 4 years' follow-up, as were depth of tumour infiltration (Clark classification) (P = 0.04) and ulceration (P = 0.04). In overall survival, tumour vascularity was the strongest prognostic factor at 4 years, high vascularity being associated with a good prognosis (P = 0.06). Clark classification was also a prognostic factor (P = 0.02) in overall survival. We conclude that high vascularization is associated with a better prognosis but is not an independent prognostic indicator.

We studied 145 children aged 7 years, who had been at day-care centers for at least 3 months during the 2 first years of their lives. The group was compared with a matched population of 145 children cared for at home. Of the 290 children, 212 participated in all phases of the study, which included a questionnaire to parents, skin prick tests with seven allergens, and a clinical examination. Day-care-center children had twice as much otitis media in infancy as "home" children (P less than 0.001), and they also tended to have more other infections. On the other hand, day-care-center children did not have more eczema in infancy, more cumulated atopic disease by the age of seven, or more positive skin tests than home children. When the groups were combined, an increased prevalence of cumulated atopic disease and positive skin tests was found in children with infections in infancy. We conclude that under the conditions of this study infections in infancy did not facilitate the development of hypersensitivity to allergens and atopic disease. The linked tendencies to develop infections and atopy could depend on some third factor.