An Aesthetic Factor Priority List of the Female Breast in Scandinavian Subjects

Background: There is little consensus about the relative determinative value of each individual factor in female breast aesthetics. When performing breast surgery with an aesthetic goal, certain factors will be more important than others. The purpose of this study was to make an aesthetic factor rank list to determine the relative contributions to overall breast aesthetics. Method: Volunteers were scanned using the 3-dimensional Vectra system. Ten Scandinavian plastic surgeons rated 37 subjects, using a validated scoring system with 49 scoring items. The correlation between specific aesthetic factors and overall breast aesthetic scores of the subjects were calculated using Pearson's r, Spearman's rho, and Kendall's tau. Results: A very strong correlation was found between overall breast aesthetic score and lower pole shape (0.876, P <0.0001). This was also true for upper pole shape (0.826, P <0.0001) and breast height (0.821, P <0.0001). A strong correlation was found between overall breast aesthetic score and nipple position (0.733, P <0.0001), breast size (0.644, P <0.0001), and breast width (0.632, P <0.0001). Factors that were only moderately correlated with aesthetic score were intermammary distance (0.496, P = 0.002), nipple size and projection (0.588, P <0.0001), areolar diameter (0.484, P <0.0001), and areolar shape (0.403, P <0.0001). Perceived symmetry was a weak factor (0.363, P = 0.027). Conclusions: Aesthetic factors of the female breast can be ranked in a priority list. Shape of the lower pole and upper pole and breast height are primary factors of female breast aesthetics. These should be prioritized in any aesthetic breast surgery. Vertical dimensional factors seem to be more determinative than horizontal factors.Peer reviewe

2-cm versus 4-cm surgical excision margins for primary cutaneous melanoma thicker than 2 mm : long-term follow-up of a multicentre, randomised trial

Background: The optimal surgical excision margins are uncertain for patients with thick (>2 mm) localised cutaneous melanomas. In our previous report of this multicentre, randomised controlled trial, with a median follow-up of 6·7 years, we showed that a narrow excision margin (2 cm vs 4 cm) did not affect melanoma-specific nor overall survival. Here, we present extended follow-up of this cohort. Methods: In this open-label, multicentre randomised controlled trial, we recruited patients from 53 hospitals in Sweden, Denmark, Estonia, and Norway. We enrolled clinically staged patients aged 75 years or younger diagnosed with localised cutaneous melanoma thicker than 2 mm, and with primary site on the trunk or upper or lower extremities. Patients were randomly allocated (1:1) to treatment either with a 2-cm or a 4-cm excision margin. A physician enrolled the patients after histological confirmation of a cutaneous melanoma thicker than 2 mm. Some patients were enrolled by a physician acting as responsible for clinical care and as a trial investigator (follow-up, data collection, and manuscript writing). In other cases physicians not involved in running the trial enrolled patients. Randomisation was done by telephone call to a randomisation office, by sealed envelope, or by computer generated lists using permuted blocks. Patients were stratified according to geographical region. No part of the trial was masked. The primary outcome in this extended follow-up study was overall survival and the co-primary outcome was melanoma-specific survival. All analyses were done on an intention-to-treat basis. The study is registered with ClinicalTrials.gov, number NCT03638492. Findings: Between Jan 22, 1992, and May 19, 2004, 936 clinically staged patients were recruited and randomly assigned to a 4-cm excision margin (n=465) or a 2-cm excision margin (n=471). At a median overall follow-up of 19·6 years (235 months, IQR 200–260), 621 deaths were reported—304 (49%) in the 2-cm group and 317 (51%) in the 4-cm group (unadjusted HR 0·98, 95% CI 0·83–1·14; p=0·75). 397 deaths were attributed to cutaneous melanoma—192 (48%) in the 2-cm excision margin group and 205 (52%) in the 4-cm excision margin group (unadjusted HR 0·95, 95% CI 0·78–1·16, p=0·61). Interpretation: A 2-cm excision margin was safe for patients with thick (>2 mm) localised cutaneous melanoma at a follow-up of median 19·6 years. These findings support the use of 2-cm excision margins in current clinical practice. Funding: The Swedish Cancer Society, Stockholm Cancer Society, the Swedish Society for Medical Research, Radiumhemmet Research funds, Stockholm County Council, Wallström funds

Targeting AXL and the DNA damage response pathway as a novel therapeutic strategy in melanoma

Receptor tyrosine kinase AXL is found upregulated in various types of cancer, including melanoma, and correlates with an aggressive cancer phenotype, inducing cell proliferation and epithelial-to-mesenchymal transition. In addition, AXL has recently been linked to chemotherapy resistance, and inhibition of AXL is found to increase DNA damage and reduce expression of DNA repair proteins. In light of this, we aimed to investigate whether targeting AXL together with DNA damage response proteins would be therapeutically beneficial. Using melanoma cell lines, we observed that combined reduction of AXL and CHK1/CHK2 signaling decreased proliferation, deregulated cell-cycle progression, increased apoptosis, and reduced expression of DNA damage response proteins. Enhanced therapeutic effect of combined treatment, as compared with mono-treatment, was further observed in a patient-derived xenograft model and, of particular interest, when applying a three-dimensional ex vivo spheroid drug sensitivity assay on tumor cells harvested directly from 27 patients with melanoma lymph node metastases. Together, these results indicate that targeting AXL together with the DNA damage response pathway could be a promising treatment strategy in melanoma, and that further investigations in patient groups lacking treatment alternatives should be pursued

A Three-dimensional Ex Vivo Viability Assay Reveals a Strong Correlation Between Response to Targeted Inhibitors and Mutation Status in Melanoma Lymph Node Metastases

Although clinical management of melanoma has changed considerably in recent years, intrinsic treatment resistance remains a severe problem and strategies to design personal treatment regimens are highly warranted. We have applied a three-dimensional (3D) ex vivo drug efficacy assay, exposing disaggregated cells from 38 freshly harvested melanoma lymph node metastases and 21 patient derived xenografts (PDXs) to clinical relevant drugs for 7 days, and examined its potential to evaluate therapy response. A strong association between Vemurafenib response and BRAF mutation status was achieved (P ex vivo results, two tumors diagnosed as BRAF wild-type by routine pathology examinations had to be re-evaluated; one was subsequently found to have a complex V600E mutation, the other a double BRAF mutation (V600E/K601 N). No BRAF inhibitor resistance mechanisms were identified, but PIK3CA and NF1 mutations were identified in two highly responsive tumors. Concordance between ex vivo drug responses using tissue from PDXs and corresponding patient tumors demonstrate that PDX models represent an indefinite source of tumor material that may allow ex vivo evaluation of numerous drugs and combinations, as well as studies of underlying molecular mechanisms. In conclusion, we have established a rapid and low cost ex vivo drug efficacy assay applicable on tumor tissue from patient biopsies. The 3D/spheroid format, limiting the influence from normal adjacent cells and allowing assessment of drug sensitivity to numerous drugs in one week, confirms its potential as a supplement to guide clinical decision, in particular in identifying non-responding patients

An Aesthetic Factor Priority List of the Female Breast in Scandinavian Subjects

Background: There is little consensus about the relative determinative value of each individual factor in female breast aesthetics. When performing breast surgery with an aesthetic goal, certain factors will be more important than others. The purpose of this study was to make an aesthetic factor rank list to determine the relative contributions to overall breast aesthetics. Method: Volunteers were scanned using the 3-dimensional Vectra system. Ten Scandinavian plastic surgeons rated 37 subjects, using a validated scoring system with 49 scoring items. The correlation between specific aesthetic factors and overall breast aesthetic scores of the subjects were calculated using Pearson’s r, Spearman’s ρ, and Kendall’s τ. Results: A very strong correlation was found between overall breast aesthetic score and lower pole shape (0.876, P < 0.0001). This was also true for upper pole shape (0.826, P < 0.0001) and breast height (0.821, P < 0.0001). A strong correlation was found between overall breast aesthetic score and nipple position (0.733, P < 0.0001), breast size (0.644, P < 0.0001), and breast width (0.632, P < 0.0001). Factors that were only moderately correlated with aesthetic score were intermammary distance (0.496, P = 0.002), nipple size and projection (0.588, P < 0.0001), areolar diameter (0.484, P < 0.0001), and areolar shape (0.403, P < 0.0001). Perceived symmetry was a weak factor (0.363, P = 0.027). Conclusions: Aesthetic factors of the female breast can be ranked in a priority list. Shape of the lower pole and upper pole and breast height are primary factors of female breast aesthetics. These should be prioritized in any aesthetic breast surgery. Vertical dimensional factors seem to be more determinative than horizontal factors