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Linda Aagaard Rasmussen,1 Henry Jensen,1 Line Flytkjaer Virgilsen,1 Lisbet Rosenkrantz Hölmich,2,3 Peter Vedsted1 1Research Centre for Cancer Diagnosis in Primary Care (CaP), Research Unit for General Practice, Aarhus, Denmark; 2Department of Plastic Surgery, Herlev and Gentofte Hospital, Herlev, Denmark; 3Department of Clinical Medicine, Copenhagen University, Copenhagen, DenmarkCorrespondence: Linda Aagaard RasmussenResearch Unit for General Practice, Aarhus, DenmarkTel +45 8716 8369Fax +45 8612 4788Email linda.rasmussen@ph.au.dkPurpose: Information on cancer recurrence is rarely available outside clinical trials. Wide exclusion criteria used in clinical trials tend to limit the generalizability of findings to the entire population of people living beyond a cancer disease. Therefore, population-level evidence is needed. The aim of this study was to develop and validate a register-based algorithm to identify patients diagnosed with recurrence after curative treatment of malignant melanoma.Patients and Methods: Indicators of recurrence were diagnosis and procedure codes recorded in the Danish National Patient Register and pathology results recorded in the Danish National Pathology Register. Medical records on recurrence status and recurrence date in the Danish Melanoma Database served as the gold standard to assess the accuracy of the algorithm.Results: The study included 1747 patients diagnosed with malignant melanoma; 95 (5.4%) were diagnosed with recurrence of malignant melanoma according to the gold standard. The algorithm reached a sensitivity of 93.7% (95% confidence interval (CI) 86.8– 97.6), a specificity of 99.2% (95% CI: 98.6– 99.5), a positive predictive value of 86.4% (95% CI: 78.2– 92.4), and negative predictive value of 99.6% (95% CI: 99.2– 99.9). Lin’s concordance correlation coefficient was 0.992 (95% CI: 0.989– 0.996) for the agreement between the recurrence dates generated by the algorithm and by the gold standard.Conclusion: The algorithm can be used to identify patients diagnosed with recurrence of malignant melanoma and to establish the timing of recurrence. This can generate population-level evidence on disease-free survival and diagnostic pathways for recurrence of malignant melanoma.Keywords: melanoma, recurrence, algorithms, validation study, registries, Denmark

Else Helene Ibfelt,1,2 Marianne Steding-Jessen,1 Susanne Oksbjerg Dalton,3 Sanne Lykke Lundstrøm,2 Merete Osler,2 Lisbet Rosenkrantz Hölmich4 1The Danish Clinical Registries, Department for Cancer and Cancer Screening, Frederiksberg, Denmark; 2Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, Frederiksberg Denmark; 3Danish Cancer Society Research Center, Department of Cancer Survivorship, Copenhagen, Denmark; 4Department for Plastic Surgery, Herlev University Hospital, Copenhagen, Denmark Background: Socioeconomic differences in survival after melanoma may be due to late diagnosis of the disadvantaged patients. The aim of the study was to examine the association between educational level, disposable income, cohabitating status and region of residence with stage at diagnosis of melanoma, including adjustment for comorbidity and tumor type.Methods: From The Danish Melanoma Database, we identified 10,158 patients diagnosed with their first invasive melanoma during 2008–2014 and obtained information on stage, localization, histology, thickness and ulceration. Sociodemographic information was retrieved from registers of Statistics Denmark and data on comorbidity from the Danish National Patient Registry. We used logistic regression to analyze the associations between sociodemographic factors and cancer stage.Results: Shorter education, lower income, living without partner, older age and being male were associated with increased odds ratios for advanced stage of melanoma at time of diagnosis even after adjustment for comorbidity and tumor type. Residence in the Zealand, Central and Northern region was also associated with advanced cancer stage.Conclusion: Socioeconomically disadvantaged patients and patients with residence in three of five health care regions were more often diagnosed with advanced melanoma. Initiatives to increase early detection should be directed at disadvantaged groups, and efforts to improve early diagnosis of nodular melanomas during increased awareness of the Elevated, Firm and Growing nodule rule and “when in doubt, cut it out” should be implemented. Further studies should investigate regional differences in delay, effects of number of specialized doctors per inhabitant as well as differences in referral patterns from primary to secondary health care across health care regions. Keywords: melanoma, cancer stage, sociodemographic factors, comorbidity, Denmark, early cancer detection

Lisbet Rosenkrantz Hölmich,1 Siri Klausen,2 Eva Spaun,3 Grethe Schmidt,4 Dorte Gad,5 Inge Marie Svane,6,7 Henrik Schmidt,8 Henrik Frank Lorentzen,9 Else Helene Ibfelt10 1Department of Plastic Surgery, 2Department of Pathology, Herlev-Gentofte Hospital, University of Copenhagen, Herlev, 3Institute of Pathology, Aarhus University Hospital, Aarhus, 4Department of Plastic and Reconstructive Surgery, Breast Surgery and Burns, Rigshospitalet – Glostrup, University of Copenhagen, Copenhagen, 5Department of Plastic Surgery, Odense University Hospital, Odense, 6Center for Cancer Immune Therapy, Department of Hematology, 7Department of Oncology, Herlev-Gentofte Hospital, University of Copenhagen, Herlev, 8Department of Oncology, 9Department of Dermatology, Aarhus University Hospital, Aarhus, 10Registry Support Centre (East) – Epidemiology and Biostatistics, Research Centre for Prevention and Health, Glostrup – Rigshospitalet, University of Copenhagen, Glostrup, Denmark Aim of database: The aim of the database is to monitor and improve the treatment and survival of melanoma patients.Study population: All Danish patients with cutaneous melanoma and in situ melanomas must be registered in the Danish Melanoma Database (DMD). In 2014, 2,525 patients with invasive melanoma and 780 with in situ tumors were registered. The coverage is currently 93% compared with the Danish Pathology Register.Main variables: The main variables include demographic, clinical, and pathological characteristics, including Breslow’s tumor thickness, ± ulceration, mitoses, and tumor–node–metastasis stage. Information about the date of diagnosis, treatment, type of surgery, including safety margins, results of lymphoscintigraphy in patients for whom this was indicated (tumors > T1a), results of sentinel node biopsy, pathological evaluation hereof, and follow-up information, including recurrence, nature, and treatment hereof is registered. In case of death, the cause and date are included. Currently, all data are entered manually; however, data catchment from the existing registries is planned to be included shortly.Descriptive data: The DMD is an old research database, but new as a clinical quality register. The coverage is high, and the performance in the five Danish regions is quite similar due to strong adherence to guidelines provided by the Danish Melanoma Group. The list of monitored indicators is constantly expanding, and annual quality reports are issued. Several important scientific studies are based on DMD data.Conclusion: DMD holds unique detailed information about tumor characteristics, the surgical treatment, and follow-up of Danish melanoma patients. Registration and monitoring is currently expanding to encompass even more clinical parameters to benefit both patient treatment and research. Keywords: melanoma, malignant melanoma, clinical database, quality database, melanoma registry, Denmark

Background: Due to a multitude of factors, skin cancer incidence is increasing and challenges medical professionals in biopsy decision-making. While skin cancer may have a profound impact on the patient and be costly for society, there is little knowledge about the number and cost of benign skin lesions biopsied as collateral damage., Objectives: This study evaluates the number and costs of skin biopsies in Denmark over 15 years, focusing on benign and malignant skin lesions and melanomas across medical settings. It aims to determine the benign to malignant ratio (BMR) and number needed to biopsy (NNB) and estimate the direct cost of benign skin lesion biopsies in the Cancer Pathway from the perspective of a public healthcare system., Methods: The study included 4,481,207 biopsy specimens from January 2007 to June 2022 from the Danish Pathology Data Bank, of which 151,988 from the Cancer Pathway were included in the primary analysis of BMR. The national reimbursement rates for biopsies were used, alongside histopathological examination costs extracted from several pathology departments, for a Monte-Carlo simulation of a simple cost and sensitivity analysis., Results: The number of biopsies increased by 39.1% from 2007 to 2021. Overall BMR for malignancy was 4.1:1, and NNB for melanoma was 31.8, but biopsies performed on clinical suspicion of malignancy or melanoma had a BMR and NNB of 1.5:1 and 2.8, respectively. The cost of benign skin biopsies performed on suspicion of cancer or melanoma in 2021 was €6.6M, predominantly in hospitals., Conclusion: A healthcare system that employs filtering functions before biopsy of skin lesions can achieve some of the lowest BMR reported in the world, but with most benign skin lesion excisions due to suspicion of malignancy performed in the expensive hospital setting. Including clinical reason for biopsy in diagnostic accuracy studies using NNB is crucial., (© 2024 The Author(s). Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Background: The rising incidence of melanoma and the high number of benign lesions excised due to diagnostic uncertainty highlight the need for effective patient triage. This study assesses the safety and accuracy of teledermoscopic triage on a high-prevalence case set with pre-triaged, challenging, melanoma-suspicious lesions., Methods: Five dermatologists independently reviewed 250 retrospectively extracted patient cases. Teledermoscopy assessments were simulated for panels of 1, 2, 3 and 5 assessors using two distinct consensus strategies, Caution Protocol and Majority Vote , and the sensitivity and specificity of the patient triages were calculated., Results: Triage by a single teledermatologist showed a sensitivity of 92.3% and a specificity of 58.7%. Sensitivity improved with the number of assessors, particularly when using the Caution Protocol , though with a considerable drop in specificity. The Majority Vote showed a more balanced improvement in sensitivity and specificity. Safety analyses indicated that diagnostic accuracy decreased with poor image quality and increased case difficulty., Discussion: Expert teledermoscopic triage of melanocytic skin lesions is highly sensitive and lowers the need for unnecessary excision procedures by half while dismissing as few as 0.4% (95% confidence interval 0-0.6%) of melanomas, even when applied to a high-prevalence pre-triaged subpopulation. Implementation of safety procedures increases accuracy. Using multiple teledermatologists increases sensitivity but at the cost of specificity unless a Majority Vote consensus strategy is applied. Future teledermoscopy guidelines should encompass safety procedures and protocols for disagreement between assessors., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Niels Kvorning Ternov is CEO and co-founder of Melatech ApS, a company that provides an e-consulting platform for dermatology. HL has received fees for education not related to the publication from Eli Lily, Leo Pharma and Galderma. CK performs teledermoscopic consultations for Melatech ApS. ÅI has received speaker honoraria from Galderma Sweden, Perrigo Sweden and Biofrontera Sweden, has a research collaboration with Dermicus, a company providing a digital platform for teledermatology, and has participated as an expert in advisory boards for Merck Sharp and Dohme (MSD) and HealthInvest Partners AB. KN has received speaker honoraria from Galderma Sweden, LEO Pharma, Novartis Sweden and UCB Sweden and has served on one advisory board for MSD. Lisbet Rosenkrantz Hölmich has received research grants from MSD, SkylineDX and Mentor/Johnson&Johnson unrelated to the current study and is the chairman of the Danish Melanoma Group and Database.

Background: Implant rotation is a known complication to breast reconstruction using anatomical implants. However, there is a lack of large studies investigating the risk of implant rotation and potential predisposing risk factors., Method: We reviewed the medical records of all patients who underwent breast reconstruction with Mentor anatomical implants from 2010 to 2021 at two Danish hospitals. We compared the risk of implant rotation between one- and two-stage breast reconstruction using univariate logistic regression. We analyzed the effect of biological mesh, immediate versus delayed reconstruction, and use of a higher final expander volume than the permanent implant volume on the risk of implant rotation. Finally, we analyzed the success rate of revision surgery for implant rotation., Results: In total, 1134 patients were enrolled. Patients who underwent two-stage breast reconstruction (n = 720) had a significantly higher risk of implant rotation than those who underwent one-stage breast reconstruction (n = 426; 11% vs. 5%, p < 0.01). There was no significant association between implant rotation and the use of biological mesh, immediate breast reconstruction, or use of a higher final expander volume than the permanent implant volume. The success rate of revision surgery after implant rotation was 73% (62/85 rotations)., Conclusions: Two-stage breast reconstruction significantly increased the risk of implant rotation compared to one-stage breast reconstruction. The overall risk of implant rotation was low and success rate of revision surgery was high. These findings suggest that anatomical implants are safe to use for breast reconstruction. However, surgeons and patients should be aware of the increased risk of implant rotation after two-stage reconstruction., (Copyright © 2024 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)

Background: Antibiotic implant irrigation is increasingly used to prevent deep infection after implant-based breast reconstruction. However, there is limited evidence of the clinical effect. In this study, the authors compare the risk of a deep infection in a Danish population of women who received antibiotic implant irrigation with either gentamicin or vancomycin, or no irrigation., Methods: The authors retrospectively reviewed consecutive patients undergoing all types of breast reconstruction with implants at Rigshospitalet and Herlev Hospital, Denmark, from 2010 to 2019. Logistic regression was used to compare the risk of deep infection between no irrigation and irrigation with gentamicin or vancomycin, and to account for the difference in risk between patient subgroups and risk factors., Results: The authors included 1508 patients who received antibiotic irrigation with gentamicin (500 patients), vancomycin (304 patients), or no irrigation (704 patients). The univariable risk analysis showed a significant decreased risk of deep infection using gentamicin irrigation compared with no irrigation (OR, 0.58; P < 0.05). However, when adjusting for risk factors for infection, there was no significant decrease in the risk of infection when using gentamicin (OR, 0.90; P = 0.71) or vancomycin (OR, 1.0; P = 0.99) compared with the control group., Conclusions: The authors found no significant effect of using antibiotic implant irrigation after isolating it from risk factors for deep infection. However, because of the limitations of the study, the authors cannot conclude that there is no effect of antibiotic implant irrigation. There is a need for a randomized, placebo-controlled trial to investigate the effect, and potential side-effects, of antibiotic implant irrigation., Clinical Question/level of Evidence: Risk, II., (Copyright © 2023 by the American Society of Plastic Surgeons.)

Purpose: To investigate the level of cellular senescence in stem cells derived from microfragmented abdominal adipose tissue harvested from patients with knee osteoarthritis (OA)., Methods: Stem cells harvested from microfragmented abdominal adipose tissue from 20 patients with knee OA, aged 29-65 years (mean = 49.8, SD = 9.58), were analysed as a function of patient age and compared with control cells exhibiting signs of cellular senescence. Steady-state mRNA levels of a panel of genes associated with senescence were measured by qPCR. Intracellular senescence-associated proteins p16 and p21, and senescence-associated β-galactosidase activity were measured by flow cytometry. Cellular proliferation was assessed using a 5-ethynyl-2'-deoxyuridine proliferation assay. Stemness was assessed by stem cell surface markers using flow cytometry and the capacity to undergo adipogenic and osteogenic differentiation in vitro., Results: No correlation was found between cellular senescence levels of the microfragmented adipose tissue-derived stem cells and patient age for any of the standard assays used to quantify senescence. The level of cellular senescence was generally low across all senescence-associated assays compared to the positive senescence control. Stemness was verified for all samples. An increased capacity to undergo adipogenic differentiation was shown with increasing patient age ( p  = 0.02). No effect of patient age was found for osteogenic differentiation., Conclusions: Autologous microfragmented adipose tissue-derived stem cells may be used in clinical trials of knee OA of patients aged 29-65 years, at least until passage 4, as they show stemness potential and negligible senescence in vitro., Level of Evidence: Not applicable., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). Journal of Experimental Orthopaedics published by John Wiley & Sons Ltd on behalf of European Society of Sports Traumatology, Knee Surgery and Arthroscopy.)

Background: Understanding the impact of breast implants on the histological response in the surrounding fibrous capsule is important; however, consensus is lacking on how to analyze implant capsules histologically. We aimed to develop a standardized histological assessment tool to be used in research potentially improving diagnostic accuracy and treatment strategies for capsular contracture., Methods: Biopsies of breast implant capsules from 480 patients who had undergone breast augmentation or reconstruction were collected and stained with hematoxylin and eosin. Initially, biopsies from 100 patients were analyzed to select histological parameters demonstrating the highest relevance and reproducibility. Then, biopsies from the remaining 380 patients were used to determine intra- and interobserver agreements of two blinded observers and agreement with a pathologist. Finally, we tested the association between the parameters and capsular contracture., Results: The histological assessment tool included ten parameters assessing the inflammatory, fibrotic, and foreign-body reaction to breast implants, each graded on two-, three-, or four-point scales. Intra- and interobserver agreements were almost perfect (0.83 and 0.80), and agreement with the pathologist was substantial (0.67). Four parameters were significantly correlated with capsular contracture, namely chronic inflammation with lymphocyte infiltration (p < 0.01), thickness of the collagen layer (p < 0.0001), fiber organization (p < 0.01), and calcification (p < 0.001)., Conclusions: This is the first validated histological assessment tool for breast implant capsules. The validated tool not only advances our understanding of capsular contracture but also sets a new standard for histological evaluation in breast implant research and clinical diagnostics., No Level Assigned: This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 ., (© 2024. The Author(s).)

Background: Capsular contracture is traditionally evaluated with the Baker classification, but this has notable limitations regarding reproducibility and objectivity., Objectives: The aim of this study was to develop and validate procedure-specific histopathological scoring systems to assess capsular contracture severity., Methods: Biopsies of breast implant capsules were used to develop histopathological scoring systems for patients following breast augmentation and breast reconstruction. Ten histological parameters were evaluated by multivariable logistic regression to identify those most associated with capsular contracture. Significant parameters (P < .05) were selected for the scoring systems and assigned weighted scores (1-10). Validation was assessed from the area under the curve (AUC) and the mean absolute error (MAE)., Results: A total of 720 biopsies from 542 patients were included. Four parameters were selected for the augmentation scoring system, namely, collagen layer thickness, fiber organization, inflammatory infiltration, and calcification, providing a combined maximum score of 26. The AUC and MAE for the augmentation scoring system were 81% and 0.8%, which is considered strong. Three parameters were selected for the reconstruction scoring system, namely, fiber organization, collagen layer cellularity, and inflammatory infiltration, providing a combined maximum score of 19. The AUC and MAE of the reconstruction scoring system were 72% and 7.1%, which is considered good., Conclusions: The new histopathological scoring systems provide an objective, reproducible, and accurate assessment of capsular contracture severity. We propose these novel scoring systems as a valuable tool for confirming capsular contracture diagnosis in the clinical setting, for research, and for implant manufacturers and insurance providers in need of a confirmed capsular contracture diagnosis., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Aesthetic Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Around 2,500 women receive a breast augmentation with silicone-based implants yearly in Denmark. A number of these women report various uncharacteristic systemic symptoms, which they attribute to the breast implants, including impaired cognition, joint pain, etc. This condition has been termed "breast implant illness" and is currently not a recognised diagnosis. The correlation between the patient's self-reported symptoms and breast implants has not been established and there is limited evidence that surgery has any effect. In this review, the current literature on the topic has been reviewed., (Published under Open Access CC-BY-NC-BD 4.0. https://creativecommons.org/licenses/by-nc-nd/4.0/.)

Background: The survival in patients diagnosed with cutaneous malignant melanoma (CMM) has improved in the Nordic countries in the last decades. It is of interest to know if these improvements are observed in all ages and for both women and men., Methods: Patients diagnosed with CMM in the Nordic countries in 1990-2016 were identified in the NORDCAN database. Flexible parametric relative survival models were fitted, except for Iceland where a non-parametric Pohar-Perme approach was used. A range of survival metrics were estimated by sex, both age-standardised and age-specific., Results: The 5-year relative survival improved in all countries, in both women and men and across age. While the improvement was more pronounced in men, women still had a higher survival at the end of the study period. The survival was generally high, with age-standardised estimates of 5-year relative survival towards the end of the study period ranging from 85% in Icelandic men to 95% in Danish women. The age-standardised and reference-adjusted 5-year crude probability of death due to CMM ranged from 5% in Danish and Swedish women to 13% in Icelandic men., Conclusion: Although survival following CMM was relatively high in the Nordic countries in 1990, continued improvements in survival were observed throughout the study period in both women and men and across age., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could appear to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Silicone leakage from breast implants is a concern with potential implications for patient health. This study aimed to quantify and model silicone leakage from implants to the breast implant capsule and to investigate whether silicone cohesiveness affected the silicone leakage rate., Methods: Silicone content in the breast implant capsule was quantified histologically by measuring the area of silicone deposits. This was used to model silicone leakage over time based on the time of implantation. The effect of cohesiveness on silicone leakage was investigated across all implant brands with declared cohesiveness and in a subanalysis comparing only Mentor cohesive I implants with cohesive II and III implants., Results: The study included 493 patients with 872 breasts and a median time of implantation of 13.0 years (range 0.4 to 51 years). The modeling of silicone leakage from intact implants showed that leakage and the acceleration of the leakage rate were significantly higher in low-cohesive implants than in highly cohesive implants (p<0.05). This was confirmed when analyzing only Mentor implants (p<0.05) and in the case of implant rupture (p<0.01) where low-cohesive implants also leaked significantly more than highly cohesive implants., Conclusions: Our results suggest that highly cohesive implants are superior to low-cohesive implants in preventing silicone leakage. Due to the accelerating rate of silicone leakage especially found in low-cohesive implants, we propose that exchange of low-cohesive implants could be discussed with patients 10 to 15 years after implantation to minimize silicone leakage even in the absence of implant rupture., (Copyright © 2024 by the American Society of Plastic Surgeons.)

Introduction: Inflammation is a hallmark of cancer and is involved in tumour growth and dissemination. However, the hallmarks of cancer are also the hallmarks of wound healing, and modulating the wound inflammatory response and immune contexture in relation to cancer surgery may represent effective targets of therapies.Repurposing anti-inflammatory drugs in a cancer setting has gained increasing interest in recent years. Interestingly, the known and thoroughly tested antifibrinolytic drug tranexamic acid reduces the risk of bleeding, but it is also suggested to play important roles in anti-inflammatory pathways, improving wound healing and affecting anti-carcinogenic mechanisms.As a novel approach, we will conduct a randomised controlled trial using perioperative treatment with tranexamic acid, aiming to prevent early relapses by >10% for patients with melanoma., Methods and Analysis: Design: investigator-initiated parallel, two-arm, randomised, blinded, Danish multicentre superiority trial., Patients: ≥T2 b melanoma and eligible for sentinel lymph node biopsy (n=1204).Project drug: tranexamic acid or placebo., Treatment: before surgery (intravenous 15 mg/kg) and daily (peroral 1000 mg x 3) through postoperative day 4., Primary Outcome: relapse within 2 years after surgery.Primary analysis: risk difference between the treatment arms (χ 2 test)., Secondary Outcomes: postoperative complications, adverse events and survival.Inclusion period: summer 2023 to summer 2026., Ethics and Dissemination: The trial will be initiated during the summer of 2023 and is approved by the National Committee on Health Research Ethics, the Danish Medicine Agency, and registered under the Data Protection Act. The study will be conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. Patients included in the study will adhere to normal Danish treatment protocols and standards of care, and we expect only mild and temporary side effects. Positive and negative results will be published in peer-reviewed journals, with authorships adhering to the Vancouver rules., Trial Registration Number: NCT05899465; ClinicalTrials.gov Identifier., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Lymphedema constitutes a major unsolved problem in plastic surgery. To identify novel lymphedema treatments, preclinical studies are vital. The surgical mouse lymphedema model is popular and cost-effective; nonetheless, a synthesis and overview of the literature with evidence-based guidelines is needed. The aim of this review was to perform a systematic review to establish best practice and support future high-quality animal studies exploring lymphedema treatments., Methods: We performed a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, searching four databases (PubMed, Embase, Web of Science, and Scopus) from inception-September 2022. The Animals in Research Reporting In Vivo Experiments 2.0 (ARRIVE 2.0) guidelines were used to evaluate reporting quality. Studies claiming to surgically induce lymphedema in the hindlimb of mice were included., Results: Thirty-seven studies were included. Four main models were used. (1) Irradiation+surgery. (2) A variation of the surgery used by (1) + irradiation. (3) Surgery only (SPDF-model). (4) Surgery only (PLND-model). Remaining studies used other techniques. The most common measurement modality was the caliper. Mean quality coefficient was 0.57. Eighteen studies (49%) successfully induced sustained lymphedema. Combination of methods seemed to yield the best results, with an overrepresentation of irradiation, the removal of two lymph nodes, and the disruption of both the deep and superficial lymph vessels in the 18 studies., Conclusion: Surgical mouse hindlimb lymphedema models are challenged by two related problems: (1) retaining lymphedema for an extended period, that is, establishing a (chronic) lymphedema model (2) distinguishing lymphedema from post-operative edema. Most studies failed to induce lymphedema and used error-prone measurements. We provide an overview of studies claiming to induce lymphedema and advocate improved research via five evidence-based recommendations to use: (1) a proven lymphedema model; (2) sufficient follow-up time, (3) validated measurement methods; (4) ARRIVE-guidelines; (5) contralateral hindlimb as control., (© 2023 The Authors. Microsurgery published by Wiley Periodicals LLC.)

Introduction The use and consumption of "products", such as cosmetic procedures and confectionery, is on a rise in the Danish population. However, it has never been evaluated if the same tendency can be observed among the providers of these products. In view of the upcoming Christmas, we decided to investigate this delicate matter. Methods This study was a survey-based cross-sectional study examining demographics, professional backgrounds, as well as frequency and preferences regarding confectionery and cosmetic procedures among confectioners and plastic surgeons. Results A total of 90 persons answered the questionnaire. Results showed that consumption of confectionery was high among both confectioners and plastic surgeons, and that the use of cosmetic procedures was higher among both confectioners and plastic surgeons than among the background population. Both groups preferred to know the person who provided "the product" within their respective area. Conclusion Most plastic surgeons do not need to know their confectioner but would like to know their cosmetic procedure provider. So, if you, as part of the department management, or simply as a well-meaning colleague, want to treat your staff/colleagues, you can safely order cake from a random confectioner but not cosmetic procedures from a random surgeon! Funding none. Trial registration not relevant., (Published under Open Access CC-BY-NC-BD 4.0. https://creativecommons.org/licenses/by-nc-nd/4.0/.)

Importance: To ensure optimal treatment and surveillance of patients with melanoma, knowledge of the clinical stage-specific risk of recurrence, mortality, and recurrence patterns across the American Joint Committee on Cancer Eighth Edition (AJCC8) substages is needed., Objective: To estimate stage-specific recurrence and melanoma-specific mortality rates, assess absolute stage-specific risks of recurrence and mortality, and describe stage-specific recurrence patterns, including conditional rates., Design: Retrospective cohort study of prospectively collected nationwide population-based registry data., Setting: Nationwide, population-based cohort study., Participants: The 25 720 Danish patients, 18 years or older, diagnosed with first-time stage IA to IV cutaneous melanoma between January 1, 2008, and December 31, 2019, were included and followed up from time of primary treatment until December 31, 2021., Exposures: First diagnosis of stage IA to IV cutaneous melanoma., Main Outcomes: Stage-specific cumulative incidence of recurrence and melanoma-specific mortality, melanoma-specific recurrence-free survival, and assessed absolute stage-specific risks of recurrence and melanoma-specific mortality. Secondary outcomes were stage-specific recurrence patterns, including conditional rates, and melanoma-specific survival., Results: We followed up 25 720 patients for a median of 5.9 years (95% CI, 58.9-59.3 years). Mean age was 59.1 years (95% CI, 58.9-59.3 years). Patients with stage IIB to IIC melanoma were older, had more comorbidities at diagnosis, and had the lowest rate of pathologic staging by sentinel node biopsy (81.6%-87.4%). A total of 10.6% of patients developed recurrence; first recurrence included distant recurrence, alone or with synchronous locoregional recurrence, in 56.6% of patients. We found a comparable risk of recurrence in stages IIIA and IIB (29.7% vs 33.2%) and in stages IIIB and IIC (35.9% vs 36.8%), respectively. Melanoma-specific mortality was comparable between stages IIIA and IIA (13.0% vs 13.6%) and between stages IIIB and IIB (18.4% vs 22.0%), respectively. These risk patterns persisted in cause-specific hazards models., Conclusions and Relevance: This nationwide, population-based cohort study found that the increasing stages of the current AJCC8 staging system do not accurately reflect an increasing risk of recurrence and mortality in melanoma. The high proportion of distant recurrences suggests that hematogenous spread is a more common metastatic pathway than previously assumed, and surveillance with routine functional/cross-sectional imaging should be considered for stages IIB to IV. Future efforts should be put toward developing new tools for risk stratification and determining the survival effect of routine imaging in surveillance.

Background: With a growing population of cancer survivors in Denmark, the evaluation of health-related quality of life (HRQoL) has become increasingly important. We describe variations in HRQoL between educational groups in a national population of cancer survivors., Methods: We conducted a cross-sectional questionnaire study among breast, prostate, lung, and colon cancer survivors diagnosed in 2010-2019 in Denmark. We used the EORTC QLQ-C30 to assess HRQoL including physical, role, emotional, cognitive, social functioning, and symptoms (fatigue, nausea and vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Information on educational level and clinical data were extracted from national registers and clinical databases. Levels of impaired functioning and severe symptoms were identified using newly established thresholds for clinical importance. Multivariate logistic regression was used to examine associations between education and HRQoL. All statistical tests were 2-sided., Results: In total, 27,857 (42%) participated in the study. Up to 72% and 75% of cancer survivors with short education (≤9 years) reported impaired functioning and severe symptoms, respectively. Cancer survivors with short compared to long education (>12 years) were more likely to report impaired functioning and severe symptoms, with for example significantly higher odds ratios (ORs) for impaired physical function (breast OR = 2.41, 99% CI = 2.01-2.89; prostate OR = 1.81, 99% CI = 1.48-2.21; lung OR = 2.97, 99% CI = 1.95-4.57; and colon cancer OR = 1.69, 99% CI = 1.28-2.24)., Conclusions: Cancer survivors with short education are at greater risk of impaired HRQoL than survivors with long education 2-12 years after diagnosis. This underscores the need for systematic screening and symptom management in cancer aftercare, in order to reach all cancer survivors, also cancer survivors with short education., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Skin cancer diagnostics is challenging, and mastery requires extended periods of dedicated practice., Objective: The aim of the study was to determine if self-paced pattern recognition training in skin cancer diagnostics with clinical and dermoscopic images of skin lesions using a large-scale interactive image repository (LIIR) with patient cases improves primary care physicians' (PCPs') diagnostic skills and confidence., Methods: A total of 115 PCPs were randomized (allocation ratio 3:1) to receive or not receive self-paced pattern recognition training in skin cancer diagnostics using an LIIR with patient cases through a quiz-based smartphone app during an 8-day period. The participants' ability to diagnose skin cancer was evaluated using a 12-item multiple-choice questionnaire prior to and 8 days after the educational intervention period. Their thoughts on the use of dermoscopy were assessed using a study-specific questionnaire. A learning curve was calculated through the analysis of data from the mobile app., Results: On average, participants in the intervention group spent 2 hours 26 minutes quizzing digital patient cases and 41 minutes reading the educational material. They had an average preintervention multiple choice questionnaire score of 52.0% of correct answers, which increased to 66.4% on the postintervention test; a statistically significant improvement of 14.3 percentage points (P<.001; 95% CI 9.8-18.9) with intention-to-treat analysis. Analysis of participants who received the intervention as per protocol (500 patient cases in 8 days) showed an average increase of 16.7 percentage points (P<.001; 95% CI 11.3-22.0) from 53.9% to 70.5%. Their overall ability to correctly recognize malignant lesions in the LIIR patient cases improved over the intervention period by 6.6 percentage points from 67.1% (95% CI 65.2-69.3) to 73.7% (95% CI 72.5-75.0) and their ability to set the correct diagnosis improved by 10.5 percentage points from 42.5% (95% CI 40.2%-44.8%) to 53.0% (95% CI 51.3-54.9). The diagnostic confidence of participants in the intervention group increased on a scale from 1 to 4 by 32.9% from 1.6 to 2.1 (P<.001). Participants in the control group did not increase their postintervention score or their diagnostic confidence during the same period., Conclusions: Self-paced pattern recognition training in skin cancer diagnostics through the use of a digital LIIR with patient cases delivered by a quiz-based mobile app improves the diagnostic accuracy of PCPs., Trial Registration: ClinicalTrials.gov NCT05661370; https://classic.clinicaltrials.gov/ct2/show/NCT05661370., (©Gustav Gede Nervil, Niels Kvorning Ternov, Tine Vestergaard, Henrik Sølvsten, Annette Hougaard Chakera, Martin Grønnebæk Tolsgaard, Lisbet Rosenkrantz Hölmich. Originally published in JMIR Dermatology (http://derma.jmir.org), 09.08.2023.)

Morel-Lavallée lesion (MLL) is a closed degloving injury caused by traumatic sheering of subcutaneous tissue from the underlying fascia. MLL can be classified as acute (less-than 3 months) or chronic (greater-than 3 months or if a capsule has formed). Acute lesions are treated with compression, percutaneous aspiration, sclerodesis, suction-curettage or open surgery depending on vitality of the overlying skin, if fractures are present next to the lesion or if infection has occurred. Chronic lesions are treated with sclerodesis, suction-curettage or open surgery. Drain and vacuum-assisted closure placement should be used post-operatively, as argued in this review.

TINF2 encodes the TINF2 protein, which is a subunit in the shelterin complex critical for telomere regulation. Three recent studies have associated six truncating germline variants in TINF2 that have previously been associated with a cancer predisposition syndrome (CPS) caused by elongation of the telomeres. This has added TINF2 to the long telomere syndrome genes, together with other telomere maintenance genes such as ACD , POT1 , TERF2IP , and TERT . We report a clinical study of 102 Danish patients with multiple primary melanoma (MPM) in which a germline truncating variant in TINF2 (p.(Arg265Ter)) was identified in four unrelated participants. The telomere lengths of three variant carriers were >90% percentile. In a routine diagnostic setting, the variant was identified in two more families, including an additional MPM patient and monozygotic twins with thyroid cancer and other cancer types. A total of 10 individuals from six independent families were confirmed carriers, all with cancer history, predominantly melanoma. Our findings suggest a major role of TINF2 in Danish patients with MPM. In addition to melanoma, other cancers in the six families include thyroid, renal, breast, and sarcoma, supporting a CPS in which melanoma, thyroid cancer, and sarcoma predominate. Further studies are needed to establish the full spectrum of associated cancer types and characterize lifetime cancer risk in carriers., Competing Interests: The authors declare no competing interests., (© 2023.)

Background: Many cancer survivors experience late effects after cancer. Comorbidity, health literacy, late effects, and help-seeking behavior may affect healthcare use and may differ among socioeconomic groups. We examined healthcare use among cancer survivors, compared with cancer-free individuals, and investigated educational differences in healthcare use among cancer survivors., Methods: A Danish cohort of 127,472 breast, prostate, lung, and colon cancer survivors from the national cancer databases, and 637,258 age- and sex-matched cancer-free individuals was established. Date of entry was 12 months after diagnosis/index date (for cancer-free individuals). Follow-up ended at death, emigration, new primary cancer, December 31st, 2018, or up to 10 years. Information about education and healthcare use, defined as the number of consultations with general practitioner (GP), private practicing specialists (PPS), hospital, and acute healthcare contacts 1-9 years after diagnosis/index date, was extracted from national registers. We used Poisson regression models to compare healthcare use between cancer survivors and cancer-free individuals, and to investigate the association between education and healthcare use among cancer survivors., Results: Cancer survivors had more GP, hospital, and acute healthcare contacts than cancer-free individuals, while the use of PPS were alike. One-to-four-year survivors with short compared to long education had more GP consultations (breast, rate ratios (RR) = 1.28, 95% CI = 1.25-1.30; prostate, RR = 1.14, 95% CI = 1.10-1.18; lung, RR = 1.18, 95% CI = 1.13-1.23; and colon cancer, RR = 1.17, 95% CI = 1.13-1.22) and acute contacts (breast, RR = 1.35, 95% CI = 1.26-1.45; prostate, RR = 1.26, 95% CI = 1.15-1.38; lung, RR = 1.24, 95% CI = 1.16-1.33; and colon cancer, RR = 1.35, 95% CI = 1.14-1.60), even after adjusting for comorbidity. One-to-four-year survivors with short compared to long education had less consultations with PPS, while no association was observed for hospital contacts., Conclusion: Cancer survivors used more healthcare than cancer-free individuals. Cancer survivors with short education had more GP and acute healthcare contacts than survivors with long education. To optimize healthcare use after cancer, we need to better understand survivors' healthcare-seeking behaviors and their specific needs, especially among survivors with short education., (© 2023. The Author(s).)

Background: Repurposing already approved drugs in a cancer setting has gained increasing interest in recent years. Tranexamic acid is an anti-fibrinolytic drug that has recently been suggested as an anti-cancer drug due to its anti-inflammatory and anti-carcinogenic effects in animal studies. In this study, we aimed to investigate the possible melanoma-preventive role of tranexamic acid in Danish women., Method: In this nested case-control study, we identified female cases 18-60 years with first-time melanoma during 2000-2015 and age-matched them with 10 female controls. The odds ratio (OR) of melanoma with tranexamic acid ever- or high use (≥ 100,000 mg) was estimated using conditional logistic regression., Results: A total of 7986 women with incident melanoma were eligible for study inclusion and were matched to 79,860 controls. Most exposed cases and controls were exposed to low cumulative doses of tranexamic acid corresponding to around 5 days of continuous treatment (1000 mg 3 times daily) for the presumed main indication, i.e., menorrhagia. The crude OR associating tranexamic ever use with melanoma was 1.04 (95% CI 0.98-1.11, p = 0.20), and the adjusted OR was 1.03 (0.97-1.10, p = 0.32). We found no dose-response pattern or effect measure modification by age, histologic type, localization, or clinical stage. However, prolonged use with cumulative doses of tranexamic acid (≥ 100,000 mg) was associated with an increased risk of melanoma (adjusted OR 1.23,95 %, CI 0.96-1.56), compared with non-use., Conclusion: We found no association between tranexamic acid use and the risk of melanoma in Danish women. This could be explained by underlying dose- or biological factors, and sporadic use patterns. A higher risk of melanoma was seen among prolonged users which could be due to surveillance bias., Competing Interests: Conflict of interests Anton Pottegård reports participation in research projects funded by Alcon, Almirall, Astellas, Astra-Zeneca, Boehringer-Ingelheim, Novo Nordisk, Servier, and LEO Pharma, all regulator-mandated phase IV studies, all with funds paid to the institution where he was employed (no personal fees) and with no relation to the work reported in this paper. All other authors declare no financial or personal conflicts of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction: Case-based training improves novices pattern recognition and diagnostic accuracy in skin cancer diagnostics. However, it is unclear how pattern recognition is best taught in conjunction with the knowledge needed to justify a diagnosis., Objectives: The aim of this study was to examine whether an explanation of the underlying histopathological reason for dermoscopic criteria improves skill acquisition and retention during case-based training in skin cancer diagnostics., Methods: In this double-blinded randomized controlled trial, medical students underwent eight days of case-based training in skin cancer diagnostics, which included access to written diagnosis modules. The modules dermoscopic subsections differed between the study groups. All participants received a general description of the criteria, but the intervention group additionally received a histopathological explanation., Results: Most participants (78%) passed a reliable test in skin cancer diagnostics, following a mean training time of 217 minutes. Access to histopathological explanations did not affect participants' learning curves or skill retention., Conclusions: The histopathological explanation did not affect the students, but the overall educational approach was efficient and scalable.

Background: The effect of routine imaging in melanoma surveillance is unknown. In 2016, Denmark was the first country in the world to implement routine imaging with positron emission tomography-computed tomography with fluorodeoxyglucose (FDG PET-CT) in a nationwide, population-based surveillance program. This study aimed to determine the impact of surveillance with routine FDG PET-CT on hazard, cumulative incidence, and absolute risk of overall, locoregional, and distant recurrence detection in patients with stage IIB to IIID cutaneous melanoma., Methods: This retrospective, population-based, nationwide cohort study used prospectively collected data from five national health registries to compare hazard, cumulative incidence, and absolute risk of recurrence in patients with cutaneous melanoma diagnosed in 2008-2010 (cohort 1, followed with clinical examinations) and patients with cutaneous melanoma diagnosed in 2016-2017 (cohort 2, followed with clinical examinations and routine FDG PET-CT at 6, 12, 24, and 36 months)., Results: The study included 1480 patients with stage IIB to IIID cutaneous melanoma. Cumulative incidences of overall and distant recurrence were higher in cohort 2, with a peak difference at three years (32.3 % vs 27.5 % and 25.8 % vs. 18.5 %, respectively). The hazard of recurrence was higher in cohort 2 during the first two years, with hazard rates for overall and distant recurrence of 1.16 (95 % confidence interval [CI], 0.93-1.44) and 1.51 (95 % CI, 1.16-1.96), respectively. The patterns persisted in absolute risk estimates., Conclusions: Patients with stage IIB to IIID melanoma followed with routine FDG PET-CT had a 51 % increased hazard of distant recurrence detection within the first two years of surveillance. Future studies must determine whether this earlier recurrence detection translates into improved survival., (© 2023. Society of Surgical Oncology.)

Purpose: To investigate if viable stem cells could be isolated and expanded from cryopreserved microfragmented adipose tissue (AT) harvested from patients with knee osteoarthritis., Methods: Microfragmented abdominal AT from knee osteoarthritis patients was cryopreserved at -80 °C in cryoprotectant-medium. The samples were thawed for stem cell isolation by tissue explant culture (TEC) and enzymatic digestion (ED), respectively. Viability, population doublings, and doubling time were assessed by trypan blue staining and flow cytometry. Cell type and senescence-associated β-galactosidase activity were analyzed by flow cytometry. Osteogenic and adipogenic differentiation was assessed quantitatively by Alizarin-Red-S and Oil-Red-O staining, respectively., Results: Microfragmented AT from 7 patients was cryopreserved for a period of 46-150 days (mean (SD) 115.9 days (44.3 days)). Viable stem cells were successfully recovered and expanded from all patients using both isolation methods with no significant difference in viable population doublings or doubling time from passage 1 to 3 (p > 0.05). Low levels of senescence-associated β-galactosidase activity was detected for both methods with no significant difference between TEC and ED (p = 0.17). Stemness was verified by stem cell surface markers and osteogenic and adipogenic differentiation performance. Adventitial stem cells (CD31 - CD34 + CD45 - CD90 + CD146 - ), pericytes (CD31 - CD34 - CD45 - CD90 + CD146 + ), transitional pericytes (CD31 - CD34 + CD45 - CD90 + CD146 + ), and CD271 + stem cells (CD31 - CD45 - CD90 + CD271 + ) were identified using both methods. More pericytes were present when using TEC (25% (24%)) compared to ED (3% (2%)) at passage 4 (p = 0.04)., Conclusions: Viable stem cells can be isolated and expanded from cryopreserved microfragmented AT using both TEC and ED. TEC provides more clinically relevant pericytes than ED., (© 2023. The Author(s).)

Introduction: This study of breast augmentations performed under local anesthesia with intercostal blocks and light sedation describes the outcomes and evaluates benefits and complications., Method: From December 2005 until August 2019, 335 women consecutively underwent bilateral breast augmentation procedures. The anesthetic protocol consisted of an initial intravenous bolus of 1 mg midazolam and 0.25 mg alfentanil preoperatively. In 2017, this was changed to 2-4 mg midazolam intramuscularly, 1 mg midazolam intravenously, and 2.5 µg sufentanil intravenously. Intercostal blocks were injected at the midaxillary line into the intercostal spaces two to seven. The operating field was infiltrated with tumescent local anesthesia. Retrospective data extraction from patients' medical charts was done, registering demographics, dosage of anesthesia, surgical characteristics, complications, and reoperation rates., Results: Two hundred and eighty-one women underwent primary augmentation and 54 had implant replacement. The most common complications included suboptimal cosmetic results, asymmetry, and healing-related problems. The overall rate of reoperation was 16.1% within an average follow-up period of 2 years, ranging from 0 to 12.5 years. The majority of the reoperations were due to cosmetic reasons. The change in anesthetic regime was associated with a significantly ( p  < 0.0001) decreased need for supplementary medication with no increased risk of complications., Conclusion: Breast augmentations in local anesthesia with intercostal blocks and light sedation can be performed safely and can serve as an alternative to procedures in general anesthesia.

Rectus diastasis is defined by thinning and widening of linea alba and is a part of pregnancy. In some patients, the diastasis persists giving symptoms such as core instability, and cosmetic complaints. Treatment consists of exercise and surgery by either a plastic surgeon or a general surgeon. Lately, rectus diastasis has gained both national and international attention but it is not clear which patients will benefit from surgery or which operative technique has the best outcome. This review describes postgestational rectus diastasis and summarizes treatment possibilities based on the latest literature.

Background: Immune checkpoint inhibitors and targeted therapies have dramatically improved outcomes in patients with advanced melanoma, but approximately half these patients will not have a durable benefit. Phase 1-2 trials of adoptive cell therapy with tumor-infiltrating lymphocytes (TILs) have shown promising responses, but data from phase 3 trials are lacking to determine the role of TILs in treating advanced melanoma., Methods: In this phase 3, multicenter, open-label trial, we randomly assigned patients with unresectable stage IIIC or IV melanoma in a 1:1 ratio to receive TIL or anti-cytotoxic T-lymphocyte antigen 4 therapy (ipilimumab at 3 mg per kilogram of body weight). Infusion of at least 5×10 9 TILs was preceded by nonmyeloablative, lymphodepleting chemotherapy (cyclophosphamide plus fludarabine) and followed by high-dose interleukin-2. The primary end point was progression-free survival., Results: A total of 168 patients (86% with disease refractory to anti-programmed death 1 treatment) were assigned to receive TILs (84 patients) or ipilimumab (84 patients). In the intention-to-treat population, median progression-free survival was 7.2 months (95% confidence interval [CI], 4.2 to 13.1) in the TIL group and 3.1 months (95% CI, 3.0 to 4.3) in the ipilimumab group (hazard ratio for progression or death, 0.50; 95% CI, 0.35 to 0.72; P<0.001); 49% (95% CI, 38 to 60) and 21% (95% CI, 13 to 32) of the patients, respectively, had an objective response. Median overall survival was 25.8 months (95% CI, 18.2 to not reached) in the TIL group and 18.9 months (95% CI, 13.8 to 32.6) in the ipilimumab group. Treatment-related adverse events of grade 3 or higher occurred in all patients who received TILs and in 57% of those who received ipilimumab; in the TIL group, these events were mainly chemotherapy-related myelosuppression., Conclusions: In patients with advanced melanoma, progression-free survival was significantly longer among those who received TIL therapy than among those who received ipilimumab. (Funded by the Dutch Cancer Society and others; ClinicalTrials.gov number, NCT02278887.)., (Copyright © 2022 Massachusetts Medical Society.)

Background and Objective: The aim of this study was to investigate the diagnostic accuracy of ultrasound guided fine needle aspiration cytology (FNAC) and core needle biopsy (CNB) in different clinical scenarios for melanoma patients with lesions suspected of metastasis., Methods: We included all patients at our department attending follow-up after surgery for cutaneous melanoma, who had undergone either FNAC or CNB between December 2016 and June 2019. Biopsy results were classified into one of four categories and verified with follow-up including imaging, re-biopsy or histology upon excision. The diagnostic accuracy of FNAC and CNB were calculated overall, and based on location of suspected metastasis, reason for suspicion and stage., Results: We identified 232 biopsies in 164 patients; 109 FNACs and 123 CNBs. For FNAC, overall sensitivity was 83.3% and negative predictive value was 88.4%. For CNB, overall sensitivity was 92.4% and negative predictive value was 88.0%. There were significantly fewer nondiagnostic results using CNB compared to FNAC (χ 1 2  = 6.7, p = 0.0095)., Conclusions: There were no significant differences between the diagnostic accuracy of FNAC and CNB in the different clinical scenarios. We found significantly fewer nondiagnostic biopsies when using CNB, although this may reflect the type of lesions selected for each approach., (© 2022 Wiley Periodicals LLC.)

Introduction: Periprosthetic infection is one of the most severe complications following implant-based breast reconstruction affecting 5%-10% of the women. Currently, many surgeons apply antibiotics locally on the breast implant to reduce the risk of postoperative infection, but no randomised, placebo-controlled trials have tested the treatment's efficacy., Methods and Analysis: The BREAST-AB trial (BREAST-AntiBiotics) is an investigator-initiated, multicentre, randomised, placebo-controlled, double-blind trial of local treatment with gentamicin, vancomycin and cefazolin on breast implants in women undergoing implant-based breast reconstruction. The trial drug consists of 80 mg gentamicin, 1 g vancomycin and 1 g cefazolin dissolved in 500 mL of isotonic saline. The placebo solution consists of 500 mL isotonic saline. The trial drug is used to wash the dissected tissue pocket and the breast implant prior to insertion. The primary outcome is all-cause explantation of the breast implant within 180 days after the breast reconstruction surgery. This excludes cases where the implant is replaced with a new permanent implant, for example, for cosmetic reasons. Key long-term outcomes include capsular contracture and quality of life. The trial started on 26 January 2021 and is currently recruiting., Ethics and Dissemination: The trial was approved by the Regional Ethics Committee of the Capital Region (H-20056592) on 1 January 2021 and the Danish Medicines Agency (2020070016) on 2 August 2020. The main paper will include the primary and secondary outcomes and will be submitted to an international peer-reviewed journal., Trial Registration Number: NCT04731025., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Inguinal lymph node dissection (ILND) is associated with a high complication rate. Retrospective studies suggest that incisional negative pressure wound therapy (iNPWT) might reduce complications, especially seroma, following ILND., Methods: This was a prospective multicenter, randomized (1:1), open-labeled, parallel-group trial. Patients with macrometastic melanoma to the inguinal lymph nodes and eligible for ILND were randomized to receive either iNPWT for 14 postoperative days or conventional wound dressing. The primary outcome was seroma incidence. Secondary outcomes included surgical-site infection, wound rupture, wound necrosis, hematoma, rehospitalization and readmission rates between groups. All outcomes were registered 3 months after ILND and analyzed according to the intention-to-treat principle., Results: The trial was terminated early due to a low recruitment rate as a consequence of a change in the national treatment protocol, and the estimated sample size was not reached. Twenty patients were included and randomized in the study. The trial showed less seroma formation between the iNPWT 6/11 (55%) and control 7/9 (78%) groups; however, this was not statistically significant ( p  = 0.29). Similarly, there were no differences in the rates of surgical-site infection ( p  = 0.63), wound rupture ( p  = 0.19), wound necrosis ( p  = 0.82), hematoma ( p  = 0.19), reoperation ( p  = 0.82) or readmission ( p  = 0.34) between groups., Conclusion: There was a tendency toward fewer complications in the iNPWT group, however this trial was underpowered and could not confirm the hypothesis that iNPWT reduces complications after ILND. Future randomized controlled trials are required to fully evaluate the treatment potential of iNPWT., Trial Registration: The trial was prospectively registered at https://clinicaltrials.gov/ct2/show/NCT03433937., Competing Interests: None., (© 2022 The Authors. Published by Elsevier Ltd on behalf of British Association of Plastic, Reconstructive and Aesthetic Surgeons.)

Introduction: The incidence of thin and early-stage melanoma is increasing in many populations, but the clinical significance of these lesions remains partly unknown., Methods: Firstly, melanoma deaths in Denmark (2009-2018) were followed back to establish melanoma debut in these persons. Secondly, using national registries of cancer incidence and mortality, 27,036 persons with thin or early-stage melanoma were followed-up for melanoma death., Results: It is estimated that in 11% of the persons who died from melanoma, the debut was a thin or early-stage melanoma. On follow-up of persons with thin or early-stage melanoma, the 20-year risk of dying from melanoma was 3%., Conclusion: The absolute risk of melanoma death after a diagnosis with thin or early-stage melanoma is low. A subgroup of patients who are at a high risk may possibly be identified by a combination of stage, thickness, ulceration and dermal mitoses., Funding: none., Trial Registration: not relevant., (Articles published in the DMJ are “open access”. This means that the articles are distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits any non-commercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.)

Benign skin tumours are commonly seen by general practitioners. They are important to differentiate from skin malignancies. Most benign skin lesions are diagnosed based on the history and clinical features. However, if the clinical diagnosis is uncertain, a skin biopsy, e.g. excisional or punch for histopathological examination is necessary to rule out malignancy. Seborrheic keratoses are the most common benign skin tumours with an increasing incidence with age. Other common benign skin lesions include melanocytic naevi, acrochordons and dermatofibromas, which may resemble malignant neoplasms.

While the Danish Health Authority has withdrawn the vaxzevria vaccine from the Danish vaccination programme due to reports of rare cases of severe side effects, this case report presents a potential beneficial side effect of this vaccine. A patient presented, three days after her first jab, with localized itching and bleeding from a pigmented tumour on her lower leg, which was therefore excised, and, unexpectedly, diagnosed as a melanoma. We speculate if the vaccine-induced immune reaction resulted in increased immune activity within the tumour environment, and thus facilitated the early diagnosis of melanoma.

Objective: To investigate the clinical, pathological, and genetic characteristics of patients with vaginal melanoma in a nationwide setting., Materials/methods: All patients diagnosed with vaginal melanoma from 1980 to 2018 were collected by searching the digital archives of the Danish Registry of Pathology (Patobank). Patient specimens were examined, the histological diagnoses were validated, and targeted next-generation sequencing (NGS) of known frequent hot spots in 163 genes was performed., Results: Fifty-two patients were included. The incidence for primary melanoma of the vagina in the Danish population (5.5 million people) was calculated to be 0.24 cases/million/year from 1980 to 2018. For all patients, the median OS was 17.5 months (95% CI: 13.0-24.0), and the 5-year OS was 19.4% (95% CI: 10.9-34.3). We identified frequent mutations in ATRX (7/25 cases) and TP53 (7/25 cases). Mutations found in TP53 were associated with a significant decrease in OS (p = 0.043), whereas mutations in the ATRX gene alone did not show a significant impact on OS (p = 0.3649). Patients who harbored co-mutations in both ATRX and TP53 showed a significant reduction in OS (p = 0.0081), with a median OS of 9.5 months compared to 20 months in those without the co-mutation., Conclusions: Vaginal melanoma is a rare disease with a poor prognosis presumably due to vague symptoms and the anatomical location of the disease. Co-mutations in ATRX and TP53 and mutations in TP53 alone were associated with a poor prognosis, and these genes are potentially interesting targets for future therapy., Competing Interests: Declaration of Competing Interest None of the authors had a personal or financial conflict of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: We evaluated the outcome of sentinel lymph node biopsies (SLNB) in patients with thin melanoma before and after the implementation of AJCC 8th edition (AJCC8) and identified predictors of positive sentinel lymph nodes (+SLN)., Methods: Patients diagnosed with T1 melanomas (Breslow thickness ≤1 mm) during 2016-2017 as per AJCC 7th edition (AJCC7) (n = 3414) and 2018-2019 as per AJCC8 (n = 3734) were identified in the Danish Melanoma Database., Results: More SLNBs were performed in the AJCC8 cohort compared to the AJCC7 (22.2% vs. 16.2%, p < 0.001), with no significant difference in +SLN rates (4.7% vs. 6.7%, p = 0.118). In the AJCC7 + SLN subgroup, no melanomas were ulcerated, 94.6% had mitotic rate (MR) ≥ 1, 67.6% were ≥0.8 mm and 32.4% would be T1a according to AJCC8. In the AJCC8 + SLN subgroup, 10.3% were ulcerated, 74.4% had MR≥ 1, 97.4% were ≥0.8 mm and 23.1% would be T1a according to AJCC7. On multivariable analysis younger age and MR ≥ 1 were significant predictors of +SLN., Conclusion: More SLNBs were performed in T1 melanomas after transition to AJCC8 without an increase in +SLN rate. None of the AJCC8 T1b criteria were significant predictors of +SLN. We suggest that mitosis and younger age should be considered as indications for SLNB in thin melanoma., (© 2021 Wiley Periodicals LLC.)

Breast cancer is the most common cancer diagnosed in women, and early stages are treated with lumpectomy and irradiation. Irradiation, however, leads to reduced vascularization and fibrosis, which may influence the cosmetic outcome unfavourably and increase complications after subsequent surgery on irradiated breasts. Patients with significant asymmetry after treatment may desire corrective reduction mammoplasty or mastopexy, but this may be associated with increased complication rates. This systematic review and meta-analysis aimed to investigate postoperative complication rates after bilateral reduction mammoplasty or mastopexy in women who had undergone unilateral lumpectomy and irradiation. PubMed, Medline, EMBASE and Cochrane databases were searched for eligible studies. After screening titles and abstracts, 14 full text studies were reviewed, and 7 of these were included in the analysis. The meta-analysis showed a significantly higher complication rate in the irradiated breast compared to the non-irradiated breast, rate ratio 4.82 (95% CI: 1.58, 14.70), p  = 0.006. The complication rate was 54% in the irradiated breast (58/107) compared to 8% (9/107) in the non-irradiated breast ( p  = 0.034). This study suggests that reduction mammoplasty or mastopexy in the previously irradiated breast is associated with a significantly increased risk of complications. Careful patient selection and information are paramount in the treatment of this patient group.

Introduction: The use of routine imaging with 18F-FDG PET-CT (PET-CT) in melanoma surveillance is debated and evidence of its diagnostic value and yield in asymptomatic patients is limited. Denmark introduced nationwide routine surveillance with PET-CT in high-risk patients in 2016. The aim of this study was to examine the sensitivity, specificity, negative and positive predictive values, numbers-needed-to-scan and clinical impact of routine PET-CT in the surveillance of asymptomatic stage IIB-III melanoma patients., Materials and Methods: Data was retrieved from the population-based Danish Melanoma Database and patient records. All patients diagnosed with stage IIB-III melanoma at two University Hospitals in 2016 and 2017 were included. Patients underwent surveillance with clinical examinations and PET-CT scans at 6, 12, 24 and 36 months., Results: In 138 patients, 243 routine PET-CTs were performed within a median follow-up time of 17.7 months. Routine PET-CT detected recurrence at least once in 25 patients (18.1%), including distant recurrence in 19 patients (13.8%). Stage IIB patients had the lowest recurrence rate (11.1%). Numbers-needed-to-scan to detect one distant recurrence was 12.8 patients and median time-to-recurrence was 6.8 months. Sensitivity was 100%, specificity was 94.7% and negative and positive predictive values were 100% and 74.4%, respectively. False positive findings prompted 22 additional investigations (of which ten invasive) in 17 patients (12.3%)., Conclusion: Routine PET-CT has a high sensitivity and specificity when used in high-risk melanoma surveillance. Time-to-recurrence and stage-specific recurrence rates indicate high gain of early routine imaging at six months especially for stage IIC and III patients., Competing Interests: Declaration of competing interest The authors have no financial or commercial conflicts to report., (Copyright © 2021 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Objective: Immediate direct-to-implant breast reconstruction with acellular dermal matrix (ADM) is the method of choice for many plastic surgeons and patients, but the use of ADM remains a controversial subject in the literature. This study aimed to investigate complications, reconstructive failure and possible risk factors in direct-to-implant breast reconstruction with ADM (primarily Strattice™)., Methods: We retrospectively examined all patients undergoing immediate direct-to-implant breast reconstruction with ADM, during a five-year period (2014-2019) at a university clinic. Study outcomes were all complications and explantations. Complications were stratified within and after 6 months postoperatively and subcategorized by type of intervention. Explantations were subcategorized into loss of implant or salvage with immediate insertion of a tissue expander, the same or a new implant., Results: We included 154 patients and 232 breasts. Complications within 6 months per patient included hematoma (4%), seroma (8%), infection (9%), necrosis, wound dehiscence and delayed wound healing (19%). The total complication rate per patient was 34%. Explantation occurred in 20 patients (13%) of which 9 (6% of all) had implant loss. Preoperative radiotherapy was a significant predictor of explantation (adjusted OR 4.9, 95% confidence interval (CI), 1.0-23.5; p = 0.045), and smoking was also associated with risk of explantation, although only borderline significant (adjusted OR 4.0, 95% CI, 1.0-15.8; p = 0.050)., Conclusion: This study demonstrates acceptable rates of re-operations and implant loss compared to other studies but highlights the importance of proper patient selection with regards to risk factors to minimize complications., Competing Interests: Declaration of competing interest The authors have no financial conflicts of interest to report., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Breast implant-associated anaplastic large cell lymphoma is an uncommon malignancy associated with textured breast implants, and since 2014 13 Danish cases have been identified. Early diagnosis is important to minimise morbidity. Most patients present with swelling of the breast due to seroma within the fibrous capsule, fewer with a tumour. The diagnosis is based on cytology/histology with finding of typical anaplastic large cells, positive for CD30 and negative for anaplastic lymphoma kinase. Staging includes bone marrow examination and PET-CT scan, and a minority need systemic treatment, as argued in this review.

Background: Osteoarthritis is a destructive joint disease that leads to degeneration of cartilage and other morphological changes in the joint. No medical treatment currently exists that can reverse these morphological changes. Intra-articular injection with autologous, micro-fragmented adipose tissue has been suggested to relieve symptoms., Methods/design: The study is a blinded randomized controlled trial with patients allocated in a 1:1 ratio to 2 parallel groups. Patients suffering from pain and functional impairment due to osteoarthritis Kellgren-Lawrence grades 2-3 in the tibiofemoral joint are eligible for inclusion. The intervention group is treated with an intra-articular injection with autologous, micro-fragmented adipose tissue prepared using the Lipogems® system. The control group receives an intra-articular injection with isotonic saline. In total, 120 patients are to be included. The primary outcome is The Knee injury and Osteoarthritis Outcome Score (KOOS4) evaluated at 6 months. Secondary outcomes are KOOS at 3, 12 and 24 months; the Tegner activity score; treatment failure; and work status of the patient. The analysis will be conducted both as intention-to-treat and per-protocol analysis., Discussion: This trial is the first to investigate the efficacy of autologous, micro-fragmented adipose tissue in a randomized controlled trial. The study uses the patient-reported outcome measure Knee Injury and Osteoarthritis Outcome Score (KOOS4) after 6 months as the primary outcome, as it is believed to be a valid measure to assess the patient's opinion about their knee and associated problems when suffering from osteoarthritis., (© 2021. The Author(s).)

Whether there is an association between measured and genetically predicted telomere length and melanoma mortality is unclear. We tested the hypothesis that measured and genetically predicted telomere length is associated with mortality after a melanoma diagnosis. We followed 2,101 patients with melanoma from hospital clinics and the general population for risk of death for up to 26 years. All had telomere length measured in DNA from leukocytes, and 2052 of these were genotyped for the three single nucleotide polymorphisms rs7726159 (TERT), rs1317082 (TERC), and rs2487999 (OBFC1); all three genotypes are associated with telomere length and combined into an allele count from 0 to 6. For each telomere-lengthening allele, the hazard ratios (HRs) for mortality in the age-adjusted and multivariable-adjusted Cox analysis were 1.12 (95% confidence interval: 1.02-1.23) and 1.11 (1.01-1.23). However, for each standard deviation increase in measured telomere length, HR for mortality was 0.97 (0.88-1.08). In conclusion, in more than 2000 melanoma patients from hospital clinics and from the general population, genetically predicted long telomeres were associated with increased mortality, but measured leukocyte telomere length was not., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)