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Why was the cohort set up? The number of cancer survivors is increasing worldwide, largely due to ageing populations, advances in early detection and cancer treatment.1 The 5-year prevalences of cancer survivors in Denmark have increased by almost 200% from 2000 to 2020, and close to 6% of the Danish population have been diagnosed with cancer.2 Extensive research has established that globally, but also in countries with equal and free access to health care, there is social inequality in stage at cancer diagnosis, treatment provided and survival.3 Since the introduction of cancer treatment by surgery, then radiation and later systemic chemotherapy, late effects have been a part of the aftermath accompanying survival. Late effects are defined as physiological and psychological symptoms or disorders which occur during or after end of treatment and which may become long-term or chronic.1 Little is known about social inequality in late effects. A Danish national study of 458 646 adult cancer survivors showed a significantly increased risk of other diseases in all but one of 11 major diagnostic groups, such as diseases in the nervous system and endocrine, cardiovascular, metabolic and respiratory disorders, for cancer survivors across cancer types up to 17 years after treatment compared with cancer-free individuals. This cohort study included only cancer survivors free of the diseases in the diagnostic group prior to the date of the cancer diagnosis.4 A prospective cohort from the USA of more than 12 000 people observed a 37% higher risk of cardiovascular disease and up to 52% higher risk of heart failure in adult cancer survivors compared with cancer-free individuals, depending on cancer type and treatment.5 Additionally, systematic reviews and meta-analyses found that up to 49% of cancer survivors suffer from fatigue6 and 47% suffer from pain.7 A Danish nationwide study reported that 57% have impaired sex life.8 Furthermore, a systematic review of 20 s

BACKGROUND: Capsular contracture is traditionally evaluated using the Baker classification. However, this classification has notable limitations in reproducibility and objectivity.OBJECTIVES: 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 using multivariable logistic regression to identify those most associated with capsular contracture. Significant parameters (p < 0.05) were selected for the scoring systems and assigned weighted scores (1-10). Validation was performed using area under the curve (AUC) and mean absolute error (MAE).RESULTS: A total of 720 biopsies from 542 patients were included. Four parameters were selected for the augmentation scoring system including 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 was 81% and 0.8% which is considered strong. Three parameters were selected for the reconstruction scoring system including fiber organization, collagen layer cellularity, and inflammatory infiltration, providing a combined maximum score of 19. The AUC and MAE of the reconstruction scoring system was 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 the capsular contracture diagnosis in the clinical setting, for research, and for implant manufacturers and insurance providers in need of a confirmed capsular contracture diagnosis.

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., 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.

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. ©2023 Kvorning Ternov et al., 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.

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: 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 improv

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% (9

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., 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.

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.

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.

This retrospective study describes the reconstruction of 18 nasal defects with chondrocutaneous (composite) grafts. Composite grafts are versatile one-stage options for defects ≤2.5 cm at the lower third of the nose and are particularly useful in reconstruction of small full-thickness defects and superficial defects bordering or involving the alar rim.

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.

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.

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.

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.