Perioperative treatment with tranexamic acid in melanoma (PRIME): protocol for a Danish multicentre randomised controlled trial investigating the prognostic and treatment-related impact of the plasminogen-plasmin pathway

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 (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.

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Febbraio 2024

BioMEL: a translational research biobank of melanocytic lesions and melanoma

Introduction
Diagnosing invasive cutaneous melanoma (CM) can be challenging due to subjectivity in distinguishing equivocal nevi, melanoma in situ and thin CMs. The underlying molecular mechanisms of progression from nevus to melanoma must be better understood. Identifying biomarkers for treatment response, diagnostics and prognostics is crucial. Using biomedical data from biobanks and population-based healthcare data, translational research can improve patient care by implementing evidence-based findings. The BioMEL biobank is a prospective, multicentre, large-scale biomedical database on equivocal nevi and all stages of primary melanoma to metastases. Its purpose is to serve as a translational resource, enabling researchers to uncover objective molecular, genotypic, phenotypic and structural differences in nevi and all stages of melanoma. The main objective is to leverage BioMEL to significantly improve diagnostics, prognostics and therapy outcomes of patients with melanoma.

Methods and analysis
The BioMEL biobank contains biological samples, epidemiological information and medical data from adult patients who receive routine care for melanoma. BioMEL is focused on primary and metastatic melanoma, but equivocal pigmented lesions such as clinically atypical nevi and melanoma in situ are also included. BioMEL data are gathered by questionnaires, blood sampling, tumour imaging, tissue sampling, medical records and histopathological reports.

Ethics and dissemination
The BioMEL biobank project is approved by the national Swedish Ethical Review Authority (Dnr. 2013/101, 2013/339, 2020/00469, 2021/01432 and 2022/02421-02). The datasets generated are not publicly available due to regulations related to the ethical review authority.

Trial registration number
NCT05446155.

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Febbraio 2024

High Melanoma Rates in the American Indian and Alaska Native Population—A Unique Challenge

In the Navajo language, cancer is broadly described as łóód dóó nádzi híí, which translates directly as a “sore that does not heal.” Accurate determination of cancer incidence in a specified population is a critical first step toward addressing disease burden. Previous studies have shown that racial misclassification is a problem that hinders epidemiologic research in American Indian/Alaska Native populations and underestimates American Indian/Alaska Native cancer incidence. In this issue of JAMA Dermatology, Townsend et al use a method that corrects for racial misclassification among American Indian/Alaska Native patients with melanoma and show that the non-Hispanic American Indian/Alaska Native population has the second highest incidence of melanoma and a rising incidence of late-stage melanoma diagnoses. This melanoma incidence (10.7 per 100 000) is nearly double those previously published (4.5 to 5.5 per 100 000) behind non-Hispanic White patients (21.9 to 32.2 per 100 000). These findings suggest that previous studies may have overlooked American Indian/Alaska Native health disparities and underscore the importance of minimizing racial misclassification in this population.

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Febbraio 2024

Perspectives and Strategies to Minimize Harm From Melanoma Diagnosis

Kerr et al report a study of pathologists who reviewed slides of melanocytic nevi and melanomas. The pathologists were asked to grade the atypia of lesions as low vs high and to distinguish them from invasive melanoma. Seeking to identify pathologist characteristics associated with tumor categorization, the authors found that dermatopathologists were more likely than general pathologists to classify lesions as higher grade and to diagnose low-risk (pT1a, nonmitogenic) invasive melanoma. This difference was not seen for intermediate- or high-risk melanomas. There were important limitations to the study. No outcomes data were available, including that it was not known whether the melanomas classified as low risk were indeed indolent. Furthermore, grading melanocytic nevi and grouping cases with high-grade atypia together with melanoma in situ is controversial. Nonetheless, the findings of the study raise the question of whether subspecialization in dermatopathology may be a factor contributing to the epidemiologic phenomenon of overdiagnosis—that is, the discordance in the rise of melanoma incidence and relatively constant annual mortality rates over many decades. The findings also invite a discussion about strategies to minimize harm from overdiagnosis for both patients and the health care system.

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Dicembre 2023

Abstract 12587: Cardiac Tamponade and Pericardial Effusion in a Patient With Stage 3 Malignant Melanoma Treated With Pembrolizumab

Circulation, Volume 148, Issue Suppl_1, Page A12587-A12587, November 6, 2023. Introduction:The introduction of immunotherapy has revolutionized the treatment of cancer, with improved clinical outcomes. One of such agents include Pembrolizumab a humanized antibody which acts as an immune check point inhibitor by binding to Programmed cell death Protein 1 receptors. One principal setback is its autoimmune-dysfunctional side effect.Case Presentation:A 74-year-old male with BRAF-negative malignant melanoma status post resection, with recurrent neoplasm involving lymph nodes of the base of the left neck presented to the emergency department with palpitations, diarrhea and difficulty in breathing. Symptoms began three weeks after his fourth course of adjuvant therapy. On presentation he was hemodynamically unstable with positive Kussmaul sign on examination. His heart sounds were muffled, with clear lung bases bilaterally. Results of EKG and echo are has shown below.Decision-Making:Patient was commenced on Intravenous fluid normal saline, oxygen therapy, was evaluated by cardiology and had emergency pericardiocentesis with about 250mls of fluid drained from the pericardial cavity and improvement of symptoms. Pericardial fluid analysis showed acute inflammation without malignant cells. Patient was placed on steroids and a consensus was reached to discontinue Pembrolizumab and pursue other lines of treatment as determined by the hospital tumor board.Discussion:The exact incidence of pericardial disease in cancer patients treated with Immune check inhibitors including Pembrolizumab is unknown. When effusion occurs, urgent intervention should be performed to prevent life threatening cardiac events. Treatment with steroids has shown improved outcomes and should be encouraged.Conclusion:Pericardial effusion is a fatal complication of Pembrolizumab. Though incidence remains rare, a high index of suspicion should be maintained in Patients receiving this immune check point inhibitor. The Decision to continue therapy after a cardiovascular event such as Pericardial Effusion should be individualized.

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Novembre 2023