Campus Bio Medico University Hospital

INTRODUCTION: Strengthening The Reporting Of Cohort Studies in Surgery (STROCSS) guidelines were developed in 2017 in order to improve the reporting quality of observational studies in surgery and updated in 2019. In order to maintain relevance and continue upholding good reporting quality among observational studies in surgery, we aimed to update STROCSS 2019 guidelines. METHODS: A STROCSS 2021 steering group was formed to come up with proposals to update STROCSS 2019 guidelines. An expert panel of researchers assessed these proposals and judged whether they should become part of STROCSS 2021 guidelines or not, through a Delphi consensus exercise. RESULTS: 42 people (89%) completed the DELPHI survey and hence participated in the development of STROCSS 2021 guidelines. All items received a score between 7 and 9 by greater than 70% of the participants, indicating a high level of agreement among the DELPHI group members with the proposed changes to all the items. CONCLUSION: We present updated STROCSS 2021 guidelines to ensure ongoing good reporting quality among observational studies in surgery.

BACKGROUND: Current guidelines recommend at least 24 hours of electrocardiographic (ECG) monitoring after an ischemic stroke to rule out atrial fibrillation. However, the most effective duration and type of monitoring have not been established, and the cause of ischemic stroke remains uncertain despite a complete diagnostic evaluation in 20 to 40% of cases (cryptogenic stroke). Detection of atrial fibrillation after cryptogenic stroke has therapeutic implications. METHODS: We conducted a randomized, controlled study of 441 patients to assess whether long-term monitoring with an insertable cardiac monitor (ICM) is more effective than conventional follow-up (control) for detecting atrial fibrillation in patients with cryptogenic stroke. Patients 40 years of age or older with no evidence of atrial fibrillation during at least 24 hours of ECG monitoring underwent randomization within 90 days after the index event. The primary end point was the time to first detection of atrial fibrillation (lasting >30 seconds) within 6 months. Among the secondary end points was the time to first detection of atrial fibrillation within 12 months. Data were analyzed according to the intention-to-treat principle. RESULTS: By 6 months, atrial fibrillation had been detected in 8.9% of patients in the ICM group (19 patients) versus 1.4% of patients in the control group (3 patients) (hazard ratio, 6.4; 95% confidence interval [CI], 1.9 to 21.7; P<0.001). By 12 months, atrial fibrillation had been detected in 12.4% of patients in the ICM group (29 patients) versus 2.0% of patients in the control group (4 patients) (hazard ratio, 7.3; 95% CI, 2.6 to 20.8; P<0.001). CONCLUSIONS: ECG monitoring with an ICM was superior to conventional follow-up for detecting atrial fibrillation after cryptogenic stroke. (Funded by Medtronic; CRYSTAL AF ClinicalTrials.gov number, NCT00924638.).

INTRODUCTION: Strengthening The Reporting Of Cohort Studies in Surgery (STROCSS) guidelines were developed in 2017 in order to improve the reporting quality of observational studies in surgery and updated in 2019. In order to maintain relevance and continue upholding good reporting quality among observational studies in surgery, we aimed to update STROCSS 2019 guidelines. METHODS: A STROCSS 2021 steering group was formed to come up with proposals to update STROCSS 2019 guidelines. An expert panel of researchers assessed these proposals and judged whether they should become part of STROCSS 2021 guidelines or not, through a Delphi consensus exercise. RESULTS: 42 people (89%) completed the DELPHI survey and hence participated in the development of STROCSS 2021 guidelines. All items received a score between 7 and 9 by greater than 70% of the participants, indicating a high level of agreement among the DELPHI group members with the proposed changes to all the items. CONCLUSION: We present updated STROCSS 2021 guidelines to ensure ongoing good reporting quality among observational studies in surgery.

Background and objectives: This paper addresses psychological resilience, a multidisciplinary theoretical construct with important practical implications for health sciences. Although many definitions have been proposed in several contexts, an essential understanding of the concept is still lacking up to now. This negatively affects comparisons among research results and makes objective measurement difficult. The aim of this review is to identify shared elements in defining the construct of resilience across the literature examined in order to move toward a conceptual unification of the term. Materials and methods: A literature review was performed using the electronic databases ‘PubMed’ and ‘PsycINFO’. Scientific studies written in English between 2002 and May 2019 were included according to the following key terms: ‘Psychological’, ‘resilience’, and ‘definition’. Results: The review identifies five macro-categories that summarize what has been reported in the recent literature concerning the resilience phenomenon. They serve as a preliminary and necessary step toward a conceptual clarification of the construct. Conclusions: We propose a definition of psychological resilience as the ability to maintain the persistence of one’s orientation towards existential purposes. It constitutes a transversal attitude that can be understood as the ability to overcome the difficulties experienced in the different areas of one’s life with perseverance, as well as good awareness of oneself and one’s own internal coherence by activating a personal growth project. The conceptual clarification proposed will contribute to improving the accuracy of research on this topic by suggesting future paths of investigation aimed at deeply exploring the issues surrounding the promotion of resilience resources.

BACKGROUND: Immune-inflammatory biomarkers (IIBs) showed a prognostic relevance in patients with metastatic CRC (mCRC). We aimed at evaluating the prognostic power of a new comprehensive biomarker, the Pan-Immune-Inflammation Value (PIV), in patients with mCRC receiving first-line therapy. METHODS: In the present pooled-analysis, we included patients enrolled in the Valentino and TRIBE trials. PIV was calculated as: (neutrophil count × platelet count × monocyte count)/lymphocyte count. A cut-off was determined using the maximally selected rank statistics method. Generalised boosted regression (GBR), the Kaplan-Meier method and Cox hazards regression models were used for survival analyses. RESULTS: A total of 438 patients were included. Overall, 208 patients (47%) had a low-baseline PIV and 230 (53%) had a high-baseline PIV. Patients with high PIV experienced a worse PFS (HR, 1.66; 95% CI, 1.36-2.03, P < 0.001) and worse OS (HR, 2.01; 95% CI, 1.57-2.57; P < 0.001) compared to patients with low PIV. PIV outperformed the other IIBs in the GBR model and in the multivariable models. CONCLUSION: PIV is a strong predictor of survival outcomes with better performance than other well-known IIBs in patients with mCRC treated with first-line therapy. PIV should be prospectively validated to better stratify mCRC patients undergoing first-line therapy.

BACKGROUND: The 65-kD isoform of glutamic acid decarboxylase (GAD65) is a major autoantigen in type 1 diabetes. We hypothesized that alum-formulated GAD65 (GAD-alum) can preserve beta-cell function in patients with recent-onset type 1 diabetes. METHODS: We studied 334 patients, 10 to 20 years of age, with type 1 diabetes, fasting C-peptide levels of more than 0.3 ng per milliliter (0.1 nmol per liter), and detectable serum GAD65 autoantibodies. Within 3 months after diagnosis, patients were randomly assigned to receive one of three study treatments: four doses of GAD-alum, two doses of GAD-alum followed by two doses of placebo, or four doses of placebo. The primary outcome was the change in the stimulated serum C-peptide level (after a mixed-meal tolerance test) between the baseline visit and the 15-month visit. Secondary outcomes included the glycated hemoglobin level, mean daily insulin dose, rate of hypoglycemia, and fasting and maximum stimulated C-peptide levels. RESULTS: The stimulated C-peptide level declined to a similar degree in all study groups, and the primary outcome at 15 months did not differ significantly between the combined active-drug groups and the placebo group (P=0.10). The use of GAD-alum as compared with placebo did not affect the insulin dose, glycated hemoglobin level, or hypoglycemia rate. Adverse events were infrequent and mild in the three groups, with no significant differences. CONCLUSIONS: Treatment with GAD-alum did not significantly reduce the loss of stimulated C peptide or improve clinical outcomes over a 15-month period. (Funded by Diamyd Medical and the Swedish Child Diabetes Foundation; ClinicalTrials.gov number, NCT00723411.).

BACKGROUND: Desmoid tumors are rare, locally aggressive, highly recurrent soft-tissue tumors without approved treatments. METHODS: We conducted a phase 3, international, double-blind, randomized, placebo-controlled trial of nirogacestat in adults with progressing desmoid tumors according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Patients were assigned in a 1:1 ratio to receive the oral γ-secretase inhibitor nirogacestat (150 mg) or placebo twice daily. The primary end point was progression-free survival. RESULTS: From May 2019 through August 2020, a total of 70 patients were assigned to receive nirogacestat and 72 to receive placebo. Nirogacestat had a significant progression-free survival benefit over placebo (hazard ratio for disease progression or death, 0.29; 95% confidence interval, 0.15 to 0.55; P<0.001); the likelihood of being event-free at 2 years was 76% with nirogacestat and 44% with placebo. Between-group differences in progression-free survival were consistent across prespecified subgroups. The percentage of patients who had an objective response was significantly higher with nirogacestat than with placebo (41% vs. 8%; P<0.001), with a median time to response of 5.6 months and 11.1 months, respectively; the percentage of patients with a complete response was 7% and 0%, respectively. Significant between-group differences in secondary patient-reported outcomes, including pain, symptom burden, physical or role functioning, and health-related quality of life, were observed (P≤0.01). Frequent adverse events with nirogacestat included diarrhea (in 84% of the patients), nausea (in 54%), fatigue (in 51%), hypophosphatemia (in 42%), and maculopapular rash (in 32%); 95% of adverse events were of grade 1 or 2. Among women of childbearing potential receiving nirogacestat, 27 of 36 (75%) had adverse events consistent with ovarian dysfunction, which resolved in 20 women (74%). CONCLUSIONS: Nirogacestat was associated with significant benefits with respect to progression-free survival, objective response, pain, symptom burden, physical functioning, role functioning, and health-related quality of life in adults with progressing desmoid tumors. Adverse events with nirogacestat were frequent but mostly low grade. (Funded by SpringWorks Therapeutics; DeFi ClinicalTrials.gov number, NCT03785964.).

Dry eye disease (DED) is a distressing ocular condition. Due to its multifactorial nature, clinical and biological signs of DED can be inconsistent and sometimes discordant with symptomatology. Consequently, no gold-standard model for determining DED severity exists. This can impact treatment decisions and complicate evaluation of disease progression, particularly within the stringent context of clinical trials. The multinational ODISSEY European Consensus Group is comprised of ophthalmologists who contend with ocular surface disease issues on a daily basis. This group convened to establish a clear and practical algorithm for evaluation and diagnosis of severe DED. Using a consensus-based approach, they assessed 14 commonly used DED severity criteria. The panel agreed that following confirmed DED diagnosis, just two criteria, symptom-based assessment and corneal fluorescein staining were sufficient to diagnose the presence of severe DED in the majority of patients. In the event of discordance between signs and symptoms, further evaluation using additional determinant criteria was recommended. This report presents the ODISSEY European Consensus Group recommended algorithm for DED evaluation, which facilitates diagnosis of severe disease even in the event of discordance between signs and symptoms. It is intended that this algorithm will be useful in a clinical and developmental setting.

BACKGROUND AND AIMS: Atezolizumab plus bevacizumab (AtezoBev) is the standard of care for first-line treatment of unresectable HCC. No evidence exists as to its use in routine clinical practice in patients with impaired liver function. APPROACH AND RESULTS: In 216 patients with HCC who were consecutively treated with AtezoBev across 11 tertiary centers, we retrospectively evaluated treatment-related adverse events (trAEs) graded (G) according to Common Terminology Criteria for Adverse Events v5.0, including in the analysis all patients treated according to label (n = 202, 94%). We also assessed overall survival (OS), progression-free survival (PFS), overall response (ORR), and disease control rates (DCR) defined by Response Evaluation Criteria in Solid Tumors v1.1. Disease was mostly secondary to viral hepatitis, namely hepatitis C (n = 72; 36%) and hepatitis B infection (n = 35, 17%). Liver function was graded as Child-Pugh (CP)-A in 154 patients (76%) and CP-B in 48 (24%). Any grade trAEs were reported by 143 patients (71%), of which 53 (26%) were G3 and 3 (2%) G4. Compared with CP-A, patients with CP-B showed comparable rates of trAEs. Presence and grade of varices at pretreatment esophagogastroduodenoscopy did not correlate with bleeding events. After a median follow-up of 9.0 months (95% CI, 7.8-10.1), median OS was 14.9 months (95% CI, 13.6-16.3), whereas median PFS was 6.8 months (95% CI, 5.2-8.5). ORR and DCR were respectively 25% and 73%, with no difference across CP classes. CONCLUSIONS: This study confirms reproducible safety and efficacy of AtezoBev in routine practice. Patients with CP-B reported similar tolerability compared with CP-A, warranting prospective evaluation of AtezoBev in this treatment-deprived population.

While the links between metabolic dysfunction associated steatotic liver disease liver disease (MASLD) and obesity, insulin resistance are widely appreciated, there are a host of complex interactions between the liver and other endocrine axes. While it can be difficult to definitively distinguish direct causal relationships and those attributable to increased adipocyte mass, there is substantial evidence of direct and indirect specific endocrine dysregulation and severity of MASLD. Strong evidence of direct and indirect effects exists for low levels of growth hormone, sex hormones, and thyroid hormone with development and severity of disease. The impact of steroid hormones, e.g. cortisol and dehydropepiandrosterone, and adipokines is much more divergent. Thoughtful assessment, based on individual risk factors and findings, and also of management of non-insulin endocrine axes should be performed in the evaluation and management of MASLD. Multiple therapeutic pharmaceutical targets have emerged that leverage various endocrine axes to reduce the fibroinflammatory cascade in metabolic dysfunction associated steatohepatitis (MASH).

CONTEXT: Hypercalcemia of malignancy (HCM) in patients with advanced cancer is often caused by excessive osteoclast-mediated bone resorption. Patients may not respond to or may relapse after iv bisphosphonate therapy. OBJECTIVE: We investigated whether denosumab, a potent inhibitor of osteoclast-mediated bone resorption, reduces serum calcium in patients with bisphosphonate-refractory HCM. DESIGN, SETTING, AND PARTICIPANTS: In this single-arm international study, participants had serum calcium levels corrected for albumin (CSC) >12.5 mg/dL (3.1 mmol/L) despite bisphosphonates given >7 and ≤30 days before screening. INTERVENTION: Patients received 120 mg sc denosumab on days 1, 8, 15, and 29 and then every 4 weeks. MAIN OUTCOME MEASURES: The primary endpoint was the proportion of patients with CSC ≤11.5 mg/dL (2.9 mmol/L) (response) by day 10. Secondary endpoints included response by visit, duration of response, and the proportion of patients with a complete response (CSC ≤10.8 mg/dL [2.7 mmol/L]) by day 10 and during the study. RESULTS: Patients (N = 33) had solid tumors or hematologic malignancies. By day 10, 21 patients (64%) reached CSC ≤11.5 mg/dL, and 12 patients (33%) reached CSC ≤10.8 mg/dL. During the study, 23 patients (70%) reached CSC ≤11.5 mg/dL, and 21 patients (64%) reached CSC ≤10.8 mg/dL. Estimated median response duration was 104 days. The most common serious adverse events were hypercalcemia worsening (5 patients, 15%) and dyspnea (3 patients, 9%). CONCLUSIONS: In patients with HCM despite recent iv bisphosphonate treatment, denosumab lowered serum calcium in 64% of patients within 10 days, inducing durable responses. Denosumab may offer a new treatment option for HCM.

ABSTRACT In this narrative review, we present data gathered over four decades (1980–2020) on the epidemiology, pathophysiology and genetics of primary hyperparathyroidism (PHPT). PHPT is typically a disease of postmenopausal women, but its prevalence and incidence vary globally and depend on a number of factors, the most important being the availability to measure serum calcium and parathyroid hormone levels for screening. In the Western world, the change in presentation to asymptomatic PHPT is likely to occur, over time also, in Eastern regions. The selection of the population to be screened will, of course, affect the epidemiological data (ie, general practice as opposed to tertiary center). Parathyroid hormone has a pivotal role in regulating calcium homeostasis; small changes in extracellular Ca++ concentrations are detected by parathyroid cells, which express calcium-sensing receptors (CaSRs). Clonally dysregulated overgrowth of one or more parathyroid glands together with reduced expression of CaSRs is the most important pathophysiologic basis of PHPT. The spectrum of skeletal disease reflects different degrees of dysregulated bone remodeling. Intestinal calcium hyperabsorption together with increased bone resorption lead to increased filtered load of calcium that, in addition to other metabolic factors, predispose to the appearance of calcium-containing kidney stones. A genetic basis of PHPT can be identified in about 10% of all cases. These may occur as a part of multiple endocrine neoplasia syndromes (MEN1–MEN4), or the hyperparathyroidism jaw-tumor syndrome, or it may be caused by nonsyndromic isolated endocrinopathy, such as familial isolated PHPT and neonatal severe hyperparathyroidism. DNA testing may have value in: confirming the clinical diagnosis in a proband; eg, by distinguishing PHPT from familial hypocalciuric hypercalcemia (FHH). Mutation-specific carrier testing can be performed on a proband's relatives and identify where the proband is a mutation carrier, ruling out phenocopies that may confound the diagnosis; and potentially prevention via prenatal/preimplantation diagnosis. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR). Abstract The prevalence and incidence of PHPT vary around the world and depend on a number of factors, the most important being availability of serum calcium (and parathyroid hormone) measurement for screening, which in the Western world has shifted its presentation to an asymptomatic disorder. Clonally dysregulated overgrowth of one or more parathyroid glands together with reduced expression of CaSRs is the most important pathophysiologic basis of PHPT, which may also occur as a part of inherited syndromes or as a nonsyndromic isolated endocrinopathy in 10% of cases. Genetic testing has roles in establishing the clinical diagnosis, although its value requires assessments using GRADE(176) methodology, which is recommended for future consideration.

Benign thyroid nodules are a common clinical occurrence and usually do not require treatment unless symptomatic. During the last years, ultrasound-guided minimally invasive treatments (MIT) gained an increasing role in the management of nodules causing local symptoms. In February 2018, the Italian MIT Thyroid Group was founded to create a permanent cooperation between Italian and international physicians dedicated to clinical research and assistance on MIT for thyroid nodules. The group drafted this list of statements based on literature review and consensus opinion of interdisciplinary experts to facilitate the diffusion and the appropriate use of MIT of thyroid nodules in clinical practice. (#1) Predominantly cystic/cystic symptomatic nodules should first undergo US-guided aspiration; ethanol injection should be performed if relapsing (level of evidence [LoE]: ethanol is superior to simple aspiration = 2); (#2) In symptomatic cystic nodules, thermal ablation is an option when symptoms persist after ethanol ablation (LoE = 4); (#3) Double cytological benignity confirmation is needed before thermal ablation (LoE = 2); (#4) Single cytological sample is adequate in ultrasound low risk (EU-TIRADS ≤3) and in autonomously functioning nodules (LoE = 2); (#5) Thermal ablation may be proposed as first-line treatment for solid, symptomatic, nonfunctioning, benign nodules (LoE = 2); (#6) Thermal ablation may be used for dominant lesions in nonfunctioning multinodular goiter in patients refusing/not eligible for surgery (LoE = 5); (#7) Clinical and ultrasound follow-up is appropriate after thermal ablation (LoE = 2); (#8) Nodule re-treatment can be considered when symptoms relapse or partially resolve (LoE = 2); (#9) In case of nodule regrowth, a new cytological assessment is suggested before second ablation (LoE = 5); (#10) Thermal ablation is an option for autonomously functioning nodules in patients refusing/not eligible for radioiodine or surgery (LoE = 2); (#11) Small autonomously functioning nodules can be treated with thermal ablation when thyroid tissue sparing is a priority and ≥80% nodule volume ablation is expected (LoE = 3).

Abstract The SARS-CoV-2 pandemic significantly affected oncology practice across the globe. There is uncertainty as to the contribution of patients' demographics and oncologic features to severity and mortality from COVID-19 and little guidance as to the role of anticancer and anti–COVID-19 therapy in this population. In a multicenter study of 890 patients with cancer with confirmed COVID-19, we demonstrated a worsening gradient of mortality from breast cancer to hematologic malignancies and showed that male gender, older age, and number of comorbidities identify a subset of patients with significantly worse mortality rates from COVID-19. Provision of chemotherapy, targeted therapy, or immunotherapy did not worsen mortality. Exposure to antimalarials was associated with improved mortality rates independent of baseline prognostic factors. This study highlights the clinical utility of demographic factors for individualized risk stratification of patients and supports further research into emerging anti–COVID-19 therapeutics in SARS-CoV-2–infected patients with cancer. Significance: In this observational study of 890 patients with cancer diagnosed with SARS-CoV-2, mortality was 33.6% and predicted by male gender, age ≥65, and comorbidity burden. Delivery of cancer therapy was not detrimental to severity or mortality from COVID-19. These patients should be the focus of shielding efforts during the SARS-CoV-2 pandemic. This article is highlighted in the In This Issue feature, p. 1426

INTRODUCTION: Anthracyclines are widely prescribed anticancer agents that cause a dose-related cardiotoxicity, often aggravated by nonanthracycline chemotherapeutics or new generation targeted drugs. Anthracycline cardiotoxicity may occur anytime in the life of cancer survivors. Understanding the molecular mechanisms and clinical correlates of cardiotoxicity is necessary to improve the therapeutic index of anthracyclines or to identify active, but less cardiotoxic analogs. AREAS COVERED: The authors review the pharmacokinetic, pharmacodynamic and biochemical mechanisms of anthracycline cardiotoxicity and correlate them to clinical phenotypes of cardiac dysfunction. Attention is paid to bioactivation mechanisms that converted anthracyclines to reactive oxygen species (ROS) or long-lived secondary alcohol metabolites. Preclinical aspects and clinical implications of the "oxidative stress" or "secondary alcohol metabolite" hypotheses are discussed on the basis of literature that cuts across bench and evidence-based medicine. Interactions of anthracyclines with comorbidities or unfavorable lifestyle choices were identified as important cofactors of the lifetime risk of cardiotoxicity and as possible targets of preventative strategies. EXPERT OPINION: Anthracycline cardiotoxicity is a multifactorial process that needs to be incorporated in a translational framework, where individual genetic background, comorbidities, lifestyles and other drugs play an equally important role. Fears for cardiotoxicity should not discourage from using anthracyclines in many oncologic settings. Cardioprotective strategies are available and should be used more pragmatically in routine clinical practice.

Background: Radiofrequency ablation (RFA) and laser ablation (LA) are effective treatments for benign thyroid nodules. Due to their relatively recent introduction into clinical practice, there are limited long-term follow-up studies. This study aimed to evaluate technique efficacy, rate of regrowth, and retreatment over 5 years after RFA or LA and to identify predictive factors of outcome. Methods: In this multicenter retrospective study, the rates of technique efficacy, regrowth, and retreatment were evaluated in 406 patients treated with either RFA or LA, and followed for 5 years after initial treatment. Propensity score matching was used to compare treatments. Cumulative incidence studies with hazard models were used to describe regrowth and retreatment trends, and to identify prognostic factors. Logistic regression models and receiver operating characteristic analyses were used for risk factors and their cutoffs. Results: RFA and LA significantly reduced benign thyroid nodule volume, and this reduction was generally maintained for 5 years. Technique efficacy (defined as a reduction ≥50% after 1 year from the treatment) was achieved in 74% of patients (85% in the RFA and 63% in the LA group). Regrowth occurred in 28% of patients (20% in the RFA and 38% in the LA group). In the majority of cases, further treatment was not required as only 18% of patients were retreated (12% in the RFA and 24% in the LA group). These data were confirmed by propensity score matching. Cumulative incidence studies showed that RFA was associated with a lower risk of regrowth and a lower risk of requiring retreatment over time. Overall, technique inefficacy and regrowth were associated with low-energy delivery. Retreatments were more frequent in young patients, in large nodules, in patients with lower volume reduction at 1 year, and in cases of low-energy delivery (optimal cutoff was 918 J/mL for RFA). Conclusions: Both thermal ablation techniques result in a clinically significant and long-lasting volume reduction of benign thyroid nodules. The risk of regrowth and needing retreatment was lower after RFA. The need for retreatment was associated with young age, large baseline volume, and treatment with low-energy delivery.

Melanoma is an aggressive form of skin cancer resulting from the malignant transformation of melanocytes. Recent therapeutic approaches, including targeted therapy and immunotherapy, have improved the prognosis and outcome of melanoma patients. BRAF is one of the most frequently mutated oncogenes recognised in melanoma. The most frequent oncogenic BRAF mutations consist of a single point mutation at codon 600 (mostly V600E) that leads to constitutive activation of the BRAF/MEK/ERK (MAPK) signalling pathway. Therefore, mutated BRAF has become a useful target for molecular therapy and the use of BRAF kinase inhibitors has shown promising results. However, several resistance mechanisms invariably develop leading to therapeutic failure. The aim of this manuscript is to review the role of BRAF mutational status in the pathogenesis of melanoma and its impact on differentiation and inflammation. Moreover, this review focuses on the mechanisms responsible for resistance to targeted therapies in BRAF-mutated melanoma and provides an overview of circulating biomarkers including circulating tumour cells, circulating tumour DNA, and non-coding RNAs.

Since their introduction in the 1960s, anthracyclines have been a significant breakthrough in oncology, introducing dramatic changes in the treatment of solid and hematologic malignancies. Although new-generation targeted drugs and cellular therapies are revolutionizing contemporary oncology, anthracyclines remain the cornerstone of treatment for lymphomas, acute leukemias, and soft tissue sarcomas. However, their clinical application is limited by a dose-dependent cardiotoxicity that can reduce cardiac performance and eventually lead to overt heart failure. The field of cardio-oncology has emerged to safeguard the cardiovascular health of cancer patients receiving these therapies. It focuses on controlling risk factors, implementing preventive strategies, ensuring appropriate surveillance, and managing complications. This state-of-the-art review summarizes the current indications for anthracyclines in modern oncology, explores recent evidence on pathophysiology and epidemiology, and discusses advances in cardioprotection measures in the anthracycline-treated patient. Additionally, it highlights key clinical challenges and research gaps in this area.

We determined whether the early improvement in symptoms and function after microfracture in the management of articular cartilage defects of the talus is maintained at mid term follow-up. Factors influencing outcome and postoperative magnetic resonance imaging were also evaluated. We performed data collection prospectively using the Hannover Scoring System for the ankle (HSS) and a Visual Analog Scale (VAS) for pain and function preoperatively, at 1 +/- 0.1 year (45 ankles), 2 +/- 0.4 years (45 ankles), and at an average of 5.8 +/- 2.0 years (39 ankles) postoperatively. MRI was used to assess cartilage repair tissue based on the following variables: degree of defect repair and filling of the defect, integration to border zone, surface of the repair tissue, structure of the repair tissue and subchondral bone alterations. Comparing the outcome scores of the last follow-up to the previous follow-up points, the HSS and the VAS (pain, function and satisfaction) showed no deterioration. Four ankles, however, underwent further surgery to address the chondral defect and were regarded as failures. A body mass index greater than 25 kg/m(2) and having severe post-traumatic cartilage damage appeared to be negative prognostic factors. Results for patients older than 50 years were not inferior to those in younger patients. Microfracture arthroplasty induces repair of localized articular cartilage defects of the talus maintaining the encouraging early results at mid term follow-up.

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