[Cross sectional study of odontological incidences on board the spanish Navy flagship Juan Carlos I during its first international peacekeeping mission]. / Estudio observacional descriptivo de la incidencia odontológica a bordo del buque insignia de la Armada española Juan Carlos I en su primera misión internacional de mantenimiento de la paz.

OBJECTIVE: Oral health is an essential component of the general well-being and quality of life of the population. In Spain, access to dental services and emergency dental care for civilians is relatively straightforward. However, this is not the case for military personnel, especially those deployed on Navy ships that lack dental capabilities and in isolated areas where access to specialized healthcare services is complex and risky. The aim of this study was to evaluate the incidence and management of dental pathology among Spanish military personnel aboard the LHD 61 Juan Carlos I during its first International Peacekeeping Operation. METHODS: A descriptive observational study was conducted on the accumulated incidences of dental pathology and treatments performed between May 1 and June 26, 2018. The population sample consisted of 448 Spanish military personnel aboard the ship. The data were obtained from the databases of the dental activity logbook and the military statistical and health data management systems, which serve to assess the actual health status of the force. RESULTS: A total of 70 patients were treated for dental problems, with gingivitis and caries being the most prevalent conditions, accounting for 23.07% and 18.68% of cases, respectively. The most common treatments performed were dental reconstructions/fillings, making up 40% of the total, and tartar removal, accounting for 21%. CONCLUSIONS: Understanding the incidence of dental pathologies on Spanish Navy ships allows us to establish the training needs of the onboard medical personnel, as well as determine the material resources that should be provided to naval units. Prevention plans and pre-deployment dental check-ups should be conducted well in advance to address any dental issues on land before personnel are deployed.

OBJETIVO: La salud bucodental es un componente esencial para el bienestar general y la calidad de vida de la población. En España el acceso a los servicios odontológicos y a la atención de la urgencia bucodental del personal civil es relativamente sencilla, pero no ocurre lo mismo para el personal militar, especialmente para el que se encuentra desplegado en buques de la Armada que no cuentan con capacidad odontológica y en zonas de aislamiento donde el acceso a los servicios sanitarios especializados es complejo y arriesgado. El objetivo de este estudio fue evaluar la incidencia y manejo de la patología odontológica ocurrida en los militares españoles a bordo del buque LHD 61 Juan Carlos I durante su primera Operación Internacional de Mantenimiento de la Paz. METODOS: Se realizó un estudio observacional descriptivo de incidencias acumuladas de la patología y los tratamientos odontológicos realizados entre el 1 de mayo y el 26 de junio de 2018. La muestra poblacional fue de 448 militares españoles a bordo del buque. Los datos se obtuvieron de las bases de datos del libro de registro de actividad odontológica y de los sistemas militares de estadística y gestión de datos sanitarios que sirven para conocer el estado real de salud de la fuerza. RESULTADOS: Se atendieron un total de 70 pacientes por problemas bucodentales, donde la gingivitis y la caries fueron las enfermedades que más incidencia presentaron, con un 23,07% y un 18,68%, respectivamente. Los tratamientos más realizados fueron las reconstrucciones/obturaciones dentales con un 40% y las tartrectomías con un 21% del total. CONCLUSIONES: El conocimiento de la incidencia de las patologías odontológicas en buques de la Armada Española nos permite establecer las necesidades formativas del personal de sanidad embarcado, así como determinar con qué recursos materiales se debe de dotar a las unidades navales. Los planes de prevención y los reconocimientos odontológicos previos al despliegue deben realizarse con antelación suficiente para poder sanar en tierra las patologías del personal que va a ser desplegado.

Venous thromboembolism (VTE) developing after ankle sprain. Comparison with VTE after knee arthroplasty.

BACKGROUND: Venous thromboembolism (VTE) is a critical complication after non-major trauma or surgery. While the risk and severity of VTE following major orthopedic surgery is well-documented, there is significant knowledge gap regarding, non-major trauma such as ankle sprains. METHODS: We analyzed data from the RIETE registry to assess the clinical characteristics, VTE prophylaxis usage, and outcomes in patients with VTE following ankle sprain versus those post elective knee arthroplasty. We aimed to assess the risk and severity of VTE in a population traditionally considered at lower risk. Risk stratification was performed using the TRiP(cast) score. RESULTS: Among 1,250 patients with VTE, those with ankle sprain (n = 459) were much younger than those post knee arthroplasty (n = 791), less often female, had fewer comorbidities, and received VTE prophylaxis less often (27% vs. 93 %). During anticoagulation, 26 patients developed recurrent VTE, 31 had major bleeding, and 12 died (fatal PE 3, fatal bleeding 2). There were no differences between the two groups in the rates of VTE recurrences (rate ratio (RR): 1.65; 95%CI: 0.69-3.88) or death (RR: 1.12; 95%CI: 0.33-3.46), but patients with VTE after ankle sprain had a lower rate of major bleeding (RR: 0.39; 95%CI: 0.13-0.99). CONCLUSIONS: Ankle sprain patients are often undertreated for VTE prophylaxis and have similar severity of VTE than those undergoing elective knee surgery, indicating the need for a more customized approach to VTE management.

Radiological usual interstitial pneumonia pattern is associated with two-year mortality in patients with idiopathic pulmonary fibrosis.

Introduction: The new diagnostic guidelines for idiopathic pulmonary fibrosis (IPF) did not rule out the possibility of combining the radiological patterns of usual interstitial pneumonia (UIP) and probable UIP, given the similar management and diagnostic capacity. However, the prognostic implications of these patterns have not been fully elucidated, with different studies showing heterogeneous results. We applied the new criteria to a retrospective series of patients with IPF, assessing survival based on radiological patterns, findings, and their extension. Methods: Two thoracic radiologists reviewed high-resolution computed tomography images taken at diagnosis in 146 patients with IPF, describing the radiological findings and patterns. The association of each radiological finding and radiological patterns with two-year mortality was analysed. Results: The two-year mortality rate was 40.2% in IPF patients with an UIP radiological pattern versus 7.1% in those with probable UIP. Compared to the UIP pattern, probable UIP was protective against mortality, even after adjusting for age, sex, pulmonary function, and extent of fibrosis (hazard ratio (HR) 0.23, 95% confidence interval (CI) 0.06-0.99). Receiving antifibrotic treatment was also a protective factor (HR 0.51, 95%CI 0.27-0.98). Honeycombing (HR 3.62, 95%CI 1.27-10.32), an acute exacerbation pattern (HR 4.07, 95%CI 1.84-8.96), and the overall extent of fibrosis (HR 1.04, 95%CI 1.02-1.06) were predictors of mortality. Conclusions: In our series, two-year mortality was higher in patients with IPF who presented a radiological pattern of UIP versus probable UIP on the initial scan. Honeycombing, an acute exacerbation pattern, and a greater overall extent of fibrosis were also predictors of increased mortality. The prognostic differences between the radiological pattern of UIP and probable UIP in our series would support maintaining them as two differentiated patterns.

Transcriptomic Profiling of Pleural Effusions: Differences in Malignant and Infectious Fluids.

Background and Objectives: Different cellular and molecular processes are involved in the production of malignant and infectious pleural effusions. However, the underlying mechanisms responsible for these differences or their consequences remain incompletely understood. The objective of this study was to identify differences in gene expression in pleural exudates of malignant and infectious aetiology and establish the possible different biological processes involved in both situations. Materials and Methods: RNA transcriptomic analysis was performed on 46 pleural fluid samples obtained during diagnostic thoracocenteses from 46 patients. There were 35 exudates (19 malignant and 16 infectious effusions) and 11 transudates that were used as a reference control group. Differential gene expression analysis for both exudative groups was identified. An enrichment score using the Human Kegg Orthology database was used for establishing the biological processes associated with malignant and infectious pleural effusions. Results: When comparing malignant exudates with infectious effusions, 27 differentially expressed genes with statistical significance were identified. Network analysis showed ten different biological processes for malignant and for infectious pleural effusions. In malignant fluids, processes related to protein synthesis and processing predominate. In infectious exudates, biological processes in connection with ATP production prevail. Conclusions: This study demonstrates differentially expressed genes in malignant and infectious pleural effusions, which could have important implications in the search for diagnostic or prognostic biomarkers. In addition, for the first time, biological processes involved in these two causes of pleural exudates have been described.

Cell Therapy of Vascular and Neuropathic Complications of Diabetes: Can We Avoid Limb Amputation?

Globally, a leg is amputated approximately every 30 seconds, with an estimated 85 percent of these amputations being attributed to complications arising from diabetic foot ulcers (DFU), as stated by the American Diabetes Association. Peripheral arterial disease (PAD) is a risk factor resulting in DFU and can, either independently or in conjunction with diabetes, lead to recurring, slow-healing ulcers and amputations. According to guidelines amputation is the recommended treatment for patients with no-option critical ischemia of the limb (CTLI). In this article we propose cell therapy as an alternative strategy for those patients. We also suggest the optimal time-frame for an effective therapy, such as implanting autologous mononuclear cells (MNCs), autologous and allogeneic mesenchymal stromal cells (MSC) as these treatments induce neuropathy relief, regeneration of the blood vessels and tissues, with accelerated ulcer healing, with no serious side effects, proving that advanced therapy medicinal product (ATMPs) application is safe and effective and, hence, can significantly prevent limb amputation.

Rationale for combined therapies in severe-to-critical COVID-19 patients.

An unprecedented global social and economic impact as well as a significant number of fatalities have been brought on by the coronavirus disease 2019 (COVID-19), produced by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Acute SARS-CoV-2 infection can, in certain situations, cause immunological abnormalities, leading to an anomalous innate and adaptive immune response. While most patients only experience mild symptoms and recover without the need for mechanical ventilation, a substantial percentage of those who are affected develop severe respiratory illness, which can be fatal. The absence of effective therapies when disease progresses to a very severe condition coupled with the incomplete understanding of COVID-19's pathogenesis triggers the need to develop innovative therapeutic approaches for patients at high risk of mortality. As a result, we investigate the potential contribution of promising combinatorial cell therapy to prevent death in critical patients.

Feasibility of a screening algorithm for chronic thromboembolic pulmonary hypertension: The OSIRIS study.

INTRODUCTION: Chronic thromboembolic pulmonary hypertension (CTEPH) is a long-term sequel to pulmonary embolism (PE) whose incidence varies according to different published studies. We have carried out this study to determine its incidence within 2 years after index pulmonary embolism and to study limitations to an early diagnosis. MATERIAL AND METHODS: OSIRIS is a multicentre, longitudinal cohort study. Patients were followed for 3, 6, 12, and 24 months after pulmonary embolism using a structured three-step algorithm. A physician-centered questionnaire at least one positive response in a screening proceeded to the second step, transthoracic echocardiography. The third step consisted of ventilation/perfusion lung scintigraphy and right heart catheterisation. A transthoracic echocardiography was performed in patients without positive response in the screening questionnaire after 2 years. CTEPH diagnosis required haemodynamic confirmation by right heart catheterisation and mismatched perfusion defects on lung scintigraphy. RESULTS: A total of 1191 patients were enrolled in 18 Spanish hospitals. Cumulative CTEPH incidence after 2-years PE was: 2.49 % (95 % CI: 1.68-3.56) and the incidence rate of CTEPH was 1.1 cases per 1000 person-months (95 % CI: 0.725; 1.60). The CTEPH algorithm presented a lack of adherence of 29 %; patient and physician preferences posed barriers to the triage algorithm The screening questionnaire, in patients who completed the follow-up, shows a specificity of 91.3 % (89.0-93.2 %) and negative predictive value of 99.4 % (98.4-99.8 %).. CONCLUSIONS: OSIRIS provides practiced clinical based data on the chronic thromboembolic pulmonary hypertension incidence and identified barriers to the implementation of a 3-step triage algorithm for its detection. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT03134898.

Comparison of Presentation, Treatment, and Outcomes of Venous Thromboembolism in Long-Term Immobile Patients Based on Age.

BACKGROUND: Chronic immobility is prevalent, especially as people age. However, little is known about venous thromboembolism (VTE) outcomes in this population. OBJECTIVE: To compare the presentation, treatment, and outcomes in chronically immobile (>8 weeks) patients older vs. younger than 75 who presented with VTE. DESIGN: An observational international registry of patients with VTE. PARTICIPANTS: Patients with acute VTE from the "Registro Informatizado Enfermedad TromboEmbolica" (RIETE) registry who were chronically immobile. MAIN MEASURES: Baseline characteristics, presenting signs and symptoms, treatment and outcomes including major bleeding, recurrent VTE, and mortality. KEY RESULTS: Among 4612 immobile patients (mean age 75.7 years, 34% male), 2127 (46%) presented with pulmonary embolism (PE). Patients >75 years presented more often with dyspnea (44% vs. 38%) or altered mental status (23% vs. 8.1%) and less often with chest pain (13% vs. 18%). The median duration of anticoagulation was shorter in older compared with younger patients [126 vs. 169 days]. During the first 90 days of anticoagulation, major bleeding (4.0% vs. 2.2%), PE-related death (2.5% vs. 1.1%), and bleeding-related death (0.78% vs. 0.26%) occurred more frequently among older patients. In 3550 patients who received anticoagulation beyond 90 days, older patients had more major bleeding [4.23 vs. 2.21 events per 100 patient years]. After anticoagulation discontinuation, recurrent VTE and major bleeding occurred in 11.8 and 9.25 and 1.49 and 0.69 events per 100 patient years, respectively, both in similar rates in both groups. In multivariable analysis, after stopping anticoagulation, VTE recurrence was inversely associated with long-term facility residence [OR 0.51 (0.28-0.92)], anemia [OR 0.63 (0.42-0.95)], and anticoagulation duration < 90 days [OR 0.38 (0.27-0.54)]. CONCLUSIONS: Chronically immobilized patients older than 75 years presenting with VTE experience a high rate of adverse events including major bleeding and recurrent VTE. When considering treatment beyond 90 days, we should account for bleeding, recurrence risk, and associated mortality.

Obstructive sleep apnoea is related to melanoma aggressiveness through paraspeckle protein-1 upregulation.

BACKGROUND: In patients with obstructive sleep apnoea (OSA), intermittent hypoxia induces overexpression of paraspeckle component (PSPC)1, a master modulator of transforming growth factor (TGF)-ß signalling, which promotes cell cancer progression through epithelial-mesenchymal transition (EMT) and acquisition of cancer stem cell (CSC)-like features. However, the persistence of intermittent hypoxia-induced effects on PSPC1, and their consequences in cancer patients are not known. To this effect, circulating PSPC1 levels were compared in patients with cutaneous melanoma with or without OSA, and their relationship with tumour aggressiveness along with the in vitro effects of soluble PSPC1 and intermittent hypoxia on melanoma cell aggressiveness mechanisms were assessed. METHODS: In 292 cutaneous melanoma patients, sleep studies and serum levels of PSPC1 and TGF-ß were evaluated. The effect of PSPC1 on expression of EMT and CSC transcription factors was assessed using melanoma cell lines with patient sera under both normoxia and intermittent hypoxia conditions. RESULTS: PSPC1 levels were higher in patients with moderate-severe OSA compared with mild OSA or non-OSA patients. Serum levels of PSPC1 were associated with several cutaneous melanoma clinical aggressiveness indicators. Both intermittent hypoxia exposures and serum from OSA patients upregulated TGF-ß expression and amplified the expression of transcription factors associated with EMT activation and acquisition of CSC characteristics. CONCLUSION: In cutaneous melanoma patients, OSA severity is associated with higher PSPC1 serum levels, which jointly with intermittent hypoxia would enhance the self-reprogramming capabilities of EMT and CSC feature acquisition of melanoma cells, promoting their intrinsic aggressiveness.

First evidence of microplastics isolated in European citizens' lower airway.

Microplastics (MPs) have been detected in all environmental locations, including the atmosphere. However, few studies have investigated the presence of airborne MPs in the human respiratory system. Our research purpose was to investigate these pollutants in the lower human airways of 44 adult European citizens, using bronchoalveolar lavage fluid (BALF) collection as a minimally invasive method, that enables the detection of these pollutants in living patients. We studied the relationship between the patients' life habits and physiological parameters, based on background information and medical and occupational history, and the concentration of MPs isolated from their respiratory systems. Our results indicate that most MPs were in the form of microfibers (MFs) (97.06%), with an average concentration of 9.18 ± 2.45 items/100 mL BALF, and only 5.88% (0.57 ± 0.27 items/100 mL BALF) were particulate MPs, without a significant relationship with environmental, physiological, or clinical factors. The average size was 1.73 ± 0.15 mm, with the longest dimension (9.96 mm) corresponding to a polyacrylic fiber. Taken together, the results demonstrated the occurrence of MPs in the lower human airway, although more studies are necessary to elucidate the negative effects these pollutants could induce in the human respiratory system and its associated diseases.

Mosaic attenuation in non-fibrotic areas as a predictor of non-usual interstitial pneumonia pathologic diagnosis.

The new radiological diagnostic criteria for diagnosing idiopathic pulmonary fibrosis (IPF) seek to optimize the indications for surgical lung biopsy (SLB). We applied the new criteria to a retrospective series of patients with interstitial lung disease (ILD) who underwent SLB in order to analyse the correlation between the radiological findings suggestive of another diagnosis (especially mosaic attenuation and its location with respect to fibrotic areas) and the usual interstitial pneumonia (UIP) pathologic diagnosis. Two thoracic radiologists reviewed the HRCT images of 83 patients with ILD and SLB, describing the radiological findings and patterns based on the new criteria. The association of each radiological finding with radiological patterns and histology was analysed. Mosaic attenuation is highly prevalent in both the UIP and non-UIP pathologic diagnosis and with similar frequency (80.0% vs. 78.6%). However, the presence of significant mosaic attenuation (≥ 3 lobes) only in non-fibrotic areas was observed in 60.7% of non-UIP pathologic diagnosis compared to 20.0% in UIP. This finding was associated with other diagnoses different from IPF, mostly connective tissue disease-associated interstitial lung disease (CTD-ILD) and hypersensitivity pneumonitis (HP). In our series of pathologically confirmed ILD, mosaic attenuation in non-fibrotic areas was a predictor of non-UIP pathologic diagnosis, and was associated with other diagnoses different from UIP, mostly CTD-ILD and HP. If confirmed in larger series, this finding could constitute a valuable tool for improving the interpretation of radiological.

Prognostic Impact of Active Cigarette Smoking on Mortality in Patients with Acute Venous Thromboembolic Events, Findings from Real World Data.

Background and Objectives: The influence of smoking habits on mortality, VTE recurrence, and major bleeding in patients receiving anticoagulant therapy for venous thromboembolism (VTE) has not been consistently evaluated. Materials and Methods: We used data from the RIETE (Registro Enfermedad TromboEmbólica) registry to compare mortality, VTE recurrence, and major bleeding risk in smoking versus non-smoking patients with acute VTE. Results: 50,881 patients (43,426 non-smoking and 7455 smoking patients) were included. After a median follow-up of 8.8 months, 7110 patients died (fatal PE 292 and fatal bleeding 281), 3243 presented VTE recurrence, and 1579 had major bleeding. At multivariate analysis, smoking behavior was associated with a higher hazard of death, (HR: 1.28; 95% CI: 1.19-1.40). The risk of VTE recurrence was marginally increased in smoking patients compared to non-smoking patients (1.14; 95% CI: 1.02-1.27). Major bleeding did not differ in smoking and non-smoking patients (1.15; 95% CI: 0.96-1.38). The presence of cancer did not appear to influence the association between smoking habits and death (HR: 1.34; 95% CI: 1.22-1.47 in cancer patients and HR: 1.23; 95% CI: 1.04, 1.45 in non-cancer patients, respectively) Conclusions: the risk of death after an acute episode of VTE appeared to be higher in smoking than in non-smoking patients and this risk is higher between patients presenting PE at the onset of symptoms.

Outcome of Cancer-Associated Venous Thromboembolism Is More Favorable among Patients with Hematologic Malignancies than in Those with Solid Tumors.

BACKGROUND: The natural history of patients with hematologic cancer and venous thromboembolism (VTE) has not been consistently evaluated. We aimed to compare the rates of symptomatic recurrent VTE, major bleeding, or death during anticoagulant therapy in patients with VTE associated with hematologic versus solid cancers. METHODS: Consecutive patients with active cancer recruited in RIETE were evaluated. Their baseline characteristics, treatments, and outcomes during the course of anticoagulation were compared. Univariate and multivariate competing-risk analyses were performed. RESULTS: As of December 2020, 16,694 patients with cancer and VTE were recruited. Of these, 1,062 (6.4%) had hematologic cancers. Hematologic patients were less likely to initially present with pulmonary embolism (46 vs. 55%) and more likely with upper extremity deep vein thrombosis (25 vs. 18%). They also were more likely to have severe thrombocytopenia at baseline (5.6 vs. 0.7%) or to receive chemotherapy (67 vs. 41%). During the course of anticoagulation (median, 150 vs. 127 days), 1,071 patients (6.4%) developed VTE recurrences, 806 (4.8%) suffered major bleeding, and 4,136 (24.8%) died. Patients with hematologic cancers had lower rates of recurrent VTE (rate ratio [RR]: 0.73; 95% confidence interval [CI]: 0.56-0.95), major bleeding (RR: 0.72; 95% CI: 0.53-0.98), or all-cause death (RR: 0.49; 95% CI: 0.41-0.57) than those with solid cancers. Patients with multiple myeloma showed the best outcomes. CONCLUSION: Patients with hematologic cancers, particularly multiple myeloma, and VTE had better outcomes than those with solid cancers. These findings are relevant for the interpretation of previous clinical trials and the design of future studies.

Efficacy and safety of intramuscular administration of allogeneic adipose tissue derived and expanded mesenchymal stromal cells in diabetic patients with critical limb ischemia with no possibility of revascularization: study protocol for a randomized controlled double-blind phase II clinical trial (The NOMA Trial).

BACKGROUND: Chronic lower limb ischemia develops earlier and more frequently in patients with type 2 diabetes mellitus. Diabetes remains the main cause of lower-extremity non-traumatic amputations. Current medical treatment, based on antiplatelet therapy and statins, has demonstrated deficient improvement of the disease. In recent years, research has shown that it is possible to improve tissue perfusion through therapeutic angiogenesis. Both in animal models and humans, it has been shown that cell therapy can induce therapeutic angiogenesis, making mesenchymal stromal cell-based therapy one of the most promising therapeutic alternatives. The aim of this study is to evaluate the feasibility, safety, and efficacy of cell therapy based on mesenchymal stromal cells derived from adipose tissue intramuscular administration to patients with type 2 diabetes mellitus with critical limb ischemia and without possibility of revascularization. METHODS: A multicenter, randomized double-blind, placebo-controlled trial has been designed. Ninety eligible patients will be randomly assigned at a ratio 1:1:1 to one of the following: control group (n = 30), low-cell dose treatment group (n = 30), and high-cell dose treatment group (n = 30). Treatment will be administered in a single-dose way and patients will be followed for 12 months. Primary outcome (safety) will be evaluated by measuring the rate of adverse events within the study period. Secondary outcomes (efficacy) will be measured by assessing clinical, analytical, and imaging-test parameters. Tertiary outcome (quality of life) will be evaluated with SF-12 and VascuQol-6 scales. DISCUSSION: Chronic lower limb ischemia has limited therapeutic options and constitutes a public health problem in both developed and underdeveloped countries. Given that the current treatment is not established in daily clinical practice, it is essential to provide evidence-based data that allow taking a step forward in its clinical development. Also, the multidisciplinary coordination exercise needed to develop this clinical trial protocol will undoubtfully be useful to conduct academic clinical trials in the field of cell therapy in the near future. TRIAL REGISTRATION: ClinicalTrials.gov NCT04466007 . Registered on January 07, 2020. All items from the World Health Organization Trial Registration Data Set are included within the body of the protocol.

Proangiogenic factor midkine is increased in melanoma patients with sleep apnea and induces tumor cell proliferation.

Midkine (MDK) might mediate the proangiogenic effect of intermittent hypoxia (IH) in patients with obstructive sleep apnea (OSA) and cutaneous melanoma (CM). We compare circulating MDK in CM patients with and without OSA, and their relationship with tumor aggressiveness, while exploring in vitro effects of soluble MDK on human lymphatic endothelial (HLEC) and melanoma cell proliferation. In 360 CM patients, sleep studies and MDK serum level measurements were performed. The effect of MDK on cell proliferation was assessed using HLEC and melanoma cell lines with patient sera under both normoxia and IH. MDK levels were higher in severe OSA compared to mild OSA or non-OSA patients, whereas no differences in VEGF levels emerged. In OSA patients, MDK levels correlated with nocturnal hypoxemia and CM mitotic rate. In vitro, MDK promotes HLEC proliferation under IH conditions. Moreover, cultures of the human melanoma cell line C81-61 with sera from patients with the highest MDK levels promoted tumor cell proliferation, which was attenuated after the addition of MDK antibody. These responses were enhanced by IH exposures. In conclusion, in CM patients, OSA severity is associated with higher MDK levels, which, appear to enhance both the lymphangiogenesis as the intrinsic aggressiveness of CM tumor cells.

Obesity attenuates the effect of sleep apnea on active TGF-ß1 levels and tumor aggressiveness in patients with melanoma.

Active transforming growth factor-ß1 (TGF-ß1), a cytokine partially regulated by hypoxia and obesity, has been related with poor prognosis in several tumors. We determine whether obstructive sleep apnea (OSA) increases serum levels of active TGF-ß1 in patients with cutaneous melanoma (CM), assess their relationship with melanoma aggressiveness and analyze the factors related to TGF-ß1 levels in obese and non-obese OSA patients. In a multicenter observational study, 290 patients with CM were underwent sleep studies. TGF-ß1 was increased in moderate-severe OSA patients vs. non-OSA or mild OSA patients with CM. In OSA patients, TGF-ß1 levels correlated with mitotic index, Breslow index and melanoma growth rate, and were increased in presence of ulceration or higher Clark levels. In CM patients, OSA was associated with higher TGF-ß1 levels and greater melanoma aggressiveness only in non-obese subjects. An in vitro model showed that IH-induced increases of TGF-ß1 expression in melanoma cells is attenuated in the presence of high leptin levels. In conclusion, TGF-ß1 levels are associated with melanoma aggressiveness in CM patients and increased in moderate-severe OSA. Moreover, in non-obese patients with OSA, TGF-ß1 levels correlate with OSA severity and leptin levels, whereas only associate with leptin levels in obese OSA patients.