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.

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.

Comparison of seven prognostic tools to identify low-risk pulmonary embolism in patients aged <50 years.

In young patients with acute pulmonary embolism (PE), the predictive value of currently available prognostic tools has not been evaluated. Our objective was to compare prognostic value of 7 available tools (GPS, PESI, sPESI, Prognostic Algorithm, PREP, shock index and RIETE) in patients aged <50 years. We used the RIETE database, including PE patients from 2001 to 2017. The major outcome was 30-day all-cause mortality. Of 34,651 patients with acute PE, 5,822 (17%) were aged <50 years. Of these, 83 (1.4%) died during the first 30 days. Number of patients deemed low risk with tools was: PREP (95.9%), GPS (89.6%), PESI (87.2%), Shock index (70.9%), sPESI (59.4%), Prognostic algorithm (58%) and RIETE score (48.6%). The tools with a highest sensitivity were: Prognostic Algorithm (91.6%; 95% CI: 85.6-97.5), RIETE score (90.4%; 95%CI: 84.0-96.7) and sPESI (88%; 95% CI: 81-95). The RIETE, Prognostic Algorithm and sPESI scores obtained the highest overall sensitivity estimates for also predicting 7- and 90-day all-cause mortality, 30-day PE-related mortality, 30-day major bleeding and 30-day VTE recurrences. The proportion of low-risk patients who died within the first 30 days was lowest using the Prognostic Algorithm (0.2%), RIETE (0.3%) or sPESI (0.3%) scores. In PE patients less 50 years, 30-day mortality was low. Although sPESI, RIETE and Prognostic Algorithm scores were the most sensitive tools to identify patients at low risk to die, other tools should be evaluated in this population to obtain more efficient results.