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Objectives: To investigate the accuracy of ultrasound in the quantification of tumor thickness (TT) and depth of invasion (DOI) of oral potentially malignant disorders and oral squamous cell carcinoma., Materials and Methods: A systematic review search was conducted in PubMed, Scopus, and Web of Science to answer the PICO question: "What is the correlation and the mean difference between ultrasound and histopathological assessment of tumor thickness and depth of invasion in patients with oral squamous cell carcinoma and oral potentially malignant disorders? The risk of bias was assessed, meta-analysis and trial sequential analysis was conducted on the available quantitative data, followed by trial sequential analysis., Results: Of 2089 results, 48 studies were considered suitable for inclusion. Meta-analysis showed a low heterogeneity for tumor thickness mean difference (I 2  = 0.00 %) with an overall standardized mean difference (SMD) of 0.13 (95 % CI: -0.07 to 0.33, p = 0.214). Tumor thickness correlation showed high heterogeneity (I 2  = 93.41 %). For depth of invasion, the mean difference had moderate heterogeneity (I 2  = 8.98 %) with an overall SMD of 0.27 (95 % CI: 0.06 to 0.48, p = 0.013). However, correlation analysis showed moderate heterogeneity (I 2  = 56.22 %). Trial sequential analysis confirmed the tumor thickness results but indicated more studies are required for depth of invasion to meet the required information size., Conclusion: There were no statistically significant differences between the results of ultrasound and histological examination, the clinical use of this device cannot yet be confirmed., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Periodontitis affects up to 40% of adults over 60 years old and is a consequence of gingivitis. Periodontitis is characterized by a chronic inflammation, periodontal damage, and alveolar bone resorption. The nuclear factor erythroid 2-related factor 2 (NFE2L2 or NRF2)/Kelch-like ECH-Associated Protein 1 (KEAP1) (NRF2/KEAP1) signaling pathway plays a key role in periodontitis by modulating redox balance and inflammation of the periodontium. However, NRF2 expression is decreased in gingival tissues of patients with periodontitis while oxidative stress is significantly increased in this pathology. Oxidative stress and lipopolysaccharide (LPS) produced by gram-negative bacteria favor the production of inflammatory causing periodontal inflammation and favoring alveolar bone. In this review, we analyzed the current literature regarding the role of natural and synthetic compounds in modulating the NRF2/KEAP1 pathway in in vitro and in vivo models of periodontitis in order to evaluate new potential treatments of periodontitis that can improve the outcome of this disease.

Abstract: In patients on oral anticoagulant (OAC) therapy undergoing percutaneous coronary intervention (PCI) with stent, international guidelines endorse the use of direct oral anticoagulants (DOAC) rather than vitamin K antagonists (VKA) and dual antithrombotic therapy (DAT) rather than triple antithrombotic therapy (TAT). The aim of this study was to evaluate contemporary real-world data on antithrombotic regimens and outcome in patients on OAC undergoing PCI with stent. Consecutive patients on OAC undergoing PCI were enrolled in the multicenter, prospective, observational PERSEO registry (NCT03392948). Primary end point was net adverse clinical events (NACE) with VKA versus DOAC, whereas a secondary prespecified end point was NACE with DAT versus TAT both at 1-year follow-up. From February 2018 to February 2022; in total, 1234 consecutive patients were included. The main indication for OAC was atrial fibrillation (86%), and the mean CHA 2 DS 2 VASc and HAS-BLED scores were 4 ± 2 and 3.6 ± 1, respectively. Of the 1228 patients discharged alive, 222 (18%) were on VKA and 1006 (82%) on DOAC ( P < 0.01). DAT was employed in 197 patients whereas TAT in 1028. At follow-up, NACE rate was significantly higher than VKA compared with DOAC (23% vs. 16%, P = 0.013) and confirmed after propensity score adjustment. TAT and DAT did not differ as regards NACE rate (17% vs. 19%, P = 0.864) although, compared with TAT, DAT was associated with less major bleedings (2% vs. 5%, P = 0.014), confirmed after propensity score adjustment. In conclusion, in patients on OAC undergoing PCI, DOAC, compared with VKA, was associated with a significantly lower occurrence of NACE and DAT reduced bleedings compared with TAT., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Resection of tumors of oral cavity usually causes short- or long-term sequelae such as chewing, speech and swallowing impairment. To preserve this function it is necessary to maintain the lining of the oral cavity, the mobility and sensitivity of the tongue. Reconstructive options for oral mucosal defects resulting from tumor resection included primary closure, mucosal and skin grafts, pedicle and microvascular free flaps, and dermal matrix., Study Design: Retrospective study on patients undergoing reconstruction of intraoral defects, after removal of T1, T2 malignant tumors, by placement of bilayer dermal matrix., Methods: From 2021 to 2022, 47 patients with oral mucosa defects after removal of squamous cell carcinoma were treated. All patients were affected by a T1-T2 squamous cell carcinoma. For each patient, data were collected regarding the site of the disease, the initial staging, the size of the surgical defect, the complications and the outcome months after the operation., Results: In all treated cases the surgical defect involved the mucosa of the cheek, the oral floor or the tongue with an average size of 5.45cm 2 . Patients who underwent this type of reconstruction benefited from excellent healing of intraoral wounds and good restoration of oral function 6 months after surgery. Out of the total number of patients, membrane attachment failure was reported in only two cases., Conclusion: As emerges from the data reported in our study, the dermal matrix represents a valid alternative in oncological reconstructive surgery for small/medium-sized intraoral mucosal defects because it allows re-epithelialization of the wound., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: There is little data on the outcome of balloon aortic valvuloplasty (BAV) in relation to valve dimensions and calcification patterns. The procedure is not standardized, particularly the choice of balloon size., Methods: This retrospective multicenter study focused on BAV efficacy and safety by analyzing the relationship between balloon size, annulus geometry (i.e., diameters, perimeter, and area), and calcification patterns (total burden and calcium distribution over each individual leaflet). From March 2018 to March 2023, all consecutive patients who underwent clinically indicated BAV and ECG-gated multidetector computed tomography of the aorta were included, except those with a bicuspid valve. Calcium score was calculated on contrast-enhanced images based on a luminal attenuation threshold of +100 HU., Results: One hundred and fifteen patients were included. Procedural success was 82.6 %. The balloon-to-annulus ratio (BAR) relative to diameter, perimeter, and area was higher in patients with successful BAV. Patients with unsuccessful BAV had a significantly higher aortic valve calcium burden. The complication rate was 4.3 % and there was no association with valve geometry or calcium burden. A trend towards a reduced complication rate was found as calcium asymmetry increased. BAR minimum annulus diameter was the best parameter in predicting procedural success, with a cut-off at 0.85., Conclusions: BAV efficacy is correlated directly with balloon size in relation to annulus dimension and inversely with total calcium burden. The minimum diameter of the valve may be adopted as a reference for balloon sizing., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

High resolution analysis of collagen bundles could provide information on tumor onset and evolution. This study was focused on the microarchitecture and biomolecular organization of collagen bundles in oral tongue squamous cell carcinoma (OTSCC). Thirty-five OTSCC biopsy samples were analyzed by synchrotron-based phase-contrast microcomputed tomography and Fourier transform infrared imaging (FTIRI) spectroscopy. PhC-microCT evidenced the presence of reduced and disorganized collagen in the tumor area compared to the extratumoral (ExtraT) one. FTIRI also revealed a reduction of folded secondary structures in the tumor area, and highlighted differences in the peritumoral (PeriT) areas in relation with the OTSCC stage, whereby a significantly lower amount of collagen with less organized fibers was found in the PeriT stroma of advanced-OTSCC stages. Interestingly, no significant morphometrical mismatches were detected in the same region by PhC-microCT analysis. These results suggest that biomolecular alterations in the OTSCC stroma temporally anticipate structural modifications of collagen bundle microarchitecture., Competing Interests: The authors declare no competing interests., (© 2024 The Authors.)

Competing Interests: Funding Support and Author Disclosures The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Aims: The role of coronary calcification on clinical outcomes among different revascularization strategies in patients presenting with acute coronary syndromes (ACSs) has been rarely investigated. The aim of this investigation is to evaluate the role of coronary calcification, detected by coronary angiography, in the whole spectrum of patients presenting with acute ACS., Methods and Results: The present study was a post hoc analysis of the MATRIX programme. The primary endpoint was major adverse cardiovascular events (MACE), defined as the composite of all-cause mortality, myocardial infarction (MI), or stroke up to 365 days. Among the 8404 patients randomized in the MATRIX trial, data about coronary calcification were available in 7446 (88.6%) and therefore were included in this post hoc analysis. Overall, 875 patients (11.7%) presented with severe coronary calcification, while 6571 patients (88.3%) did not present severe coronary calcification on coronary angiography. Fewer patients with severe coronary calcification underwent percutaneous coronary intervention whereas coronary artery bypass grafting or medical therapy-only was more frequent compared with patients without severe calcification. At 1-year follow-up, MACE occurred in 237 (27.1%) patients with severe calcified coronary lesions and 985 (15%) patients without severe coronary calcified lesions [hazard ratio (HR) 1.91; 95% confidence interval (CI) 1.66-2.20, P < 0.001]. All-cause mortality was 8.6% in patients presenting with and 3.7% in those without severe coronary calcification (HR 2.38, 1.84-3.09, P < 0.001). Patients with severe coronary calcification incurred higher rate of MI (20.1% vs. 11.5%, HR 1.81; 95% CI 1.53-2.1, P < 0.001) and similar rate of stroke (0.8% vs. 0.6%, HR 1.35; 95% CI 0.61-3.02, P = 0.46)., Conclusion: Patients with ACS and severe coronary calcification, as compared to those without, are associated with worse clinical outcomes irrespective of the management strategy., Competing Interests: Conflict of interest: J.S.S. has received minor speaking honoraria from Terumo, Cordis, Biotronik, and Medtronic. H.M.G.-G. reports the following institutional grant support: Biotronik, Boston Scientific, Medtronic, Abbott, Neovasc, Shockwave, Phillips, and Corflow. G.A. reports minor speaking honoraria from Chiesi, Daiichi Sankyo, Boeringer Ingelheim, Bayer, Pfizer, and Biosensors. D.H. has participated on data safety monitoring board or advisory board of switch. S.L. has received consulting fees from AstraZeneca, Bayer, BMS/Pfizer, Chiesi, Daiichi-Sankyo, Icon, and Novonordisk. M.S. has received consulting fees from Abbott Vascular and iVascular. A.v.H. reports unrestricted grants from Medtronic, Abbott Vascular, and Boehringer Ingelheim and consulting fees from Celecor Therapeutics. P.V. reports consulting fees from Daiichi Sankyo, CSL Behring, Pfizer/Bristol Meyers Squibb alliance, Bayer AG, and Novartis; minor speaking honoraria from Daicchi Sankyo and Pfizer/Bristol Meyers Squibb alliance. M.V. reports consulting fees from Abbott, Alvimedica, Bayer Healthcare, Biotronik, Boston Scientific Corporation, Chiesi Farmaceutici, CoreFlow, Daiichi Sankyo, Idorsia, Medtronic, Novartis Pharma, PHASEBIO, Terumo, University of Basel, Vesalio, and Vifor Pharma. The rest of authors have no disclosures to declare., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The benefit of complete revascularization in older patients (≥75 years of age) with myocardial infarction and multivessel disease remains unclear., Methods: In this multicenter, randomized trial, we assigned older patients with myocardial infarction and multivessel disease who were undergoing percutaneous coronary intervention (PCI) of the culprit lesion to receive either physiology-guided complete revascularization of nonculprit lesions or to receive no further revascularization. Functionally significant nonculprit lesions were identified either by pressure wire or angiography. The primary outcome was a composite of death, myocardial infarction, stroke, or any revascularization at 1 year. The key secondary outcome was a composite of cardiovascular death or myocardial infarction. Safety was assessed as a composite of contrast-associated acute kidney injury, stroke, or bleeding., Results: A total of 1445 patients underwent randomization (720 to receive complete revascularization and 725 to receive culprit-only revascularization). The median age of the patients was 80 years (interquartile range, 77 to 84); 528 patients (36.5%) were women, and 509 (35.2%) were admitted for ST-segment elevation myocardial infarction. A primary-outcome event occurred in 113 patients (15.7%) in the complete-revascularization group and in 152 patients (21.0%) in the culprit-only group (hazard ratio, 0.73; 95% confidence interval [CI], 0.57 to 0.93; P = 0.01). Cardiovascular death or myocardial infarction occurred in 64 patients (8.9%) in the complete-revascularization group and in 98 patients (13.5%) in the culprit-only group (hazard ratio, 0.64; 95% CI, 0.47 to 0.88). The safety outcome did not appear to differ between the groups (22.5% vs. 20.4%; P = 0.37)., Conclusions: Among patients who were 75 years of age or older with myocardial infarction and multivessel disease, those who underwent physiology-guided complete revascularization had a lower risk of a composite of death, myocardial infarction, stroke, or ischemia-driven revascularization at 1 year than those who received culprit-lesion-only PCI. (Funded by Consorzio Futuro in Ricerca and others; FIRE ClinicalTrials.gov number, NCT03772743.)., (Copyright © 2023 Massachusetts Medical Society.)

Background: Oral tongue squamous cell carcinoma (OTSCC) represents the most common malignancy of the oral cavity. Tumor budding (TB) is a reliable prognostic factor in OTSCC; however, a standardized scoring system is not still validated., Aims: The study aims to evaluate the prognostic role of TB in 211 OTSCC patients treated between 1997 and 2018., Materials & Methods: TB was evaluated on hematoxylin and eosin-stained sections in the hotspot area of the infiltrative front (×200-magnification). It was scored using a two-tier system, a three-tier system, and according to BD-model and revised-Grading system. Univariate and multivariate Cox regression analyses of disease-specific survival (DSS) and disease-free survival (DFS) were performed. A p < 0.05 was considered as statistically significant., Results: The two-tier and three-tier systems resulted an independent prognostic factor of DSS. High-risk patients had a 2.21 and 3.08 times increased probability of poor DSS compared with low-risk group. It is significantly increased even for intermediate-risk group. No significant differences emerged classifying patients according to BD-model and revised-Grading system., Discussion: These data confirm the prognostic value of TB in predicting DSS in OTSCC. Classifying patients into two groups using the 5-bud cutoff significantly discriminates their outcomes., Conclusion: Since the established role of DOI and the poor prognostic value of grading, TB could be considered an independent prognostic marker., (© 2022 Wiley Periodicals LLC.)

Oral lichen planus usually occurs in adults; there are no clear data regarding the incidence and the clinical features of oral lichen planus in children. This paper reports clinical findings, treatments, and outcomes of 13 Italian patients with oral lichen planus in childhood diagnosed between 2001 and 2021. The most common finding was keratotic lesions with reticular or papular/plaque-like patterns, confined to the tongue in seven patients. Although oral lichen planus in childhood is rare and the malignant transformation index is unknown, specialists must be aware of its characteristics and oral mucosal lesions must be correctly diagnosed and managed., (© 2023 The Authors. Pediatric Dermatology published by Wiley Periodicals LLC.)

Background: Survival rate for oral tongue squamous cell carcinoma (OTSCC) is still poor and, despite Tumor-Node-Metastasis staging system has been recently updated, patients included under the same stage still show difference in prognosis. Perineural invasion (PNI) emerged to be an indicator of tumor aggressive behavior and unfortunate events. In this study, we investigate the clinic and prognostic value of PNI in a cohort of OTSCC patients., Methods: About 200 patients with OTSCC were retrospectively evaluated the presence of PNI. PNI was furtherly descripted as uni-/multifocal and as intra-/peritumoral. Disease-Specific and Relapse-Free Survival (DSS; RFS) were estimated; moreover, we included PNI in the current AJCC 8th Staging System, improving the prognostication model., Results: Perineural invasion was found in 40.5% of patients. Intratumoral PNI predicted patients at high risk of being diagnosed with lymph-node metastasis. Tumors with positive PNI reported a worse DSS (Hazard Ratio=1.878, p-value = 0.008). Moreover, patients exhibiting both multifocal intra- and peritumoral PNI reported poorest DSS (Hazard Ratio = 2.409, p-value = 0.010). Patients were reclassified in a new staging system in case of multifocal PNI, providing better stratification capacity., Conclusions: Perineural invasion might serve as an additional prognostic factor in OTSCC, and by integrating PNI in the staging system, further improvements in prognostication might be reached., (© 2021 Wiley Periodicals LLC.)

Background: The occurrence of acute kidney injury (AKI) among patients with acute coronary syndrome (ACS) undergoing invasive management is associated with worse outcomes. However, the prognostic implications of transient or in-hospital persistent AKI may differ., Objectives: The aim of this study was to evaluate the prognostic implications of transient or in-hospital persistent AKI in patients with ACS., Methods: In the MATRIX (Minimizing Adverse Haemorrhagic Events by Transradial Access Site and Systemic Implementation of Angiox) trial, 203 subjects were excluded because of incomplete information or end-stage renal disease, with a study population of 8,201 patients. Transient and persistent AKI were defined as renal dysfunction no longer or still fulfilling the AKI criteria (>0.5 mg/dL or a relative >25% increase in creatinine) at discharge, respectively. Thirty-day coprimary outcomes were the out-of-hospital composite of death, myocardial infarction, or stroke (major adverse cardiovascular events [MACE]) and net adverse cardiovascular events (NACE), defined as the composite of MACE or Bleeding Academic Research Consortium type 3 or 5 bleeding., Results: Persistent and transient AKI occurred in 750 (9.1%) and 587 (7.2%) subjects, respectively. After multivariable adjustment, compared with patients without AKI, the risk for 30-day coprimary outcomes was higher in patients with persistent AKI (MACE: adjusted HR: 2.32; 95% CI: 1.48-3.64; P < 0.001; NACE: adjusted HR: 2.29; 95% CI: 1.48-3.52; P < 0.001), driven mainly by all-cause mortality (adjusted HR: 3.43; 95% CI: 2.03-5.82; P < 0.001), whereas transient AKI was not associated with higher rates of MACE or NACE. Results remained consistent when implementing the KDIGO (Kidney Disease Improving Global Outcomes) criteria., Conclusions: Among patients with ACS undergoing invasive management, in-hospital persistent but not transient AKI was associated with higher risk for 30-day MACE and NACE. (Minimizing Adverse Haemorrhagic Events by Transradial Access Site and Systemic Implementation of Angiox [MATRIX]; NCT01433627)., Competing Interests: Funding Support and Author Disclosures The trial was sponsored by Società Italiana di Cardiologia Invasiva (a nonprofit organization), which received grant support from The Medicines Company and Terumo. This substudy did not receive any direct or indirect funding. Prof Leonardi has received grants and personal fees from AstraZeneca; and has received personal fees from Daiichi Sankyo, Bayer, Pfizer/Bristol Myers Squibb, ICON, Chiesi, and Novo Nordisk (all outside the submitted work). Prof Vranckx has received personal fees from Bayer, Daiichi Sankyo, and CLS Behring (all outside the submitted work). Dr Tebaldi has received research grants from GADA and Abbott Vascular; and has received personal fees from Abbott (all outside the submitted work). Prof Andò has received personal fees and nonfinancial support from Daiichi Sankyo, Boeringer Ingelheim, and Amgen; and has received personal fees from AstraZeneca, Chiesi, and Biosensors (all outside the submitted work). Dr Brugaletta has received a research grant to the institution from AstraZeneca; has received personal fees from Abbott Vascular (outside the submitted work); and has served as an advisory board member for Boston Scientific, iVascular, and Teleflex. Dr Adamo has received speaker fees from Abbott Vascular and Medtronic (all outside the submitted work). Prof Windecker has received research and educational grants to the institution from Abbott, Amgen, AstraZeneca, Bristol Myers Squibb, Bayer, Biotronik, Boston Scientific, Cardinal Health, Cardiovalve, CSL Behring, Daiichi Sankyo, Edwards Lifesciences, Guerbet, Infraredx, Johnson & Johnson, Medicure, Medtronic, Novartis, Polares, OrPha Suisse, Pfizer, Regeneron, Sanofi, Sinomed, Terumo, and V-Wave; has served as an unpaid advisory board member and/or unpaid member of the steering or executive groups of trials funded by Abbott, Abiomed, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Boston Scientific, Biotronik, Cardiovalve, Edwards Lifesciences, MedAlliance, Medtronic, Novartis, Polares, Sinomed, Terumo, V-Wave, and Xeltis (but has not received personal payments from pharmaceutical companies or device manufacturers); and is a member of the steering or executive committee groups of several investigator-initiated trials that receive funding from industry without impact on his personal remuneration. Prof Valgimigli has received grants and personal fees from Abbott, Terumo, and AstraZeneca; has received personal fees from Chiesi, Bayer, Daiichi Sankyo, Amgen, Alvimedica, Biosensors, and Idorsia; and has received grants from Medicure (outside the submitted work). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Oral squamous cell carcinoma represents the most aggressive and frequent form of head and neck cancer. Due to drug resistance, the 5-year survival rate of patients with advanced disease is less than 50%. In order to identify molecular targets for effective oral cancer treatment, we focused on paraoxonase-2 enzyme. Indeed, based on data previously obtained from preliminary immunohistochemistry and Western blot analyses performed on tissue specimens, the enzyme was found to be upregulated in tumor compared with normal oral mucosa. Therefore, paraoxonase-2 gene silencing was achieved in HSC-3 and HOC621 oral cancer cell lines, and the effect on cell proliferation, viability, apoptosis induction and sensitivity to cisplatin and 5-fluorouracil treatment was evaluated. Fourier Transform InfraRed Microspectroscopy analyzed alterations of cellular macromolecules upon treatment. Enzyme level and cell proliferation were also determined in cisplatin-resistant clones obtained from HOC621 cell line, as well as in parental cells. Reported data showed that paraoxonase-2 knockdown led to a reduction of cell proliferation and viability, as well as to an enhancement of sensitivity to cisplatin, together with the activation of apoptosis pathway. Spectroscopical data demonstrated that, under treatment with cisplatin, oxidative damage exerted on lipids and proteins was markedly more evident in cells down-regulating paraoxonase-2 compared to controls. Interestingly, enzyme expression, as well as cell proliferation were significantly higher in cisplatin-resistant compared with control HOC621 cells. Taken together these results seem to candidate the enzyme as a promising target for molecular treatment of this neoplasm.

Background: The comparative effectiveness of transradial (TRA) compared with transfemoral (TFA) access in acute coronary syndrome (ACS) patients undergoing complex percutaneous coronary intervention (PCI) remains unclear., Methods: Among 8404 ACS patients in the Minimising Adverse Haemorrhagic Events by Transradial Access Site and Systemic Implementation of AngioX (MATRIX)-Access trial, 5233 underwent noncomplex (TRA: n = 2590; TFA: n = 2643) and 1491 complex (TRA: n = 777; TFA: n = 714) PCI. Co-primary outcomes were major adverse cardiovascular events (MACE, the composite of all-cause mortality, myocardial infarction, or stroke) and the composite of MACE and Bleeding Academic Research Consortium (BARC) type 3 or 5 bleeding (net adverse cardiovascular events [NACE]) at 30 days., Results: Rates of 30-day MACE (HR 0.94, 95% CI 0.72-1.22) or NACE (HR 0.89, 95% CI 0.69-1.14) did not significantly differ between groups in the complex PCI group, whereas both primary end points were lower (HR 0.84, 95% CI 0.70-1.00; HR 0.83, 95% CI 0.70-0.98; respectively) with TRA among noncomplex PCI patients, with negative interaction testing (P int  = 0.473 and 0.666, respectively). Access-site BARC type 3 or 5 bleeding was lower with TRA, consistently among complex (HR 0.18, 95% CI 0.05-0.63) and noncomplex (HR 0.41, 95% CI 0.20-0.85) PCI patients, whereas the former group had a greater absolute risk reduction of 1.7% (number needed to treat: 59) owing to their higher absolute risk., Conclusions: Among ACS patients, PCI complexity did not affect the comparative efficacy and safety of TRA vs TFA, whereas the absolute risk reduction of access-site major bleeding was greater with TRA compared with TFA in complex as opposed to noncomplex PCI., (Copyright © 2022 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Tumor Budding (TB) represents a single cancer cell or a small cluster of less than five cancer cells on the infiltrative tumor front. Accumulating evidence suggests TB is an independent prognostic factor in oral squamous cell carcinoma (OSCC). However, its exact role is not yet elucidated, and a standardized scoring system is still necessary. The study aims to extensively review the literature data regarding the prognostic role of TB in OSCC. The results of TB are an independent prognostic factor of poor survival outcomes in OSCC. To date, the manual detection of hematoxylin and eosin-staining or pancytokeratin-immunostaining sections are the most commonly used methods. Between the several cut-offs, the two-tier system with five buds/field cut-offs provides better risk stratification. The prognostic role of the BD model in predicting survival outcomes was extensively validated; however, the inclusion of DOI, which is already a staging parameter, encouraged other authors to propose other models, integrating TB count with other adverse risk factors, such as the tumor-stroma ratio and tumor-infiltrated lymphocytes. The prognostic relevance of TB in OSCC highlights its evaluation in daily pathological practice. Therefore, the TB detection method and the TB scoring system should be validated based on tumor stage and site.

Background: Sebaceous carcinoma is a very rare, aggressive, malignant tumor arising in the adnexal epithelium of the sebaceous gland. Sebaceous carcinoma in the oral cavity is extremely rare, with only 14 cases reported in literature. We reported the fourth case of sebaceous carcinoma involving the lip CASE PRESENTATION: A 71-year-old Caucasian male smoker presented an ulcerated lesion in the lateral region of the lower lip. The patient stated that the lesion had been present for 1 year. The past medical history was unremarkable. Extraoral examination revealed a markedly ulcerated, exophytic, irregularly shaped, indurated mass of the lower right labial region, measuring 1.8 cm in size. The nodular lesion, located at the point of transition between mucosa and skin, showed a central ulceration. No other intraoral lesions were identified. The clinical differential diagnosis included squamous cell carcinoma, basal cell carcinoma with sebaceous differentiation, and salivary gland neoplasms. Operation was performed under local anesthesia. On histopathological examination, the tumor was composed by nodules or sheet of cells separated by a fibrovascular stroma. The neoplastic tissue was deeply infiltrating, involving the submucosa and even the underlying muscle. Neoplastic cells showed a range of sebaceous differentiation with finely vacuolated rather than clear cytoplasm. Neoplastic cells were positive for S-100 protein and epithelial membrane antigen, but negative for carcinoembryonic antigen. Based on these findings, a diagnosis of sebaceous carcinoma of the lower lip was rendered., Conclusion: The histogenesis, differential diagnosis, and clinicopathological conditions of this disease according to literature are reviewed. Sebaceous carcinoma should be distinguished from other tumors full of vacuolated clear cells. A periodic acid-Schiff stain and immunohistochemical stain for Ki-67, P53, cytokeratin, S-100, epithelial membrane antigen, and androgen receptor can be useful for the diagnosis., (© 2022. The Author(s).)

Odontogenic tumors are rare lesions with unknown etiopathogenesis. Most of them are benign, but local aggressiveness, infiltrative potential, and high recurrence rate characterize some entities. The MAP-kinase pathway activation can represent a primary critical event in odontogenic tumorigenesis. Especially, the BRAF V600E mutation has been involved in 80-90% of ameloblastic lesions, offering a biological rationale for developing new targeted therapies. The study aims to evaluate the BRAF V600E mutation in odontogenic lesions, comparing three different detection methods and focusing on the Sequenom MassARRAY System. 81 surgical samples of odontogenic lesions were subjected to immunohistochemical analysis, Sanger Sequencing, and Matrix-Assisted Laser Desorption/Ionization-Time of Flight mass spectrometry (Sequenom). The BRAF V600E mutation was revealed only in ameloblastoma samples. Moreover, the presence of BRAF V600E was significantly associated with the mandibular site (ρ = 0.627; P value <0.001) and the unicystic histotype (ρ = 0.299, P value <0.001). However, any significant difference of 10-years disease-free survival time was not revealed. Finally, Sequenom showed to be a 100% sensitive and 98.1% specific, suggesting its high-performance diagnostic accuracy. These results suggest the MAP-kinase pathway could contribute to ameloblastic tumorigenesis. Moreover, they could indicate the anatomical specificity of the driving mutations of mandibular ameloblastomas, providing a biological rational for developing new targeted therapies. Finally, the high diagnostic accuracy of Sequenom was confirmed., (© 2022. The Author(s).)

Background: The inter-individual differences in taste perception find a possible rationale in genetic variations. We verified whether the presence of four different single nucleotide polymorphisms (SNPs) in genes encoding for bitter (TAS2R38; 145G > C; 785T > C) and sweet (TAS1R3; −1572C > T; −1266C > T) taste receptors influenced the recognition of the basic tastes. Furthermore, we tested if the allelic distribution of such SNPs varied according to BMI and whether the associations between SNPs and taste recognition were influenced by the presence of overweight/obesity. Methods: DNA of 85 overweight/obese patients and 57 normal weight volunteers was used to investigate the SNPs. For the taste test, filter paper strips were applied. Each of the basic tastes (sweet, sour, salty, bitter) plus pure rapeseed oil, and water were tested. Results: Individuals carrying the AV/AV diplotype of the TAS2R38 gene (A49P G/G and V262 T/T) were less sensitive to sweet taste recognition. These alterations remained significant after adjustment for gender and BMI. Moreover, a significant decrease in overall taste recognition associated with BMI and age was found. There was no significant difference in allelic distribution for the investigated polymorphisms between normal and overweight/obese patients. Conclusions: Our findings suggest that overall taste recognition depends on age and BMI. In the total population, the inter-individual ability to identify the sweet taste at different concentrations was related to the presence of at least one genetic variant for the bitter receptor gene but not to the BMI.

Background: Current ESC guidelines recommend the use of intra-coronary pressure guidewires for functional assessment of intermediate-grade coronary stenoses. Angiography-derived quantitative flow ratio (QFR) is a novel method of assessing these stenoses, and guiding percutaneous coronary intervention (PCI)., Methods/design: The PIONEER IV trial is a prospective, all-comers, multi-center trial, which will randomize 2,540 patients in a 1:1 ratio to PCI guided by angiography-derived physiology or usual care, with unrestricted use in both arms of the Healing-Targeted Supreme sirolimus-eluting stent (HT Supreme). The stent's fast, biologically healthy, and robust endothelial coverage allows for short dual-antiplatelet therapy (DAPT); hence the antiplatelet regimen of choice is 1-month DAPT, followed by ticagrelor monotherapy. In the angiography-derived physiology guided arm, lesions will be functionally assessed using on-line QFR, with stenting indicated in lesions with a QFR ≤0.80. Post-stenting, QFR will be repeated in the stented vessel(s), with post-dilatation or additional stenting recommended if the QFR<0.91 distal to the stent, or if the delta QFR (across the stent) is >0.05. Usual care PCI is performed according to standard clinical practice. The primary endpoint is a non-inferiority comparison of the patient-oriented composite endpoint (POCE) of all-cause death, any stroke, any myocardial infarction, or any clinically, and physiologically driven revascularization with a non-inferiority risk-difference margin of 3.2%, at 1-year post-procedure. Clinical follow-up will be up to 3 years., Summary: The PIONEER IV trial aims to demonstrate non-inferiority of QFR-guided PCI to usual care PCI with respect to POCE at 1-year in patients treated with HT Supreme stents and ticagrelor monotherapy., Clinical Trial Registration: ClinicalTrials.gov UNIQUE IDENTIFIER: NCT04923191 CLASSIFICATIONS: Interventional Cardiology., (Copyright © 2022. Published by Elsevier Inc.)

Background: TATE has been proposed as a prognostic factor in oral cancer staging; however, the controversial literature data limit its application in the routine diagnosis. The aim of this study was to evaluate the prognostic value of TATE in patients with oral tongue cancer. The second aim was to identify any difference in the methods of eosinophil quantification or in the cutoff values reported in literature., Methods: Clinic-pathological data of 204 patients treated at "Ospedali Riuniti" Hospital, Ancona, Italy, were collected. Evaluation of TATE was performed on hematoxylin-and-eosin-stained slides and correlation with survival outcomes was evaluated. The number of eosinophils per square millimeter was evaluated by using two methods, namely density (TATE-1) and classical (TATE-2) methods. For each of the 2 methods tested, patients were stratified into two or three groups, according to the most used cutoff values reported in literature., Results: Regardless of the method of eosinophil quantification or the cutoff values used, patients with high TATE had a significantly better disease-specific survival. The density method (TATE-1) showed a better predictive performance, in particular when applying a single cutoff of 67 eosinophils/mm 2 , two cutoffs of 10 and 100 eosinophils/mm 2 , or two cutoffs of 50 and 120 eosinophils/mm 2 ., Conclusion: The evaluation of TATE is simple, cost-effective, and easy to implement in daily practice with the aim of improving risk stratification of patients affected by oral tongue cancer. Results of prognostic performance analysis suggest using density (TATE-1) method as the standard approach to evaluate TATE in future studies, enhancing replicability., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose: To asses trueness of the intaglio surface of milled dentures fabricated according to a fully digital protocol starting from intraoral scans in a clinical study by means of 3-dimensional (3D) digital analysis., Materials and Methods: Ten maxillary and 10 mandibular dentures, designed from intraoral scans and milled in-house, were studied. Intraoral scans were compared with the scans of intaglio surface of milled dentures. To this end, they were aligned, trimmed and used in a metrology software to measure their mean 3D distance, absolute mean deviation, and other parameters. Measured differences for all parameters were statistically investigated. Subgroup analysis for the maxillary and mandibular dentures was performed using independent samples t-test or, in case of non-normal distribution, by means of Mann-Whitney test., Results: Using a mean of 24.9 ±2.8 measurement points/mm 2 , a mean 3D distance of 0.0006 ±0.007 mm between intraoral scans and the scans of the intaglio surface of milled dentures was measured. The corresponding absolute mean deviation was 0.055 ±0.032 for maxillary dentures and 0.061 ±0.016 for mandibular dentures; such a difference between arches was statistically significant (p = 0.035)., Conclusions: Milled dentures fabricated using a fully digital protocol and intraoral scans have accurate intaglio surfaces. It is reasonable to assume that they may achieve an adequate fit., (© 2021 by the American College of Prosthodontists.)

Inferior alveolar nerve (IAN) block injections are commonly used in clinical practice, but they are not free from complications. The aim of the present systematic review is to assess the nerve-related adverse effects of IAN block anesthesia. A structured and systematic search was performed on the major electronic databases (PubMed, Cochrane Library, Web of Science, Scopus and CINAHL) for studies published in English until 30 September 2021. A total of 131 articles were identified through database searching using combinations of keywords. Fifteen papers were included and assessed for eligibility. Overall, nerve damage following an IAN block anesthesia injection is a rare occurrence, probably due to the direct nerve trauma of the needle, a neurotoxic effect of the used anesthetic solution and/or a combination of them. From a medico-legal point of view, a balanced discussion prior to nerve block anesthesia should be pursued in order to avoid patients' reluctance to undergo necessary dental treatment due to the remote eventuality of nerve injury.

Background: COVID-19 disease first appeared in 2019 and quickly spread worldwide, causing a global pandemic. The oral cavity represents a target of SARS-CoV-2, and oral lesions are observed in both non-hospitalized and hospitalized patients. This systematic review aims to investigate the frequency of oral manifestations in COVID-19 hospitalized patients., Methods: An electronic search was conducted in PubMed, Scopus, and Web of Science databases, including articles published up to September 2021. The review protocol was based on PRISMA-P. The risk of bias of the studies was assessed using the Joana Briggs Institute. The certainty of evidence was assessed using the GRADE instrument., Results: Fifty-nine articles were included: 19 case reports, 17 case series, 2 case-control studies, 13 cross-sectional studies, 4 observational studies, and 4 retrospective studies. Oral ulcers, cheilitis, and tongue lesions were more common in patients before hospitalization, while perioral pressure ulcers, macroglossia, blisters, and oral candidiasis were more recurrent in patients during hospitalization. The first could be related directly to COVID-19, while the latter could be caused by medical devices, treatments, prone position, and immunological impairment., Conclusions: An accurate oral examination during the hospital admission of all confirmed COVID-19 cases is encouraged to recognize oral early manifestations and to apply appropriate treatments.

The head and neck tumors (HNT) are a heterogeneous group of diseases ranging from benign to malignant lesions, with distinctive molecular and clinical behaviors. Several studies have highlighted the presence of an altered metabolic phenotype in HNT, such as the upregulation of nicotinamide N-methyltransferase (NNMT). However, its biological effects have not been completely disclosed and the role of NNMT in cancer cell metabolism remains unclear. Therefore, this comprehensive review aims to evaluate the available literature regarding the biological, diagnostic, and prognostic role of NNMT in HNT. NNMT was shown to be significantly overexpressed in all of the evaluated HNT types. Moreover, its upregulation has been correlated with cancer cell migration and adverse clinical outcomes, such as high-pathological stage, lymph node metastasis, and locoregional recurrences. However, in oral squamous cell carcinoma (OSCC) these associations are still debated, and several studies have failed to demonstrate the prognostic significance of NNMT. The shRNA-mediated gene silencing efficiently suppressed the NNMT gene expression and exhibited a clear inhibitory effect on cell proliferation, promoting the expression of apoptosis-related proteins and modulating the cell cycle. NNMT could represent a new molecular biomarker and a new target of molecular-based therapy, although further studies on larger patient cohorts are needed to explore its biological role in HNT.

Oral cancer is the most common tumor of the head and neck region. Its management is based on surgical and systemic therapies. Taste disorders represent the most common side effect of these treatments; indeed, dysgeusia is noted by 70% of oral cancer patients. Despite survival remaining the primary endpoint of cancer patients, taste impairments can cause psychological distress. This comprehensive review describes the last decade's knowledge from the literature regarding taste alterations in patients with oral and oropharyngeal squamous cell carcinoma. A total of 26 articles in English, including prospective, cross-sectional, and case-control studies, and clinical trials were evaluated. Literature analysis shows that anti-cancer treatments can destroy taste cells, decrease and alter their receptors, and interrupt nerve transmission. Furthermore, the tumour itself can destroy the oral mucosal lining, which encloses the taste buds. Dysgeusia typically occurs in 3-4 weeks of treatments, and usually taste sensation is recovered within 3-12 months. However, some patients exhibit incomplete or no recovery, even several years later. Thus, dysgeusia can become a chronic issue and negatively influence patients' quality of life, worsening their dysphagia and their nutritional status. Physicians should be focused on preventing oncological treatment-related symptoms, offering the most suitable personalized support during therapy.

Oral squamous cell carcinoma (OSCC) is the most prevalent form of cancer of lips and oral cavity, and its diagnostic delay, caused by misdiagnosis at the early stages, is responsible for high mortality ratios. Biopsy and histopathological assessment are the gold standards for OSCC diagnosis, but they are time-consuming, invasive, and do not always enable the patient's compliance, mainly in cases of follow-up with the need for more biopsies. The use of adjunctive noninvasive imaging techniques improves the diagnostic approach, making it faster and better accepted by patients. The present review aims to focus on the most consolidated diagnostic techniques, such as vital staining and tissue autofluorescence, and to report the potential role of some of the most promising innovative techniques, such as narrow-band imaging, high-frequency ultrasounds, optical coherence tomography, and in vivo confocal microscopy. According to their contribution to OSCC diagnosis, an ideal three-step diagnostic procedure is proposed, to make the diagnostic path faster, better, and more accurate.

Objective: The study was designed to: (1) confirm safety and feasibility of mini-invasive radial balloon aortic valvuloplasty (BAV); (2) assess its impact in terms of quality of life and frailty; and (3) evaluate whether changes in frailty after BAV are associated with death in patients undergoing transcatheter aortic valve implantation (TAVI)., Methods: 330 patients undergoing BAV in 16 Italian centres were prospectively included. The primary endpoint was the occurrence of major and minor Valve Academic Research Consortium (VARC)-2 bleeding. Secondary endpoints were scales of quality of life, frailty, evaluated at baseline and 30 days, and their relationship with the occurrence of all-cause death., Results: BAV was performed by radial access in 314 (95%) patients. No VARC-2 major and six (1.8%) VARC-2 minor bleedings occurred in the study population. Quality of life, as well as frailty status, significantly improved 30 days after BAV. At 1 year, patients undergoing TAVI with baseline essential frailty toolset (EFT) <3 or achieving an EFT <3 after BAV had a comparable occurrence of all-cause death (15% vs 19%, p=0.58). On the contrary, patients with EFT ≥3 at 30 days despite BAV showed the worst prognosis (all-cause death: 40% vs 15% and 19%, p=0.006 and p=0.05, respectively)., Conclusions: Mini-invasive radial BAV is safe, feasible and associated with a low rate of vascular complications. Patients improving EFT 30 days after BAV showed a favourable outcome after TAVI., Trial Registration Number: NCT03087552., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Even if un to improve long-term prognosis, balloon aortic valvuloplasty (BAV) may be useful in selected patients with symptomatic severe aortic stenosis either as a bridge to surgical or transcatheter valve replacement (aortic valve replacement [AVR] or transcatheter aortic valve implantation [TAVI]) or as a triage strategy for patients with uncertain indications. International guidelines recommend BAV as: a "bridge" to AVR/TAVI, a "trial" in patients with undetermined symptoms, or a "bridge-to-decision" in case of comorbidities. However, in clinical practice, BAV is also used as a palliative measure to improve hemodynamics and quality of life in many patients who are excluded from AVR/TAVI. Finally, BAV is often performed during TAVI to facilitate prosthesis delivery, optimize frame expansion, or for bioprosthetic valve fracture in selected valve-in-valve procedures. Technical innovations, which allow for a mini-invasive approach via transradial access and pacing delivered through the wire, have led to a decrease in complications over time. This review focuses on contemporary BAV with a specific emphasis on new indications, innovative techniques, and specific complex patient subgroups., (© 2020 Wiley Periodicals, Inc.)

Tumor-associated macrophages (TAMs) are part of the tumor microenvironment, broadly divided into M1 and M2 phenotypes. M1 macrophages, commonly identified by staining the CD11c antigen, have an antitumour immunity role, while M2 macrophages, expressing the CD163 antigen, are involved in tumor progression. Little is known about M1 and M2 phenotypes in the context of the oral tongue squamous cell carcinomas (OTSCC), a subgroup of oral cancer with peculiar clinical behavior. This study evaluated the macrophage polarization in OTSCC specimens to examine their prognostic relevance. To this end, specimens from 71 OTSCC patients graded as G1 or G3 were investigated for CD11c and CD163 expression. Immunohistochemical staining of TAMs was evaluated in tumor nests, tumor inflammation area (TIA), and tumor stroma. To analyze the expression of CD11c and CD163, the percentage of positive cells was scored as 0 (negative), 1 (<10%), 2 (11% to 50%), 3 (51% to 80%), and 4 (>80%). The staining intensity was scored as 0 (negative), 1 (weak), 2 (moderate), and 3 (intense). Higher expression of both CD163+ and CD11c+ macrophages in inflammation area positively correlated with G3 grade, both in extension and intensity. Focusing on G3 tumors, survival curves showed better disease-free survival in patients with high CD11c expression in the TIA. Presence of CD163 expression in TIA was associated with worse disease-free survival. This study evaluated, for the first time, the distribution of M1 and M2 macrophages in relation to the pathologic grade in OTSCC, highlighting the prognostic relevance of analyzing the localization of TAMs., Competing Interests: The authors declare no conflict of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The aim of this Italian multicenter study was to evaluate the diagnostic performance of a minimally invasive method for the detection of oral squamous cell carcinoma (OSCC) based on 13-gene DNA methylation analysis in oral brushing samples., Methods: Oral brushing specimens were collected in 11 oral medicine centers across Italy. Twenty brushing specimens were collected by each center, 10 from patients with OSCC, and 10 from healthy volunteers. DNA methylation analysis was performed in blindness, and each sample was determined as positive or negative based on a predefined cutoff value., Results: DNA amplification failed in 4 of 220 (1.8%) samples. Of the specimens derived from patients with OSCC, 93.6% (103/110) were detected as positive, and 84.9% (90/106) of the samples from healthy volunteers were negative., Conclusion: These data confirmed the diagnostic performance of our novel procedure in a large cohort of brushing specimens collected from 11 different centers and analyzed in blindness., (© 2021 Wiley Periodicals LLC.)

Background: The COVID-19 pandemic has put several healthcare systems under severe pressure. The present analysis investigates how the first wave of the COVID-19 pandemic affected the myocardial infarction (MI) network of Emilia-Romagna (Italy)., Methods: Based on Emilia-Romagna mortality registry and administrative data from all the hospitals from January 2017 to June 2020, we analysed: i) temporal trend in MI hospital admissions; ii) characteristics, management, and 30-day mortality of MI patients; iii) out-of-hospital mortality for cardiac cause., Findings: Admissions for MI declined on February 22, 2020 (IRR -19.5%, 95%CI from -8.4% to -29.3%, p  = 0.001), and further on March 5, 2020 (IRR -21.6%, 95%CI from -9.0% to -32.5%, p  = 0.001). The return to pre-COVID-19 MI-related admission levels was observed from May 13, 2020 (IRR 34.3%, 95%CI 20.0%-50.2%, p <0.001). As compared to those before the pandemic, MI patients admitted during and after the first wave were younger and with fewer risk factors. The 30-day mortality remained in line with that expected based on previous years (ratio observed/expected was 0.96, 95%CI 0.84-1.08). MI patients positive for SARS-CoV-2 were few (1.5%) but showed poor prognosis (around 5-fold increase in 30-day mortality). In 2020, the number of out-of-hospital cardiac deaths was significantly higher (ratio observed/expected 1.17, 95%CI 1.08-1.27). The peak was reached in April., Interpretation: In Emilia-Romagna, MI hospitalizations significantly decreased during the first wave of the COVID-19 pandemic. Management and outcomes of hospitalized MI patients remained unchanged, except for those with SARS-CoV-2 infection. A concomitant increase in the out-of-hospital cardiac mortality was observed., Funding: None., Competing Interests: The Authors have nothing to disclose., (© 2021 The Author(s).)

The role of bruxism in children and adolescents with Down syndrome, the most often diagnosed congenital syndrome, is still unclear. Therefore, this study aims to conduct a narrative review of the literature about bruxism in children and adolescents with Down syndrome to identify the prevalence, risk factors, and possible treatments of this disorder. Although an accurate estimate of its prevalence could not be inferred, it appears that bruxism is more prevalent in Down syndrome individuals rather than in the general pediatric population. No gender difference was observed, but a reduction in its prevalence was described with increasing age (around 12 years). The variability in the diagnostic techniques contributed to the heterogeneity of the literature data. Clinicopathological features of Down syndrome, such as muscle spasticity, oral breathing, and a predisposition to obstructive sleep apnea, may suggest a higher prevalence of bruxism in this patient group. Finally, given the paucity of studies on the management of bruxism in this population, it was not possible to outline a standard protocol for the non-invasive treatment of cases in which an observational approach is not sufficient.

Oral squamous cell carcinoma is the most common head and neck malignancy, characterised by high invasive capacity, lymph node metastasis, and high recurrence rate. Among the morphological features of oral cancer, the tumour-associated tissue eosinophilia has gained growing interest in the last years. Eosinophils are a minor subpopulation of leukocytes, representing 1-3% of all circulating white blood cells. The presence of high levels of eosinophils is associated with several diseases, but their role in cancer pathophysiology is controversial. In particular, an uncertain and contradictory relationship exists between the exact role of tumour-associated tissue eosinophilia and oral cancer development. Many studies have shown that tumour-associated tissue eosinophilia increases both in the progression of oral potentially malignant disorders as well as in the grade and stage progression of oral cancer. Despite this, both negative and positive prognostic outcomes have been associated with eosinophil infiltration. The heterogeneous results may be partially due both to several methodological inconsistencies and to an incorrect interpretation of the physiological role of eosinophils. Therefore, further studies to elucidate the contribution of eosinophil infiltration are needed, focusing on the existence of eosinophil subpopulations regulated by the cancer immune microenvironment. Furthermore, the correct reporting of prognostic marker research is encouraged, in order to ensure the reproducibility and the comparability of the results from different studies.

Background: Nitric oxide (NO) produced in the oral cavity is a powerful resource for the human body, especially when NO-syntethase production is not adequate. The role of oral microbiome in determining blood pressure levels has been linked to the active role of some bacterial species involved in the nitro-reducing process. In the present study we investigated the correlation between selected oral microbiome characteristics, nitric oxide (NO) concentration in saliva and their association with hypertension., Methods: A case-control study including 48 (25 normotensive and 23 hypertensive subjects), subjects between 50 and 70 years old, was carried out at the dental clinic of an Italian teaching hospital. Characteristics of participants have been evaluated by means of a physical examination, and by an assisted interview. A real-time polymerase chain reaction in samples of saliva and plaque was used to detect Aggregatibacter actinomycetemcomitans, Prevotella intermedia, Tannerella forsythia, Porphyromonas gingivalis, Treponema denticola, Streptococcus mutans, Streptococcus sanguinis, Veillonella dispar and Neisseria subflava as well as total bacterial count. Nitric oxide in saliva was evaluated by the ELISA method., Results: Normotensive subjects, compared with hypertensive subjects, had significantly higher concentration of NO (165.77 ± 61.7 vs 57.49 ± 19.61 μmol/l; p = 0.023), and higher bacterial concentration of the supragingival plaque (4.73E+07 ± 4.33+07 vs 4.02E+07 ± 4.00+07; p = 0.024). Bacterial species, usually associated to good oral health status, such as Neisseria subflava, were significantly more present in normotensive subjects than in hypertensive ones (9090.88 ± 5481.49 vs 4791.35 ± 4349.37; p < 0.001). considering the concentration of bacteria as a biomarker of the development of hypertension., Conclusions: The results support the association between hypertension, oral microbiome and salivary nitric oxide, in fact do the results allow us to establish any biomarkers (microbial or biochemical, NO) that allow early therapeutic intervention., (Copyright © 2020 Elsevier Inc. All rights reserved.)

A high level of unmet oral health needs is very common among elderly people. In a society that is getting older and that has been hit so hard by the coronavirus pandemic, the development of new strategies aimed at enhancing general and oral health status should be crucial in order to promote healthy aging. The aim of this systematic review is to assess the feasibility of Teledentistry in communities or in a domiciliary setting where elderly people live. A structured and systematic research was performed on the major electronic databases for studies published in English until 30 June 2020: the PubMed, Cochrane Library, Web of Science, Scopus, and CINAHL databases. A total of 13 articles were identified through database searching using combinations of keywords. Out of 13 papers, eight abstracts were reviewed to assess if they were coherent with the aim of the study, and full texts were retrieved. After abstract reviews, seven articles were selected for closer inspection. Of these, six were assessed for eligibility. Four papers were aimed at assessing patients and health practitioners experiences about Teledentistry, three studies reported a cost analysis and cost description of Teledentistry in residential aged care facilities, and two studies investigated the feasibility and accuracy of Teledentistry for diagnosis dental pathology. The implementation of Teledentistry in residential aged care facilities and in home-assistance programs could be a viable tool for the management of oral care in people who cannot access dental care.

Background: The optimal timing to administer a P2Y12 inhibitor in patients presenting with a non-ST elevation acute coronary syndrome remains a topic of debate. Pretreatment with ticagrelor before coronary anatomy is known as a widely adopted strategy. However, there is poor evidence on how this compares with administration of a P2Y12 inhibitor after defining coronary anatomy (i.e., downstream administration). Moreover, there are limited head-to-head comparisons of the two P2Y12 inhibitors-ticagrelor and prasugrel-currently recommended by the guidelines., Study Design: DUBIUS is a phase 4, multicenter, parallel-group, double randomized study conducted in NSTE-ACS patients designed to compare a pretreatment strategy (including only ticagrelor) versus a downstream strategy (including prasugrel or ticagrelor) and to compare downstream prasugrel with downstream ticagrelor. A total of 2520 patients will be randomly assigned to pretreatment with ticagrelor or to no pretreatment. The PCI group of the downstream arm will be further randomized to receive prasugrel or ticagrelor. The two primary hypotheses are that the downstream strategy is superior to the upstream strategy and that downstream ticagrelor is non-inferior to downstream prasugrel, both measured by the incidence of a composite efficacy and safety endpoint of death from vascular causes, non-fatal MI, or non-fatal stroke, and Bleeding Academic Research Consortium (BARC) type 3, 4, and 5 bleedings., Conclusions: The DUBIUS study will provide important evidence related to the benefits and risks of pretreatment with ticagrelor compared with a strategy of no pretreatment. Moreover, the clinical impact of using downstream ticagrelor compared with downstream prasugrel will be assessed., Trial Registration: ClinicalTrials.gov NCT02618837 . Registered on 1 December 2015.

Background: Although oral P2Y 12 inhibitors are key in the management of patients with non-ST-segment elevation acute coronary syndrome, the optimal timing of their administration is not well defined., Objectives: The purpose of this study was to compare downstream and upstream oral P2Y 12 inhibitors administration strategies in patients with non-ST-segment elevation acute coronary syndrome undergoing invasive treatment., Methods: We performed a randomized, adaptive, open-label, multicenter clinical trial. Patients were randomly assigned to receive pre-treatment with ticagrelor before angiography (upstream group) or no pre-treatment (downstream group). Patients in the downstream group undergoing percutaneous coronary intervention were further randomized to receive ticagrelor or prasugrel. The primary hypothesis was the superiority of the downstream versus the upstream strategy on the combination of efficacy and safety events (net clinical benefit)., Results: We randomized 1,449 patients to downstream or upstream oral P2Y 12 inhibitor administration. A pre-specified stopping rule for futility at interim analysis led the trial to be stopped. The rate of the primary endpoint, a composite of death due to vascular causes; nonfatal myocardial infarction or nonfatal stroke; and Bleeding Academic Research Consortium type 3, 4, and 5 bleeding through day 30, did not differ significantly between the downstream and upstream groups (percent absolute risk reduction: -0.46; 95% repeated confidence interval: -2.90 to 1.90). These results were confirmed among patients undergoing percutaneous coronary intervention (72% of population) and regardless of the timing of coronary angiography (within or after 24 h from enrollment)., Conclusions: Downstream and upstream oral P2Y 12 inhibitor administration strategies were associated with low incidence of ischemic and bleeding events and minimal numeric difference of event rates between treatment groups. These findings led to premature interruption of the trial and suggest the unlikelihood of enhanced efficacy of 1 strategy over the other. (Downstream Versus Upstream Strategy for the Administration of P2Y 12 Receptor Blockers In Non-ST Elevated Acute Coronary Syndromes With Initial Invasive Indication [DUBIUS]; NCT02618837)., Competing Interests: Author Relationship With Industry This work was funded by the Italian Society of Interventional Cardiology (SICI-GISE). Dr. Tarantini has received Speakers Bureau fees from AstraZeneca, Daiichi-Sankyo, and Eli Lilly. Dr. Mojoli has received individual payments for participating on the Advisory Boards of The Medicines Company and Abbott Vascular; and has been a speaker at scientific congresses from AstraZeneca, Daiichi-Sankyo, Chiesi Farmaceutici, and Servier; and his institution has received an unconditioned research grant from Chiesi Farmaceutici. Dr. Varbella has received consulting fees/honoraria from AstraZeneca, Daiichi-Sankyo, Bayer, Pfizer, Boehringer Ingelheim, Servier, Amgen, Sanofi, Piam, Alvi Medica, Teleflex, and Stenty. Dr. Caporale has received an Advisory Board fee from AstraZeneca. Dr. Rigattieri has received a consulting fee from AstraZeneca; and has received a Speakers Bureau fee from Eli Lilly. Dr. Andò has received individual payments as a consultant, for serving on the Advisory Board, or as a speaker at scientific congresses from AstraZeneca, Daiichi-Sankyo, Chiesi Farmaceutici, Pfizer–Bristol Myers Squibb, Boehringer Ingelheim, and Biosensors. Dr. Saia has received Speakers Bureau fees from AstraZeneca and Daiichi-Sankyo. Dr. Ferlini has received individual payment as a consultant, for serving on the Advisory Board, or as a speaker at scientific congresses from AstraZeneca, Chiesi Farmaceutici, Bayer, Biosensors, Sanofi, and Boehringer Ingelheim. Dr. Angiolillo has received consulting fees or honoraria as an individual from Abbott, Amgen, Aralez, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol Myers Squibb, Chiesi, Daiichi-Sankyo, Eli Lilly, Haemonetics, Janssen, Merck, PhaseBio, PLx Pharma, Pfizer, Sanofi, and The Medicines Company; has received payment as an individual for participation in review activities from CeloNova and St. Jude Medical; and has received institutional payments for grants from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi-Sankyo, Eisai, Eli-Lilly, Gilead, Idorsia, Janssen, Matsutani Chemical Industry Co., Merck, Novartis, Osprey Medical, Renal Guard Solutions, and the Scott R. MacKenzie Foundation. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2020 American College of Cardiology Foundation. All rights reserved.)

Aims: The aim of this work was to investigate the prognostic impact of revascularization of non-culprit lesions in patients with ST-segment elevation myocardial infarction (STEMI) and multivessel disease by performing a meta-analysis of available randomized clinical trials (RCTs)., Methods and Results: Data from six RCTs comparing complete vs. culprit-only revascularization in STEMI patients with multivessel disease were analysed with random effect generic inverse variance method meta-analysis. The endpoints were expressed as hazard ratio (HR) with 95% confidence interval (CI). The primary outcome was cardiovascular death. Main secondary outcomes of interest were all-cause death, myocardial infarction (MI), and repeated coronary revascularization. Overall, 6528 patients were included (3139 complete group, 3389 culprit-only group). After a follow-up ranging between 1 and 3 years (median 2 years), cardiovascular death was significantly reduced in the group receiving complete revascularization (HR 0.62, 95% CI 0.39-0.97, I2 = 29%). The number needed to treat to prevent one cardiovascular death was 70 (95% CI 36-150). The secondary endpoints MI and revascularization were also significantly reduced (HR 0.68, 95% CI 0.55-0.84, I2 = 0% and HR 0.29, 95% CI 0.22-0.38, I2 = 36%, respectively). Needed to treats were 45 (95% CI 37-55) for MI and 8 (95% CI 5-13) for revascularization. All-cause death (HR 0.81, 95% CI 0.56-1.16, I2 = 27%) was not affected by the revascularization strategy., Conclusion: In a selected study population of STEMI patients with multivessel disease, a complete revascularization strategy is associated with a reduction in cardiovascular death. This reduction is concomitant with that of MI and the need of repeated revascularization., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Objectives: The frequency of oral squamous cell carcinoma in young adults has increased in the last decades, and there are conflicting results in literature about its prognosis in young subjects. The aim of this study was to analyse the clinical and pathological features of oral squamous cell carcinoma in a cohort of young adults in order to investigate the presence of new independent prognostic markers., Materials and Methods: Only HPV-negative young patients (under 40-year-old) affected by oral squamous cell carcinoma were considered in this study. Clinical and pathological data were collected. Patients were re-staged according to the 8th edition of AJCC., Results: Overall, 66 patients were considered in this study. Perineural invasion significant correlated with both 7th and 8th edition of AJCC, and lymphovascular invasion (p-value < .05). The multivariate survival analysis showed that patients with perineural invasion had a significant worse prognosis (HR = 6.384 95% C.I. 1.304-31.252; p-value = .022)., Conclusions: Perineural invasion emerged as an independent prognostic factor for disease-specific survival in young patients with oral squamous cell carcinoma. Furthermore, the evaluation of this parameter is simple, inexpensive and can be used to augment the risk stratification of oral cancer based on the 8th edition of AJCC., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. All rights reserved.)

Aims: The purpose of this study was to verify the impact on the number and characteristics of coronary invasive procedures for acute coronary syndrome (ACS) of two hub centers with cardiac catheterization facilities, during the first month of lockdown following the COVID-19 pandemic., Materials and Methods: Procedural data of ACS patients admitted between 10 March and 10 April 2020 were compared with those of the same period of 2019., Results: We observed a 23.4% reduction in ACS admissions during 2020, with a decrease for both ST-elevation myocardial infarction (STEMI) (-5.6%) and non-ST-elevation myocardial infarction (-34.5%), albeit not statistically significant (P = 0.2). During the first 15 days of the examined periods, the reduction in ACS admissions reached 52.5% (-25% for STEMI and -70.3% for non-ST-elevation myocardial infarction, P = 0.04). Among STEMI patients, the rate of those with a time delay from symptoms onset longer than 180 min was significantly higher during the lockdown period (P = 0.01). Radiograph exposure (P = 0.01) was higher in STEMI patients treated in 2020 with a slightly higher amount of contrast medium (P = 0.1) and number of stents implanted (P = 0.1), whereas the number of treated vessels was reduced (P = 0.03). Percutaneous coronary intervention procedural success and in-hospital mortality were not different between the two groups and in STEMI patients (P NS for all)., Conclusion: During the early phase, the COVID-19 outbreak was associated with a lower rate of admissions for ACS, with a substantial impact on the time delay presentation of STEMI patients, but apparently without affecting the in-hospital outcomes.

Aims: One of the objectives of current research is to customise the treatment of cancer patients. The achievement of this objective requires stratification of patients based on the most significant prognostic factors. The aims of this study were to evaluate the prognostic value of the tumour-stroma ratio (TSR), defined as the proportion of tumour cells relative to surrounding stroma, in patients with oral tongue squamous cell carcinoma (OTSCC), and to develop a prognostic nomogram based on the most significant clinicopathological features., Methods and Results: Clinicopathological data of 211 patients treated at 'Ospedali Riuniti' General Hospital (Ancona, Italy) for OTSCC were collected. One hundred and thirty-nine patients were restaged according to the 8th edition American Joint Committee on Cancer (AJCC) staging system. Evaluation of the TSR was performed on haematoxylin and eosin-stained slides, and correlation with survival outcomes was evaluated. In addition, with the aim of integrating the independent value of the TSR with the 8th edition AJCC staging system, a prognostic nomogram for OTSCC has been developed. OTSCC with a low TSR (i.e. a high proportion of stroma and a low proportion of tumour cells) was shown to have negative prognostic value in terms of disease-specific survival, with a hazard ratio (HR) of 1.883 and a 95% confidence interval (CI) of 1.033-3.432 (P = 0.039), and overall survival (HR = 1.747, 95% CI 0.967-3.154; P = 0.044), independently of other histological and clinical parameters. For the cohort of 139 patients restaged according to the 8th edition AJCC staging system, variables correlating with a poor prognosis were: the TSR, perineural invasion, and sex. The nomogram built on these parameters showed good predictive capacity, outperforming the 8th edition AJCC staging system in stratifying disease-specific survival in OTSCC patients., Conclusions: Including the TSR in the predictive model could improve risk stratification of OTSCC patients and aid in making treatment decisions., (© 2020 John Wiley & Sons Ltd.)

Background: Myocardial infarction (MI) in elderly patients is associated with unfavorable prognosis, and it is becoming an increasingly prevalent condition. The prognosis of elderly patients is equally impaired in ST-segment elevation (STE) or non-STE (NSTE), and it is markedly worsened by the common presence of multivessel disease (MVD). Given the limited evidence available for elderly patients, it has not yet been established whether, as for younger patients, a complete revascularization strategy in MI patients with MVD should be advocated. We present the design of a dedicated study that will address this research gap., Methods and Design: The FIRE trial is a prospective, randomized, international, multicenter, open-label study with blinded adjudicated evaluation of outcomes. Patients aged 75 years and older, with MI (either STE or NSTE), MVD at coronary artery angiography, and a clear culprit lesion will be randomized to culprit-only treatment or to physiology-guided complete revascularization. The primary end point will be the patient-oriented composite end point of all-cause death, any MI, any stroke, and any revascularization at 1 year. The key secondary end point will be the composite of cardiovascular death and MI. Quality of life and physical performance will be evaluated as well. All components of the primary and key secondary outcome will be tested also at 3 and 5 years. The sample size for the study is 1,400 patients., Implications: The FIRE trial will provide evidence on whether a specific revascularization strategy should be applied to elderly patients presenting MI and MVD to improve their clinical outcomes., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: In patients with squamous cell carcinoma of the oral tongue (OTSCC), current tumor node metastasis staging system fails to identify at-risk patients associated with early relapse and poor prognosis despite complete surgical resection. Given the importance of tumor-infiltrating lymphocytes (TILs) in the development of cancers, here we investigated the prognostic significance of the immune phenotype in OTSCC., Methods: Hematoxylin-eosin stained sections of OTSCCs from 211 patients were evaluated. Cancers were classified as (a) immune-inflamed when TILs were found next to tumor cell nests; (b) immune-excluded when TILs were found in the stroma, outside the tumor; and (c) immune-desert for tumors lacking lymphocyte infiltrate. The prognostic significance of these immune phenotypes classes was investigated. Data were further validated on an independent cohort from The Cancer Genome Atlas database., Results: Immune-desert phenotype was the least represented group of OTSCCs in our cohort (11.8%) and served as an independent prognostic factor. Patients with immune-desert tumors exhibited worse disease-specific survival (HR = 2.673; [CI: 95% 1.497-4.773]; P = .001), overall survival (HR = 2.591; [CI: 95% 1.468-4.572]; P = .001), and disease-free survival (HR = 2.313; [CI: 95% 1.118-4.786]; P = .024) at multivariate analysis., Conclusions: We identified a specific subgroup of OTSCCs with poor prognosis. Tumor-infiltrating lymphocytes density and localization could serve as an integrative parameter to the current staging system and inform the selection of most appropriate treatments. In particular, the tumor immune phenotype could improve the stratification of patients with more aggressive disease., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)