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Background: The purpose of this study was to investigate the expression of nuclear EGFR (nEGFR) and the stem cell marker ABCG2 in oral leukoplakia (OL) and oral erythroplakia (OE) and to assess their significance as prognostic biomarkers for malignant transformation. Methods: In this study we included 50 patients with oral potentially malignant disorders (OPMD), 31 with OL and 19 with OE, in whom we examined the expression of nEGFR and ABCG2 by immunohistochemical methods. Results: Twenty-one (42%) of 50 patients with OL and OE developed oral squamous cell carcinoma (OSCC). The malignant transformation was increased 12, 84-fold (95% CI, 2.15-76.44, p = 0.005) in OPMD expressing both ABCG2 and nEGFR. Expression of nEGFR is a strong indicator of malignant transformation, unlike ABCG2 expression, respectively. Conclusions: Determining the co-expression of the biomarkers nEGFR and ABCG2 in OPMD may serve us to determine the risk of malignant transformation in OSCC.

The aim of this study was to determine, by immunohistochemical methods, the expression of nEGFR and markers of cell proliferation (Ki-67), cell cycle (mEGFR, p53, cyclin D1), and tumor stem cells (ABCG2) in 59 pathohistological samples of healthy oral mucosa, 50 oral premalignant changes (leukoplakia and erythroplakia), and 52 oral squamous cell carcinomas (OSCC). An increase in the expression of mEGFR and nEGFR was found with the development of the disease (p < 0.0001). In the group of patients with leukoplakia and erythroplakia, we found a positive correlation between nEGFR and Ki67, p53, cyclin D1, and mEGFR, whereas in the group of patients with OSCC, we found a positive correlation between nEGFR and Ki67, mEGFR (p < 0.05). Tumors without perineural (PNI) invasion had a higher expression of p53 protein than tumors with PNI (p = 0.02). Patients with OSCC and overexpression of nEGFR had shorter overall survival (p = 0.004). The results of this study suggest a potentially important independent role of nEGFR in oral carcinogenesis.

Aim To evaluate the burden and predictors of throm - boembolic complications in a large real-life cohort of hos - pitalized patients with established coronavirus disease 2019 (COVID-19). Methods We retrospectively reviewed the records of 4014 consecutive adult patients admitted to a tertiary-level insti - tution because of COVID-19 from March 2020 to March 2021 for the presence of venous and arterial thrombotic events. Results Venous-thromboembolic (VTE) events were pres - ent in 5.3% and arterial thrombotic events in 5.8% patients. The majority of arterial thromboses occurred before or on the day of admission, while the majority of VTE events oc - curred during hospitalization. The majority of both types of events occurred before intensive care unit (ICU) admis - sion, although both types of events were associated with a higher need for ICU use and prolonged immobilization. In multivariate logistic regression, VTE events were inde - pendently associated with metastatic malignancy, known thrombophilia, lower mean corpuscular hemoglobin con - centration, higher D-dimer, lower lactate dehydrogenase, longer duration of disease on admission, bilateral pneu - monia, longer duration of hospitalization, and immobiliza - tion for at least one day. Arterial thromboses were inde - pendently associated with less severe COVID-19, higher Charlson comorbidity index, coronary artery disease, pe - ripheral artery disease, history of cerebrovascular insult, as - pirin use, lower C reactive protein, better functional status on admission, ICU use, immobilization for at least one day, absence of hyperlipoproteinemia, and absence of meta - static malignancy. Conclusion Among hospitalized COVID-19 patients, ve - nous and arterial thromboses differ in timing of presenta - tion, association with COVID-19 severity, and other clinical characteristics.

Coronavirus disease 2019 (COVID-19) pandemic resulted in global healthcare crises and strained health resources, both in the acute and chronic phase of the disease. Similarly to post-acute viral syndromes described in survivors of other virulent coronavirus epidemics, there are increasing reports of persistent and prolonged symptoms after acute COVID-19. These reports and studies have helped contribute to the recognition of post-COVID-19, a syndrome characterized by persistent symptoms and/or delayed or long-term complications beyond 4 weeks from the onset of symptoms. Here, we provide a comprehensive review of different manifestations of post-COVID conditions and propose a framework for the identification of patients at higher risk for post- COVID and their coordinated management through dedicated COVID-19 outpatient clinics.

Aim: To evaluate the predictive properties of several common prognostic scores regarding survival outcomes in hospitalized COVID-19 patients. Methods: We retrospectively reviewed the medical records of 4014 consecutive COVID-19 patients hospitalized in our tertiary level institution from March 2020 to March 2021. Prognostic properties of the WHO COVID-19 severity classification, COVID-GRAM, Veterans Health Administration COVID-19 (VACO) Index, 4C Mortality Score, and CURB-65 score regarding 30-day mortality, in-hospital mortality, presence of severe or critical disease on admission, need for an intensive care unit treatment, and mechanical ventilation during hospitalization were evaluated. Results: All of the investigated prognostic scores significantly distinguished between groups of patients with different 30-day mortality. The CURB-65 and 4C Mortality Score had the best prognostic properties for prediction of 30-day mortality (area under the curve [AUC] 0.761 for both) and in-hospital mortality (AUC 0.757 and 0.762, respectively). The 4C Mortality Score and COVID-GRAM best predicted the presence of severe or critical disease (AUC 0.785 and 0.717, respectively). In the multivariate analysis evaluating 30-day mortality, all scores mutually independently provided additional prognostic information, except the VACO Index, whose prognostic properties were redundant. Conclusion: Complex prognostic scores based on many parameters and comorbid conditions did not have better prognostic properties regarding survival outcomes than a simple CURB-65 prognostic score. CURB-65 also provides the largest number of prognostic categories (five), allowing more precise risk stratification than other prognostic scores.

Adenoid cystic carcinoma of head and neck (AdCCHN) is an uncommon salivary gland cancer characterized for infrequent neck metastases, and high rate of local and distant recurrence. The aim of this meta-analysis was to analyse the significance of elective neck dissection (END) in terms of overall survival (OS) in patients with AdCCHN. A systematic literature search and meta-analysis was performed. Endpoint assessed by this meta-analysis included 5-year OS (death from any cause). Statistical heterogeneity was assessed using the Cochrane Q test and I2 statistic. A pooled odds ratio (OR) was reported with 95% confidence interval (CI). There were 1934 patients in the END arm and 3083 in the observation group. The pooled OR, calculated for END vs. observation, was 0.94. Patients receiving END had similar risk for death compared to observation cohort (P=0.76). No significant difference in final outcome after patient stratification based on T stage was identified (OR for T1/T2 1.27, P=0.39; OR for T3/T4 0.95, P=0.90). Observation for cN0 neck is a reasonable option in AdCCHN. These findings suggest the need for prospective trials on indications and extent of END in AdCCHN.

High incidence of venous thromboembolic (VTE) events in coronavirus disease 2019 (COVID-19) patients has been reported despite pharmacologic thromboprophylaxis. We performed prospective bilateral lower extremity ultrasound evaluation of prolonged hospitalized COVID-19 ward patients from our institution without clinical suspicion of deep vein thrombosis (DVT). A total of 102 patient were included in the study. All patients were receiving pharmacologic thromboprophylaxis, the majority in intermediate or therapeutic doses. Asymptomatic DVT was detected in 26/102 (25.5%) patients: 22 had distal and four had proximal DVT, six had bilateral leg involvement. Pulmonary embolism was highly prevalent (17/70, 24.3%) but similarly grouped among patients with and without asymptomatic DVT. In total 37.2% of patients included in the study were recognized as having VTE. Asymptomatic DVT events were more common in intensive care unit (ICU) survivors (60% in postmechanically ventilated ICU survivors, 21.2% in ward patients, 22% in high-flow oxygen treated patients; P = 0.031), in patients with higher modified International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) VTE risk-score (median 3 vs. 2 points with and without DVT; P = 0.021) and higher body temperature on admission (median 38.7 °C vs. 37.7 °C with and without DVT; P = 0.001). No clear associations with Padua VTE risk score, demographic and other clinical characteristics, intensity of thromboprophylaxis, severity of other COVID-19 symptoms, degree of systemic inflammation or D‑dimers on admission were found (P > 0.05 for all analyses). Systematic ultrasound assessment in prolonged hospitalized severe COVID-19 patients prior to hospital discharge is needed, especially in ICU survivors, to timely recognize and appropriately treat patients with asymptomatic DVT. Supplementary Information The online version of this article (10.1007/s00508-021-01973-1) contains supplementary material, which is available to authorized users.

As a result of SARS-CoV-2 infection, inflammation develops, which promotes oxidative stress, leading to modification of phospholipid metabolism. Therefore, the aim of this study is to compare the effects of COVID-19 on the levels of phospholipid and free polyunsaturated fatty acids (PUFAs) and their metabolites produced in response to reactions with reactive oxygen species (ROS) and enzymes (cyclooxygenases-(COXs) and lipoxygenase-(LOX)) in the plasma of patients who either recovered or passed away within a week of hospitalization. In the plasma of COVID-19 patients, especially of the survivors, the actions of ROS and phospholipase A2 (PLA2) cause a decrease in phospholipid fatty acids level and an increase in free fatty acids (especially arachidonic acid) despite increased COXs and LOX activity. This is accompanied by an increased level in lipid peroxidation products (malondialdehyde and 8-isoprostaglandin F2α) and lipid mediators generated by enzymes. There is also an increase in eicosanoids, both pro-inflammatory as follows: thromboxane B2 and prostaglandin E2, and anti-inflammatory as follows: 15-deoxy-Δ-12,14-prostaglandin J2 and 12-hydroxyeicosatetraenoic acid, as well as endocannabinoids (anandamide-(AEA) and 2-arachidonylglycerol-(2-AG)) observed in the plasma of patients who recovered. Moreover, the expression of tumor necrosis factor α and interleukins (IL-6 and IL-10) is increased in patients who recovered. However, in the group of patients who died, elevated levels of N-oleoylethanolamine and N-palmitoylethanolamine are found. Since lipid mediators may have different functions depending on the onset of pathophysiological processes, a stronger pro-inflammatory response in patients who have recovered may be the result of the defensive response to SARS-CoV-2 in survivors associated with specific changes in the phospholipid metabolism, which could also be considered a prognostic factor.

It is assumed that upon SARS-CoV-2 infection granulocytes can undergo potentially destructive oxidative burst. Therefore, the aim of this study was to evaluate some parameters of redox and inflammatory signaling in granulocytes of recovered and of deceased COVID-19 pa-tients. Granulocytes were isolated from the blood of 32 COVID-19 patients on admission to the hospital (16 survived and 16 died within a week). The levels of proteins (immunoassay), eico-sanoids (UPLC-MS) and antioxidants activity (spectrophotometry) were examined. Enhanced activation of Nrf2 and NFκB and the levels of heme oxygenase and proinflammatory cytokines where found in granulocytes of all COVID-19 patients, while Cu,Zn-SOD and Mn-SOD activities were decreased, especially in deceased patients. Moreover, in patients who died increased levels of pro-inflammatory eicosanoids (PGE2 and TXB2) and decreased of anti-inflammatory (15d-PGJ2 and 5-HETE) were observed. However TXB2 was decreased, and IL-2 and IL-10 levels were in-creased in survivors, if compared both to healthy subjects and deceased patients, who did not change their cytokine generation. Therefore, it seems that by triggering transcription factors granulocytes activate redox signaling, leading to the production of pro-inflammatory eicosanoids, while reducing cellular antioxidant capacity via SOD, they express altered response to COVID-19, which might result in the onset of the vicious cycle of systemic oxidative stress in deceased patients.

Background: Spontaneous spinal subdural hematoma (SSDH) is a rare condition and causes of acute spinal cord compression, with symptoms varying from mild to severe neurological deficit. SSDH could occur as a consequence of posttraumatic, iatrogenic, or spontaneous causes, including underlying arteriovenous malformations, tumors, or coagulation disorder. Due to its rarity, it is difficult to establish standardized treatment. We present a rare case of SSDH in COVID-19 patient and course of treatment in COVID hospital. Case Description: A 71-year-old female patient was admitted due to instability, weakness of the left leg, and intensive pain in the upper part of thoracic spine as well as mild respiratory symptoms of COVID-19. She was not on pronounced anticoagulant therapy and her coagulogram at admission was within normal range. MRI revealed acute subdural hematoma at the level C VII to Th III compressing the spinal cord. The patient underwent a decompressive Th I and Th II laminectomy and hematoma evacuation. Post-operative MRI revealed a satisfactory decompression and re-expansion of the spinal cord. COVID-19 symptoms remained mild. Conclusion: SSDH represents a neurological emergency, possibly leading to significant deficit and requires urgent recognition and treatment. One of the main difficulties when diagnosing is to consider such condition when there is no history of anticoagulant treatment or previous trauma. Since high incidence of coagulation abnormalities and thromboembolic events was described COVID-19 patients, when considering the pathology of the central nervous system, the bleeding within it due to COVID-19 should be taken into account, in both brain and spine.

Aim: To assess the long-term survival after hospital discharge of patients hospitalized due to coronavirus disease 2019 (COVID-19). ----- Methods: We retrospectively reviewed data on post-discharge survival of 2586 COVID-19 patients hospitalized in our tertiary hospital from March 2020 to March 2021. ----- Results: Among 2586 patients, 1446 (55.9%) were men. The median age was 70 years, interquartile range (IQR, 60-80). The median Charlson comorbidity index was 4 points, IQR (2-5). The median length of hospital stay was 10 days, IQR (7-16). During a median follow-up of 4 months, 192 (7.4%) patients died. The median survival time after hospital discharge was not reached, and 3-month, 6-month, and 12-month survival rates were 93%, 92%, and 91%, respectively. In a multivariate analysis, mutually independent predictors of worse mortality after hospital discharge were age >75 years, Eastern Cooperative Oncology Group status 4, white blood cell count >7 ×109/L, red cell distribution width >14%, urea on admission >10.5 mmol/L, mechanical ventilation during hospital stay, readmission after discharge, absence of obesity, presence of chronic obstructive pulmonary disease, dementia, and metastatic malignancy (P

The essential role of immunoglobulin G (IgG) in immune system regulation and combatting infectious diseases cannot be fully recognized without an understanding of the changes in its N-glycans attached to the asparagine 297 of the Fc domain that occur under such circumstances. These glycans impact the antibody stability, half-life, secretion, immunogenicity, and effector functions. Therefore, in this study, we analyzed and compared the total IgG glycome—at the level of individual glycan structures and derived glycosylation traits (sialylation, galactosylation, fucosylation, and bisecting N-acetylglucosamine (GlcNAc))—of 64 patients with influenza, 77 patients with coronavirus disease 2019 (COVID- 19), and 56 healthy controls. Our study revealed a significant decrease in IgG galactosylation, sialylation, and bisecting GlcNAc (where the latter shows the most significant decrease) in deceased COVID-19 patients, whereas IgG fucosylation was increased. On the other hand, IgG galactosylation remained stable in influenza patients and COVID-19 survivors. IgG glycosylation in influenza patients was more time-dependent: In the first seven days of the disease, sialylation increased and fucosylation and bisecting GlcNAc decreased ; in the next 21 days, sialylation decreased and fucosylation increased (while bisecting GlcNAc remained stable). The similarity of IgG glycosylation changes in COVID-19 survivors and influenza patients may be the consequence of an adequate immune response to enveloped viruses, while the observed changes in deceased COVID-19 patients may indicate its deviation.

Aim To describe epidemiological characteristics and base - line clinical features, laboratory findings at intensive care unit (ICU) admission, and survival rates of critically ill coro - navirus disease 2019 (COVID-19) patients treated at a ter - tiary institution specialized for COVID-19 patients. Methods This retrospective study recruited 692 patients (67.1% men). Baseline demographic data, major comorbid - ities, anthropometric measurements, clinical features, and laboratory findings at admission were compared between survivors and non-survivors. Results The median age was 72 (64-78) years. The median body mass index was 29.1 kg/m 2 . The most relevant comor - bidities were diabetes mellitus (32.6%), arterial hyperten - sion (71.2%), congestive heart failure (19.1%), chronic kid - ney disease (12.6%), and hematological disorders (10.3%). The median number of comorbidities was 3 and median Charlson Comorbidity Index (CCI) was 5. A total of 61.8% patients received high-flow nasal oxygen therapy (HFNO) and 80.5% received mechanical ventilation (MV). Median duration of HFNO was 3, and that of MV was 7 days. ICU mortality rate was 72.7%. Survivors had significantly lower age, number of comorbidities, CCI, sequential organ failure assessment score, serum ferritin, C-reactive protein, D-dim - er, and procalcitonin, interleukin-6, lactate, white blood cell, and neutrophil counts. They also had higher lymphocyte counts, Pa O 2 /FiO 2 ratio, and glomerular filtration rate at ad - mission. Length of ICU stay was 9 days. The median surviv - al was 11 days for mechanically ventilated patients, and 24 days for patients who were not mechanically ventilated. Conclusion The parameters that differentiate survivors from non-survivors are in agreement with published data. Further multivariate analyses are warranted to identify in - dividual mortality risk factors

Aim To investigate how age, sex, and comorbidities affect the survival of hospitalized coronavirus disease 2019 (COVID-19) patients. Methods We retrospectively analyzed the records of 4014 consecutive adults hospitalized for COVID-19 in a tertiarylevel institution from March 2020 to March 2021. Results The median age was 74 years. A total of 2256 (56.2%) patients were men. The median Charlson-comor - bidity-index (CCI) was 4 points; 3359 (82.7%) patients had severe or critical COVID-19. A significant interaction be - tween age, sex, and survival ( P

Aim To investigate clinical and prognostic associations of red cell distribution width (RDW) in hospitalized coronavi - rus disease 2019 (COVID-19) patients. Methods We retrospectively analyzed the records of 3941 consecutive COVID-19 patients admitted to a tertiary-level institution from March 2020 to March 2021 who had avail - able RDW on admission. Results The median age was 74 years. The median Charl - son comorbidity index (CCI) was 4. The majority of pa - tients (84.1%) on admission presented with severe or criti - cal COVID-19. Patients with higher RDW were significantly more likely to be older and female, to present earlier dur - ing infection, and to have higher comorbidity burden, worse functional status, and critical presentation of COVID-19 on admission. RDW was not significantly associated with C-re - active protein, occurrence of pneumonia, or need for oxy - gen supplementation on admission. During hospital stay, patients with higher RDW were significantly more likely to require high-flow oxygen therapy, mechanical ventilation, intensive care unit, and to experience prolonged immobi - lization, venous thromboembolism, bleeding, and bacte - rial sepsis. Thirty-day and post-hospital discharge mortality gradually increased with each rising RDW percent-point. In a series of multivariate Cox-regression models, RDW demon - strated robust prognostic properties at >14% cut-off level. This cut-off was associated with inferior 30-day and postdischarge survival independently of COVID-19 severity, age, and CCI; and with 30-day survival independently of COVID severity and established prognostic scores (CURB-65, 4Cmortality, COVID-gram and VACO-index). Conclusion RDW has a complex relationship with COVID19-associated inflammatory state and is affected by prior comorbidities. RDW can improve the prognostication in hospitalized COVID-19 patients.

Tracheomegaly (TM) is a rare appearance that is radiologically defined as an excessive enlargement of the tracheal diameter. We present a comprehensive analysis of tracheal diameter measurements and TM incidence in patients admitted and treated due to COVID-19 pneumonitis and its association with possible respiratory complications. In this retrospective study, we included 1015 patients divided into three groups: 383 patients treated using mechanical ventilation (MV), 132 patients treated using high-flow ventilation (HFV), and 500 randomly selected patients using nasal catheter (NC) oxygenation. The tracheal lumen diameter was measured continuously using a chest X-ray, and the cuff/trachea (C/T) diameter ratio was calculated. We detected TM in 71 patients (18.54%). Regression analysis showed statistical significance in MV patients for the trachea diameter at the level of the cuff, maximal trachea diameter and C/T diameter ratio, and days on MV. Respiratory complications showed a significant association with the C/T diameter ratio. The C/T diameter ratio was shown to be a reliable potential predictor of the occurrence of respiratory complications. The results of the study highlight the importance of the early detection and prevention of TM in COVID-19 patients on MV using a chest X-ray and measurement of the C/T diameter ratio.

Background: Liver involvement in Coronavirus disease 2019 (COVID-19) has been recognised. We aimed to investigate the correlation of non-invasive surrogates of liver steatosis, fibrosis and inflammation using transient elastography (TE) and FibroScan-AST (FAST) score with (a) clinical severity and (b) 30-day composite outcome of mechanical ventilation (MV) or death among patients hospitalized due to COVID-19. Method: Patients with non-critical COVID-19 at admission were included. Liver stiffness measurement (LSM) and controlled attenuation parameter (CAP) were assessed by TE. Clinical severity of COVID-19 was assessed by 4C Mortality Score (4CMS) and need for high-flow nasal cannula (HFNC) oxygen supplementation. Results: 217 patients were included (66.5% males, median age 65 years, 4.6% with history of chronic liver disease). Twenty-four (11.1%) patients met the 30-day composite outcome. Median LSM, CAP and FAST score were 5.2 kPa, 274 dB/m and 0.31, respectively, and neither was associated with clinical severity of COVID-19 at admission. In multivariate analysis FAST &gt, 0.36 (OR 3.19, p = 0.036), 4CMS (OR 1.68, p = 0.002) and HFNC (OR 7.03, p = 0.001) were independent predictors of adverse composite outcome. Conclusion: Whereas LSM and CAP failed to show correlation with COVID-19 severity and outcomes, FAST score was an independent risk factor for 30-day mortality or need for MV.

Background: Derangement of liver blood tests (LBT) is frequent in patients with Coronavirus disease 2019 (COVID-19). We aimed to evaluate (a) the prevalence of deranged LBT as well as their association with (b) clinical severity at admission and (c) 30-day outcomes among the hospitalized patients with COVID-19. Methods: Consecutive patients with COVID-19 hospitalized in the regional referral center over the 12-month period were included. Clinical severity of COVID-19 at hospital admission and 30-day outcomes (need for intensive care, mechanical ventilation, or death) were analyzed. Results: Derangement of LBT occurred in 2854/3812 (74.9%) of patients, most frequently due to elevation of AST (61.6%), GGT (46.1%) and ALT (33.4%). Elevated AST, ALT, GGT and low albumin were associated with more severe disease at admission. However, in multivariate Cox regression analysis, when adjusted for age, sex, obesity and presence of chronic liver disease, only AST remained associated with the risk of dying (HR 1.5081 and 2.1315, for elevations 1–3 × ULN and &gt, 3 × ULN, respectively) independently of comorbidity burden and COVID-19 severity at admission. Patients with more severe liver injury more frequently experienced defined adverse outcomes. Conclusions: Deranged LBTs are common among patients hospitalized with COVID-19 and might be used as predictors of adverse clinical outcomes.

Neurinom ili švanom rijetki je benigni tumor koji potječe od Schwannovih stanica ovojnice živca. To je spororastući, solitarni i inkapsulirani tumor. Može nastati u bilo kojoj dobi, ali najčešće se javlja između 30. i 60. godine života. Na glavi i vratu neurinomi se javljaju u mlađih osoba, u dobi od 20. do 30. godine. Citološka je dijagnoza važna zbog odabira pravilnog liječenja, otkrivanja recidiva ili pojave novog neurinoma na drugome živcu. Citološke punkcije mogu se raditi „naslijepo” ili češće pod kontrolom ultrazvuka. Tijekom sedam godina, od 1. siječnja 2007. do 31. prosinca 2013., punktirano je 14 322 pacijenta na Odjelu za kliničku citologiju i citometriju KB-a Dubrava, a samo u 10 (0,07 %) pacijenata postavljena je citološka dijagnoza neurinoma. Najviše punktiranih neurinoma bilo je u području glave i vrata, u sedam pacijenata od njih 10. Retrospektivno smo analizirali preparate i nalaze i odredili točnost citologije uspoređujući citološku dijagnozu s patohistološkim nalazom. U šest je pacijenata patohistološki potvrđena citološka dijagnoza neurinoma. U četiri pacijenta čija je patohistološka dijagnoza bila neurinom, citološka je dijagnoza glasila mezenhimalni tumor u tri pacijenta, a u četvrtog tumor vretenastih stanica, što su sve bile dijagnoze benignih lezija.

Major findings of the pilot study involving 21 critically ill patients during the week after admission to the critical care unit specialized for COVID-19 are presented. Fourteen patients have recovered, while seven passed away. There were no differences between them in respect to clinical or laboratory parameters monitored. However, protein adducts of the lipid peroxidation product 4-hydroxynonenal (HNE) were higher in the plasma of the deceased patients, while total antioxidant capacity was below the detection limit for the majority of sera samples in both groups. Moreover, levels of the HNE-protein adducts were constant in the plasma of the deceased patients, while in survivors, they have shown prominent and dynamic variations, suggesting that survivors had active oxidative stress response mechanisms reacting to COVID-19 aggression, which were not efficient in patients who died. Immunohistochemistry revealed the abundant presence of HNE-protein adducts in the lungs of deceased patients indicating that HNE is associated with the lethal outcome. It seems that HNE was spreading from the blood vessels more than being a consequence of pneumonia. Due to the limitations of the relatively small number of patients involved in this study, further research on HNE and antioxidants is needed. This might allow a better understanding of COVID-19 and options for utilizing antioxidants by personalized, integrative biomedicine approach to prevent the onset of HNE-mediated vitious circle of lipid peroxidation in patients with aggressive inflammatory diseases.

BackgroundMost respiratory viruses show pronounced seasonality, but for SARS-CoV-2 this still needs to be documented.MethodsWe examined the disease progression of COVID-19 in 6,914 patients admitted to hospitals in Europe and China. In addition, we evaluated progress of disease symptoms in 37,187 individuals reporting symptoms into the COVID Symptom Study application.FindingsMeta-analysis of the mortality risk in seven European hospitals estimated odds ratios per one day increase in the admission date to be 0.981 (0.973-0.988, pInterpretationSeverity of COVID-19 in Europe decreased significantly between March and May and the seasonality of COVID-19 is the most likely explanation.

A grade of extranodal extension (ENE) may advance risk stratification related to survival in patients with metastatic oral cavity squamous cell carcinoma (OCSCC). Pathological examination of 174 OCSCC patients who were primarily surgically treated with tumour resection and elective neck dissection was performed. Data of ENE presence, its extent (in millimetres), patients and tumour characteristics were statistically analysed with respect to disease-free survival (DFS) and overall survival (OS). Ninety patients (51.7%) were identified with occult nodal disease, with 41 patients (23.6%) presenting with ENE. Receiver operating characteristics (ROC) curve analysis set the threshold at 1.9 mm as an optimal ENE cut-off regarding both DFS and OS. Patients were divided by extent into minor ENE (≤1.9 mm) and major ENE (>1.9 mm) subgroups. The subgroup with minor ENE had significantly higher DFS and OS rates compared with major ENE. ENE cut-off threshold at 1.9 mm discriminates low and high-risk subgroups of patients with occult OCSCC in terms of DFS and OS.

The aim of this paper is to give an overview of the most common malignant tumors of the nose and paranasal sinuses, histological types and new TNM classification and principles of oncological resection and methods of reconstruction defects based on experiences in single institutions. Patients treated at the Department of Maxillofacial and Oral Surgery of Dubrava University Hospital in Zagreb for a 20-year period are shown here. The frequency and distribution of certain types of malignant tumors of the nose and paranasal sinuses, indications and extent of surgical procedures for individual histological types, localizations and stages of the disease are presented in more detail. The principles of the nose and middle face defect reconstruction, advantages and disadvantages of individual methods are presented in detail as well. The conclusion outlines possible guidelines and algorithms for the surgical treatment and follow-up management of oncologic patients with nasal and paranasal sinus tumors.

Adenoid cystic carcinoma of head and neck (AdCCHN) is salivary gland malignancy known for its slow progression accompanied with perineural invasion, rare lymphatic spread to the neck, high rate of local recurrence and delayed onset of distant metastases. While local recurrence and distant metastases are most common patterns of relapse and cause of death in AdCCHN, it has been debated whether lymph node involvement affects the course of the disease. The aim of this systematic review was to address this important issue and to recommend guidelines on clinically node-negative neck management in patients with AdCCHN. A systematic review of the published literature on cases of elective neck dissection (END) among patients with AdCCHN was performed. This analysis included a total of 5767 AdCCHN patients with 2450 ENDs, ranging from 10 to 1190. Elective lymphadenectomy was employed in 42.5% of patients with AdCCHN (range 9.2–100%). The overall rate of occult neck metastases in patients with AdCCHN was reported to range between 0 and 43.7%, the average being 13.9%. If performed, END should be limited to levels I–III of the ipsilateral neck since occult metastases are exclusively located within these neck regions. Although END is associated with a prolonged regional recurrence-free period, it influence on final outcome or survival is still controversial. This review strongly supports conduction of prospective trials on indications, prognostic significance and extent of END in AdCCHN.

We have recently published a meta-analysis in which we have concluded that cisplatin-based chemoradiotherapy should remain standard of definitive treatment for human papilloma virus associated oropharyngeal cancer. In this letter to the editor we have addressed a potential flaws our meta-analysis.

Background The purpose of this study was to identify clinicopathological and immunohistochemical factors predicting delayed lymph node metastases and survival in early oral squamous cell carcinoma (OSCC). Methods The study included 85 consecutive patients with clinically T1 to T2N0 OSCC who were primarily surgically treated between 2000 and 2004. Results There were 68 men and 17 women (median age, 61 years; range, 34–82 years). Of all the patients, 25 (29.4%) developed delayed lymph node metastases within 3 to 42 months after treatment of the primary tumor. Multivariate logistic regression analysis identified poorly differentiated tumors, low laminin, and high fibronectin expression as prognosticators of delayed lymph node metastases. Cox's proportional hazards regression analysis demonstrated that moderately differentiated tumors and delayed lymph node metastases had predictive value regarding survival. Conclusion Large prospective investigations with reproducibility and the clinical translatability of immunohistochemical methods are needed in order to provide new and effective therapeutic strategies in the future. © 2016 Wiley Periodicals, Inc. Head Neck 39: 694–701, 2017

Bone morphogenetic protein 6 (BMP6) has unique properties regarding structure and function in supporting bone formation during development and adult life. Despite its known role in various malignant tumors, the prognostic significance of BMP6 expression in oral squamous cell carcinoma (OSCC) remains unknown. The aim of the study was to investigate immunohistochemical expression of BMP6 in OSCC in correlation with clinical and pathological parameters, disease recurrence and survival. In addition, we investigated other parameters in order to identify prognosticators of neck metastases and final outcome. The study included 120 patients with clinically T1-3N0 OSCC who were primarily surgically treated between 2003 and 2008. There were 99 (82.5%) male and 21 (17.5%) female patients. The five-year disease- specific survival for the whole cohort was 79.7%. Tumors smaller than 2 cm in diameter showed higher incidence of strong BMP6 expression. No statistical correlation was observed between other clinico- pathological factors and BMP6 expression. Expression of BMP6 was not associated with disease recurrence and survival. BMP6 may not serve as prognosticator of final outcome or recurrence in clinically node-negative OSCC subjects. In multivariate analysis predictors of poorer survival were positive surgical margin, moderate tumor cell differentiation and pathological involvement of levels IV and/or V.

Neurinom ili švanom rijetki je benigni tumor koji potječe od Schwannovih stanica ovojnice živca. To je spororastući, solitarni i inkapsulirani tumor. Može nastati u bilo kojoj dobi, ali najčešće se javlja između 30. i 60. godine života. Na glavi i vratu neurinomi se javljaju u mlađih osoba, u dobi od 20. do 30. godine. Citološka je dijagnoza važna zbog odabira pravilnog liječenja, otkrivanja recidiva ili pojave novog neurinoma na drugome živcu. Citološke punkcije mogu se raditi „naslijepo” ili češće pod kontrolom ultrazvuka. Tijekom sedam godina, od 1. siječnja 2007. do 31. prosinca 2013., punktirano je 14 322 pacijenta na Odjelu za kliničku citologiju i citometriju KB-a Dubrava, a samo u 10 (0,07 %) pacijenata postavljena je citološka dijagnoza neurinoma. Najviše punktiranih neurinoma bilo je u području glave i vrata, u sedam pacijenata od njih 10. Retrospektivno smo analizirali preparate i nalaze i odredili točnost citologije uspoređujući citološku dijagnozu s patohistološkim nalazom. U šest je pacijenata patohistološki potvrđena citološka dijagnoza neurinoma. U četiri pacijenta čija je patohistološka dijagnoza bila neurinom, citološka je dijagnoza glasila mezenhimalni tumor u tri pacijenta, a u četvrtog tumor vretenastih stanica, što su sve bile dijagnoze benignih lezija., Neurinoma (schwannoma) is a rare benign tumor that originates from Schwann cells of the nerve sheath. Neurinoma is a slow-growing, solitary and encapsulated tumor. These neoplasms may occur at any age but are more common between the ages of 30 and 60. Neurinoma of the head and neck occurs in younger people, at the ages of 20 and 30. Cytological diagnosis is important for the accurate treatment, detection of recurrence of the disease and diagnosing a new neurinoma on another nerve. Fine needle aspiration cytology (FNAC) can be done with or without ultrasound guidance. During 7 years - from 1 January 2007 until 31 December 2013, 14 322 FNAC have been done at the Department of Cytology and Cytometry, Dubrava University Hospital and only 10 (0.07%) patients had cytological diagnosis of neurinoma. The most FNAC of neurinoma was done in the head and neck, in 7 patients out of 10. We have analysed retrospectively cytology slides and reports and we determined the accuracy of cytology by comparing cytological diagnoses with pathohistological findings. Cytological diagnosis of neurinoma was accurate in 6 patients according to pathohistological diagnosis. In 4 patients with pathohistological diagnosis of neurinoma cytological diagnoses were mesenchymal tumor in 3 patients and spindle cell tumor in one patient, all of them were benign lesions.

Purpose: Human papilloma virus (HPV)-associated oropharyngeal cancer (OPC) is a special entity among head and neck squamous cell carcinomas (HNSCCs). Given its favorable prognosis, one of the de-escalating strategies in the treatment of OPC includes the introduction of cetuximab (C225) instead of cisplatin (CDDP) in conjunction with radiotherapy. An updated meta-analysis of published studies has been performed, which directly compared the efficacy of CDDP vs. C225 given concurrently with radiotherapy as definitive treatment of p16-positive OPC. ----- Methods: A systematic literature search was performed for studies published between 2006 and 2018. A total of 1490 citations were obtained and 8 studies met inclusion criteria, with a total of 1665 patients. ----- Results: The data from seven studies were available for the analysis of 2-year overall survival (OS). Calculated pooled OR for CDDP-based chemoradiotherapy vs. C225-based bioradiotherapy, was 0.45 (P < 0.0001). The data from eight studies were available for the analysis of 2-year locoregional recurrence (LRR). Calculated pooled OR for CDDP-based chemoradiotherapy vs. C225-based bioradiotherapy was 0.35 (P < 0.0001). Patients receiving CDDP with irradiation had 2.2- and 2.9-fold decreased risk for death from any cause and LRR, respectively. ----- Conclusions: For patients with HPV-positive OPC, radiotherapy plus C225 showed inferior OS and higher LRR rates compared with radiotherapy plus CDDP. CDDP-based chemoradiotherapy should remain standard of definitive treatment of p16-positive OPC.

Accessory parotid gland tumours (APGTs) are very rare. Regarding their anatomical location, an adequate surgical approach is necessary to provide safe resection and satisfactory postoperative results. The aims of this study were to present our tertiary centre experience in surgical treatment and management of APGTs and to review the literature regarding their treatment, particularly in terms of surgical modalities. Data of 13 patients with primarily surgically treated APGTs have been collected and analysed. Well- documented English- literature articles of surgically treated APGTs have been extracted from the PubMed, Scopus and Web of Science databases ending in May 2018, and analysed. Mean age at diagnosis was 41.1 years. The most common benign histological subtype was pleomorphic adenoma (53.8%), while mucoepidermoid carcinoma (23.1%) was most common in malignant counterparts. The malignancy rate was 38.5%. Postoperative results were satisfactory, and the follow-up period was uneventful in all patients except one who died of locoregional recurrence. A total of 57 papers with reported series in APGTs have been identified with a total of 306 APGT cases. From oncological, functional and aesthetic standpoints, approaches through a standard parotidectomy provide satisfactory results.

Mucoepidermoid carcinoma (MEC) is the most common malignancy of the salivary glands. The clinical behaviour of MEC is largely unpredictable, ranging from indolent tumour growth to highly aggressive metastatic spread. The objective of this study was to determine the clinicopathological predictors of recurrence and survival in patients with head and neck MEC. The medical records of 64 patients who underwent surgical treatment for head and neck MEC between 1982 and 2010 were reviewed. The main outcome measures were disease-free survival (DFS) and overall survival (OS). Clinicopathological parameters evaluated were age, sex, anatomical subsite, histological grade, tumour stage, tumour size, adjuvant therapy, and nodal and margin status. For the entire cohort, the 5-year DFS was 82.8% and the 5-year OS was 67.2%. Histological grade and tumour subsite were statistically significant predictors of OS. Furthermore, tumour stage and nodal status were statistically significant predictors with respect to OS. Advanced tumour stage, high histological grade, submandibular/sublingual localization, and positive nodal status were independent predictors of the prognosis in patients with head and neck MEC. Further studies into the molecular biology of MEC are needed in order to provide new therapeutic strategies for patients with locally aggressive and highly metastatic carcinomas.

Background The purpose of our article was to describe a tertiary center's experience with patients with primarily surgically treated early-stage intraoral cancer with a second primary malignancy confirmed during follow-up. Methods A total of 183 patients were primarily surgically treated for oral cancer between 2000 and 2004. Among these, 24 patients (13.1% (24/183)) met inclusion criteria. Results There were 22 men (91.7%) and 2 women (8.3%) with a median age of 59.5 years. Patients with head and neck cancer with a second primary malignancy had significantly higher survival compared to nonhead and neck cancer with a second primary malignancy. Patients with head and neck cancer with second primary malignancy were diagnosed during the period of 14 to 45 months (median 29 months), whereas nonhead and neck cancer with second primary malignancy occurred in a period of 7 to 46 months (median 19 months). Conclusion This study highlights the importance of optimizing screening strategies for second primary malignancies. In order to improve the survival of patients with head and neck squamous cell carcinoma (HNSCC), effective programs of screening and/or chemoprevention of second primary malignancies are essential.

Microcystic adnexal carcinoma (MAC) is a rare, infiltrating, locally aggressive cutaneous neoplasm of combined follicular and eccrine/apocrine histogenesis, usually presenting on the upper lip or face. Differentiation from other adnexal tumours is very important because the clinical management of these tumours is radically different, and misdiagnosis may lead to incorrect treatment. A case of recurrent MAC in the upper lip, treated with multiple excisions and postoperative radiation therapy (PORT), is presented herein. There have been no signs or symptoms of recurrence since the subsequent reconstructive surgery and PORT. Based on reports in the literature it appears that although immunohistochemistry can be helpful in distinguishing between MAC and other adnexal tumours, careful histopathological examination is essential for an accurate diagnosis. Perineural and intramuscular invasion strongly suggest the diagnosis of MAC. Its predilection for the facial area often limits the width of surgical excision. In such cases, PORT may be considered.

Background Human papilloma virus (HPV)- associated oropharyngeal cancer (OPC) is a special entity among head and neck squamous cell carcinomas (HNSCCs) characterised by higher survival rates compared to similar stage HPV-negative OPC. Due to favorable prognosis, a significant interest in ‘’less toxic’’ therapies (de-escalating strategies) in the treatment of HPV-associated OPC had been introduced. One of the approaches included introduction of cetuximab (C225) instead of cisplatin (CDDP) in conjunction with radiotherapy as a definitive treatment option in these patients. The aim of the updated meta- analysis was to compare the efficacy of CDDP vs. C225 given concurrently with radiotherapy as definitive treatment of HPV-associated OPC, with inclusion of the latest trials investigating this specific issue. To our knowledge this is currently the largest investigation on this matter. Methods A systematic literature search was performed for studies published between 2006 and 2018. A total of 1490 citations were obtained and 8 studies met inclusion criteria, resulting in inclusion of 1665 patients in this meta- analysis. Results Analysis of pooled studies showed no significant heterogeneity or publication bias. Two-year overall survival (OS) calculated pooled odds ratio (OR) for CDDP-based chemoradiotherapy vs. C225-based bioradiotherapy, was 0.45 (P < 0.0001). Two- year locoregional recurrence (LRR) calculated pooled OR for CDDP-based chemoradiotherapy vs. C225-based bioradiotherapy was 0.35 (P < 0.0001). Patients receiving CDDP concurrently with radiotherapy had 2.2- and 2.9-fold decreased risk for death from any cause and LRR, respectively. Conclusions According to the evidence demonstrated by our meta-analysis, CDDP-based chemoradiotherapy should remain the standard of definitive treatment of HPV- associated OPC. Further investigations are necessary in order to define optimal treatment in HPV-negative HNSCCs. Legal entity responsible for the study Petar Suton. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Ameloblastoma is a benign odontogenic tumour that may have aggressive biological behavior with local recurrence and metastasis after the surgical resection. We report a case of cytology of recurrent ameloblastoma. The first tumour was diagnosed in the left mandible in 57-yers-old woman thirteen years ago. The patient was operated on, the tumour was enucleated, pathohistological diagnosis of ameloblastoma was put and DNA analysis by flow cytometry of the tumour was performed. DNA analysis showed that the tumour was diploid but proliferative. Two years after the operation, a new tumour appeared on the scar. Fine needle aspiration cytology with ultrasound guidance of the tumour was performed; cytological diagnosis of recurrent ameloblastoma was put and confirmed by pathohistology. Until now the patient is well without any new recurrent ameloblastoma.

The presence of extracapsular spread (ECS) in patients with oral squamous cell carcinoma (OSCC) indicates a poor prognosis and is associated with a higher risk of regional recurrence and distant metastasis. The aim of this study was to analyse this important feature of cervical lymph nodes in the clinically node-negative setting. The study included 61 patients with clinically T1–T3N0 OSCC who underwent primary surgical treatment; 52 were male and nine were female, and their median age was 57 years. The 5-year disease-free survival, disease-specific survival, and overall survival rates were 30.6%, 28.3%, and 14.3%, respectively, in the ECS group compared to 61.9%, 61.9%, and 48.2%, respectively, in the pN+/ECS-negative group and 76.7%, 81.9%, and 47.0%, respectively, in the pN0 group. The differences between the survival curves were highly significant ( P =0.023, P =0.003, and P =0.029, respectively). The incidence of local (50% vs. 14.9%, P =0.011) and regional (28.6% vs. 2.1%, P =0.008) recurrence was significantly greater in the ECS group compared to the other subgroups of patients. Furthermore, the time to recurrence was significantly shorter in the ECS subjects. The presence of ECS in patients with oral cancer indicates a poor prognosis. ECS is a frequent feature in clinically node-negative settings and may be more common in smaller lymph nodes than is generally appreciated.

The accessory parotid gland (APG) is salivary tissue anterior to and anatomically separate from the parotid gland. APG is a common anatomical variation, but APG tumours are extremely rare. The authors report 6 patients with APG tumours emphasizing the diagnosis, clinical features, indications and rationales for different treatment approaches. Patients with primary tumours of the parotid gland or APG tumours who underwent surgical treatment were included. APG tumours comprised 1.23% of overall parotid tumours (6/488) and had a malignancy rate of 33.3% (2/6). There were three male and three female patients with a mean age of 39 years (range 14-70 years). 5 of 6 parotidectomies entailed superficial lobectomy, while one was a total parotidectomy with composite resection of masseter muscle. Concomitant selective lymphadenectomy was carried out in 3 of 6 patients. At 5 years disease-free survival was 83.3%. Mean follow-up was 161 months (range 14-253 months). Although nonsalivary diagnoses frequently occur in the buccal area, APG tumours should be considered in every differential diagnosis in patients presenting with a mid-cheek mass. From oncosurgical, cosmetic and functional standpoints, treatment by facelift parotidectomy or 'S-incision' with concomitant superficial lobectomy is the recommended surgical approach; high-grade malignancies require total parotidectomy with regional lymphadenectomy.