TGFß carrying exosomes in plasma: potential biomarkers of cancer progression in patients with head and neck squamous cell carcinoma.

OBJECTIVES: Contributions of TGFß to cancer progression are well documented. However, plasma TGFß levels often do not correlate with clinicopathological data. We examine the role of TGFß carried in exosomes isolated from murine and human plasma as a contributor to disease progression in head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS: The 4-nitroquinoline-1-oxide (4-NQO) mouse model was used to study changes in TGFß expression levels during oral carcinogenesis. In human HNSCC, TGFß and Smad3 protein expression levels and TGFB1 gene expression were determined. Soluble TGFß levels were evaluated by ELISA and TGFß bioassays. Exosomes were isolated from plasma using size exclusion chromatography, and TGFß content was quantified using bioassays and bioprinted microarrays. RESULTS: During 4-NQO carcinogenesis, TGFß levels in tumour tissues and in serum increased as the tumour progressed. The TGFß content of circulating exosomes also increased. In HNSCC patients, TGFß, Smad3 and TGFB1 were overexpressed in tumour tissues and correlated with increased soluble TGFß levels. Neither TGFß expression in tumours nor levels of soluble TGFß correlated with clinicopathological data or survival. Only exosome-associated TGFß reflected tumour progression and correlated with tumour size. CONCLUSIONS: Circulating TGFß+ exosomes in the plasma of patients with HNSCC emerge as potential non-invasive biomarkers of disease progression in HNSCC.

Supine sleep patterns as a part of phenotyping patients with sleep apnea-a pilot study.

PURPOSE: Polysomnography (PSG) is considered the best objective study to diagnose and quantify sleep disorders. However, PSG involves multiple electrodes and is usually performed in a sleep laboratory that in itself may change the physiology of sleep. One of the parameters that can change during PSG is the sleep position, leading to more supine sleep. The aim of this study was to quantify the amount of supine sleep during PSG and compare it to consecutive nights of a home sleep apnea test (HSAT) in the same patients. METHODS: This prospective study evaluated 22 consecutive patients undergoing PSG followed by HSAT. Sleep position was analyzed during PSG and subsequently on 2 to 6 nights (mean 3.7 nights) at home, and the amount of supine sleep was recorded during each night. RESULTS: Of 22 patients, there were 12 men (55%). The median age was 60.0 years for women and 45.5 years for men. Median proportion of supine sleep during PSG and HSAT was 61% and 26% (p < 0.001), respectively. Four "phenotypes" were identified according to their sleep position during PSG and HSAT, with 5 patients sleeping mainly supine during all nights, 7 patients sleeping mainly non-supine during all nights, 3 patients sleeping in different positions during each night, and 7 patients sleeping supine during PSG but non-supine at home, during HSAT. CONCLUSIONS: There is a higher proportion of supine sleep during PSG compared to home sleep. We identified a subgroup of patients who slept mainly supine during PSG and mainly non-supine during HSAT. PSG may overestimate OSA severity in a specific phenotype of patients.

The effect of in-lab polysomnography and home sleep polygraphy on sleep position.

PURPOSE: Little is known regarding the influence of in-laboratory polysomnography (PSG) equipment on sleep position, especially on the prevalence of supine positioning, which in many cases may lead to a more severe sleep apnea diagnosis. The aim of this study was to assess the percentage of supine sleep during an in-laboratory PSG compared to that seen during a home sleep apnea test (HSAT). METHODS: This was a retrospective cohort study comparing in-laboratory PSG and HSAT using a peripheral arterial tone (PAT) technology device. RESULTS: Of 445 PSG and 416 HSAT studies analyzed, there was no significant difference in the proportion of supine sleep time between PSG (44%) and HSAT (45%, p = 0.53). Analysis of the differences in sleep position (supine versus non-supine), analyzed by sex, BMI (≥ 30 kg/m2 versus < 30 kg/m2), and age (≥ 60 years versus < 60 years), was significant only for women, who had more supine sleep during HSAT at 61 ± 24% than during PSG at 45 ± 26% (p < 0.001). CONCLUSION: Overall there was no difference in the percentage of supine sleep when comparing in-laboratory PSG to HSAT. However, women had more supine sleep with HSAT than with PSG.

TLRs and RAGE are elevated in carotid plaques from patients with moderate-to-severe obstructive sleep apnea syndrome.

BACKGROUND: There is growing evidence that obstructive sleep apnea (OSA) promotes vascular endothelial dysfunction and atherogenesis. Pathways that mediate this pathology may include Toll-like receptors (TLRs) and receptor for advanced glycation end products (RAGE) which play a significant role in proinflammatory processes. The aim of this study was to measure the expression of the above-mentioned receptors in relation to OSA severity in carotid plaques obtained during open endarterectomy. METHODS: This prospective study included patients with a sleep study prior to surgery and a plaque specimen obtained during standard open endarterectomy. Immunohistochemistry of TLR2, TLR4, TLR7, TLR9, RAGE, HMGB1, and NF-κB was performed on atherosclerotic plaques from carotid arteries of patients with and without OSA. RESULTS: There were 46 patients (22 women, mean age 73.2 ± 1.3 years): 14 control patients, 13 with mild, 11 with moderate, and 8 with severe OSA. The expression of all TLRs and RAGE increased proportionately with increasing OSA severity. The largest differences between patients with severe OSA and no OSA were found for TLR2 (2.88 ± 0.35 vs. 1.27 ± 0.47, p < 0.001), TLR4 (2.88 ± 0.35 vs. 1.64 ± 0.5, p < 0.001), TLR9 (2.38 ± 0.52 vs. 1.45 ± 0.52, p < 0.01), and RAGE (2.5 ± 0.53 vs. 1.82 ± 0.6, p < 0.05). CONCLUSION: TLR2, TLR4, TLR9, and RAGE expression was significantly increased in carotid plaques of patients with moderate-to-severe OSA when compared with control patients with no OSA and those with mild OSA. TLR and RAGE-mediated pathways may play a significant role in OSA-dependent atherogenesis.

Functional identification of abductor and adductor branches for laryngeal transplantation.

PURPOSE: This is a feasibility study of functional identification of the abductor and adductor recurrent laryngeal nerve branches, which could be used in the donor's larynx for functional laryngeal transplantation. METHODS: The study was performed on swine (n = 3) and human (n = 4) models of a donor larynx. The recurrent laryngeal nerve and its branches were found. Using stimulator, abductor and adductor branches were identified, and glottis closing and opening were captured with an endoscope. RESULTS: The result was positive if two ENT specialists noticed at least one adduction and one abduction movement in the same subject. It was obtained in three out of three swine and three out of four humans. CONCLUSIONS: This study shows a way of reinnervation of a transplanted larynx which might result in a functional organ. It describes the first step of the procedure: functional identification of the abductor and adductor branches of the recurrent laryngeal nerve in the donor before the larynx is excised for transplantation.

(68)Ga-DOTATATE PET in juvenile angiofibroma.

BACKGROUND: As somatostatin receptors (SSTRs) may be overexpressed in rapidly growing vessels, the aim of this study was the analysis of in vivo and in vitro SSTR2A expression in juvenile angiofibroma (JA). MATERIAL & METHODS: A group of six male adolescents with a diagnosis of primary, recurrent/residual JA was enrolled in the study. All patients underwent (68)Ga-DOTATATE PET/computed tomography (CT) followed by immunohistochemical staining for SSTR expression. RESULTS: (68)Ga-DOTATATE PET/CT showed accumulation in areas matching the pathologic tissue in the nasopharynx of all patients studied with SUVmax of 5.1 ± 0.9 (ranging from 3.6 to 6.4). In all cases, the immunohistochemical examination showed a presence of SSTR2A with a high staining index. CONCLUSION: In vitro SSTR2A cytoplasm expression was found to be high in all tumor specimens. However, the uptake of (68)Ga-DOTATATE was weak in the PET/CT studies. We postulate that the intracellular localization of the SSTR2A in JA may cause this discrepancy.

Obstructive sleep apnea and cancer: effects of intermittent hypoxia?

Obstructive sleep apnea (OSA) is a common disorder characterized by pauses in regular breathing. Apneic episodes lead to recurrent hypoxemia-reoxygenation cycles with concomitant cellular intermittent hypoxia. Studies suggest that intermittent hypoxia in OSA may influence tumorigenesis. This review presents recent articles on the potential role of OSA in cancer development. Relevant research has focused on: molecular pathways mediating the influence of intermittent hypoxia on tumor physiology, animal and epidemiological human studies linking OSA and cancer. Current data relating OSA to risk of neoplastic disease remain scarce, but recent studies reveal the potential for a strong relation. More work is, therefore, needed on the impact of OSA on many cancer-related aspects. Results may offer enlightenment for improved cancer diagnosis and treatment.

Long-term parental satisfaction with adenotonsillectomy: a population study.

OBJECTIVE: This study reports the presence of sleep-disordered breathing (SDB) symptoms among first graders. We evaluated the severity of symptoms and parental satisfaction in children who had undergone adenotonsillectomy (T&A) compared to children who never had T&A. METHODS: A population-based, cross-sectional study was conducted. Parent-reported questionnaire data including age, weight, height, BMI, history of T&A, and SDB symptoms (snoring intensity, observed dyspneas, mouth breathing during sleep) were analyzed. RESULTS: Of 3580 eligible children, 2504 (69.9 %) returned questionnaires. Two hundred fifty-nine (10.3 %) children had a history of T&A. Within this group, 76 % of parents were still satisfied with their child's outcome after surgery. The satisfaction rate decreased from 88.9 % in those who had surgery within 1 year to 71.3 % in those who had surgery ≥3 years prior. The mean values of intensity for all analyzed SDB symptoms on a five-point scale were significantly higher for children who had ever undergone T&A when compared to those who never underwent surgery [e.g., snoring (2.11 vs 1.87; P = 0.0004), dyspneas (1.64 vs 1.22; P < 0.0001), and mouth breathing during sleep (2.95 vs 2.58; P < 0.0001)]. For those who had undergone T&A, 24 % of caregivers were not satisfied with the surgical outcome and the symptom intensity was highest (snoring = 3.16, dyspneas = 2.20, and mouth breathing = 4.23) for these children. CONCLUSIONS: The mean SDB symptom intensity was significantly higher in children who had undergone T&A when compared to those who had not. The elevated symptom intensity in those children whose caregivers were not satisfied after T&A suggests possible SDB recurrence and need for further evaluation.

Rhabdomyosarcoma of the head and neck in children.

Rhabdomyosarcoma (RMS) is the most frequent soft tissue sarcoma in children. It is localized in the head and neck region in 40% of cases. Treatment of RMS is complex, including multi-drug chemotherapy, radiotherapy and surgery. The progress that has been accomplished in oncology in recent decades significantly improved outcomes. The 5-year survival rate raised from 25% in 1970 to 73% in 2001, according to IRS-IV data. The outcome is influenced by primary tumor localization, clinical staging, histological tumor type and age at the moment of diagnosis. The relatively rare incidence of these tumors resulted in difficulties in creating more standardized therapeutic protocols. Comparison of outcomes in large patients groups led to an increase in the number of patients with complete remission. Although survival rates of RMS patients have improved, searching for new therapeutic modalities and substances is still essential to improve outcomes in cases of more advanced stages and unfavorable tumor localizations.

Frontiers in clinical and molecular diagnostics and staging of metastatic clear cell renal cell carcinoma.

The last few years have brought advances in the understanding of the molecular biology of metastatic clear cell renal cell carcinoma (RCC). Both preclinical research and clinical trials brought together results from the latest advancements in RCC diagnostic and staging. Understanding of the complex molecular alterations involved in the development and progression of RCC enables development of immunohistochemical and genetic diagnostic tools and is also opening the doors for experimental targeted therapies. At the same time, improvements of medical and molecular imaging improves the sensitivity and specificity of metastatic disease diagnosis. Moreover, independent validation of molecular profiles across high-throughput platforms, methods, laboratories and cancer populations has recently been successfully performed in RCC. Generation of informative, clinical diagnostic tools is likely to contribute to development of novel personalized diagnostic and treatment protocols and ensure prolonged survival of RCC patient in the near future.

Clinical and molecular prognostic and predictive biomarkers in clear cell renal cell cancer.

The natural history of clear cell renal cell cancer is highly unpredictable with various progressors and with populations where small renal masses may be accompanied by metastatic disease. Currently, there is a critical need to determine patient risk and optimize treatment regimes. For these patients, molecular markers may offer significant information in terms of prognostic and predictive values, as well as determination of valid therapeutic targets. Until now, only a few of the many identified clear cell renal cell cancer biomarkers have been clinically validated in large cohorts. And only several biomarkers are integrated in predictive or prognostic models. Therefore, a large cohesive effort is required to advance the field of clear cell renal cell cancer prognostic biomarkers through systematic discovery, verification, validation and clinical implementation.

[Selected biological markers in various vascular lesions of the head and neck]. / Wybrane markery biologiczne w niektórych zmianach naczyniowych glowy i szyi.

Vascular anomalies are divided according to the contemporary system of classification into two groups: tumors and malformations. However, there is no consensus on juvenile angiofibroma's place in that system. The general characteristics of selected markers of angiogenesis and tissue remodeling are presented in the series in the context of current knowledge in the field of pathophysiology of vascular lesions. The mentioned markers are currently the subjects of multidirectional studies in oncology, as they take part in the process of neoangiogenesis and proliferation of tumors. Nevertheless, they have not been widely examined in vascular lesions. The indirect goal of that series is to indicate the possible research direction on vascular lesions to determine their molecular profile, to create a more specific system of classification, and above all to develop new diagnostic and treatment methods.

Serum EPO and VEGF levels in patients with sleep-disordered breathing and acute myocardial infarction.

BACKGROUND: A high level of endogenous erythropoietin (EPO) may be associated with a smaller infarct size determined by the release of necrosis markers. Sleep-disordered breathing (SDB) is a well-known risk factor for cardiovascular diseases. In contrast, protective effects of SDB have also been described. The potential role of increased levels of EPO and vascular endothelial growth factor (VEGF) is suggested in this process. The study aimed to explore the EPO and VEGF serum levels in SDB and non-SDB patients during the acute phase of myocardial infarction. METHODS: Thirty-seven patients undergoing successful primary percutaneous coronary intervention in the acute myocardial infarction have been examined for the levels of EPO, VEGF, and troponin I (Tn). In the following, patients had an overnight polysomnography to determine breathing disturbances during sleep. RESULTS: Both on admission day (day 1) and day 3 of hospitalization, EPO levels showed statistically significant differences in both SDB-positive and SDB-negative patient groups (p = 0.003 and p = 0.018, respectively). There was no statistically significant difference in VEGF levels. No correlation was found between the EPO and Tn levels. CONCLUSIONS: SDB patients tend to have higher levels of EPO during acute myocardial infarction. No statistically significant differences in VEGF levels were observed.

Automatic Heart Rate Detection during Sleep Using Tracheal Audio Recordings from Wireless Acoustic Sensor.

BACKGROUND: Heart rate is an essential diagnostic parameter indicating a patient's condition. The assessment of heart rate is also a crucial parameter in the diagnostics of various sleep disorders, including sleep apnoea, as well as sleep/wake pattern analysis. It is usually measured using an electrocardiograph (ECG)-a device monitoring the electrical activity of the heart using several electrodes attached to a patient's upper body-or photoplethysmography (PPG). METHODS: The following paper investigates an alternative method for heart rate detection and monitoring that operates on tracheal audio recordings. Datasets for this research were obtained from six participants along with ECG Holter (for validation), as well as from fifty participants undergoing a full night polysomnography testing, during which both heart rate measurements and audio recordings were acquired. RESULTS: The presented method implements a digital filtering and peak detection algorithm applied to audio recordings obtained with a wireless sensor using a contact microphone attached in the suprasternal notch. The system was validated using ECG Holter data, achieving over 92% accuracy. Furthermore, the proposed algorithm was evaluated against whole-night polysomnography-derived HR using Bland-Altman's plots and Pearson's Correlation Coefficient, reaching the average of 0.82 (0.93 maximum) with 0 BPM error tolerance and 0.89 (0.97 maximum) at ±3 BPM. CONCLUSIONS: The results prove that the proposed system serves the purpose of a precise heart rate monitoring tool that can conveniently assess HR during sleep as a part of a home-based sleep disorder diagnostics process.

Epidemiological and clinical characteristics of 407 salivary glands neoplasms in surgically treated patients in 2010-2020.

INTRODUCTION Tumors of the salivary glands account for approximately 3 to 4% of all head and neck neoplasms. It is estimated that 10-15% of them are malignant. The most common benign tumor is pleomorphic adenoma, while the most common malignant tumors are adenoid cystic carcinoma and mucoepidermoid carcinoma. Neoplasms of the salivary glands are extremely histologically diverse, which results from the complex embryogenesis of the salivary glands. The identified risk factors for tumors of the salivary glands are: ultraviolet radiation, ionizing radiation, viral infections, nicotine and alcohol. MATERIAL AND METHOD The aim of the study was an epidemiological analysis of patients with salivary gland neoplasms, the distribution and histopathological characteristics of individual neoplasms treated at the Department of Otorhinolaryngology of the Medical University of Warsaw in 2010-2020. The diagnoses were analyzed according to the latest WHO 2017 histological classification of salivary gland tumors. In addition, the material was supplemented with data on the 5-year survival rates of patients with malignant neoplasms obtained from the Registry of Marital Status. RESULTS AND DISCUSSION The material contained 407 neoplasms of the salivary glands over a 11-year period, of which malignant neoplasms accounted for 17.4%. The malignant tumors were dominated by: adenoid cystic carcinoma (28,2%), mucoepidermoid carcinoma (12,7%), and acinic cell carcinoma (9,9%). Lymphomas (15,5%) were also a large group. The benign neoplasms were dominated by pleomorphic adenoma (54.1%) and Warthin's tumor (36%). Tumors of the salivary gland the most often affected the parotid gland (92%). CONCLUSIONS The obtained data are consistent with the general epidemiological data described in the current literature.

Selected ALKBH dioxygenases are overexpressed in salivary gland tumours.

Salivary gland tumours (SGTs) are a heterogeneous group of benign tumours of various origins and pathologies, showing a number of DNA modifications. Previously, in malignant head and neck cancer (HNSCC), we found overexpression of ALKBH proteins, the homologs of Escherichia coli AlkB 2-oxoglutarate and Fe(II) dependent dioxygenase. Moreover, we proved the connection of some of these dioxygenases with cancer development. Here, we studied the expression of five of these ALKBH dioxygenases: 1, 3, 4, 5, and FTO in benign SGTs. Using Western blot analysis, we found overexpression of three proteins: ALKBH1, 4, and FTO in SGT as compared to the surrounding, unaffected tissue. ALKBH4 was overexpressed in 76% of patient samples, whereas ALKBH1 and FTO in 65% of the samples. These results differ from those obtained in HNSCC, where FTO overexpression has been observed in 90% of patient samples. We also investigated the relationships between ALKBHs' expression levels in normal and SGT tissues and identified two correlated pairs: ALKBH1-ALKBH3 and ALKBH1-ALKBH5. Additionally, in tumour tissue ALKBHs: ALKBH1, ALKBH3, ALKBH4, and ALKBH5 levels were correlated with each other. Together, these findings show that the ALKBH proteins exhibit pro cancerogenic action in SGT, even though the levels ALKBHs are generally lower in benign SGT than in malignant HNSCC. We suggest that the overexpression of the ALKBHs, especially FTO, may be used as a cancer marker and for its grading.

Sleep Position Detection with a Wireless Audio-Motion Sensor-A Validation Study.

It is well documented that body position significantly affects breathing indices during sleep in patients with obstructive sleep apnea. They usually worsen while changing from a non-supine to a supine position. Therefore, body position should be an accurately measured and credible parameter in all types of sleep studies. The aim of this study was to specify the accuracy of a neck-based monitoring device (Clebre, Olsztyn, Poland) mounted at the suprasternal notch, in determining a supine and non-supine sleeping position, as well as specific body positions during sleep, in comparison to polysomnography (PSG). A sleep study (PSG along with a neck-based audio-motion sensor) was performed on 89 consecutive patients. The accuracy in determining supine and non-supine positions was 96.9%±3.9% and 97.0%±3.6%, respectively. For lateral positions, the accuracy was 98.6%±2% and 97.4%±4.5% for the right and left side, respectively. The prone position was detected with an accuracy of 97.3%±5.6%. The study showed a high accuracy in detecting supine, as well as other gross positions, during sleep based on a sensor attached to the suprasternal notch, compared to the PSG study. We feel that the suprasternal notch is a promising area for placing wireless sleep study devices.

Cancer Stem Cell Markers in Rhabdomyosarcoma in Children.

(1) Background: The aim of the present study was to assess the cancer stem cell (CSC) markers CD24, CD44, CD133, and ALDH1A1 in rhabdomyosarcoma (RMS) in children and to define their prognostic role in this group of patients. (2) Methods: The study material was archival tissue specimens collected from 49 patients under 18 years of age and who had been diagnosed with RMS. Immunohistochemistry (IHC) was used to evaluate the expression of the selected CSC markers in the tumor tissue. Expression was evaluated using a semiquantitative IRS scale based on the one developed by Remmele and Stenger and was correlated with the clinical and pathomorphological parameters of prognostic importance in RMS. (3) Results: Expression of the selected CSC markers CD24, CD44, CD133, and ALDH1A1 was demonstrated in 83.7%, 55.1%, 81.6%, and 100% of the RMS patients, respectively. The expression of all of the assessed CSC markers was statistically significantly higher in the study group versus the control group. No significant correlation was found between the expression of the selected CSC markers and clinical and pathological prognostic factors that were analyzed. The expression of the CSC markers did not have a significant influence on RMS survival rates. (4) Conclusions: The results of the conducted study confirm the expression of selected CSC markers in rhabdomyosarcoma tissue in children. The study did not support the prognostic relevance of the expression of any of the assessed CSC markers. However, further studies are needed to fully understand the relevance of the selected CSC markers in RMS carcinogenesis.

Laryngeal embryonal rhabdomyosarcoma in an adult - a case presentation in the eyes of geneticists and clinicians.

BACKGROUND: Rhabdomyosarcoma is a solid tumor, resulting from dysregulation of the skeletal myogenesis program. For rhabdomyosarcomas (RMS) with a predilection for the head and neck, genitourinary tract, extremities, trunk, retroperitoneum, the larynx is still an unusual site. Till now only several cases of this laryngeal tumor have been described in world literature in the adult population. The entire spectrum of genetic factors underlying RMS development and progression is unclear until today. Multiple signaling pathways seem to be involved in ERMS development and progression. CASE PRESENTATION: In this paper we report an interesting RMS case in which the disease was located within the glottic region. We report an embryonal rhabdomyosarcoma of the larynx in 33 year-old man. After unsuccessful chemotherapy hemilaryngectomy was performed. In follow up CT no signs of recurrence were found. Recently patient is recurrence free for 62 months. CONCLUSIONS: Considering the histological diagnosis and the highly aggressive nature of the lesion for optimal diagnosis positron electron tomography (PET) and computerized tomography (CT) of the neck and thorax should be performed. At this time surgical treatment with adjuvant radiotherapy seems to be the treatment of choice for this disease. Rhabdomyosarcoma of the larynx has a better prognosis than elsewhere in the body, probably because of its earlier recognition and accessibility to radical surgery.