Oncological and functional outcomes of transoral laser surgery for hypopharyngeal carcinoma.

BACKGROUND: Surgical resection or radiotherapy (RT) are standard approaches for early-staged hypopharyngeal squamous cell carcinoma (HPSCC). Transoral laser microsurgery (TOLMS) seems to provide good oncological and functional results with few local complications. The aim of our study was to analyze the outcomes of TOLMS, with or without neck dissection or RT, in the treatment of HPSCC in a tertiary referral center. METHODS: A retrospective study was conducted in patients with early T-category (T1-T2) HPSCC treated by TOLMS. RESULTS: A total of 34 patients were included in the study. The series includes 17 (50%) T1 and 17 (50%) T2 classified tumors. The 5-year overall survival and disease-specific survival rates were 51% and 66%, respectively, with a 5-year local control rate of 92%. All patients reassumed oral diet and none of them had a tracheostomy at the end of the follow-up. CONCLUSIONS: TOLMS offers an effective treatment option in terms of oncologic control and function preservation in locally circumscribed HPSCC.

Signaling Pathways mTOR and ERK as Therapeutic Targets in Sinonasal Intestinal-Type Adenocarcinoma.

Despite advances in surgery and radiotherapy, the overall prognosis of sinonasal intestinal-type adenocarcinoma (ITAC) is poor, and new treatment options are needed. Recent studies have indicated alterations in cellular signaling pathways that may serve as targets for modern inhibitors. Our aim was to evaluate the frequency of mTOR and ERK pathway upregulation in a retrospective series of 139 ITAC and to test the efficacy and mechanism of action of candidate targeted inhibitors in cell line ITAC-3. An immunohistochemical analysis on p-AKT, p-mTOR, p-S6, p-4E-BP1, and p-ERK indicated, respectively, a 68% and 57% mTOR and ERK pathway activation. In vitro studies using low doses of mTOR inhibitor everolimus and ERK inhibitor selumetinib showed significant growth inhibition as monotherapy and especially as combined therapy. This effect was accompanied by the downregulation of mTOR and ERK protein expression. Our data open a new and promising possibility for personalized treatment of ITAC patients.

Asymptomatic swallowing disorders may be present in individuals with laryngeal and hypopharyngeal cancer treated with chemo-radiotherapy.

PURPOSE: Patients with advanced laryngeal and hypopharyngeal cancer are often treated with chemo-radiotherapy to avoid total laryngectomy. Subclinical swallowing disorders could be present in these patients even though patients do not complain of any symptoms. We sought to evaluate the impact of chemoradiation on swallowing and quality of life. METHODS: We studied 21 patients undergoing chemo-radiotherapy for advanced laryngeal and hypopharyngeal cancer. All patients were tumor-free and none reported symptoms related to dysphagia during follow-up or showed altered routine screening tests (EAT-10) to detect it. Swallowing functions were assessed using volume-viscosity swallow test (V-VST) and fiberoptic endoscopic evaluation of swallowing (FEES). Quality of life was assessed with the EORT-H&N35, and SWAL-QOL scales. RESULTS: Frequent alterations in swallowing efficacy (100%) and safety (85.5%) were detected with V-VST and FEES. Quality-of-life scales showed a reduction in their scores between 12 and 17%, mainly in the areas of symptoms. CONCLUSION: Swallowing disorders are common after chemo-radiotherapy, even in patients who do not clinically manifest these disorders, contributing to a decrease in patients' quality of life. FEES and V-VST are useful procedures to detect asymptomatic swallowing disorders.

Monitoring the Frequency and Duration of Hypoglycemia in Preterm Infants and Identifying Associated Factors.

BACKGROUND: Hypoglycemia is common in very low birth weight neonates and may have adverse effects. Material and Method: Sixty preterm infants were monitored using continuous glucose monitoring (CGMS) and capillary techniques during the first week of life. Hypoglycemia was defined as glucose ≤47 mg/dL (≤2.6 mmol/L). Results: Hypoglycemic episodes were detected in 41.66% (95% CI: 29.07-55.12). In 69.64% the duration was greater than thirty minutes, in 26.78% (95% CI: 15.83-40.3) hypoglycemia exceeded two hours. Hypoglycemia was observed most frequently during the first 48 hours. In 35.7%, hypoglycemia was not detected with capillary tests. The agreement between the two techniques was good (r = 0.77, p < 0.001), Hypoglycemia was associated with a lower birth weight (OR: 0.99, p = 0.06). Conclusions: Hypoglycemia is frequent with significant duration in very low birth weight neonates. CGMS could be considered for use in these neonates to improve their glycemic control and prevent the associated morbidity.

Monitoring the incidence, duration and distribution of hyperglycaemia in very-low-birth-weight newborns and identifying associated factors.

Objectives Hyperglycaemia is a common metabolic disorder in very-low-birth-weight (VLBW) infants and is associated with increased morbidity and mortality. The objective is to describe the incidence, duration, episodes and distribution of hyperglycaemia during the first 7 days of life of VLBW infants. Methods This is a prospective cohort study of 60 newborns weighing <1,500 g. Blood glucose levels were monitored with a continuous glucose monitoring system (CGMS) during the first 7 days of life. Hyperglycaemia was defined as glucose ≥180 mg/dL (≥10 mmol/L). Results Incidence of hyperglycaemia recorded with the CGMS was 36.6% (95%CI: 24.6-50.1). In almost 74.6±5.48% of these cases the duration of the episode exceeded 30 min and in 45.25% (95%CI: 2.26-57.82) it exceeded 2 h. The condition occurred most frequently during the first 72 h of life. One-fifth of cases were not detected with scheduled capillary tests and 84.6% of these had hyperglycaemic episode durations of 30 min or more. Agreement between the two techniques was very good (r=0.90, p<0.001) and the CGMS proved to be reliable, accurate and safe. Hyperglycaemia detected by a CGMS is associated with lower gestational age (OR: 0.66, p=0.002), lower birth weight (OR: 0.99, p=0.003), the use of ionotropic drugs (OR: 11.07, p=0.005) and death (OR: 10.59, p=0.03), and is more frequent in preterm infants with sepsis (OR: 2.73, p=0.1). No other association was observed. Conclusions A CGMS could be useful during the first week of life in VLBW infants due to the high incidence and significant duration of hyperglycaemia and the high proportion of cases that remain undetected. The advantage of the CGMS is that it is able to detect hyperglycaemic episodes that the capillary test does not.

Mimicking Anti-Viruses with Machine Learning and Entropy Profiles.

The quality of anti-virus software relies on simple patterns extracted from binary files. Although these patterns have proven to work on detecting the specifics of software, they are extremely sensitive to concealment strategies, such as polymorphism or metamorphism. These limitations also make anti-virus software predictable, creating a security breach. Any black hat with enough information about the anti-virus behaviour can make its own copy of the software, without any access to the original implementation or database. In this work, we show how this is indeed possible by combining entropy patterns with classification algorithms. Our results, applied to 57 different anti-virus engines, show that we can mimic their behaviour with an accuracy close to 98% in the best case and 75% in the worst, applied on Windows' disk resident malware.

Oncological and functional outcomes of transoral laser surgery for laryngeal carcinoma.

INTRODUCTION: Transoral laser microsurgery (TLM) has become the standard approach for treatment of early-stage laryngeal carcinoma in most institutions due to their good oncological and functional results with few local complications. The purpose of this study was to analyze the oncological and functional results of TLM in the treatment of laryngeal tumors at our Hospital. MATERIALS AND METHODS: Patients with laryngeal squamous cell carcinoma (LSCC) treated from 1998 to 2013 with TLM with curative intention, and with a minimum follow-up of 24 months, were reviewed. RESULTS: 203 patients with LSCC were included. 195 patients were men (96%) and 8 women (4%), with a mean age of 63 years. The series includes 134 (66%) T1, 40 (20%) T2, and 29 (14%) T3-classified tumors. 116 tumors (57%) were in the glottis, 79 (39%) in the supraglottis and 8 (4%) in the anterior commissure. 16 patients (8%) received adjuvant radiotherapy. Initial local control was obtained in 75.5% of patients. The 5-year overall survival rate was 84% and the 5-year disease-specific survival was 90%. The presence of nodal metastasis (p < 0.001) and the involvement of the surgical margins (p = 0.004) were associated with a lower disease-specific survival in the multivariate analysis. All but three patients with local control of the disease reassumed oral diet, and none were tracheostomy-dependent. The 5-year laryngeal preservation rate was 85%. CONCLUSIONS: TLM is a minimally invasive treatment for early and moderately-advanced laryngeal carcinomas, with good oncologic and functional outcomes, and few complications as well.

Auritidibacter ignavus in ear discharge of paediatric patients: Two cases reports and literature review.

INTRODUCTION: The development and research of new technologies for identifying microorganisms, has allowed the identification of hitherto unknown bacteria. Auritidibacter ignavus is a newly described Gram-positive rod possibly associated with otitis, although its role as an etiologic agent in otitis is currently controversial. METHODS: We report two cases of recurrent otitis in paediatric patients in which A. ignavus was isolated and review the previous cases reported in the literature. RESULTS: All the isolates were identified as A. ignavus by proteomic and genomic methods. Both patients recovered from their symptoms. CONCLUSION: A. ignavus was recovered from ear discharges of paedriatic patients with chronic ear problems. All the cases previously reported in the literature were adults. More evidence is needed for the association between A. ignavus and otitis, since data regarding this species are still scarce.

Next-generation sequencing reveals remarkable genetic stability in primary and corresponding recurrent intestinal-type sinonasal adenocarcinoma.

BACKGROUND: Recurrent intestinal-type sinonasal adenocarcinoma (ITAC) can occur several years after primary treatment and with different histology. We aimed to clarify if such recurrences could be second primary tumors and to identify actionable mutations as targets for personalized treatment of recurrent ITAC. METHODS: Twelve pairs of primary and recurrent ITAC were histologically examined and analyzed by next-generation sequencing. RESULTS: Histological differences between primary and recurrent tumor pairs were observed in five cases. Frequent mutations included TP53, APC, TSC2, ATM, EPHA2, BRCA2, LRP1B, KRAS, and KMT2B. There was 86% concordance of somatic mutations between the tumor pairs, while four cases carried additional mutations in the recurrence. CONCLUSIONS: We found all cases to be clonal recurrences and not second primary tumors. Moreover, tumor pairs showed a remarkable genomic stability, suggesting that personalized treatment of a recurrence may be based on actionable molecular genetic targets observed in the primary tumor.

Characterization of a Preclinical In Vitro Model Derived from a SMARCA4-Mutated Sinonasal Teratocarcinosarcoma.

Sinonasal teratocarcinosarcoma (TCS) is a rare tumor that displays a variable histology with admixtures of epithelial, mesenchymal, neuroendocrine and germ cell elements. Facing a very poor prognosis, patients with TCS are in need of new options for treatment. Recently identified recurrent mutations in SMARCA4 may serve as target for modern therapies with EZH1/2 and CDK4/6 inhibitors. Here, we present the first in vitro cell line TCS627, established from a previously untreated primary TCS originating in the ethmoid sinus with invasion into the brain. The cultured cells expressed immunohistochemical markers, indicating differentiation of epithelial, neuroepithelial, sarcomatous and teratomatous components. Whole-exome sequencing revealed 99 somatic mutations including SMARCA4, ARID2, TET2, CDKN2A, WNT7A, NOTCH3 and STAG2, all present both in the primary tumor and in the cell line. Focusing on mutated SMARCA4 as the therapeutic target, growth inhibition assays showed a strong response to the CDK4/6 inhibitor palbociclib, but much less to the EZH1/2 inhibitor valemetostat. In conclusion, cell line TCS627 carries both histologic and genetic features characteristic of TCS and is a valuable model for both basic research and preclinical testing of new therapeutic options for treatment of TCS patients.

Bovine tuberculosis in Spain, is it really the final countdown?

Bovine tuberculosis (bTB) is a severe zoonotic disease that has major impacts on both health and the economy, and which has been subjected to specific eradication programmes in many countries for decades. This manuscript highlights the relevance of this disease in the context of the European Union (EU) and summarizes the epidemiological situation and the main tools (e.g. antemortem diagnostic tests, slaughterhouse surveillance, laboratories, comprehensive databases, etc.) used to control and eradicate bTB in the various EU countries with a focus on the situation in Spain. A comprehensive description of the specific bTB epidemiological situation in Spain is provided, together with an assessment of the evolution of different epidemiological indicators throughout the last decades. Moreover, the main features of the Spanish bTB eradication programme and its control tools are described, along with the studies carried out in Spain that have allowed the updating of and improvement to the programme over the years with the aim of eradication, which has been established for 2030.

A Novel External Auditory Canal Squamous Cell Carcinoma Cell Line Sensitive to CDK4/6 Inhibition.

OBJECTIVE: To characterize cell line CAE606 derived from a squamous cell carcinoma (SCC) of the external auditory canal (EAC) and to show its usefulness as a model for testing candidate therapeutic agents. STUDY DESIGN: Preclinical translational research. SETTING: Biomedical research institute. METHODS: The cell line was initiated from a moderately differentiated T2N0M0 EAC SCC. We studied its histologic and genetic features as well as growth and invasion parameters. Sensitivity to cell CDK4/6 cell cycle inhibitor palbociclib was analyzed. RESULTS: CAE606 cells expressed heavy molecular weight cytokeratin, p63, and vimentin. The population doubling time was 25.8 hours, and the cells showed fast collective cell migration in a wound-healing assay. Short tandem repeat analysis confirmed it to be derived from the primary tumor of the patient. Next-generation sequencing revealed alterations in cell cycle regulation genes, including inactivating mutations in CDKN2A and TP53 and high-level amplification of CCND1 and EGFR. CAE606 showed a strong decrease of phospo-Rb expression upon exposure to the CDK4/6 inhibitor palbociclib, causing significant growth inhibition with an IC50 of 0.46 µM. CONCLUSION: This is the first report of a stable EAC SCC cell line. Its genetic features make it a useful tool for preclinical testing of new therapeutic agents for EAC SCC, particularly those targeting cell cycle regulation in combination with radio- and chemotherapy or other specific signaling pathway inhibitors.

Gene amplification and protein overexpression of EGFR and ERBB2 in sinonasal squamous cell carcinoma.

BACKGROUND: Sinonasal squamous cell carcinomas (SNSCCs) are rare tumors with no etiologic link to tobacco or alcohol, as opposed to other squamous cell carcinomas of the head and neck. Despite improvements in the field of surgery and radiotherapy, patients with these tumors still face a very unfavorable prognosis, partly because of their localization in a complex anatomic area, which has special relevance for surgery and postoperative treatment. Therefore, there is a need for new therapeutic possibilities for patients with these tumors. METHODS: Gene copy numbers of epidermal growth factor receptor (EGFR) and v-erb-b2 erythroblastic leukemia viral oncogene homolog 2 (ERBB2) were analyzed by fluorescence in situ hybridization and multiplex ligand-dependent probe amplification, and protein expression was evaluated by immunohistochemistry in 54 SNSCC specimens. The results were correlated with clinicopathologic and follow-up data. RESULTS: EGFR gene copy number increases were observed in 20 of 45 tumors (44%), and 21 of 54 tumors (39%) had EGFR protein overexpression. Eight of 38 tumors (21%) had ERBB2 copy number increases, and 4 of 54 tumors (7%) exhibited elevated protein expression levels. Both copy number increases and protein overexpression of EGFR and ERBB2 were mutually exclusive. v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations were absent in 37 tumors that were analyzed. CONCLUSIONS: A substantial proportion of SNSCCs carried alterations in EGFR or ERBB2. Together with the absence of KRAS mutations, these findings indicate that therapies targeting these molecules may be promising additions to the therapeutic options for patients with SNSCC.

Transoral CO2 laser surgery for supraglottic cancer.

There are several therapeutic options for laryngeal cancer, including those that provide a functional preservation without worsening the oncological results, such as transoral laser microsurgery (TLM). The aim of this study was to analyze both oncological and functional results of TLM in supraglottic cancer. We studied 49 consecutive patients with a primary supraglottic carcinoma who underwent a TLM between the years 1999 and 2009. Nineteen patients were classified as stage I-II and 30 as stage III-IV disease. Forty-five patients underwent also neck dissection. Thirteen patients received postoperative radiotherapy. The minimum follow-up was 24 months. Three- and five-year disease-specific survival rate was 93.2 and 82.2 %, respectively. Of the patients, 36.7 % had some complication after surgery, aspiration being the most frequent (16.32 %). Of the 43 patients who were alive, 39 (91 %) without evidence of disease 3 years after diagnosis had a functional larynx. Our results suggest that TLM is a safe and effective treatment for supraglottic cancer, with a low morbidity rate and excellent functional results.

Embolization for Carotid Blowout in Head and Neck Cancer: Case Report of Five Patients.

Carotid blowout syndrome (CBS) is defined as a rupture of common carotid artery or its branches. Endovascular intervention has been advocated as first line of treatment for CBS. This Case Report describes 5 patients with prior history of head and neck cancer who presented with CBS. Two patients presented as acute, 2 as impending, and one as threatened CBS. The lesions found were pseudoaneurysm and focal vascular irregularities involving the common carotid artery, cervical internal carotid artery and lingual artery. Embolization and occlusion with detachable coils of the artery was used in all patients. Technical success and immediate hemostasis were achieved in all patients. One patient presented transient cranial nerve palsy. No recurrent CBS was reported during the follow-up. In our experience, coil embolization, if possible, is a safe and efficient technique in treatment of CBS secondary to head and neck cancers.

Voice outcomes in patients with advanced laryngeal and hypopharyngeal cancer treated with chemo-radiotherapy.

Objective: Patients with locally advanced laryngeal and hypopharyngeal cancer (LHC) are often treated with chemo-radiotherapy to avoid total laryngectomy, although voice problems may occur even if not markedly manifest. We sought to evaluate the impact of chemoradiation on voice and quality of life. Methods: We studied 21 patients with locally advanced LHC with tumour control at least two years after chemo-radiotherapy. None manifested clinical symptoms related to the treatment and maintained an activity considered as within normal limits. All patients had a voice handicap index (VHI) of less than 15. Voice function was evaluated by perceptual vocal analysis (CAPE-V) and aerodynamic and acoustic study. Quality of life was assessed with the EORTC-H&N35 (voice items 46, 53 and 54). Results: Voice changes were frequent, with alterations in all CAPE-V attributes, and predominantly type II and III spectrograms in acoustic analysis (78%). The EORTC-H&N35 scale showed a reduction in scores in 10-40% of items related to voice. Conclusions: Subclinical voice disorders are common after chemo-radiotherapy. Although patients consider vocal impairment to be very minor and to not interfere with their daily life, it may contribute to a reduced quality of life.

CANVAS: A New Genetic Entity in the Otorhinolaryngologist's Differential Diagnosis.

OBJECTIVE: The biallelic inheritance of an expanded intronic pentamer (AAGGG)exp in the gene encoding replication factor C subunit 1 (RFC1) has been found to be a cause of cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS). This study describes clinical and genetic features of our patients with clinical suspicion of the syndrome. STUDY DESIGN: A retrospective descriptive study from an ataxia database comprising 500 patients. SETTING: The study was performed at the Otorhinolaryngology Department of a hospital in the north of Spain. METHODS: Specific genetic testing for CANVAS was performed in 13 patients with clinical suspicion of complete or incomplete syndrome. The clinical diagnosis was supported by quantitative vestibular hypofunction, cerebellar atrophy, and abnormal sensory nerve conduction testing. RESULTS: Nine of 13 (69%) patients met clinical diagnostic criteria for definite CANVAS disease. The first manifestation of the syndrome was lower limb dysesthesia in 8 of 13 patients and gait imbalance in 5 of 13. Eleven of 13 (85%) patients were carriers of the biallelic (AAGGG)exp in RFC1. CONCLUSION: A genetic cause of CANVAS has recently been discovered. We propose genetic screening for biallelic expansions of the AAGGG pentamer of RFC1 in all patients with clinical suspicion of CANVAS, since accurate early diagnosis could improve the quality of life of these patients.

Intragenic NF1 deletions in sinonasal mucosal malignant melanoma.

Mucosal malignant melanoma (MMM) is a rare and aggressive tumor. Despite effective local therapies, tumor recurrence and metastasis remain frequent. The genetics of MMM remain incompletely understood. This study is aimed to identify actionable genetic alterations by next-generation sequencing. Fifteen MMM samples were analyzed by next-generation and Sanger sequencing. Gene copy number alterations were analyzed by MLPA. Mutation status was correlated with pERK, pAKT, and Ki-67 expression and follow-up data. Inactivating mutations and intragenic deletions in neurofibromatosis type-1 (NF1) were identified in 3 and 2 cases, respectively, (in total 5/15, 33%) and activating mutations in NRAS and KRAS (3/15, 20%) cases. Other mutated genes included CDKN2A, APC, ATM, MITF, FGFR1, and FGFR2. BRAF and KIT mutations were not observed. Cases with NF1 alterations tended to have worse overall survival. The mutational status was not associated with pERK, pAKT, or Ki-67 immunostaining. MMM carries frequent gene mutations activating the MAPK pathway, similar to cutaneous melanoma. In contrast, NF1 is the most frequently affected gene. Intragenic NF1 deletions have not been described before and may go undetected by sequencing studies. This finding is clinically relevant as NF1-mutated melanomas have worse survival and could benefit from therapy with immune checkpoint and MEK inhibitors.