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.

The presence of dysphagia in patients with cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS): a subjective and objective study.

PURPOSE: The aim of this study was to determine the prevalence of dysphagia in patients with cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS), characterizing this condition, both in its objective dimension and in terms of quality of life (QoL). METHODS: A cross-sectional study was developed in 11 patients diagnosed of CANVAS. In all patients, clinical records were reviewed and the Eating assessment tool 10 (EAT-10) was performed as screening of oropharyngeal dysphagia. To evaluate the QoL impairment secondary to dysphagia, we applied the swallowing quality of life questionnaire (SWAL-QOL) and the MD Anderson Dysphagia Inventory (MDADI). To evaluate the deglutition mechanisms impaired, two objective-instrumental studies were performed: the volume-viscosity swallow test (V-VST) and the fiberoptic endoscopic evaluation of swallowing (FEES). RESULTS: 82% of the patients presented an abnormal EAT-10 score. A correlation was found between the EAT-10 and MDADI and between both QoL questionnaires. After the FEES and V-VST analysis, all 11 patients presented some degree of swallow effectiveness impairment, and most of them safety alterations as well. CONCLUSION: CANVAS remains an underestimated and underdiagnosed condition and the prevalence of swallowing disorders in those patients is higher than expected. Despite the possibility that EAT-10 works as a useful screening test to predict the results in the QoL questionnaires, the absence of correlation between QoL test and instrumental results suggests that to properly evaluate the patients swallowing status, objective instrumental procedures must be conducted.

Next-generation sequencing for identification of actionable gene mutations in intestinal-type sinonasal adenocarcinoma.

Intestinal-type sinonasal adenocarcinoma (ITAC) is a rare tumor carrying poor prognosis and needing new treatment options. The aim of this study was to identify actionable gene mutations that can guide new personalized target-specific therapies in ITAC patients. A series of 48 tumor and 27 corresponding germline DNA samples were analyzed by next generation sequencing using a panel of 120 genes. In total, 223 sequence variants were found in 70 genes. Matched tumor/germline comparison in 27 cases revealed that 57% were in fact germline variants. In 20 of these 27 cases, 58 somatic variants in 33 different genes were identified, the most frequent being PIK3CA (5 cases), APC and ATM (4 cases), and KRAS, NF1, LRP1B and BRCA1 (3 cases). Many of the somatic gene variants affected PI3K, MAPK/ERK, WNT and DNA repair signaling pathways, although not in a mutually exclusive manner. None of the alterations were related to histological ITAC subtype, tumor stage or survival. Our data showed that thorough interpretation of somatic mutations requires sequencing analysis of the corresponding germline DNA. Potentially actionable somatic mutations were found in 20 of 27 cases, 8 of which being biomarkers of FDA-approved targeted therapies. Our data implicate new possibilities for personalized treatment of ITAC patients.

Genomic profiling of intestinal-type sinonasal adenocarcinoma reveals subgroups of patients with distinct clinical outcomes.

BACKGROUND: Patients with intestinal-type sinonasal adenocarcinoma (ITAC) have an unfavorable prognosis and new therapeutic approaches are needed to improve clinical management. METHODS: Genetic analysis of 96 ITACs was performed by microarray comparative genomic hybridization and immunohistochemistry and correlated to previously obtained mutation, methylation, and protein expression data, and with pathological characteristics and clinical outcome. RESULTS: Seven copy number alterations (CNAs) were significantly associated with unfavorable clinical outcome: gains at 1q22-23, 3q28-29, 6p22, and 13q31-33, and losses at 4p15-16, 4q32-35, and 10q24. Unsupervised cluster analysis resulted in 5 subgroups of ITAC with significantly distinct genetic signatures and clinical outcomes, independently of disease stage or histological subtype. CONCLUSION: These data may guide studies to identify driver genes and signaling pathways involved in ITAC. In addition, the subclassification of genetic subgroups of patients with distinct clinical behavior can aid therapeutic decision making and may ultimately lead to personalized therapy with targeted inhibitors.

Absence of chromosomal translocations and protein expression of ALK in sinonasal adenocarcinomas. / Ausencia de translocaciones cromosómicas y de expresión proteica de ALK en los adenocarcinomas nasosinusales.

INTRODUCTION: Chromosomal translocations at 2p23 cause overexpression of anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase involved in signalling pathways that regulate cell proliferation. This translocation occurs in 5% of lung adenocarcinoma and has been demonstrated to be useful as a therapeutic target for crizotinib. sinonasal adenocarcinomas (SNAC) are histologically similar to lung adenocarcinomas; the aim of this study was to evaluate the presence of ALK alterations in SNAC. METHOD: Break-apart fluorescent in-situ hybridization was used to analyse the presence of ALK translocations in 96 tumour samples. In addition, ALK protein expression was studied by immunohistochemistry. RESULTS: The samples of SNAC did not show ALK translocation. Moreover, ALK protein expression was absent in all cases. CONCLUSIONS: These results suggest that ALK is not involved in SNAC.

Parapharyngeal space primary tumours. / Tumores primarios del espacio parafaríngeo.

INTRODUCTION AND OBJECTIVES: The aim of this study is to present our experience with the diagnostic and therapeutic approaches for parapharyngeal space tumours. PATIENTS AND METHOD: This study is a retrospective review of 90 patients diagnosed with tumours of the parapharyngeal space and treated surgically between 1984 and 2015. Patients whose tumours were not primary but invaded the parapharyngeal space expanding from another region, tumours originating in the deep lobe of the parotid gland and head and neck metastasis were excluded from this study. RESULTS: 74% percent of the parapharyngeal space neoplasms were benign and 26% were malignant. Pleomorphic adenoma was the most common neoplasm (27%), followed by paragangliomas (25%), miscellaneous malignant tumours (16%), neurogenic tumours (12%), miscellaneous benign tumours (10%), and malignant salivary gland tumours (10%). The transcervical approach was used in 56 cases, cervical-transparotid approach in 15 cases, type A infratemporal fossa approach in 13 cases, transmandibular approach in 4 cases and transoral approach in 2 cases. The most common complications were those deriving from nervous injuries. CONCLUSIONS: Most parapharyngeal space tumours can be removed surgically with a low rate of complications and recurrence. The transcervical approach is the most frequently used.

Gene Methylation Profiling in Sinonasal Adenocarcinoma and Squamous Cell Carcinoma.

OBJECTIVE: To identify epigenetic events in intestinal-type sinonasal adenocarcinoma (ITAC) and sinonasal squamous cell carcinoma (SNSCC) and to evaluate their relation to clinicopathologic features and follow-up data. STUDY DESIGN: Retrospective study. SETTING: Academic research hospital. SUBJECTS AND METHODS: The methylation status of 23 genes in 50 ITACs and 32 SNSCCs was analyzed by methylation-specific multiplex ligation-dependent probe amplification and its relation to clinicopathologic features and follow-up data. RESULTS: Gene methylation was observed in 50% of all tumors. Recurrent methylated genes in SNSCC were RASSF1 and CDH13 (for both, 6 of 32 cases), CHFR (4 of 32 cases), and TIMP3 (2 of 32 cases). None of these genes showed significant correlation to clinicopathologic features or overall survival. In ITAC, recurrent methylated genes were CDH13 (18 of 50 cases), ESR1 (13 of 50 cases), APC (7 of 50 cases), TIMP3 (5 of 50 cases), CASP8 (3 of 50 cases), and HIC1 and RASSF1 (for both, 2 of 50 cases). Papillary and colonic ITAC subtypes carried a mean of 1.26 gene methylations per tumor versus 0.63 in solid and mucinous subtypes. Methylation of TIMP3 was associated with a significantly worse survival in ITAC patients. CONCLUSION: ITAC carries a higher number and a different profile of gene methylations as compared with SNSCC. Gene methylation plays a greater role in papillary and colonic ITAC subtypes, which may indicate a different tumorigenic pathway for these ITAC subtypes. These findings could be used as prognosticators and may have implications for future individualized therapies based on epigenetic changes.

Integration of HIV infant testing into immunization programmes: a systematic review.

BACKGROUND: Integration of HIV infant testing into immunization sessions is one of the strategies designed to increase coverage of early infant diagnosis. OBJECTIVE: To determine the evidence on the outcomes of such integration. METHODS: A systematic review of peer-reviewed and grey literature was undertaken from electronic sources such as MEDLINE, Google Scholar, websites of international agencies, past conferences and ministries of health reports published between year 2002 and 2013. Randomized controlled trials, observational and qualitative studies were searched and those meeting selection criteria were selected and relevant information extracted using structured tool. Statistical pooling was not possible owing to the heterogeneity of the study designs and outcome measures. RESULTS: Of the nine articles which met the selection criteria, none used a randomized controlled design. Of these, five articles measured mother's acceptability of their infants being tested for HIV during its first pentavalent or DPT vaccination visit, and 89·5-100% accepted. Four articles reported the proportion of mothers who returned for HIV test results, ranging from 56·8% to 86·0%. Increased uptake of HIV testing following integration was confirmed by two articles. Only one study in Tanzania determined the uptake of vaccinations following integration, with urban facilities showing stable or slight increase of monthly vaccine uptake while decreases were observed across the rural sites. In two articles, stigma was perceived by service-providers and mothers as the potential risk following integration, particularly in rural settings. DISCUSSION: Despite the limited number of articles, the findings in this systematic review suggest that HIV testing during immunization clinic visits is acceptable and feasible as a possible model for service delivery. However, the impact on vaccination uptake needs further study.

Establishment and characterization of an orthotopic sinonasal squamous cell carcinoma mouse model.

BACKGROUND: Despite therapeutic improvements, patients with sinonasal squamous cell carcinoma (SCC) still face an unfavorable prognosis and there is great need for alternative treatments. METHODS: SCCNC4 cells, originally derived from a T2N1M0 primary and untreated sinonasal SCC, were inoculated in the maxillary sinus of immunodeficient mice. Histology, invasive behavior, and genetic features were evaluated and compared with the original primary tumor. RESULTS: The mice developed tumors that invaded bone, surrounding tissues, and brain, showing the same poor differentiation as the original primary tumor. Genetic analysis revealed an almost identical pattern of copy number alterations, except for the deletion and loss of expression of the genes CDKN2A and PTEN. CONCLUSION: This article shows the feasibility of an orthotopic mouse model of SCC of the maxillary sinus. Completed by genome-wide genetic profiling data, this model will be useful for preclinical testing of specific gene-targeted anticancer drugs.

Sinonasal desmoplastic small round cell tumor.

Desmoplastic small round cell tumor (DSRCT) is a rare malignancy with poor prognosis that generally involves the peritoneum. Only rare cases occur outside the abdomen. Its diagnosis can be achieved only by immunohistochemistry and cytogenetic studies. We describe a case of a 61-year-old man referred to our department with a primary sinonasal tumor. The DSRCT diagnosis was confirmed by the presence of a polyphenotypic immunoprofile (positive for cytokeratin, desmin, and neuronspecific enolase) and the characteristic EWS-WT1 gene fusion resulting from the t(11;22)(p13;q12) reciprocal translocation. This reported case of DSRCT draws attention to the importance of including DSRCT in the differential diagnosis of sinonasal tumors.

Molecular characterisation of sinonasal carcinomas and their clinical implications.

Sinonasal carcinomas are rare tumours with an unfavourable prognosis whose management is difficult and complex, leading to high morbidity and mortality despite improvements in the field of surgery and radiotherapy. An elevated number of these tumours can be attributed to occupational exposure. In comparison with other head and neck malignancies, studies of molecular changes in these tumours are infrequent. This review was focused on findings about the epidemiology and molecular and phenotypic characterisation of sinonasal carcinomas, which can potentially be useful for diagnosis and treatment. The increasing knowledge about the molecular biology that underlies their carcinogenesis may help to identify precursor lesions, prognostic markers and markers that predict chemoradiotherapy response and, finally, to identify potential molecular targets that will expand treatment options.

Endoscopic craniofacial resection. Indications and technical aspects.

INTRODUCTION: Anterior craniofacial resection (CFR) is a standardised procedure for the treatment of tumours involving the anterior skull base. We present our experience in the endoscopic treatment of these tumours. MATERIAL AND METHOD: A retrospective analysis was performed of patients treated by endoscopic anterior CFR in our Department from 2004 until 2011. RESULTS: Thirty-two patients were analysed. Mean follow-up was 28 months (range: 6-84 months). The most frequent pathological entity was adenocarcinoma (60%), followed by undifferentiated carcinoma (13%). According to TNM classification, malignant epithelial tumour staging was T3 in 9%, T4a in 53% and T4b in 19% of the malignant epithelial tumours. The complication rate was 6% and the resection was complete in 91% of cases. During follow-up, 9% of patients developed recurrence. The 5-year overall survival rate was 70% and the 5-year disease-free survival rate was 85% CONCLUSION: These results seem to indicate that properly planned endoscopic CFR may be a valid alternative to traditional open approaches for the management of malignancies of the anterior skull base.

Endoscopic endonasal approach for the treatment of anterior skull base tumours.

INTRODUCTION: The increasing expertise of transnasal endoscopic surgery has recently expanded its indications to include the management of tumours affecting the skull base. We report our experience with endoscopic management of these tumours, emphasising the indications and surgical technique used. MATERIAL AND METHOD: A retrospective analysis was performed of patients treated by an endoscopic endonasal approach (EEA) in our department from 2004 until 2011. RESULTS: Sixty-three patients were analysed. We performed an endoscopic craniofacial resection in 32 patients (51%), an expanded EEA in 22 (35%), a transclival approach in 6 (9%) and a transpterygoid approach in 3 (5%). The most frequent benign tumour was nasopharyngeal angiofibroma (24%), while adenocarcinoma (30%) was the most common among malignancies. Mean follow-up was 26 months (range: 6 to 84 months). The complication rate was 5% and resection was complete in 56 cases (89%). The 5-year overall-survival was 71% in patients with malignant tumours and the effectiveness was 100% in benign tumours. CONCLUSION: Our results support that endoscopic surgery, when properly planned, represents a valid alternative to standard surgical approaches for the management of skull base tumours.

Treatment of juvenile angiofibromas: 18-year experience of a single tertiary centre in Spain.

BACKGROUND: The management of juvenile angiofibroma (JA) has changed during the last decades but it still continues to be a challenge. The objective of this study was to review the used treatment and our outcomes. METHODS: From 1992 to 2010, 48 cases of JA were treated at our department. Charts were reviewed for standard demographic, tumour size and location, vascular supply and results of embolization, surgical approach, operative results, adjuvant therapies, recurrence and postoperative follow-up. RESULTS: Most tumours were Andrews-Fisch stages III and IV and surgery was used as the main treatment in all cases. We used an open surgical approach in 37 (77%) patients and 11 (23%) were treated endoscopically. The most common open approach used in this series was the subtemporal-preauricular approach. Until 1995, all tumours were operated on by a conventional open approach. Afterwards, early-stage tumours were operated on through an endoscopic approach. Ten patients were treated through surgery followed by radiosurgery. Two (4%) patients had recurrent disease. CONCLUSIONS: These tumours should be treated at centres with expertise in skull base surgery to achieve complete surgical resections with low morbidity. Radiosurgery after surgery seems to be a valuable option in the long-term control of some extended JAs.

Oncological results after surgical treatment of squamous cell cancer of the lateral wall of the oropharynx.

OBJECTIVES: The gold standard of treatment of cancer of the lateral wall of the oropharynx continues to be unclear, especially in advanced stages. In this study, we report our experience with surgical treatment of these cancers and describe the functional and oncological results of the procedures. STUDY DESIGN: Retrospective review. METHODS: A total of 155 previously untreated patients with squamous cell carcinoma of the lateral wall of the oropharynx who underwent a surgical resection of the lesion at our department from January 1990 to January 2008 were included. Sixty-seven percent of these patients received postoperative radiotherapy. The records of these patients were reviewed to obtain measures such as local and regional control, disease-specific survival, and speech and swallowing function. RESULTS: Six patients had a stage I disease, 15 had a stage II disease, 31 had a stage III disease, 86 had a stage IVA, and 17 had stage IVB disease. The overall recurrence rate was 60%, and the local recurrence rate was 40%. The 5-year overall survival and disease-specific survival rates were 33% and 43%, respectively. Five-year disease-specific survival rates by stage were as follows: 100%, 59%, 57%, 31%, and 33% for stages I to IVB, respectively. Multivariate analysis showed two parameters that were independent predictors of a reduced disease-specific survival: cervical lymph node metastases pN2-3 (P = .027) and primary tumor classified as pT3-4 (P = .029). In 122 patients, a tracheotomy was performed, and it couldn't be sealed in 23% of them. Oral alimentation was successfully recovered in 93% of the patients. CONCLUSIONS: Surgical treatment of cancer of the lateral wall of the oropharynx provides acceptable oncological and functional results, especially in early and moderately advanced stages (stages I-III). In advanced stages (stage IV), we obtained good functional preservation rates but poor oncological outcomes. Consequently, these groups of patients could be considered for another treatment modality, such as radiochemotherapy.

[Evolution in the treatment of juvenile nasopharyngeal angiofibroma]. / Evolución en el tratamiento de los angiofibromas nasofaríngeos juveniles.

INTRODUCTION: Juvenile nasopharyngeal angiofibroma (JNA) is a rare benign tumour in adolescent males. It may be associated with a significant morbidity because of its anatomical location and its locally destructive growth pattern. Severe haemorrhage constitutes a high risk in JNA and its surgical management could be complex. MATERIAL AND METHOD: We retrospectively analysed the clinical data from 43 patients with JNA surgically treated in our Department from 1993 until 2010. Mean postoperative follow-up time was 85 months. RESULTS: Analysis was performed on 42 males and one female. Mean patient age was 16 years old. The most common presenting symptoms were unilateral epistaxis (56%) and nasal obstruction (56%). Using the Fisch staging scale, tumours were classified as stage I in 2 patients, stage II in 9, stage III-a in 13, stage III-b in 13 and stage IV-a in 6. Preoperative selective embolisation was performed on 32 patients (74%). Thirty-three patients (77%) underwent an open surgical approach and 10 (23%) were treated by endoscopic approach. Complete resection of the lesion was achieved in 35 patients (81%) and tumour recurrence was observed in 2 (5%). All lesions treated via transnasal endoscopic approach were stage I and stage II lesions. CONCLUSION: Surgery is the treatment of choice for JNA. An endoscopic approach is feasible for early-stage lesions (Fisch I and II) and conservative external approaches are still useful in advanced stages (Fisch III and IV). The open approaches proved helpful with respect to exposure, safety, cosmetic outcome and low morbidity. Preoperative embolisation, if possible, is mandatory.

Establishment and genetic characterization of an immortal tumor cell line derived from intestinal-type sinonasal adenocarcinoma.

BACKGROUND: Intestinal-type sinonasal adenocarcinoma (ITAC) is a rare tumor etiologically related to professional exposure to wood dust. The overall prognosis is poor, mainly due to the difficulty to resect the tumor completely in this anatomically complex region. Therefore, there is great need for alternative treatments. However, the lack of a good tumor model system for ITAC has hampered the development and testing of new therapeutic agents. Here, we report the establishment and characterization of the first human ITAC cell line named ITAC-3. METHODS: The cell line was initiated from small explants of a T4bN0M0 colonic type ITAC from the ethmoid sinus. Growth and invasion parameters as well as genetic characteristics were analyzed. RESULTS: The population doubling time was 18 h and the cell line was capable of invasion in matrigel. Chromosomal analysis showed a tetraploid karyotype with both numerical and structural aberrations. High resolution microarray CGH analysis identified many copy number alterations, including homozygous deletions. TP53 carried a mutation c.818G>T in exon eight concurring with a strong nuclear protein overexpression. Immunohistochemical analysis showed protein overexpression of EGFR and normal expression of ß-catenin and p16. CONCLUSION: This is the first report of the establishment of a cell line derived from a primary ITAC. The genomic profile of the cell line was the same as the primary tumor from which it was derived. This new cell line will be a useful tool for the development and testing of new therapeutic agents for this tumor type.

Vitamina A: Aspectos clínicos y uso terapeútico / Vitamin A: Clinical aspects and therapeutic

La vitamina A es esencial para la visión, el crecimiento y diferenciación celular, la reproducción y la integridad del sistema inmune. Su deficiencia constituye uno de los principales problemas de Salud pública en países en desarrollo, manifestada por la xeroftalmia y ceguera permanente, que afecta predominantemente a niños pre-escolares, estimándose que anualmente aparecen 1.000.000 de casos nuevos de deficiencia. La toxicidad ha sido asociada con un consumo excesivo de suplementos de vitamina A, pero los casos de hipervitaminosis A no pasan de los 200 anuales. En humanos, se han asociado las malformacionescongénitas con el uso indiscriminado de altas dosis de vitamina A por la madre. Actualmente, se están desarrollando numerosas investigaciones que revelan la utilidad terapeútica de esta vitamina en la prevención y tratamiento del cáncer, enfermedades dermatológicas y en pacientes que reciben soporte nutricional. El propósito de este articulo es revisar los conocimientos actuales acerca de la deficiencia, toxicidad y usos terapeúticos de la vitamina A