Translational genomics of sinonasal cancers.

The sinonasal cavities harbor a wide variety of histologically distinct cancers, the majority very aggressive with 5-year survival rates between 30-60% and local recurrence as the main cause of death. This is a complex anatomic area, close to structures such the eyes and the brain, which is of special relevance for surgery and postoperative radiotherapy. The low incidence of these rare tumors hampers accumulation of experience with diagnosis and clinical managment as well as knowledge on recurrent genetic aberrations or testing of new treatment strategies. However, recent years have seen a growing number of publications on genetic aberrations providing data that can aid or fine-tune classification and provide molecular targets for treatment with specific inhibitors. In addition, new sinonasal cancer models are created that enable preclinical testing of candidate inhibitor drugs. With more and more novel targeted therapies being developed, options for personalized treatment of sinonasal cancer patients are now opening up.

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.

Minimally invasive video-assisted parathyroidectomy (MIVAP) without intraoperative PTH determination.

BACKGROUND: Minimally invasive video-assisted parathyroidectomy (MIVAP) has become a standard approach to primary hyperparathyroidism (pHPT) since described. Although intraoperative parathyroid hormone assay (IOPTH) has been generalized as a complementary technique to MIVAP, its actual impact on the surgical success of this technique is not without controversy. The aim of this study was to describe our results in the management of pHPT with successful preoperative localization, by MIVAP technique, without IOPTH determination, confirming in a larger series our preliminary results. METHODS: A retrospective descriptive study was conducted in pHPT patients treated by MIVAP with no IOPTH determination in a tertiary hospital between 2007 and 2019. RESULTS: A total of 167 patients were included in the study. Biochemical cure was achieved in 96.4%, and 94.1% did not present any surgical complication. The mean duration of surgery was 61 min, and the mean length of hospital stay was 1.8 days CONCLUSIONS: In case of positive preoperative localization studies, MIVAP is a safe and effective technique for the surgical treatment of pHPT due to a parathyroid adenoma, regardless of IOPTH determination, with a success rate > 95% and a low complication rate.

Prognostic and Therapeutic Implications of Immune Classification by CD8+ Tumor-Infiltrating Lymphocytes and PD-L1 Expression in Sinonasal Squamous Cell Carcinoma.

Sinonasal squamous cell carcinoma (SNSCC) is an aggressive tumor predominantly arising in the maxillary sinus and nasal cavities. Advances in imaging, surgical and radiotherapeutic techniques have reduced complications and morbidity; however, the prognosis generally remains poor, with an overall 5-year survival rate of 30-50%. As immunotherapy may be a new therapeutic option, we analyzed CD8+ tumor-infiltrating lymphocytes (TILs) and the tumor microenvironment immune type (TMIT, combining CD8+ TILs and PD-L1) in a series of 57 SNSCCs. Using immunohistochemistry, tissue samples of 57 SNSCCs were analyzed for expression of CD8 on TILs and of PD-L1 on tumor cells. The results were correlated to the clinical and survival data. In total, 88% (50/57) of the tumors had intratumoral CD8+ TILs; 19% (11/57)-CD8high (>10%); and 39/57 (68%)-CD8low (1-10%). PD-L1 positivity (>5%) was observed in 46% (26/57) of the SNSCCs and significantly co-occurred with CD8+ TILs (p = 0.000). Using univariate analysis, high intratumoral CD8+ TILs and TMIT I (CD8high/PD-L1pos) correlated with a worse survival rate. These results indicate that SNSCCs are immunogenic tumors, similar to head and neck squamous cell carcinomas. Nineteen percent of the cases were both CD8high and PD-L1pos and this subgroup may benefit from therapy with immune checkpoint inhibitors.

Current management of sinonasal undifferentiated carcinoma.

BACKGROUND: The management of sinonasal undifferentiated carcinoma (SNUC) remains unclear. Low incidence and poor outcomes make treatment standardization difficult. The objective of this study was to review the used treatment and our outcomes. METHODS: From 2001 to 2013, 17 cases of SNUC were treated at our department. Charts were reviewed for standard demographic, tumour size and extension, histological features, treatment strategies, surgical approach, adjuvant therapies, outcomes and complications. RESULTS: All patients presented with extensive local disease and 2 patients also had neck metastases. All patients were treated using a multimodality approach: 10 patients underwent surgery and postoperative chemoradiation, 1 patient was treated with surgery and adjuvant radiotherapy, 3 patients were treated with neoadjuvant chemotherapy, surgery and postoperative chemoradiation and the remaining 3 patients were treated with chemoradiotherapy. After median follow-up of 39 months 6 patients developed recurrences. The 3-year local control rate was 76% and the 5-year rate of overall survival was 58%. CONCLUSIONS: Management and outcomes of SNUC have improved due to advances in surgery and radiotherapy. Gross tumour resection followed by postoperative radiotherapy should be the standard of care in patients with SNUC. High-precision high-dose radiotherapy should be implemented to try to improve the outcomes.

Analysis of MYB oncogene in transformed adenoid cystic carcinomas reveals distinct pathways of tumor progression.

Adenoid cystic carcinomas can occasionally undergo dedifferentiation, a phenomenon also referred to as high-grade transformation. However, cases of adenoid cystic carcinomas have been described showing transformation to adenocarcinomas that are not poorly differentiated, indicating that high-grade transformation may not necessarily reflect a more advanced stage of tumor progression, but rather a transformation to another histological form, which may encompass a wide spectrum of carcinomas in terms of aggressiveness. The aim of this study was to gain more insight in the biology of this pathological phenomenon by means of genetic profiling of both histological components. Using microarray comparative genomic hybridization, we compared the genome-wide DNA copy-number changes of the conventional and transformed area of eight adenoid cystic carcinomas with high-grade transformation, comprising four with transformation into moderately differentiated adenocarcinomas and four into poorly differentiated carcinomas. In general, the poorly differentiated carcinoma cases showed a higher total number of copy-number changes than the moderately differentiated adenocarcinoma cases, and this correlated with a worse clinical course. Special attention was given to chromosomal translocation and protein expression of MYB, recently being considered to be an early and major oncogenic event in adenoid cystic carcinomas. Our data showed that the process of high-grade transformation is not always accompanied by an accumulation of genetic alterations; both conventional and transformed components harbored unique genetic alterations, which indicate a parallel progression. Our data further demonstrated that the MYB/NFIB translocation is not necessarily an early event or fundamental for the progression to adenoid cystic carcinoma with high-grade transformation.

Free flaps in orbital exenteration: a safe and effective method for reconstruction.

The aim of this study was to investigate the course of reconstructive treatment and outcomes with use of free flaps after orbital exenteration for malignancy. Charts of patients who had free flap reconstruction after orbital exenteration were retrospectively reviewed and the surgical technique was evaluated. Demographics, histology, surgical management, complications, locoregional control, and survival were analyzed. We performed 22 flaps in 21 patients. Reconstruction was undertaken mainly with anterolateral thigh (56 %), radial forearm (22 %), or parascapular (22 %) free flaps. Complications occurred in 33 % of patients and the flap's success rate was 91 %. The 5-year locoregional control and survival rates were 42 and 37 %, respectively. Free tissue transfer is a reliable, safe, and effective method for repair of defects of the orbit and periorbital structures resulting from oncologic resection. The anterolateral thigh flap is a versatile option to reconstruct the many orbital defects encountered.

From laryngeal epithelial precursor lesions to squamous carcinoma of the larynx: the role of cell cycle proteins and ß-catenin.

Novel markers to accurately predict the risk of malignant transformation in laryngeal epithelial precursor lesions (EPL) are needed. We tried to identify some molecular alterations occurring in laryngeal tumorigenesis. In this study, 60 paraffin-embedded EPL and 17 metachronous invasive carcinomas were immunostained for markers associated with proliferation (Ki67), cell cycle control (p53, p21, p16, p27, cyclin D1), and cell adhesion and invasion (laminin and ß-catenin). Aberrant expression of p16 and p53 and positivity at cytoplasm for ß-catenin and cyclin D1 were detected significantly in EPL with progression to invasive laryngeal carcinoma. All cases with basal and suprabasal reactivity of p53 showed ß-catenin overexpression. We found that ß-catenin protein expression increased significantly with the grade of dysplasia. This is one of the studies with the largest number of laryngeal EPL and invasive carcinoma studied sequentially. Our data confirm the role of some cell cycle regulatory proteins in the development of laryngeal carcinoma. Cytoplasmic retention of ß-catenin in EPL seems to be related with more aggressive biological behavior. Combined increased p53 and cytoplasmic ß-catenin protein expression could be biologically important in laryngeal tumorigenesis. Further research is required to clarify the involvement of ß-catenin in the mechanism associated with malignant transformation in laryngeal tissues.

Anterior skull base oncocytoma.

Oncocytic neoplasms are tumors composed of oncocytes (ie, epithelial cells with a large cytoplasm that is rich in mitochondria). Most cases are benign and originate from the salivary glands. Although there have been a few reported cases of oncocytomas being found in the sinonasal tract, most if not all cases seem not to involve the anterior skull base. We report a rare case of oncocytoma involving the anterior skull base occurring in a 44-year-old male patient. Preoperative carotid angiography and selective embolization was performed. The patient underwent an expanded endoscopic endonasal anterior craniofacial resection, which allowed complete resection of the tumor, with a low morbidity. The pathological diagnosis was oncocytoma. At 36 months after the initial treatment, the patient is free of disease. Based on our literature search, this may be the first such reported case. A brief review of the available literature examining the known body of knowledge regarding these neoplasms is presented.

Sox2 and ßIII-Tubulin as Biomarkers of Drug Resistance in Poorly Differentiated Sinonasal Carcinomas.

Poorly differentiated sinonasal carcinomas (PDCs) are tumors that have a poor prognosis despite advances in classical treatment. Predictive and prognostic markers and new personalized treatments could improve the oncological outcomes of patients. In this study, we analyzed SOX2 and ßIII-tubulin as biomarkers that could have prognostic and therapeutic impacts on these tumors. The cohort included 57 cases of PDCs: 36 sinonasal undifferentiated carcinoma (SNUC) cases, 13 olfactory neuroblastoma (ONB) cases, and 8 sinonasal neuroendocrine carcinoma (SNEC) cases. Clinical follow-up data were available for 26 of these cases. Sox2 expression was detected using immunohistochemistry in 6 (75%) SNEC cases, 19 (53%) SNUC cases, and 6 (46%) ONB cases. The absence of Sox2 staining correlated with a higher rate of recurrence (p = 0.015), especially distant recurrence. The majority of cases showed ßIII-tubulin expression, with strong positivity in 85%, 75%, and 64% of SNEC, ONB, and SNUC cases, respectively. Tumors with stronger ßIII-tubulin expression demonstrated longer disease-free survival than those with no expression or low expression (p = 0.049). Sox2 and ßIII-tubulin expression is common in poorly differentiated sinonasal tumors and has prognostic and therapeutic utility.

Levels and patterns of expression of hypoxia-inducible factor-1α, vascular endothelial growth factor, glucose transporter-1 and CD105 in adenoid cystic carcinomas with high-grade transformation.

AIMS: To compare the expression of proteins regulated by hypoxia between adenoid cystic carcinoma (ACC) with and without high-grade transformation (HGT). METHODS AND RESULTS: In eight ACC-HGT and 18 ACC without HGT, expression of hypoxia-inducible factor-1 (HIF-1α), vascular endothelial growth factor (VEGF), glucose transporter-1 (GLUT-1) and microvascular density (MVD) by CD105 (a hypoxia-inducible protein expressed in angiogenic endothelial cells) was determined. Expression levels of HIF-1α and VEGF as well as CD105-MVD did not differ significantly between: (i) transformed and conventional areas (TA and CA, respectively) of ACC-HGT, (ii) CA and ordinary ACC. HIF-1α was detected in 100% of cases and presented a diffuse expression pattern. No significant association was found between levels of HIF-1α expression and tumour size, metastasis and recurrence. GLUT-1 showed a prostromal expression pattern and was observed exclusively in TA (three of six cases) and in only three of 14 ACC. CONCLUSIONS: Both the absence of significant alterations in levels of expression of HIF-1α, VEGF and CD105 and the patterns of expression of HIF-1α and GLUT-1 suggest that hypoxia may not play a key role in the process of high-grade transformation of ACC. Although HIF-1α expression is a common finding in ACC, it cannot be used as a marker of tumour aggressiveness.

Eradication of bovine tuberculosis at a herd-level in Madrid, Spain: study of within-herd transmission dynamics over a 12 year period.

BACKGROUND: Eradication of bovine tuberculosis (bTB) through the application of test-and-cull programs is a declared goal of developed countries in which the disease is still endemic. Here, longitudinal data from more than 1,700 cattle herds tested during a 12 year-period in the eradication program in the region of Madrid, Spain, were analyzed to quantify the within-herd transmission coefficient (ß) depending on the herd-type (beef/dairy/bullfighting). In addition, the probability to recover the officially bTB free (OTF) status in infected herds depending on the type of herd and the diagnostic strategy implemented was assessed using Cox proportional hazard models. RESULTS: Overall, dairy herds showed higher ß (median 4.7) than beef or bullfighting herds (2.3 and 2.2 respectively). Introduction of interferon-gamma (IFN-γ) as an ancillary test produced an apparent increase in the ß coefficient regardless of production type, likely due to an increase in diagnostic sensitivity. Time to recover OTF status was also significantly lower in dairy herds, and length of bTB episodes was significantly reduced when the IFN-γ was implemented to manage the outbreak. CONCLUSIONS: Our results suggest that bTB spreads more rapidly in dairy herds compared to other herd types, a likely cause being management and demographic-related factors. However, outbreaks in dairy herds can be controlled more rapidly than in typically extensive herd types. Finally, IFN-γ proved its usefulness to rapidly eradicate bTB at a herd-level.

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.

Validation of "Self-Evaluation of Communication Experiences after Laryngectomy" (SECEL) Questionnaire for Spanish-Speaking Laryngectomized Patients.

BACKGROUND: Laryngectomized patients have communicative limitations when they lose their phonatory function after surgery. The scale "Self-Evaluation of Communication Experiences after Laryngectomy" (SECEL) assesses the impact of total laryngectomy on quality of life related to communication. The aim of this study was to translate and adapt the SECEL from English to Spanish and to apply this first version to a group of patients to check its reliability and validity. MATERIALS AND METHODS: One-hundred-and-one laryngectomized patients completed the SECEL scale adjusted to Spanish, the Voice Handicap Index (VHI-30), the Hospital Anxiety and Depression Scale (HADS) and the EORTC QLQ-H&N35 questionnaire. RESULTS: The Spanish version of the SECEL questionnaire has the same format and conceptual, semantic and idiomatic meaning as the original. The resulting model is composed of 21 items dimensioned in two highly correlated factors that are clear, meaningful, and replicable leading to measures that are reliable enough to be used in clinical evaluation. CONCLUSION: The Spanish translation and validation of the SECEL questionnaire were performed. It can be considered an appropriate tool to assess communication skills from laryngectomized people.

Biomarkers for Immunotherapy in Poorly Differentiated Sinonasal Tumors.

The sinonasal cavities harbor a wide variety of rare cancer types. Histopathological classification can be challenging, especially for poorly differentiated tumors. Despite advances in surgery and radio-chemotherapy, the 5-year survival rate is still very low. Thus, there is an unmet clinical need for new therapeutic options. We retrospectively evaluated poorly differentiated tumors of 9 different histological subtypes from 69 patients who had received conventional treatments for the presence of CD8+ tumor-infiltrating lymphocytes (TILs), as well as the expression of PD-L1 and microsatellite instability (MSI) markers MLH1, MSH2, MSH6 and PMS2, as biomarkers for immunotherapy. CD8+ TILs were present in 23/69 (33%) cases, PD-L1 expression was observed in 23/69 (33%), and markers for MSI positivity in 5/69 (7%) cases. CD8+ TILs correlated with PD-L1 positivity, while both were mutually exclusive with MSI markers. None of the biomarkers were associated with clinical features as age, gender or tumor stage. Cases with CD8+ TILs and PD-L1 positivity showed a tendency toward worse disease-specific survival. Immune checkpoint inhibitors are emerging as new options for treatment of many tumor types. Our results indicate that also a substantial subset of patients with poorly differentiated sinonasal tumors may be a candidate to be treated with this promising new therapy.

Mycobacterium caprae infection in livestock and wildlife, Spain.

Mycobacterium caprae is a pathogen that can infect animals and humans. To better understand the epidemiology of M. caprae, we spoligotyped 791 animal isolates. Results suggest infection is widespread in Spain, affecting 6 domestic and wild animal species. The epidemiology is driven by infections in caprids, although the organism has emerged in cattle.

Use of lateral circumflex femoral artery system free flaps in skull base reconstruction.

We present a 10-year retrospective study at a tertiary center designed to evaluate the advantages, complications, and comparative results using lateral circumflex femoral artery (LCFA) system free flaps for cranial base reconstruction. In this study, a cranial base defect refers to exposed intracranial contents to the skin, paranasal sinuses, nasopharynx, oropharynx, or oral cavity. These defects resulted from resections of primary or recurrent neoplasms or from secondary problems after cranial base surgery. We performed 20 flaps in 20 patients. The selection of flap was as follows: 8 combinations of anterolateral/anteromedial thigh flaps with vastus lateralis muscle or tensor fascia lata flaps, 6 ALT fasciocutaneous flaps, and 6 muscle/myocutaneous flaps. The flap's success rate was 95% (19/20). Early major complications included 1 perioperative death, and there was 1 myocardial infarction. Minor complications included 1 partial (12%) flap loss, 2 temporal cerebrospinal fluid leak, 2 donor-site hematoma, 2 minor wound breakdown, 3 facial nerve weakness, and 4 donor-site numbness. Among 20 patients undergoing LCFA system flap reconstruction, 12 are alive and disease free. Local recurrence occurred in 1 patient. She underwent ablative surgery and a new successful free flap (forearm flap); after 2 years, the patient is disease free. The LCFA system flaps in skull base reconstruction provide versatility in flap design and availability of adequate tissues to fill dead space, and it offers vascularized fascia to augment dural repairs. It also provides a very long pedicle and allows simultaneous flap harvest with low donor-site morbidity.

CD8+ Tumour-Infiltrating Lymphocytes and Tumour Microenvironment Immune Types as Biomarkers for Immunotherapy in Sinonasal Intestinal-Type Adenocarcinoma.

BACKGROUND: Intestinal-type adenocarcinoma (ITAC) is a rare tumour occurring in the ethmoid sinus. Recent years have brought advances in endoscopic surgery and precision radiotherapy; however, five-year overall survival has not improved and remains at 35-80%, depending on tumour stage and histology. Therefore, there is a need for new therapeutic options. METHODS: We evaluated CD8+ tumour-infiltrating lymphocytes (TILs) and tumour microenvironment immune type (TMIT, combining CD8+ TILs and PD-L1) as predictive biomarkers for immunotherapy in a series of 133 ITAC. All results were correlated to clinical and follow-up data. RESULTS: The presence of intratumoural CD8+ TILs was low in 57% of cases and high in 8% of cases. Tumoural PD-L1 positivity was observed in 26% of cases. CD8+ TILs and TMIT correlated with the histological subtype of ITAC and with better overall survival. The presence of stromal PD-L1-positive macrophages was related to intratumoural CD8+ TILs. PD-L1 expression on tumour cells or macrophages did not show prognostic value. CONCLUSIONS: TMIT classification did not have additional prognostic value over CD8+ TILs alone. The modest percentage of CD8high/PD-L1pos cases indicates that ITAC is a lowly immunogenic tumour type. Nevertheless, a proportion of ITAC, especially the papillary and colonic subtypes, could benefit from therapy with immune checkpoint inhibitors.

IDH2 Mutation Analysis in Undifferentiated and Poorly Differentiated Sinonasal Carcinomas for Diagnosis and Clinical Management.

A large number of tumor types arise from the mucosa of the sinonasal cavities. Although presenting clinically distinct behavior, due to poorly differentiated histologic features, they can be difficult to classify correctly. Our aim was to investigate whether IDH2 and IDH1 mutations may be specific to a subset of undifferentiated and poorly differentiated sinonasal carcinomas. A total of 125 tumor samples of 7 different histologic subtypes were analyzed for IDH mutations by sequencing and mutant-specific immunohistochemistry, and the results were correlated to clinical and follow-up data. The highest incidence of IDH2 mutations occurred in sinonasal undifferentiated carcinoma, with 11/36 (31%) cases affected. However, also, 1/9 neuroendocrine carcinomas, 2/4 high-grade non-intestinal-type adenocarcinomas, and 1/8 poorly differentiated squamous cell carcinomas carried the IDH2 mutation, whereas 1/48 intestinal-type adenocarcinomas harbored an IDH1 mutation. Immunohistochemical analysis of mutant IDH1/2 produced a number of false-negative results, but also 1 false-positive tumor was found. Disease-specific survival was more favorable in IDH2-mutant versus wild-type cases. Our data suggest that IDH-mutant sinonasal cancers, independent of their histologic subtype, may represent a distinct tumor entity with less aggressive clinical behavior. Clinically, patients with these mutations may benefit from specific IDH-guided therapies.

The Stem Cell Network model: clinical implications in cancer.

This review will discuss the aspects of stem cell biology that can contribute to explain tumor development and why standard oncology treatments sometimes fail. We also propose an integrated model of tumor progression based on the putative occurrence of Stem Cell Networks (SCNs). In a SCN, the somatic stem cells are derived from a common embryonic stem cell, share a specific molecular profile and maintain a high degree of cell-cycle synchronization. In the study of cancer, the SCN model introduces an additional conceptual frame to the interpretation of both the cancer stem cell (CSC) hypothesis and the field cancerization concept. The CSC model may explain how the cancer fields develop, justifies their sizes and shapes, contribute to explain the local recurrences in patients with free margins, the second primary tumors, the success of organ preserving surgical approaches or the trend of different tumors to metastasize to certain locations. We propose that the SCN model of cancer provides some clues for further understanding tumor progression and raises promising experimental and clinical implications.