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To identify the novel genes involved in chemoresistance in head and neck squamous cell carcinoma (HNSCC), we explored the expression profiles of the following cisplatin (CDDP) resistant (R) versus parental (sensitive) cell lines by RNA-sequencing (RNA-seq): JHU029, HTB-43 and CCL-138. Using the parental condition as a control, 30 upregulated and 85 downregulated genes were identified for JHU029-R cells; 263 upregulated and 392 downregulated genes for HTB-43-R cells, and 154 upregulated and 68 downregulated genes for CCL-138-R cells. Moreover, we crossed-checked the RNA-seq results with the proteomic profiles of HTB-43-R (versus HTB-43) and CCL-138-R (versus CCL-138) cell lines. For the HTB-43-R cells, 21 upregulated and 72 downregulated targets overlapped between the proteomic and transcriptomic data; whereas in CCL-138-R cells, four upregulated and three downregulated targets matched. Following an extensive literature search, six genes from the RNA-seq (CLDN1, MAGEB2, CD24, CEACAM6, IL1B and ISG15) and six genes from the RNA-seq and proteomics crossover (AKR1C3, TNFAIP2, RAB7A, LGALS3BP, PSCA and SSRP1) were selected to be studied by qRT-PCR in 11 HNSCC patients: six resistant and five sensitive to conventional therapy. Interestingly, the high MAGEB2 expression was associated with resistant tumours and is revealed as a novel target to sensitise resistant cells to therapy in HNSCC patients.

Simple Summary Drug resistance is the principal limiting factor to achieving good survival rates in patients with cancer. The identification of potential biomarkers for diagnosis and prognostic prediction, as well as the design of new molecular-targeted treatments, will be essential to improving head and neck squamous cell carcinoma (HNSCC) patient outcomes. In this sense, the sensitization of resistant cells and cancer stem cells (CSCs) represents a major challenge in cancer therapy. We conducted a proteomic study involving cisplatin-resistance and CSCs with the aim to unravel the molecular and cellular mechanisms by which tumor cells acquire resistance to chemotherapy. Syntenin-1 (SDCBP) was identified as an important protein involved in the chemoresistance and stemness of HNSCC tumors. Abstract To characterize the mechanisms that govern chemoresistance, we performed a comparative proteomic study analyzing head and neck squamous cell carcinoma (HNSCC) cells: CCL-138 (parental), CCL-138-R (cisplatin-resistant), and cancer stem cells (CSCs). Syntenin-1 (SDCBP) was upregulated in CCL-138-R cells and CSCs over parental cells. SDCBP depletion sensitized biopsy-derived and established HNSCC cell lines to cisplatin (CDDP) and reduced CSC markers, Src activation being the main SDCBP downstream target. In mice, SDCBP-depleted cells formed tumors with decreased mitosis, Ki-67 positivity, and metastasis over controls. Moreover, the fusocellular pattern of CCL-138-R cell-derived tumors reverted to a more epithelial morphology upon SDCBP silencing. Importantly, SDCBP expression was associated with Src activation, poor differentiated tumor grade, advanced tumor stage, and shorter survival rates in a series of 382 HNSCC patients. Our results reveal that SDCBP might be a promising therapeutic target for effectively eliminating CSCs and CDDP resistance.

Background and Purpose— Many patients with acute ischemic stroke are not eligible for thrombolysis or mechanical reperfusion therapies due to contraindications, inaccessible vascular occlusions, late presentation, or large infarct core. Sphenopalatine ganglion (SPG) stimulation to enhance collateral flow and stabilize the blood-brain barrier offers an alternative, potentially more widely deliverable, therapy. Methods— In a randomized, sham-controlled, double-masked trial at 41 centers in 7 countries, patients with anterior circulation ischemic stroke not treated with reperfusion therapies within 24 hours of onset were randomly allocated to active SPG stimulation or sham control. The primary efficacy outcome was improvement beyond expectations on the modified Rankin Scale of global disability at 90 days (sliding dichotomy), assessed in the modified intention-to-treat population. The initial planned sample size was 660 patients, but the trial was stopped early when technical improvements in device placement occurred, so that analysis of accumulated experience could be conducted to inform a successor trial. Results— Among 303 enrolled patients, 253 received at least one active SPG or sham stimulation, constituting the modified intention-to-treat population (153 SPG stimulation and 100 sham control). Age was median 73 years (interquartile range, 64–79), 52.6% were female, deficit severity on the National Institutes of Health Stroke Scale was median 11 (interquartile range, 9–15), and time from last known well median 18.6 hours (interquartile range, 14.5–22.5). For the primary outcome, improved 3-month disability beyond expectations, rates in the SPG versus sham treatment groups were 49.7% versus 40.0%; odds ratio, 1.48 (95% CI, 0.89–2.47); P =0.13. A significant treatment interaction with stroke location (cortical versus noncortical) was noted, P =0.04. In the 87 patients with confirmed cortical involvement, rates of improvement beyond expectations were 50.0% versus 27.0%; odds ratio, 2.70 (95% CI, 1.08–6.73); P =0.03. Similar response patterns were observed for all prespecified secondary efficacy outcomes. No differences in mortality or serious adverse event safety end points were observed. Conclusions— SPG stimulation within 24 hours of onset is safe in acute ischemic stroke. SPG stimulation was not shown to statistically significantly improve 3-month disability above expectations, though favorable outcomes were nominally higher with SPG stimulation. Beneficial effects may distinctively be conferred in patients with confirmed cortical involvement. The results of this study need to be confirmed in a larger pivotal study. Clinical Trial Registration— URL: https://www.clinicaltrials.gov . Unique identifier: NCT03767192.

A long-term tracheostomy can have significant negative effects on quality of life because it causes physical, functional, sensory, psychological, social, economic, and work impairments to the life of the individual. The objective of this study was to validate in Spanish a quality-of-life questionnaire for these patients.A psychometric validation study of a questionnaire in 45 patients over 18 years of age, with tracheostomy for six months, who understand Spanish and have a good understanding of the questions of the SF-36 questionnaire and a specific quality of life questionnaire for the patient with tracheostomy (TQOL-versión española). This Vquestionnaire is a modification and cultural adaptation into Spanish of the original English instrument named Tracheostomy Specific Quality of Life Questionnaire (TQOL). The two questionnaires (TQOL-versión española) and the SF-36 were completed 6 months after the tracheostomy and between 30 and 50 days after the first administration. The reliability, repeatability, and construct validity of the TQOL-versión española were evaluated. The construct validity was assessed by the correlation between the results of the TQOL-versión española and the dimensions of the SF-36 questionnaire.The reliability of the TQOL-versión española measured by Cronbach's alpha coefficient was .814, with variation between items from .783 to .817 in the sample at 6 months and from .794 in the validation sample, with variation between items from .758 to .813. There was intraclass correlation for the total score of the scale using the concordance analysis of Bland-Altman and agreement for the individual questions with the McNemar symmetry test. There was also a good correlation between the scales of the TQOL-versión española and the dimensions of the S-F36.The TQOL-versión española showed good reliability, repeatability, and construct validity, therefore it is a useful tool to assess the impact on individual patients with a tracheostomy in place for more than 6 months, and to establish strategies at the healthcare and social levels to improve the quality of daily life.

Objective Polycystic ovary syndrome (PCOS) is diagnosed based on the clinical signs, but its presentation is heterogeneous and potentially confounded by concurrent conditions, such as obesity and insulin resistance. miRNA have recently emerged as putative pathophysiological and diagnostic factors in PCOS. However, no reliable miRNA-based method for molecular diagnosis of PCOS has been reported. The aim of this study was to develop a tool for accurate diagnosis of PCOS by targeted miRNA profiling of plasma samples, defined on the basis of unbiased biomarker-finding analyses and biostatistical tools. Methods A case–control PCOS cohort was cross-sectionally studied, including 170 women classified into four groups: non-PCOS/lean, non-PCOS/obese, PCOS/lean, and PCOS/obese women. High-throughput miRNA analyses were performed in plasma, using NanoString technology and a 800 human miRNA panel, followed by targeted quantitative real-timePCR validation. Statistics were applied to define optimal normalization methods, identify deregulated biomarker miRNAs, and build classification algorithms, considering PCOS and obesity as major categories. Results The geometric mean of circulating hsa-miR-103a-3p, hsa-miR-125a-5p, and hsa-miR-1976, selected among 125 unchanged miRNAs, was defined as optimal reference for internal normalization (named mR3-method). Ten miRNAs were identified and validated after mR3-normalization as differentially expressed across the groups. Multinomial least absolute shrinkage and selection operator regression and decision-tree models were built to reliably discriminate PCOS vs non-PCOS, either in obese or non-obese women, using subsets of these miRNAs as performers. Conclusions We define herein a robust method for molecular classification of PCOS based on unbiased identification of miRNA biomarkers and decision-tree protocols. This method allows not only reliable diagnosis of non-obese women with PCOS but also discrimination between PCOS and obesity. Capsule We define a novel protocol, based on plasma miRNA profiling, for molecular diagnosis of PCOS. This tool not only allows proper discrimination of the condition in non-obese women but also permits distinction between PCOS and obesity, which often display overlapping clinical presentations.

HIV represents a persistent infection which negatively alters the immune system. New tools to reinvigorate different immune cell populations to impact HIV are needed. Herein, a novel nanotool for the specific enhancement of the natural killer (NK) immune response towards HIV-infected T-cells has been developed. Bispecific Au nanoparticles (BiAb-AuNPs), dually conjugated with IgG anti-HIVgp120 and IgG anti-human CD16 antibodies, were generated by a new controlled, linker-free and cooperative conjugation method promoting the ordered distribution and segregation of antibodies in domains. The cooperatively-adsorbed antibodies fully retained the capabilities to recognize their cognate antigen and were able to significantly enhance cell-to-cell contact between HIV-expressing cells and NK cells. As a consequence, the BiAb-AuNPs triggered a potent cytotoxic response against HIV-infected cells in blood and human tonsil explants. Remarkably, the BiAb-AuNPs were able to significantly reduce latent HIV infection after viral reactivation in a primary cell model of HIV latency. This novel molecularly-targeted strategy using a bispecific nanotool to enhance the immune system represents a new approximation with potential applications beyond HIV., This study was supported by the Spanish Secretariat of Science and Innovation and FEDER funds (grants SAF2015-67334-R and RTI2018-101082-B-I00 [MINECO/FEDER]), American National Institutes of Health (grant R21AI118411 to M.B), an unrestricted research grant from Bristol-Myers Squibb S.A.U (PfC-2015-AI424-564) to M.B, the Spanish “Ministerio de Economía y Competitividad, Instituto de Salud Carlos III” (ISCIII, PI17/01470) to M.G and the Spanish “Ministerio de Economía y Competitividad, Instituto de Salud Carlos III” (ISCIII, PI14/01058) to J.G.P, a research grant from Gilead Sciences (GLD17-00204 and GLD19-00084) to M.B, GeSIDA and the Spanish AIDS network “Red Temática Cooperativa de Investigación en SIDA” (RD16/0025/0007). The Miguel Servet program funded by the Spanish Health Institute Carlos III (CP17/00179) to M.B and J.G.P (CPII15/00014). The “Pla estratègic de recerca i innovació en salut” (PERIS), from the Catalan Government to M.G. The Spanish Secretariat of Science and Innovation Ph.D. fellowship to A.A-G (BES-2016-076382), AGAUR-FI-B-00582 Ph.D. fellowship from the Catalan Government to O.BL, and PIF-UAB Ph.D. fellowship from Universitat Autònoma de Barcelona to R.SL.

Background Although considerable progress has been made in the last 30 years in the treatment of cleft palate (CP), a multidisciplinary approach combining examinations by a paediatrician, maxillofacial surgeon, otolaryngologist and speech and language pathologist followed by surgical operation is still required. In this work, we performed an observational cross-sectional study to determine whether the CP grade or number of ventilation tubes received was associated with tympanic membrane abnormalities, hearing loss or speech outcomes. Methods Otologic, audiometric, tympanometric and speech evaluations were performed in a cohort of 121 patients (children > 6 years) who underwent an operation for CP at the Vall d’Hebron Hospital, Barcelona from 2000 to 2014. Results The most and least frequent CP types evaluated according to the Veau grade were type III (55.37%) and I (8.26%), respectively. A normal appearance of the membrane was observed in 58% individuals, of whom 55% never underwent ventilation ear tube insertion. No statistically significant associations were identified between the CP type and number of surgeries for insertion of tubes (p = 0.820). The degree of hearing loss (p = 0.616), maximum impedance (p = 0.800) and tympanic membrane abnormalities indicative of chronic otitis media (COM) (p = 0.505) among examined patients revealed no statistically significant association with the grade of CP. However, an association was identified between hypernasality and the grade of CP (p = 0.053), COM (p = 0.000), hearing loss (p = 0.000) and number of inserted ventilation tubes. Conclusion Although the placement of tympanic ventilation tubes has been accompanied by an increased rate of COM, it is still important to assess whether this is a result of the number of ventilation tubes inserted or it is intrinsic to the natural history of middle ear inflammatory disease of such patients. Our results do not support improvements in speech, hearing, or tympanic membrane abnormalities with more aggressive management of COM with tympanostomy tubes.

In wild-type cells, autophagy represents a tumour-suppressor mechanism, and dysfunction of the autophagy machinery increases genomic instability, DNA damage, oxidative stress and stem/progenitor expansion, which are events associated with cancer onset. Autophagy occurs at a basal level in all cells depending on cell type and cellular microenvironment. However, the role of autophagy in cancer is diverse and can promote different outcomes even in a single tumour. For example, in hypoxic tumour regions, autophagy emerges as a protective mechanism and allows cancer cell survival. By contrast, in cancer cells surrounding the tumour mass, the induction of autophagy by radio- or chemotherapy promotes cell death and significantly reduces the tumour mass. Importantly, inhibition of autophagy compromises tumorigenesis by mechanisms that are not entirely understood. The aim of this review is to explain the apparently contradictory role of autophagy as a mechanism that both promotes and inhibits tumorigenesis using different models. The induction/inhibition of autophagy as a mechanism for cancer treatment is also discussed.

To identify the putative relevance of autophagy in laryngeal cancer, we performed an immunohistochemistry study to analyze the expression of the proteins involved in this process, namely, LC3, ATG5 and p62/SQSTM1. Additionally, Prostate tumor-overexpressed gene 1 protein (PTOV1) was included due to its potential relevance in laryngeal cancer. Moreover, as cancer resistance might involve autophagy in some circumstances, we studied the intrinsic drug resistance capacity of primary tumor cultures derived from 13 laryngeal cancer biopsies and their expression levels of LC3, ATG5, p62 and PTOV1. Overall, our results suggest that (i) cytoplasmic p62 and PTOV1 can be considered prognostic markers in laryngeal cancer, (ii) the acquisition of resistance seems to be related to PTOV1 and autophagy-related protein overexpression, (iii) by increasing autophagy, PTOV1 might contribute to resistance in this model and (iv) the expression of autophagy-related proteins could classify a subgroup of laryngeal cancer patients who will benefit from a therapy based upon autophagy inhibition. Our study suggests that autophagy inhibition with hydroxychloroquine could be a promising strategy for laryngeal cancer patients, particularly those patients with high resistance to the CDDP treatment that in addition have autophagy upregulation.

The purpose of this study was to evaluate the effect of two doses of D-chiro-inositol (DCI) in combination with Myo-inositol (MYO) in women with PCOS undergoing ICSI. This was a multicenter controlled, randomized, double-blind parallel group study with two MYO-DCI formulations for 12 weeks. The study group (SG) was administered 550 mg of MYO + 150 mg of DCI twice daily; the control group (CG) was administered 550 mg of MYO + 13.8 mg of DCI twice daily. The participants comprised 60 women with PCOS undergoing ICSI. At baseline, no differences were found between the two groups regarding age, BMI, HOMA-IR or testosterone levels. The pregnancy and live birth rates were significantly higher in the SG than in the CG (65.5 vs. 25.9 and 55.2 vs. 14.8, respectively) [risk ratio (RR) = 0.4; 95%CI (0.2, 0.79); p = .003 and RR = 0.27; 95%CI (0.10, 0.70); p = .002 respectively]. The risk of ovarian hyperstimulation syndrome (OHSS) was lower in the SG (3.44 vs. 18.5%, p = .07). The combination of MYO-DCI at high doses of DCI improves the pregnancy rates and reduces the risk of OHSS in women with PCOS undergoing ICSI.

6081 Background: Treatment selection based on actionable alterations (AAs) is an appealing strategy for pts with R/M SGT. The GEMS-001 study (NCT02069730) at Princess Margaret Cancer Centre (PM) and the Vall D´Hebron Institute of Oncology (VHIO) pre-screening program facilitate the identification of AAs for R/M SGT pts and treatment selection. Methods: We analyzed R/M SGT treated at PM and VHIO from 2015 to 2020. Clinicopathological features, molecular alterations and treatment modalities were correlated with outcomes. The primary endpoint was overall response rate (ORR) by RECIST 1.1. Clinical benefit rate (CBR) was defined by pts with partial response or stable disease ≥4 months. Clinical actionability of multigene panel testing (NGS) and immunohistochemistry (IHC) were assessed as per institutional molecular tumor boards or investigators. Pts were opportunistically matched to available therapies from each center. Results: In total 206 pts were enrolled. On IHC, HER2 overexpression was present in 9%, Androgen Receptor (AR) 33%, Estrogen/Progesterone Receptor (ER/PR) 11% and ALK overexpression 0%. On NGS, PIK3CA mutation (mut) was in 9%, NTRK fusion 6%, NOTCH1-3 mut 5%, HRAS mut 6%, ERBB2/3 alterations (alt) 4% and FGFR1-4 alt 3%. Up to 92 pts (45%) displayed at least 1 AA and 36 pts (18%) had ≥2 AAs. A total of 60 pts (29%) were matched to AAs. Of those matched, median age was 60 years (range 33-84), M:F 21:39, 95% ECOG≤1 with a median number of prior treatment lines 0 (range 0-3), and their AAs included 26 AR, 9 HER2 or ERBB2 overexpression, 9 PIK3CA mut, 3 NTRK fusion, 3 FGFR1-3 alt and 10 other AAs (2 ER/PR overexpression, 2 EGFR mut, 1 c-kit mut, 1 BAP1 mut, 1 Non-V600 BRAF mut, 1 CDKN2A mut, 1 CHEK2 mut and 1 PTCH1 mut). Overall, ORR was 27% for the matched population. See table for outcomes. Conclusions: In our cohort, almost one third of the population received therapies matched to AAs. Our results suggest that targeted therapies have promising activity in pts with R/M SGT supporting comprehensive molecular and IHC profiling in treatment determination.[Table: see text]

Background.Many drugs used for cancer chemotherapy produce reactive oxygen species, thus leading to various complications including nephrotoxicity, cardiotoxicity, and ototoxicity.Objective.We have provided a haplogroup analysis of a cohort of cancer patients treated with chemotherapy and compared factors associated with associated hearing loss.Study Design and Methods.This observational cohort study includes a pure-tone audiometry of the patients who underwent chemotherapeutic treatment. Medical history, presence of risk factors for hearing loss, toxic habits, and association with haplogroups have been determined.Results.40% of patients developed hearing loss after administration of cisplatin, which was bilateral and symmetrical and of high frequencies. The most frequent haplogroup was H with a slight overexpression of groups V and K and a low frequency of groups J and T. No association of the haplogroup types with the hearing loss has been found; however age was revealed as an important determining factor.Conclusions.Ototoxicity caused by cisplatin is manifested as bilateral, symmetrical, and predominantly high frequency hearing loss. Although we did not find a strong correlation of haplogroups with ototoxicity, our results revealed the existence of a risk group of elderly patients over 60, which are more susceptible to hearing loss induced by cisplatin, than young adults, regardless of preexisting hearing loss.

Resumen Introduccion Los estudios de los biomarcadores inflamatorios en suero y en el condensado de aire exhalado (CAE) en la apnea obstructiva del sueno (AOS) han producido resultados contradictorios. El objetivo de este estudio es evaluar los biomarcadores en CAE y en suero en pacientes con AOS en la situacion basal y despues de la aplicacion de presion positiva continua de vias aereas (CPAP) o de cirugia de las vias aereas superiores (CVAS). Pacientes y metodos Nueve pacientes con AOS que fueron remitidos para CVAS fueron emparejados segun sus caracteristicas antropometricas y el indice de apnea-hipopnea con 20 pacientes que fueron tratados con CPAP. Se efectuaron determinaciones de pH, nitrito (NO 2 − ), nitrato e interleucina 6 en CAE, y de NO 2 − , nitrato, leucotrieno B 4 e interleucina 6 en suero. Se obtuvieron muestras de CAE y de suero en la situacion basal y 3 meses despues de la CPAP o la CVAS. Resultados El valor medio del indice de masa corporal de los pacientes fue de 30 (rango 24,9-40) kg/m 2 . Los niveles de marcadores en CAE en la situacion basal estuvieron dentro del rango normal y no presentaron diferencias significativas tras la CPAP o la CVAS. No se observaron cambios significativos en las concentraciones sericas de los biomarcadores evaluados tras la CPAP, pero la concentracion serica de NO 2 − aumento significativamente a los 3 meses de la CVAS (p = 0,0078). Conclusion En los pacientes con AOS y obesidad leve, los biomarcadores de la inflamacion o el estres oxidativo en el CAE presentaron unos niveles basales normales y se mantuvieron inalterados 3 meses despues de la CVAS o la CPAP. La CVAS, aunque no resulto efectiva por lo que respecta a la reduccion de la gravedad de la AOS, se asocio a un aumento de los niveles sericos de NO 2 − .

Introduction Studies on inflammation biomarkers in serum and in exhaled breath condensate (EBC) in obstructive sleep apnea (OSA) have shown conflicting results. The objective of this study is to assess EBC and serum biomarkers in OSA patients at baseline and after continuous positive airway pressure (CPAP) or upper airway surgery (UAS). Patients and methods Nine OSA patients referred for UAS were matched for anthropometric characteristics and apnea–hypopnea index with 20 patients receiving CPAP. pH, nitrite (NO 2 − ), nitrate, and interleukin 6 in EBC and NO 2 − , nitrate, leukotriene B 4 , and interleukin 6 in serum were determined. EBC and serum samples were collected at baseline and 3 months after CPAP or UAS. Results Patients’ mean body mass index was 30 (range 24.9–40) kg/m 2 . EBC biomarker levels at baseline were within normal range and did not differ significantly after CPAP or UAS. No significant changes were observed in the serum concentration of the biomarkers determined after CPAP but the serum concentration of NO 2 − increased significantly at 3 months after UAS ( P =.0078). Conclusion In mildly obese OSA patients, EBC biomarkers of inflammation or oxidative stress were normal at baseline and remained unchanged 3 months after UAS or CPAP. Although UAS was not effective in terms of reducing OSA severity, it was associated with an increase in serum NO 2 − .

Background Nutritional status affects survival of pts with HNC. Close to half HNC pts require enteral nutrition, with percutaneous endoscopic gastrostomy (PEG) being the preferred route. We studied whether PEG placement technique and timing impact on HNC pts outcomes. Methods We retrospectively analyzed all HNC pts who underwent PEG insertion between February 2014 and August 2018 at Vall d´Hebron University Hospital. The primary objectives were to assess overall survival (OS) and PEG complication rate in light of nutritional parameters (albumin, cholesterol and PCR) and disease stage (local and locally-advanced [LA] vs recurrent-metastatic [R/M]) when PEG is placed in a prophylactic (P-PEG) or symptomatic (S-PEG) setting with endoscopic or radiologic intervention. Results Out of 125 pts, 52% had LA disease and 48% R/M, 37% had P-PEG, 63% S-PEG [tumor related symptoms (61%), treatment toxicity (30%), nasogastric tube intolerance or dysfunction (6%), and other feeding disorders (3%)]. High albumin and cholesterol levels associated with better of OS [HR = 0.64 (CI 95% 0.42-0.98), p = 0.04 and HR = 0.65 (CI 95% 0.43-0.99), p = 0.04, respectively]. In the R/M setting, no difference in median OS was observed between P-PEG 18.9 months (m) (CI 95% 12.7-45) and S-PEG 15.6 m (CI 95% 11.5-22.2, HR = 0.89, CI 95% 0.57-1.4, p = 0.62). In the LA setting, we found numerically longer median OS in pts with P-PEG 42.2 m (CI 95% 21.9-NA) vs PEG-S 16.2 m (CI 95% 11.5-NA, HR = 0.72, CI 95% 0.37-1.94, p = 0.33). Complication rate was 28% in the P-PEG group vs 30% S-PEG group (p = 0.8). Most common complications included infection 35%, ileus and delayed gastric emptying (22%), and bronchial aspiration (13%). Complications led to treatment interruption in 4 pts (3.2%). Complication rate was lower in LA setting than in R/M setting (24% vs 35%, p = 0.2). Endoscopic PEG placement was associated with less complications (9%) than radiologic placement (47%, p = 0.08). Conclusions We confirmed that nutritional parameters impact on HNC pts OS. In the LA setting, P-PEG might be associated with a better outcome. Endoscopic PEG placement appears to be related to fewer complications. Our results will help design a PEG placement algorithm to further evaluate the role of P-PEG. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure J. Tabernero: Advisory / Consultancy: Arrays Biopharma; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Bayer; Advisory / Consultancy: BeiGene; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Chugai; Advisory / Consultancy: Genentech; Advisory / Consultancy: Inc; Advisory / Consultancy: Genmab A/S; Advisory / Consultancy: Halozyme; Advisory / Consultancy: Imugene Limited; Advisory / Consultancy: Inflection Biosciences Limited; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Kura Oncology; Advisory / Consultancy: Lilly; Advisory / Consultancy: MSD; Advisory / Consultancy: Menarini; Advisory / Consultancy: Merrimack; Advisory / Consultancy: Merus; Advisory / Consultancy: Molecular Partners, Novartis, Peptomyc, Pfizer, Pharmacyclics, ProteoDesign SL, Rafael Pharmaceuticals, F. Hoffmann-La Roche Ltd, Sanofi, SeaGen, Seattle Genetics, Servier, Symphogen, Taiho, VCN Biosciences, Biocartis, Foundation Medicine, HalioDX SAS. E. Felip: Advisory / Consultancy: AbbVie, AstraZeneca, Blue Print Medicines, Boehringer Ingelheim, BMS, Celgene, Eli Lilly, Guardant Health, Merck KGaA, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Takeda, Janssen; Speaker Bureau / Expert testimony: AbbVie, AstraZeneca, Boehringer Ingelheim, BMS, Eli Lilly, Merck KGaA, Merck sharp & dohme, Novartis, Pfizer, Roche, Takeda.; Research grant / Funding (self): Fundacion Merck Salud Grant for Oncology Innovation. R. Dienstmann: Advisory / Consultancy: Roche ; Speaker Bureau / Expert testimony: Roche, Symphogen, Ipsen, Amgen, Sanofi, MSD, Servier; Research grant / Funding (self): Merck. All other authors have declared no conflicts of interest.

In wild-type cells, autophagy represents a tumour-suppressor mechanism, and dysfunction of the autophagy machinery increases genomic instability, DNA damage, oxidative stress and stem/progenitor expansion, which are events associated with cancer onset. Autophagy occurs at a basal level in all cells depending on cell type and cellular microenvironment. However, the role of autophagy in cancer is diverse and can promote different outcomes even in a single tumour. For example, in hypoxic tumour regions, autophagy emerges as a protective mechanism and allows cancer cell survival. By contrast, in cancer cells surrounding the tumour mass, the induction of autophagy by radio- or chemotherapy promotes cell death and significantly reduces the tumour mass. Importantly, inhibition of autophagy compromises tumorigenesis by mechanisms that are not entirely understood. The aim of this review is to explain the apparently contradictory role of autophagy as a mechanism that both promotes and inhibits tumorigenesis using different models. The induction/inhibition of autophagy as a mechanism for cancer treatment is also discussed.

The study of cancer stem cells (CSCs) has shown that tumors are driven by a subpopulation of self-renewing CSCs that retain the capacity to engender the various differentiated cell populations that form tumors. The characterization of CSCs has indicated that CSCs are remarkably resistant to conventional radio- and chemo-therapy. Clinically, the remaining populations of CSC are responsible for metastasis and recurrence in patients with cancer, which can lead to the disease becoming chronic and incurable. Therefore, the elimination of CSCs is an important goal of cancer treatments. Furthermore, CSCs are subject to strong regulation by the surrounding microenvironment, which also impacts tumor responses. In this review, we discuss the mechanisms by which pathways that are defective in CSCs influence ultimately therapeutic and clinical outcomes.

To compare the efficacy and safety of ciprofloxacin otic solution 0.2% to polymyxin B-neomycin-hydrocortisone (PNH) otic solution in the treatment of acute diffuse otitis externa in children, adolescents, and adults.This was a randomized, parallel-group, evaluator-blind, active-controlled, multicenter, noninferiority study. The primary efficacy endpoint was clinical cure of otitis symptoms at the test-of-cure (TOC) visit. Clinical cure at the end-of-treatment (EOT) visit and percentages of patients with clinical improvement and resolution and/or improvement of otalgia at EOT and TOC visits were secondary efficacy endpoints.A total of 630 patients were randomized to ciprofloxacin twice daily (n = 318) or PNH 3 times daily (n = 312) for 7 days. Ciprofloxacin was shown to be noninferior to PNH. The percentage of patients with clinical cure at the TOC visit was 86.6% with ciprofloxacin and 81.1% with PNH; the treatment difference was 5.6% in favor of ciprofloxacin (95% CI: -0.9 to 12.1). At the EOT visit, clinical cure was achieved in 70.0% and 60.5% of patients, respectively, with a treatment difference in favor of ciprofloxacin (9.5%, 95 CI: 1.2 to 17.9). In all secondary efficacy variables, ciprofloxacin and PNH showed similar results, including pain duration and resolution. The clinical cure rate for patients with baseline cultures showing P. aeruginosa was 87.5% in the ciprofloxacin group and 78.6% in the PNH group, a treatment difference of 8.9% in favor of ciprofloxacin (95% CI: 0.6 to 17.3); for patients with baseline cultures showing S. aureus, the clinical cure rate was 72.7% for the ciprofloxacin group and 75.9% for the PNH group (treatment difference of 3.1% in favor of PNH, 95% CI: -21.1% to 27.4%). Most adverse events were mild and unrelated to study medication in both treatment groups. A limitation of this study is the assessment of signs and symptoms at baseline and after treatment, which does not provide data to evaluate the interim response.Ciprofloxacin otic solution 0.2% was found to be noninferior to PNH. This efficacy, good tolerability, and ease of administration make ciprofloxacin otic solution 0.2% without a topical steroid an attractive option for the treatment of acute otitis externa.

Resumen Objetivo Valorar nuestro protocolo de actuacion en los embarazos prolongados, determinando si la induccion del parto a las 42 semanas de gestacion conlleva mas beneficios maternofetales que la finalizacion posterior a este. Metodos Un total de 64 mujeres con gestaciones prolongadas no complicadas, que decidieron terminar su embarazo a las 42 semanas, se compararon con 173 mujeres que decidieron continuar su embarazo despues de dicho periodo de gestacion. Resultados Hubo una mayor tasa de cesareas y de malos resultados perinatales en el grupo de mujeres que decidio no inducir el parto en la semana 42 de gestacion. La mayor parte de estas mujeres acaba induciendose el parto algo mas adelante. Conclusiones En las gestaciones prolongadas no complicadas, la induccion del parto a las 42 semanas conlleva mejores resultados maternofetales y resulta mas eficiente que continuar con los controles durante mas tiempo.

The aim of this study is to evaluate the use of hysteroscopic Essure device placement for the treatment of hydrosalpinx (HS)-related infertility in patients with laparoscopic contraindications and compared their pregnancy outcomes following IVF-ICSI treatment with those patients having had laparoscopic tubal occlusion (LTO).From 2008 to 2014 a total of 50 patients were diagnosed with unilateral or bilateral hydrosalpinges: 29 patients had laparoscopic contraindications and were treated hysteroscopically and 21 patients were treated with laparoscopical salpingectomy.Of the 29 patients who underwent treatment with Essure(®), 21 began a cycle of in vitro fertilization (IVF), and 13 finished in embryo transfer that resulted in seven clinical pregnancies. Furthermore, in the group of women treated with salpingectomy, 17 started an IVF cycle that resulted in 12 clinical pregnancies. The clinical pregnancy rate per patient with an IVF cycle started was 33.3% and 70.6%, the live-birth rate per patient was 14.3% and 52.9%, the miscarriage rate was 57.1% and 18.2%, and the implantation rate was 16.3% and 34.1% for hysteroscopy and laparoscopy, respectively.Essure(®) placement is an alternative method for occlusion of hydrosalpinges before IVF. Monitoring the live-birth rate confirms that this option may be considered when laparoscopy is impossible or contraindicated.

6031 Background: Multiple genomic alterations were described in HNC, including squamous cell carcinomas (SCC), salivary gland (SG) and nasopharyngeal (NF) tumors. Tumor molecular profiling (TMP) may increase therapeutic alternatives in early trials for pts with refractory metastatic (met) HNC. We evaluate the impact of matched/unmatched therapy (mT/uT) in HNC with potentially targetable alterations. Methods: From 2010-16, 47 met HNC pts were treated in 57 early trials after TMP. Clinical benefit was measured by: time to progression (TTP); clinical benefit rate (CBR: complete response [CR], partial response [PR] and stable disease [SD] > 4months [m]); progression-free survival [PFS] ratio≥1.3 (PFS under molecular therapeutics/PFS upon last prior chemotherapy [pT]). Results: Median age was 51 years; median number of pT lines was 1 (0-5). In total, 26 SCC, 11 SG, 8 NF and 2 nasosinusal pts (mostly with lymph nodes and lung met) were treated with small kinases (SK) inhibitors (inh) (50%; main targets PI3K/HER/FGFR), immune-oncology (IO) drugs (40%, PD-1/PD-L1), angiogenesis inh (5%) or chaperone, cytidine analog, RNA polymerase (5%). 14/57 trials were mT including CDKinh (1 CDKN2A mutation [mut]), PI3Kinh (5 PIK3CA mut, 2 PTEN mut), PI3K/MEKinh (1 NRAS mut), HERinh (1 ERBB3mut), FGFRinh (2 FGFR1mRNA high, 1 FGF3/4/19 ligand amplified) and porcupine inh (1 ZNFR3mut). Distribution by tumor: IO (16 SCC/5 NF), SKmT (8SG/4SCC/2NF) and SKuT (9SCC/4SG). Responses: 1CR in SCC (IO), 5 PR in SCC (4 IO, 1 FGFRinh), 3 PR in NF (1 cytidin analog, 1 IO, 1 PI3K/MEKinh). Benefit: median TTP 9.33m (CI95% 7-20) with upward trend in NF and SG vs SCC (HR 0.6;p = 0.28), without differences according to target therapies (HR 0.8; p = 0.9); CBR of 58%, without differences by tumor type (p = 0.42) or therapy (SKmT, SKuT, IO; p = 0.5); 60% with PFS ratio≥1.3, significantly higher in SCC and SG (p = 0.016), particularly with IO drug and SKmT, respectively. Conclusions: Considering our preselected fit population as bias selection, individualized treatment selection with novel therapeutics based on TMP, especially in NF and SG irrespective of targets (SKmT, SKuT, IO), and in SCC with IO drugs, seems to confer substantial clinical benefit.

A 42 year-old man underwent a nasal septoplasty and awoke with vision of light perception in his right eye. An afferent pupillary defect was noted with a normal fundus examination, normal fluorescein angiography and intact optic canal on imaging studies. A diagnosis of posterior ischaemic optic neuropathy was made. No visual improvement was noted in our case despite treatment with high dose oral steroids. Follow-up showed optic atrophy on fundoscopy and retinal nerve fiber layer thinning on OCT. Visual loss after nasal septoplasty surgery is extremely rare, with few cases reported in the literature. It can occur if the optic canal is fractured, but has been most commonly reported as a complication of intranasal anesthetic injections. Vigorous pressure during injection can overcome arterial pressure causing the injected material to circulate in a retrograde manner via arterial branches and cause ischaemia of the optic nerve. A further possibility is that intranasal injection could cause emboli to enter the...

Fundamento y objetivo Evaluar el efecto de la septoplastia funcional en un grupo de pacientes con dismorfia septal y sindrome de apnea obstructiva del sueno (SAOS). Pacientes y metodo Se estudio a 34 pacientes con insuficiencia respiratoria nasal y roncopatia cronica desde 1997 hasta 2003. Se confirmo el SAOS mediante estudio polisomnografico nocturno y la dismorfia septal por exploracion otorrinolaringologica. Se estudio la evolucion de los pacientes clinicamente a 1, 3 y 6 meses y con polisomnografia a los 6 meses. Resultados Se evidencio una mejoria objetiva estadisticamente significativa en el indice de apnea-hipoapnea (paso de 45,8 a 31,9; p ≥ 0,05), en la gravedad del SAOS (un 41,2% de los pacientes pasaron a leves o dejaron de tener SAOS), en la saturacion arterial de oxigeno minima media (del 76,4 al 83,1%), asi como una mejoria subjetiva en la escala de Epworth (13 puntos comparado con 6) para la valoracion de la somnolencia y del grado de satisfaccion clinica de los pacientes (el 72% de los pacientes evidenciaron mejoria). Conclusiones La septoplastia funcional es un tratamiento efectivo en pacientes con SAOS y dismorfia septal.

Studies on inflammation biomarkers in serum and in exhaled breath condensate (EBC) in obstructive sleep apnea (OSA) have shown conflicting results. The objective of this study is to assess EBC and serum biomarkers in OSA patients at baseline and after continuous positive airway pressure (CPAP) or upper airway surgery (UAS).Nine OSA patients referred for UAS were matched for anthropometric characteristics and apnea-hypopnea index with 20 patients receiving CPAP. pH, nitrite (NO2(-)), nitrate and interleukin 6 in EBC and NO2(-), nitrate, leukotriene B4 and interleukin 6 in serum were determined. EBC and serum samples were collected at baseline and 3 months after CPAP or UAS.Patients' mean body mass index was 30 (range 24.9-40) kg/m(2). EBC biomarker levels at baseline were within normal range and did not differ significantly after CPAP or UAS. No significant changes were observed in the serum concentration of the biomarkers determined after CPAP but the serum concentration of NO2(-) increased significantly at 3 months after UAS (P=.0078).In mildly obese OSA patients, EBC biomarkers of inflammation or oxidative stress were normal at baseline and remained unchanged 3 months after UAS or CPAP. Although UAS was not effective in terms of reducing OSA severity, it was associated with an increase in serum NO2(-).

6030Background: HNC encompass a group of highly heterogeneous diseases, including oral, oropharyngeal and laryngeal squamous cell carcinomas (SCC), nasopharyngeal (NP), nasosinusal (NS) and salivar...

To evaluate the efficacy of functional septoplasty in a group of patients with septal dysmorphy and obstructive sleep apnea syndrome (OSAS).34 patients with nasal respiratory insufficiency and chronic snore were included from 1997 to 2003. All of them were diagnosed of OSAS by nocturnal polysomnography (PSG) and of septal dysmorphy by ORL physical examination. Patients were clinically followed-up at 1, 3 and 6 months after surgery. PSG was also evaluated at 6 months postsurgery.A significant objective reduction of the apnea-hypopnea index (AHI) (45.8 vs 31.9), severity of OSAS, and minimal mean oxygen saturation (76.4 to 83.1) was found. Moreover, we observed a significant improvement of subjective scales of sleepiness (13 vs 6) and the patients' satisfaction degree (72% of patients improved).Functional septoplasty is an effective treatment in patients with OSAS and septal dysmorphy.

Background Brachycephalic dogs have unique upper respiratory anatomy with abnormal breathing patterns similar to those in humans with obstructive sleep apnea syndrome (OSAS). The objective of this study was to evaluate the correlation between anatomical components, clinical signs and several biomarkers, used to determine systemic inflammation and myocardial damage (C-reactive protein, CRP; Haptoglobin, Hp; cardiac troponin I, cTnI), in dogs with brachycephalic upper airway obstructive syndrome (BAOS). Results Fifty brachycephalic dogs were included in the study and the following information was studied: signalment, clinical signs, thoracic radiographs, blood work, ECG, components of BAOS, and CRP, Hp and cTnI levels. A high proportion of dogs with BAOS (88%) had gastrointestinal signs. The prevalence of anatomic components of BAOS was: elongated soft palate (100%), stenotic nares (96%), everted laryngeal saccules (32%) and tracheal hypoplasia (29.1%). Increased serum levels of biomarkers were found in a variable proportion of dogs: 14% (7/50) had values of CRP > 20 mg/L, 22.9% (11/48) had values of Hp > 3 g/L and 47.8% (22/46) had levels of cTnI > 0.05 ng/dl. Dogs with everted laryngeal saccules had more severe respiratory signs (p Conclusions According to the low percentage of patients with elevated levels of CRP and Hp, BAOS does not seem to cause an evident systemic inflammatory status. Some degree of myocardial damage may occur in dogs with BAOS that can be detected by cTnI concentration.