Prospective Evaluation of the Efficacy of Isolated Balloon Eustachian Tuboplasty: Short- and Medium-term Follow-up Results Based on Tubomanometry, ETDQ-7, Tympanometry, and Valsalva Maneuver.

Introduction Balloon eustachian tuboplasty (BET) allows the treatment of the main etiology of eustachian tube disfunction (ETD). Objective To evaluate the efficacy of isolated BET, through objective and subjective results, in the short and medium term, in patients with chronic obstructive ETD. Methods Adult patients diagnosed with chronic obstructive ETD who underwent BET between January 2018 and December 2020 were enrolled in the study. We performed a prospective observational study of BET efficacy, by comparing subjective data, based on the Eustachian Tube Dysfunction Questionnaire-7 (ETDQ-7), and objective data, obtained by tympanometry, objective Valsalva maneuver and tubomanometry, prior to BET with these outcome tools on postprocedure follow-up. Results In total, 30 BETs were performed and analyzed. There were no complications with the procedure. Analysis of BET efficacy was performed in the short-term (average of 7.5 weeks) and in the medium-term (average of 8 months). There was a significant reduction ( p < 0.0001) in the total ETDQ-7 score from baseline to both follow-up periods. A normalization of the ETDQ-7 score was observed in 60 and 83.3% of the performed procedures, in the short- and medium-term, respectively. In tubomanometry, we verified a significant improvement ( p < 0.0001) at all pressures, with a normalization of tubomanometry values in 53.3% and 43.3% of cases in the short- and medium-term, respectively. Tympanogram normalization occurred in 71.4% of patients with abnormal preoperative assessments. Conclusion As an isolated procedure, BET results in significant improvements in symptomatology and objective metric results. This, associated with its safety profile, currently makes BET the most indicated therapeutic option in refractory obstructive ETD.

Evolution of TOP1 and TOP1MT Topoisomerases in Chordata.

Type IB topoisomerases relax the torsional stress associated with DNA metabolism in the nucleus and mitochondria and constitute important molecular targets of anticancer drugs. Vertebrates stand out among eukaryotes by having two Type IB topoisomerases acting specifically in the nucleus (TOP1) and mitochondria (TOP1MT). Despite their major importance, the origin and evolution of these paralogues remain unknown. Here, we examine the molecular evolutionary processes acting on both TOP1 and TOP1MT in Chordata, taking advantage of the increasing number of available genome sequences. We found that both TOP1 and TOP1MT evolved under strong purifying selection, as expected considering their essential biological functions. Critical active sites, including those associated with resistance to anticancer agents, were found particularly conserved. However, TOP1MT presented a higher rate of molecular evolution than TOP1, possibly related with its specialized activity on the mitochondrial genome and a less critical role in cells. We could place the duplication event that originated the TOP1 and TOP1MT paralogues early in the radiation of vertebrates, most likely associated with the first round of vertebrate tetraploidization (1R). Moreover, our data suggest that cyclostomes present a specialized mitochondrial Type IB topoisomerase. Interestingly, we identified two missense mutations replacing amino acids in the Linker region of TOP1MT in Neanderthals, which appears as a rare event when comparing the genome of both species. In conclusion, TOP1 and TOP1MT differ in their rates of evolution, and their evolutionary histories allowed us to better understand the evolution of chordates.

Tinnitus and Otosclerosis: An Exploratory Study about the Prevalence, Features and Impact in Daily Life

Abstract Introduction Tinnitus is experienced by a significant part of the patients suffering from otosclerosis. Objective To assess the prevalence of tinnitus in otosclerosis, its main features, and the impact on the daily life. Methods Patients diagnosed with otosclerosis in 2019 in a tertiary hospital were enrolled in the study. Demographic data were retrieved and, besides a regular audiometric evaluation, the patients underwent acuphenometry to assess the psychoacoustic measurements (pitch and loudness), and the Tinnitus Handicap Inventory (THI). Results In total, 66 patients fulfilled the inclusion criteria, with a female predominance (63.6%; n = 42), and a mean age of 48.7 years. The mean air-bone gap was of 26.3 dB. A total of 72.7% complained of tinnitus; it was mostly unilateral, identified in the low frequencies, namely 500 Hz, with median loudness of 7.5 dB. The median score on the THI score was of 37; most patients had a mild handicap (33.3%, n = 16), followed by those with a severe handicap (22.9%; n = 11). The female gender had a statistically significant association with the presence of tinnitus. The THI scores were higher in middle-aged patients (age groups: 40 to 49 and 50 to 59 years), which was statistically significant. No correlation was found between audiometry results and the prevalence of tinnitus or score on the THI. On the other hand, high-pitched tinnitus, compared to low pitched-tinnitus, was associated with larger air-bone gaps. Conclusion The prevalence of tinnitus in our population was in line with the prevalences reported in the literature. It caused a catastrophic handicap in 22.9% of the patients. High-pitched tinnitus was associated with higher handicap. Nonetheless, the existence of tinnitus and its severity were not associated with the degree of hearing loss.

Nasal septum deviation and Eustachian tube function: A prospective case-control study based on tympanometry, tubomanometry, and ETDQ-7.

INTRODUCTION: The influence of isolated nasal septum deviation (NSD) in the Eustachian Tube (ET) function is still undetermined. OBJECTIVE: compare ET function between patients with severe NSD and patients with adequate nasal patency in terms of symptomology and objective exams and assess the impact of septoplasty in ET function in patients with severe NSD. METHODS AND METHODOLOGY: a prospective study was conducted. In the first phase of the study, two opportunistic samples were selected: 35 patients with severe NSD for group A and 35 patients with adequate nasal patency for group B. Both groups were evaluated through Nasal obstruction Subjective Questionnaire (NOSE) and ET dysfunction questionnaire 7 (ETDQ7) -, and through two objective exams to assess ET function - tympanometry, and tubomanometry (TMM); results were compared between group A and B. In the second phase of the study, the patients from group A underwent septoplasty and were re-evaluated through ETDQ7, tympanometry and TMM; results were compared before and after surgery. RESULTS: we found a statistically significant difference between patients with NSD and patients with adequate nasal patency in NOSE and ETDQ7 (higher scores in the latter), and TMM (worse results in patients with NSD); the difference in tympanometry was not statistically significant. The side of the NSD did not correlate with the side of the dysfunction. After septoplasty, patients from group A had statistically significant lower scores in ETDQ7 and a lower proportion of patients with findings compatible with ET dysfunction using TMM. CONCLUSION: according to our results, severe NSD alone is a cause of ET dysfunction; septal surgery might improve ET function in these patients.

Evolutionary History of TOPIIA Topoisomerases in Animals.

TOPIIA topoisomerases are required for the regulation of DNA topology by DNA cleavage and re-ligation and are important targets of antibiotic and anticancer agents. Humans possess two TOPIIA paralogue genes (TOP2A and TOP2B) with high sequence and structural similarity but distinct cellular functions. Despite their functional and clinical relevance, the evolutionary history of TOPIIA is still poorly understood. Here we show that TOPIIA is highly conserved in Metazoa. We also found that TOPIIA paralogues from jawed and jawless vertebrates had different origins related with tetraploidization events. After duplication, TOP2B evolved under a stronger purifying selection than TOP2A, perhaps promoted by the more specialized role of TOP2B in postmitotic cells. We also detected genetic signatures of positive selection in the highly variable C-terminal domain (CTD), possibly associated with adaptation to cellular interactions. By comparing TOPIIA from modern and archaic humans, we found two amino acid substitutions in the TOP2A CTD, suggesting that TOP2A may have contributed to the evolution of present-day humans, as proposed for other cell cycle-related genes. Finally, we identified six residues conferring resistance to chemotherapy differing between TOP2A and TOP2B. These six residues could be targets for the development of TOP2A-specific inhibitors that would avoid the side effects caused by inhibiting TOP2B. Altogether, our findings clarify the origin, diversification and selection pressures governing the evolution of animal TOPIIA.

Clustering of adenosine A2B receptors with ectonucleotidases in caveolin-rich lipid rafts underlies immunomodulation by Leishmania amazonensis.

Extracellular adenosine plays important roles in modulating the immune responses. We have previously demonstrated that infection of dendritic cells (DC) by Leishmania amazonensis leads to increased expression of CD39 and CD73 and to the selective activation of the low affinity A2B receptors (A2B R), which contributes to DC inhibition, without involvement of the high affinity A2A R. To understand this apparent paradox, we now characterized the alterations of both adenosine receptors in infected cells. With this aim, bone marrow-derived DC from C57BL/6J mice were infected with metacyclic promastigotes of L. amazonensis. Fluorescence microscopy revealed that L. amazonensis infection stimulates the recruitment of A2B R, but not of A2A R, to the surface of infected DC, without altering the amount of mRNA or the total A2B R density, an effect dependent on lipophosphoglycan (LPG). Log-phase promastigotes or axenic amastigotes of L. amazonensis do not stimulate A2B R recruitment. A2B R clusters are localized in caveolin-rich lipid rafts and the disruption of these membrane domains impairs A2B R recruitment and activation. More importantly, our results show that A2B R co-localize with CD39 and CD73 forming a "purinergic cluster" that allows for the production of extracellular adenosine in close proximity with these receptors. We conclude that A2B R activation by locally produced adenosine constitutes an elegant and powerful evasion mechanism used by L. amazonensis to down-modulate the DC activation.

Nasal septum deviation and Eustachian tube function: A prospective case-control study based on tympanometry, tubomanometry, and ETDQ-7.

INTRODUCTION: The influence of isolated nasal septum deviation (NSD) in the Eustachian Tube (ET) function is still undetermined. OBJECTIVE: compare ET function between patients with severe NSD and patients with adequate nasal patency in terms of symptomology and objective exams and assess the impact of septoplasty in ET function in patients with severe NSD. METHODS AND METHODOLOGY: a prospective study was conducted. In the first phase of the study, two opportunistic samples were selected: 35 patients with severe NSD for group A and 35 patients with adequate nasal patency for group B. Both groups were evaluated through Nasal obstruction Subjective Questionnaire (NOSE) and ET dysfunction questionnaire 7 (ETDQ7) -, and through two objective exams to assess ET function - tympanometry, and tubomanometry (TMM); results were compared between group A and B. In the second phase of the study, the patients from group A underwent septoplasty and were re-evaluated through ETDQ7, tympanometry and TMM; results were compared before and after surgery. RESULTS: we found a statistically significant difference between patients with NSD and patients with adequate nasal patency in NOSE and ETDQ7 (higher scores in the latter), and TMM (worse results in patients with NSD); the difference in tympanometry was not statistically significant. The side of the NSD did not correlate with the side of the dysfunction. After septoplasty, patients from group A had statistically significant lower scores in ETDQ7 and a lower proportion of patients with findings compatible with ET dysfunction using TMM. CONCLUSION: according to our results, severe NSD alone is a cause of ET dysfunction; septal surgery might improve ET function in these patients.

Is pediatric cholesteatoma more aggressive in children than in adults? A comparative study using the EAONO/JOS classification.

INTRODUCTION: chronic otitis media with cholesteatoma (COMC) is a serious condition that may cause severe complications. According to the literature, in pediatric patients this entity can have a more aggressive behavior, leading to higher rates of morbidity. Consensus regarding the definition of aggressive and extensive cholesteatoma was lacking until recently. European Academy of Otology and Neurotology/Japan Otologic Society (EAONO/JOS) proposed a classification and staging system which was highly accepted by a group of otology experts. OBJECTIVE: to compare cholesteatoma characteristics between pediatric and adult patients using the EAONO/JOS stating system. MATERIAL AND METHODS: a retrospective analysis of the patients who underwent surgery for cholesteatoma treatment in a tertiary hospital was performed using EAONO/JOS classification. Congenital cholesteatoma, revision surgery, and follow-up losses were excluded. The patients were further divided into two cohorts: a pediatric group (<16 years old) and an adult group (>16 years old). The results were compared between them. RESULTS: 134 patients fulfilled the inclusion criteria, 27 were pediatric, and 107 adult patients. We found a significant difference in supratubal recess, with higher rates of extension to this location in the pediatric group. Also in the pediatric cohort, COMC was accompanied by malleus erosion in a higher frequency, with a significant difference from adults; it also presented in higher stages of the disease according to EAONO/JOS classification. We found no differences in hearing gain post-operatively. Moreover, we found that age younger than 16 years was an independent risk factor for relapse with time. DISCUSSION AND CONCLUSIONS: according to our data, cholesteatoma in pediatric age has a more aggressive and extensive nature than in adults, and age younger than 16-years-old is an independent risk factor for relapse.

Cervical Ganglioneuroma in Pediatric Age: A Case Report.

Ganglioneuroma is a rare, benign, non-invasive tumor emerging from the sympathetic system. Of these tumors, only 8% occur in the neck. In this report, we present a case of a 13-year-old girl with a 2-year history of enlarging neck mass. Her only complaint, aside from neck swelling, was dysphagia. Physical and radiological examinations revealed a large mass centered in the right carotid space. A transcervical approach was used to excise the tumor emerging from the sympathetic ganglia. The patient developed temporary Horner's syndrome postoperatively. In a few weeks, she was completely asymptomatic. Histological examination was compatible with ganglioneuroma. Surgical excision is the only definite treatment of cervical ganglioneuroma and is also the only way to confirm the diagnosis. Injury during surgery may result in significant morbidity.

Cetuximab plus platinum-based chemotherapy in head and neck squamous cell carcinoma: a retrospective study in a single comprehensive European cancer institution.

BACKGROUND: The use of cetuximab in combination with platinum (P) plus 5-fluorouracil (F) has previously been demonstrated to be effective in the treatment of metastatic squamous cell cancer of head and neck (SCCHN). We investigated the efficacy and outcome of this protocol as a first-line treatment for patients with recurrent or metastatic disease. We evaluated overall-survival (OS), progression-free-survival (PFS), overall response rate (ORR) and the treatment toxicity profile in a retrospective cohort. PATIENTS AND METHODS: This study enrolled 121 patients with untreated recurrent or metastatic SCCHN. The patients received PF+ cetuximab every 3 weeks for a maximum of 6 cycles. Patients with stable disease who received PF+ cetuximab continued to receive cetuximab until disease progressed or unacceptable toxic effects were experienced, whichever occurred first. RESULTS: The median patient age was 53 (37-78) years. The patient cohort was 86.8% male. The addition of cetuximab to PF in the recurrent or metastatic setting provided an OS of 11 months (Confidential Interval, CI, 95%, 8.684-13.316) and PFS of 8 months (CI 95%, 6.051-9.949). The disease control rate was 48.9%, and the ORR was 23.91%. The most common grade 3 or 4 adverse events in the PF+ cetuximab regimen were febrile neutropenia (5.7%), skin rash (3.8%) and mucosistis (3.8%). CONCLUSIONS: The results of this study suggest that cetuximab plus platinum-fluorouracil chemotherapy is a good option for systemic treatment in advanced SSCHN patients. This regimen has a well-tolerated toxicity profile.