Postoperative Radiotherapy for pT1- and pT2-Classified Squamous Cell Carcinoma of the External Auditory Canal.

Background: There is no consensus regarding the indication for postoperative radiotherapy (PORT) for T1- and T2-classified squamous cell carcinoma (SCC) of the external auditory canal (EAC) even with negative surgical margins. This study aimed to evaluate whether PORT provides additional benefits for these cases.

Methods: We collected retrospective data from fourteen international hospitals, including resected pT1- and pT2-classified EAC SCC with negative surgical margins.

Discovery of PF-07265028, A Selective Small Molecule Inhibitor of Hematopoietic Progenitor Kinase 1 (HPK1) for the Treatment of Cancer.

Hematopoietic progenitor kinase 1 (HPK1/MAP4K1) represents a high interest target for the treatment of cancer through an immune-mediated mechanism. Herein we present highlights of the drug discovery campaign within the lactam/azalactam series of inhibitors that yielded a small molecule (, PF-07265028), which was advanced to a phase 1 clinical trial (NCT05233436). Key components of the discovery effort included optimization of potency through mitigation of ligand strain as guided by the use of cocrystal structures, mitigation of ADME liabilities (plasma instability and fraction metabolism by CYP2D6), and optimization of kinase selectivity, particularly over immune-modulating kinases with high homology to HPK1.

Using learning-by-concordance to develop reasoning in epistaxis management with online feedback: A pilot study.

Background: Epistaxis is a recurring cause for referral to emergency departments. Its management can be complex; hence, it is critical to provide appropriate support to Otolaryngology-Head and Neck Surgery (OHNS) residents to develop clinical reasoning skills to manage such cases. Learning-by-Concordance (LbC) is a recently developed educational tool that encourages learners to think through simulated clinical scenarios.

Carcinomas of the external auditory canal: Management and results: A multicenter REFCOR propensity score matching study.

Objectives: To analyse prognostic factors and survival outcomes of malignant tumors of the external auditory canal, to investigate the role of regional surgery, and adjuvant radiotherapy in early stages and to investigate the role of surgery in operable T4 stage.

Setting: A retrospective analysis was conducted on all patients prospectively included in the national database of the French Expertize Network for Rare ENT Cancers (REFCOR) from January 2000 to December 2016.

Participants: 103 patients from 19 reference centers were included.

Squamous cell carcinoma of the temporal bone: the impact of local control on survival.

Background: Squamous cell carcinoma (SCC) of the temporal bone (TB) is a rare pathology originating from the external auditory canal (EAC). Surgery remains the gold standard to achieve local control.Aims/Objectives:The aim of this study was to evaluate overall survival (OS) and disease-free survival (DFS) after surgery of the SCC of EAC.

Discovery of KIN-3248, An Irreversible, Next Generation FGFR Inhibitor for the Treatment of Advanced Tumors Harboring FGFR2 and/or FGFR3 Gene Alterations.

Fibroblast growth factor receptor (FGFR) alterations are present as oncogenic drivers and bypass mechanisms in many forms of cancer. These alterations can include fusions, amplifications, rearrangements, and mutations. Acquired drug resistance to current FGFR inhibitors often results in disease progression and unfavorable outcomes for patients.

The Discovery of Exarafenib (KIN-2787): Overcoming the Challenges of Pan-RAF Kinase Inhibition.

RAF, a core signaling component of the MAPK kinase cascade, is often mutated in various cancers, including melanoma, lung, and colorectal cancers. The approved inhibitors were focused on targeting the BRAF mutation that results in constitutive activation of kinase signaling through the monomeric protein (Class I). However, these inhibitors also paradoxically activate kinase signaling of RAF dimers, resulting in increased MAPK signaling in normal tissues.

An Endoscopic Procedure for the Simultaneous Treatment of both Otosclerosis and Malleus Fixation.

To report the case of the simultaneous treatment of otosclerosis and malleus fixation through an entirely endoscopic transcanal approach. A targeted transcanalar epitympanotomy with annular bony ridge conservation was planned preoperatively, with 3D CT localization of the fixed part of the malleus head. The upper part of the malleus head and the superior ossified ligament of the malleus were drilled.

Design and Synthesis of Functionally Active 5-Amino-6-Aryl Pyrrolopyrimidine Inhibitors of Hematopoietic Progenitor Kinase 1.

Immune activating agents represent a valuable class of therapeutics for the treatment of cancer. An area of active research is expanding the types of these therapeutics that are available to patients via targeting new biological mechanisms. Hematopoietic progenitor kinase 1 (HPK1) is a negative regulator of immune signaling and a target of high interest for the treatment of cancer.

Otosclerosis: audiometric results and quality of life after stapedectomy with interposition or CO laser-calibrated stapedotomy without interposition.

Background: The surgical treatment of otosclerosis consists of the replacement of the stapes using a piston.

Aims/objectives: The objective of this study is to assess the audiometric results and quality of life (QOL) of patients who underwent surgery for otosclerosis by stapedectomy with fascia interposition (STIP) or by stapedotomy using CO laser (SLaser) without fascia interposition.

Material And Methods: Ninety-one patients operated on for otosclerosis by STIP (40 patients) and by SLaser (51 patients) were included.

French adaptation and validation of the Chronic Otitis Media Questionnaire-12 (COMQ-12).

Objective: Chronic otitis media (COM) can seriously impact quality of life (QOL). Disease-specific questionnaires are essential for an accurate assessment of this impact. There is no questionnaire available for French-speaking patients with COM.

Invasive Rhinosinusitis Caused by in a Patient with Autosomal Recessive CARD9 Deficiency and a Review of the Literature.

Phaeohyphomycoses comprise a heterogeneous group of fungal infections caused by dematiaceous fungi and have primarily been reported in patients with underlying acquired immunodeficiencies, such as hematological malignancies or solid-organ transplants. Over the past decade, a growing number of patients with phaeohyphomycosis but otherwise healthy were reported with autosomal recessive (AR) CARD9 deficiency. We report a 28-year-old woman who presented with invasive rhinosinusitis caused by .

Analysis of tinnitus severity and associated risk factors in patients with chronic otitis media: data from the multinational collaborative Chronic Otitis Media Questionnaire-12 study.

Background: Subjective tinnitus is a common symptom, and there is often an underlying otological cause. This study investigated the degree of tinnitus-related annoyance in patients with chronic otitis media and analysed whether associations with tinnitus severity exist.

Method: The multinational collaborative Chronic Otitis Media Questionnaire-12 study collected prospective data on 478 adult patients suffering from chronic otitis media across 9 otology referral centres in 8 countries.

Preclinical characterization of an intravenous coronavirus 3CL protease inhibitor for the potential treatment of COVID19.

COVID-19 caused by the SARS-CoV-2 virus has become a global pandemic. 3CL protease is a virally encoded protein that is essential across a broad spectrum of coronaviruses with no close human analogs. PF-00835231, a 3CL protease inhibitor, has exhibited potent in vitro antiviral activity against SARS-CoV-2 as a single agent.

Impact of Hearing Disability and Ear Discharge on Quality-of-Life in Patients with Chronic Otitis Media: Data from the Multinational Collaborative COMQ-12 Study.

Objective: This study aimed to assess how two disease-related factors, hearing disability and ear discharge, affect health-related quality-of-life (HRQoL) in patients with chronic otitis media (COM).

Study Design: Multinational prospective cohort study.

Setting: Nine otology referral centers in eight countries.

Presentation of dizziness in individuals with chronic otitis media: data from the multinational collaborative COMQ-12 study.

Purpose: In chronic otitis media (COM), disease chronicity and severity of middle ear inflammation may influence the development of inner ear deficits, increasing the risk of vestibular impairment. This secondary analysis of the multinational collaborative Chronic Otitis Media Questionnaire-12 (COMQ-12) dataset sought to determine the prevalence of vestibular symptoms in patients with COM and identify associated disease-related characteristics.

Methods: Adult patients with a diagnosis of COM in outpatient settings at nine otology referral centers across eight countries were included.

Tracheostomies after SARS-CoV-2 intubation, performed by academic otorhinolaryngologists in the Paris area of France: Preliminary results.

Objective: To analyse tracheostomies after intubation for SARS-Cov-2 infection performed by otorhinolaryngologists in 7 university hospitals in the Paris area of France during the month March 24 to April 23, 2020.

Material And Methods: A multicentre retrospective observational study included 59 consecutive patients. The main goals were to evaluate the number, characteristics and practical conditions of tracheostomies, and the COVID-19 status of the otorhinolaryngologists.

Endoscopic Decompression of the Labyrinthine Segment of the Facial Nerve.

Objective: To describe the outcome and feasibility of an exclusive endoscopic transcanal transpromontorial approach (ETTA) for decompression of the labyrinthine segment of the facial nerve (LSFN).

Patient: A 60-year-old man with a left-sided transverse fracture of temporal bone involving the LSFN, resulting in a grade VI House-Brackmann (HB) facial palsy, associated with ipsilateral total sensorineural hearing loss.

Intervention: Surgical decompression of the LSFN by ETTA.

Structure-Based Drug Design and Synthesis of PI3Kα-Selective Inhibitor (PF-06843195).

The phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway is a frequently dysregulated pathway in human cancer, and PI3Kα is one of the most frequently mutated kinases in human cancer. A PI3Kα-selective inhibitor may provide the opportunity to spare patients the side effects associated with broader inhibition of the class I PI3K family. Here, we describe our efforts to discover a PI3Kα-selective inhibitor by applying structure-based drug design (SBDD) and computational analysis.

Multinational Appraisal of the Chronic Otitis Media Questionnaire 12 (COMQ-12).

Objectives: The Chronic Otitis Media Questionnaire-12 (COMQ-12) assesses patient-reported health-related quality of life. A multinational collaborative project was performed to translate and appraise the psychometric properties of the COMQ-12 across Europe, Asia, and South America.

Methods: Eight otology units from seven countries (China, Colombia, France, Italy, Japan, Korea, Turkey) created native versions of the COMQ-12 by the process of translation and back-translation.

Discovery of Ketone-Based Covalent Inhibitors of Coronavirus 3CL Proteases for the Potential Therapeutic Treatment of COVID-19.

The novel coronavirus disease COVID-19 that emerged in 2019 is caused by the virus SARS CoV-2 and named for its close genetic similarity to SARS CoV-1 that caused severe acute respiratory syndrome (SARS) in 2002. Both SARS coronavirus genomes encode two overlapping large polyproteins, which are cleaved at specific sites by a 3C-like cysteine protease (3CL) in a post-translational processing step that is critical for coronavirus replication. The 3CL sequences for CoV-1 and CoV-2 viruses are 100% identical in the catalytic domain that carries out protein cleavage.

Embolization of Internal Carotid Artery Branches in Juvenile Nasopharyngeal Angiofibroma.

Objective: Preoperative embolization of juvenile nasopharyngeal angiofibroma (JNA) is usually performed by the occlusion of branches of the external carotid artery (ECA). However, a significant proportion of JNAs also receive blood from the internal carotid artery (ICA). The objective of this study was to report on the feasibility and clinical impact of superselective embolization of ICA branches in complex cases of JNA.