Clinical characteristics of a large familial cohort with Medullary thyroid cancer and germline Cys618Arg RET mutation in an Israeli multicenter study

ObjectiveTo determine genealogical, clinical and pathological characteristics of a cohort with Cys618Arg mutation from an Israeli multicenter MTC study.MethodsRetrospective database analysis examining RET mutations and comparing Cys618Arg and Cys634Arg/Thr/Tyr subgroups.ResultsGenetic testing was performed in 131/275 MTC patients (47.6%). RET mutations were found in 50/131 (38.2%), including Cys618Arg (28/50 cases,56%), and Cys634Arg/Thr/Tyr (15/50,30%). Through genealogical study, 31 MTC patients were found descendants of one family of Jewish Moroccan descent, accounting for 27/28 patients with documented Cys618Arg mutation and 4 patients without available genetic testing. Familial Cys618Arg cases (n=31) and Cys634Arg/Thr/Tyr cases (n=15, from 6 families) were compared. Although surgical age was similar (25.7 vs 31.3 years, p=0.19), the Cys618Arg group had smaller tumors (8.9mm vs 18.5mm, p=0.004) and lower calcitonin levels (33.9 vs 84.5 X/ULN, p=0.03). Youngest ages at MTC diagnosis were 8 and 3 years in Cys618Arg and Cys634Arg/Thr/Tyr cohorts, respectively. Long-term outcome was similar between groups. The Cys618Arg cohort had lower rates of pheochromocytoma (6.5% vs 53.3%, p=0.001) and primary hyperparathyroidism (3.2% vs 33.3%, p=0.01).ConclusionThis is the first description of RET mutation distribution in Israel. Of 131 tested MTC patients, Cys618Arg was the predominant mutation. To the best of our knowledge, this is the largest cohort of Cys618Arg mutation described. For Cys618Arg and Cys634Arg/Thr/Tyr cohorts, MTC was diagnosed earlier than expected, likely due to familial genetic screening, and MTC outcomes were similar between groups. International studies are necessary to further characterize the clinical features of Cys618 mutations due to their relative rarity

SARS-CoV-2 Detection From Voice

Automated voice-based detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could facilitate the screening for COVID19. A dataset of cellular phone recordings from 88 subjects was recently collected. The dataset included vocal utterances, speech and coughs that were self-recorded by the subjects in either hospitals or isolation sites. All subjects underwent nasopharyngeal swabbing at the time of recording and were labelled as SARS-CoV-2 positives or negative controls. The present study harnessed deep machine learning and speech processing to detect the SARS-CoV-2 positives. A three-stage architecture was implemented. A self-supervised attention-based transformer generated embeddings from the audio inputs. Recurrent neural networks were used to produce specialized sub-models for the SARS-CoV-2 classification. An ensemble stacking fused the predictions of the sub-models. Pre-training, bootstrapping and regularization techniques were used to prevent overfitting. A recall of 78% and a probability of false alarm (PFA) of 41% were measured on a test set of 57 recording sessions. A leave-one-speaker-out cross validation on 292 recording sessions yielded a recall of 78% and a PFA of 30%. These preliminary results imply a feasibility for COVID19 screening using voice

Multidimensional Voice Quality Evaluation After Transoral CO2 Laser Cordectomy: A Prospective Study

International audienceObjective: To investigate voice quality changes of patients treated by transoral laser cordectomy (TLC) for early glottic cancer according to the type of cordectomies. Methods: A total of 164 consecutive male patients with an early glottic cancer were prospectively recruited from the Department of Otolaryngology—Head and Neck Surgery of the Georges Pompidou European Hospital. Depending on the tumor characteristics, patients benefited from type I to VI CO2 cordectomy regarding the European Laryngological Society classification. The following voice quality outcomes were pre- to postoperatively assessed: voice handicap index (VHI), perceptual grade of dysphonia, roughness, breathiness, maximum phonation time, and acoustic parameters. Results: Fifty-five patients with Tis, T1, or T2 vocal fold cancer completed the study (mean age: 61.7 years). Of these patients, 34 and 21 composed group 1 (types I-III TLC) and group 2 (types IV-VI TLC), respectively. Voice handicap index, grade of dysphonia, and breathiness significantly improved from pre- to 3- and 6-month posttreatment in group 1. In group 2, only VHI significantly improved from pre- to 3- and 6-month posttreatment. Acoustic and aerodynamic measurements did not change throughout the postoperative course. Patients with types I to III TLC exhibited better postoperative voice outcomes compared to those treated by types IV to VI TLC. Conclusion: Irrespective to the types of TLC, the subjective voice quality of patients treated by CO2 laser cordectomy for early glottic cancer significantly improved from pre- to 3- and 6-month posttreatment. The usefulness of aerodynamic and acoustic measurements as postoperative outcomes of voice quality changes remain controversial and require future studies considering multidimensional assessment of voice

Effect of Opioid Receptor Activation and Blockage on the Progression and Response to Treatment of Head and Neck Squamous Cell Carcinoma

Recent studies suggest that opioids have a role in the progression of HNSCC mediated by mu opioid receptors (MOR), however, the effects of their activation or blockage remains unclear. Expression of MOR-1 was explored in seven HNSCC cell lines using Western blotting (WB). XTT cell proliferation and cell migration assays were performed on four selected cell lines (Cal-33, FaDu, HSC-2, and HSC-3), treated with opiate receptor agonist (morphine), antagonist (naloxone), alone and combined with cisplatin. All four selected cell lines display an increased cell proliferation and upregulation of MOR-1 when exposed to morphine. Furthermore, morphine promotes cell migration, while naloxone inhibits it. The effects on cell signaling pathways were analyzed using WB, demonstrating morphine activation of AKT and S6, key proteins in the PI3K/AKT/mTOR axis. A significant synergistic cytotoxic effect between cisplatin and naloxone in all cell lines is observed. In vivo studies of nude mice harboring HSC3 tumor treated with naloxone demonstrate a decrease in tumor volume. The synergistic cytotoxic effect between cisplatin and naloxone is observed in the in vivo studies as well. Our findings suggest that opioids may increase HNSCC cell proliferation via the activation of the PI3K/Akt/mTOR signaling pathway. Moreover, MOR blockage may chemo-sensitize HNSCC to cisplatin

Intra-operative use of Cone-beam computer/tomographyin a cadaveric ossified cochlea model

Objectives: to describe a cadaveric temporal bone model of labyrinthitis ossificans and investigate the utility of intraoperative cone-beam computed tomography (CBCT) in the facilitating cochlear implantation.Design: cadaveric temporal bone study.Methods: five cadaveric heads had cement introduced into the 10 cochleas. CBCT and a conventional CT scan were compared to assess the extent of cochlear obliteration. The cement was drilled-out (under CBCT guidance, if required) and cochlear implant electrode arrays (from 3 different manufacturers) inserted.Results: CBCT images demonstrated temporal bone anatomy and the extent of cochlear obliteration as clearly as conventional CT in all cases. Intraoperative CBCT guided drilling and facilitated electrode placement in two of five heads (3 of 10 ears). Streak-artifact from the electrodes of two devices partially obscured image clarity.Conclusions: the obliterated cochlear model reproduced a disease-ossified cochlear both radiographically and surgically. CBCT is useful for intraoperative imaging to facilitate electrode array placement in the obliterated or congenitally abnormal cochle

CDK 4/6 Inhibition Overcomes Acquired and Inherent Resistance to PI3Kα Inhibition in Pre-Clinical Models of Head and Neck Squamous Cell Carcinoma

Activating alterations in PIK3CA, the gene coding for the catalytic subunit of phosphoinositide-3-kinase (PI3K), are prevalent in head and neck squamous cell carcinoma (HNSCC) and thought to be one of the main drivers of these tumors. However, early clinical trials on PI3K inhibitors (PI3Ki) have been disappointing due to the limited durability of the activity of these drugs. To investigate the resistance mechanisms to PI3Ki and attempt to overcome them, we conducted a molecular-based study using both HNSCC cell lines and patient-derived xenografts (PDXs). We sought to simulate and dissect the molecular pathways that come into play in PIK3CA-altered HNSCC treated with isoform-specific PI3Ki (BYL719, GDC0032). In vitro assays of cell viability and protein expression indicate that activation of the mTOR and cyclin D1 pathways is associated with resistance to PI3Ki. Specifically, in BYL719-resistant cells, BYL719 treatment did not induce pS6 and pRB inhibition as detected in BYL719-sensitive cells. By combining PI3Ki with either mammalian target of rapamycin complex 1 (mTORC1) or cyclin D1 kinase (CDK) 4/6 specific inhibitors (RAD001 and abemaciclib, respectively), we were able to overcome the acquired resistance. Furthermore, we found that PI3Ki and CDK 4/6 inhibitors have a synergistic anti-tumor effect when combined in human papillomavirus (HPV)-negative/PIK3CA-WT tumors. These findings provide a rationale for combining PI3Ki and CDK 4/6 inhibitors to enhance anti-tumor efficacy in HNSCC patients

Noninvasive Vocal Biomarker is Associated With Severe Acute Respiratory Syndrome Coronavirus 2 Infection

Objective: To investigate the association of voice analysis with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Patients and Methods: A vocal biomarker, a unitless scalar with a value between 0 and 1, was developed based on 434 voice samples. The biomarker training was followed by a prospective, multicenter, observational study. All subjects were tested for SARS-CoV-2, had their voice recorded to a smartphone application, and gave their informed consent to participate in the study. The association of SARS-CoV-2 infection with the vocal biomarker was evaluated. Results: The final study population included 80 subjects with a median age of 29 [range, 23 to 36] years, of whom 68% were men. Forty patients were positive for SARS-CoV-2. Infected patients were 12 times more likely to report at least one symptom (odds ratio, 11.8; P<.001). The vocal biomarker was significantly higher among infected patients (OR, 0.11; 95% CI, 0.06 to 0.17 vs OR, 0.19; 95% CI, 0.12 to 0.3; P=.001). The area under the receiver operating characteristic curve evaluating the association of the vocal biomarker with SARS-CoV-2 status was 72%. With a biomarker threshold of 0.115, the results translated to a sensitivity and specificity of 85% (95% CI, 70% to 94%) and 53% (95% CI, 36% to 69%), respectively. When added to a self-reported symptom classifier, the area under the curve significantly improved from 0.775 to 0.85. Conclusion: Voice analysis is associated with SARS-CoV-2 status and holds the potential to improve the accuracy of self-reported symptom-based screening tools. This pilot study suggests a possible role for vocal biomarkers in screening for SARS-CoV-2–infected subjects

Minimum Nodal Yield in Oral Squamous Cell Carcinoma: Defining the Standard of Care in a Multicenter International Pooled Validation Study

Purpose. There is evidence to suggest that a nodal yield <18 is an independent prognostic factor in patients with clinically node negative (cN0) oral squamous cell carcinoma (SCC) treated with elective neck dissection (END). We sought to evaluate this hypothesis with external validation and to investigate for heterogeneity between institutions. Patients and Methods. We analyzed pooled individual data from 1,567 patients treated at nine comprehensive cancer centers worldwide between 1970 and 2011. Nodal yield was assessed with Cox proportional hazard models, stratified by study center, and adjusted for age, sex, pathological T and N stage, margin status, extracapsular nodal spread, time period of primary treatment, and adjuvant therapy. Two-stage random-effects meta-analyses were used to investigate for heterogeneity between institutions. Results. In multivariable analyses of patients undergoing selective neck dissection, nodal yield <18 was associated with reduced overall survival [hazard ratio (HR) 1.69; 95 % confidence interval (CI) 1.22-2.34; p = 0.002] and disease-specific survival (HR 1.88; 95 % CI 1.21-2.91; p = 0.005), and increased risk of locoregional recurrence (HR 1.53; 95 % CI 1.04-2.26; p = 0.032). Despite significant differences between institutions in terms of patient clinicopathological factors, nodal yield, and outcomes, random-effects meta-analysis demonstrated no evidence of heterogeneity between centers in regards to the impact of nodal yield on disease-specific survival (p = 0.663; I-2 statistic = 0). Conclusion. Our data confirm that nodal yield is a robust independent prognostic factor in patients undergoing END for cN0 oral SCC, and may be applied irrespective of the underlying patient population and treating institution. A minimum adequate lymphadenectomy in this setting should include at least 18 nodes

Comparison of the American Joint Committee on Cancer N1 versus N2a nodal categories for predicting survival and recurrence in patients with oral cancer: Time to acknowledge an arbitrary distinction and modify the system

Background. We hypothesized that pathological N1 (pN1) and N2a (pN2a) nodal disease portend a similar prognosis in patients with oral cancer. Methods. An international multicenter study of 739 oral squamous cell carcinoma (SCC) patients with pN1 or pN2a stage disease was conducted. Multivariable analyses were performed using Cox proportional hazard models to compare locoregional failure, disease-specific survival (DSS), and overall survival (OS). Institutional heterogeneity was assessed using 2-stage random effects meta-analysis techniques. Results. Univariate analysis revealed no difference in locoregional failure (p = .184), DSS (p = .761), or OS (p = .475). Similar results were obtained in adjusted multivariable models and no evidence of institutional heterogeneity was demonstrated. Conclusion. The prognosis of pN2a and pN1 disease is similar in oral SCC suggesting these categories could be combined in future revisions of the nodal staging system to enhance prognostic accuracy. However, these results may reflect more aggressive treatment of N2a disease; hence, we caution against using these data to deintensify treatment. (C) 2015 Wiley Periodicals, Inc