Current Status of Partial Laryngeal Surgery for Advanced Laryngeal Cancer: When and Why?

PURPOSE OF REVIEW: This paper aims to evaluate the evolution and current status of partial laryngeal surgery in the treatment of advanced laryngeal cancer (LC). Specifically, recent progress in the selection of both patients and tumors, together with surgical and rehabilitation innovations, have contributed to balancing oncological control with the maintenance of quality of life in naïve and radiorecurrent patients. The main aspect is represented by the recognized role of open partial horizontal laryngectomies (OPHLs) in this new era of laryngeal cancer treatment. RECENT FINDINGS: Recent advancements highlight OPHLs' efficacy for conservative management of intermediate to advanced stages of LC. Innovations such as supratracheal partial laryngectomy have expanded surgical options, offering a modular approach to complex cases. Improved understanding of tumor biology, enhanced imaging techniques, and more precise preoperative planning have led to better patient outcomes, emphasizing the importance of a conservative function-preserving surgical treatment. These advancements reflect a broader trend towards individualized treatment plans that prioritize both survival and quality of life. OPHLs play an important role in current management of intermediate/advanced LC, effectively balancing oncological control with the preservation of laryngeal functions. Critical factors include meticulous patient and tumor selection, the impact of surgical and technological refinements on functional outcomes, and the necessity of a multidisciplinary approach in treatment planning. Current evidence justifies the use of these interventions in many intermediate T-stage laryngeal tumors, even at risk of upstaging on pathological examination. The oncological results, the preservation of laryngeal function and the laryngectomy-free survival achieved with OPHLs appear to be highly competitive with those of non surgical organ-preservation protocols, aiming to introduce a new standard in the LC treatment.

Validity, reliability and reproducibility of the VLS parameters form for the collection of videolaryngostroboscopic basic findings.

OBJECTIVE: The videolaryngostroboscopy parameters form (VLSP form) is a diagnostic tool for the collection of videolaryngostroboscopic basic findings through the evaluation of 12 parameters. The aim of the present study is to preliminarily investigate intra- and inter-rater reliability, validity and responsiveness of the VLSP form. METHODS: A study on a total amount of 160 forms for the evaluation of VLS basic findings was carried out. 80 forms were scored through the VLSP form and 80 with the Voice Vibratory Assessment with Laryngeal Imaging (VALI) form Stroboscopy (S) by four expert phoniatricians, that blindly scored the VLS recordings of 5 subjects without voice disorders and 5 patients with organic voice disorder before and after successful phonosurgery. Intra-rater and inter-rater analysis have been performed for both forms. The scores obtained through VLSP form and VALI form S have been compared to analyse concurrent validity, while VLSP scores before and after phonosurgery have been compared to analyse responsiveness. Finally, each rater annotated the "difficulty" in rating every parameter and its "importance" for the diagnosis. RESULTS: The VLSP form showed good inter- and intra-rater reliability. It showed a good accuracy for the documentation of changes of laryngeal anatomy and function after phonosurgery, similarly to the VALI form S. The 12 parameters of the VLSP form were judged "Slightly Important" in 28.3% of the samples, "Very Important" in 64.8% of the samples, "Not Difficult" in 73.1% of the samples. CONCLUSIONS: The results of the present study suggest that the VLSP form is comparable to the VALI form S for the evaluation of videolaryngostroboscopic parameters and is a valid, reliable and reproducible diagnostic tool. It can help voice clinicians in the evaluation of VLS examinations and it allows for a punctual assessment of modifications in laryngeal anatomy and function in pathological conditions and after phonosurgery.

Immediate effects of the semi-occluded bubble mask technique using VocalFeel® device as vocal warm-up in singers.

OBJECTIVE: The present study aims at investigating the immediate effects of the Semi-Occluded Bubble Mask Technique (SOBM) performed with the device VocalFeel® as a vocal warm-up in a group of professional singers. STUDY DESIGN: A randomized controlled study was carried out. METHODS: Forty-four vocally healthy professional singers were randomly divided into two groups on recruitment: an experimental group and a control group. The same vocal warm-up exercise was performed by the experimental group with the SOMB technique and by the control group without semi-occlusion. Self assessments, acoustic analysis and aerodynamic analysis of Peak Nasal Inspiratory Flows (PNIF) and Peak Oral Inspiratory Flows (POIF) were performed. RESULTS: Significant improvements after the SOBM technique were detected in the experimental group concerning some acoustic parameters (Jitt%; Shimm%) and aerodynamic measures (PNIF and POIF). No significant improvements after the warm-up exercise were observed in the control group. Significant differences between the experimental and the control group were found for ΔJitt%, ΔShimm%, ΔNHR, ΔPOIF and self assessments. CONCLUSIONS: The results of the present study support the efficacy of a vocal warm-up performed with the SOBM technique using VocalFeel® device in terms of acoustic quality, aerodynamic measures and perceived phonatory comfort in professional singers.

Partial Laryngectomy for pT4a Laryngeal Cancer: Outcomes and Limits in Selected Cases.

A large multi-institutional case series of laryngeal cancer (LC) T4a was carried out, including 134 cases treated with open partial horizontal laryngectomies (OPHL) +/- post-operative radiation therapy (PORT). The goal was to understand better whether OPHL can be included among the viable options in selected pT4a LC patients who refuse a standard approach, represented by total laryngectomy (TL) + PORT. All 134 patients underwent OPHL type I (supraglottic), II (supracricoid), or III (supratracheal), according to the European Laryngological Society Classification. Comparing clinical and pathological stages showed pT up-staging in 105 cases (78.4%) and pN up-staging in 19 patients (11.4%). Five-year data on overall survival, disease-specific survival, disease-free survival, freedom from laryngectomy, and laryngo-esophageal dysfunction-free survival (rate of patients surviving without a local recurrence or requiring total laryngectomy and without a feeding tube or a tracheostomy) were, respectively, 82.1%, 89.8%, 75.7%, 89.7%, and 78.3%. Overall, complications were observed in 22 cases (16.4%). Sequelae were observed in 28 patients (20.9%). No patients died during the postoperative period. This large series highlights the good onco-functional results of low-volume pT4a laryngeal tumors, with minimal or absent cartilage destruction, treated with OPHLs. The level of standardization of the indication for OPHL should allow consideration of OPHL as a valid therapeutic option in cases where the patient refuses total laryngectomy or non-surgical protocols with concomitant chemo-radiotherapy.

Nasal Breathing Through a Damp Gauze Enhances Surface Hydration of the Vocal Folds and Optimizes Vocal Function.

OBJECTIVE: The present study proposes a direct surface hydration system based on nasal breathing through a damp gauze. The goal is to observe whether such direct hydration procedure positively modifies vocal fold functionality by improving voice quality and enhancing the mobility and pliability of the vocal fold mucosa. METHODS: Sixty-one young adults without voice problems were enrolled and were randomly divided into three double-blinded treatment groups. In the first group (the gauze group), participants breathed through the nose wrapped in a damp gauze for 10 minutes while doing vocal warm-up exercises to facilitate water penetration into the mucosal layers of the vocal folds. The second group (the exercise group) performed the same warm-up exercises as the gauze group for 10 minutes without hydration procedures. The third group (the control group) talked using their normal speaking voice for 10 minutes. The participants were evaluated before and after the treatment tasks with three tests: a laryngostroboscopic examination (ie, the glottic closure, the amplitude of the mucosal wave, and the maximum opening of the glottic space); voice acoustic analysis (multidimensional voice program); and a perceptual voice evaluation (GRBAS scale). RESULTS: Results showed that after the use of a damp gauze, glottic closure, the amplitude of the mucosal wave, the maximum opening of the glottic space, the shimmer, and the B of GRBAS all improved. CONCLUSION: Findings showed significantly better vocal results for the participants of the gauze group, suggesting the damp gauze procedure to be an effective, fast, and economical procedure to improve and optimize vocal fold functionality. It can be hypothesized that the obtained results are related to an improvement in vocal folds surface hydration and viscoelasticity.

Spontaneous Vocal Fold Polyps Remission after Lockdown for Covid-19 Pandemic: Does Vocal Load Matter?

OBJECTIVE: During the Italian lockdown for Covid-19 emergency, due to stay-at-home orders, many people experienced an unusual period of voice rest. The present case series aims at reporting the spontaneous regression of some vocal fold polyps during the Italian lockdown for SARS-CoV2 pandemic. METHODS: Five patients with voice complaints presenting to a tertiary referral center and diagnosed with vocal fold polyps before the lockdown were included. Because of the lockdown restrictive measures, planned elective surgical procedures were suspended. The patients were re-assessed immediately after lockdown. Multidimensional voice assessments were conducted before and after the lockdown period through laryngostroboscopies, perceptual voice evaluations, electroacoustic analysis and self assessments. RESULTS: The patients included in the present case series experienced a complete or nearly complete remission of symptoms. Videolaryngostroboscopies documented a complete or nearly complete regression of the polyps. Voices considerably improved both perceptually and electroacoustically. Self assessments showed a reduction of voice-related complaints. CONCLUSIONS: The present study suggests that daily vocal load reduction may play a critical role in the conservative management of vocal fold polyps.

Validation of the Acoustic Voice Quality Index (AVQI) Version 03.01 in Italian.

OBJECTIVE: The aim of the present study is to validate the Acoustic Voice Quality Index version 03.01 in the Italian language (AVQIv3-IT). METHODS: A total of 150 native Italian speakers with normal voices (n = 50) and with various voice disorders (n = 100) were enrolled. Voice samples of a sustained vowel (SV) [a:] and five phonetically balanced continuous speech (CS) samples were recorded. The most appropriate syllable number for a standardized voiced CS approximating 3 seconds was identified. Perceptual evaluations of the overall voice quality were performed by three expert voice clinicians using the G score of the GRBAS scale. AVQIs were calculated using a 3 seconds mid-vowel selection of the SV [a:] and the standardized syllable number of the CS. Finally, concurrent validity and diagnostic accuracy of AVQIv3-IT were analysed. RESULTS: The most appropriate syllable number for a standardized CS approximating 3 seconds in Italian was identified as 25. The perceptual ratings showed robust intra- and inter-rater reliability. A strong correlation was found between AVQI scores and overall voice quality perceptual evaluations (r = 0.81, P < 0.001). The best diagnostic outcome for AVQIv3-IT was found for a threshold of 2.35 (sensitivity of 90% and specificity of 92%). CONCLUSIONS: AVQIv3-IT was demonstrated to be a valid and robust tool for quantifying overall acoustic voice quality in the Italian speaking population.

Acetylation-Specific Interference by Anti-Histone H3K9ac Intrabody Results in Precise Modulation of Gene Expression.

Among Histone post-translational modifications (PTMs), lysine acetylation plays a pivotal role in the epigenetic regulation of gene expression, mediated by chromatin modifying enzymes. Due to their activity in physiology and pathology, several chemical compounds have been developed to inhibit the function of these proteins. However, the pleiotropy of these classes of proteins represents a weakness of epigenetic drugs. Ideally, a new generation of epigenetic drugs should target with molecular precision individual acetylated lysines on the target protein. We exploit a PTM-directed interference, based on an intrabody (scFv-58F) that selectively binds acetylated lysine 9 of histone H3 (H3K9ac), to test the hypothesis that targeting H3K9ac yields more specific effects than inhibiting the corresponding HAT enzyme that installs that PTM. In yeast scFv-58F modulates, gene expression in a more specific way, compared to two well-established HAT inhibitors. This PTM-specific interference modulated expression of genes involved in ribosome biogenesis and function. In mammalian cells, the scFv-58F induces exclusive changes in the H3K9ac-dependent expression of specific genes. These results suggest the H3K9ac-specific intrabody as the founder of a new class of molecules to directly target histone PTMs, inverting the paradigm from inhibiting the writer enzyme to acting on the PTM.

Voice and communication after open partial horizontal laryngectomies: A cross-sectional outcome study.

OBJECTIVE: The present study evaluates voice and communication after open partial horizontal laryngectomies (OPHLs), according to surgery and patient-related variables. METHODS: Fifty-eight patients were included: 18 type I OPHL, 20 type II OPHL and 20 type III OPHL. Acoustic, aerodynamic, endoscopic, perceptual and self-assessment analyses were carried out. Surgery-related variables and patient-related variables were considered for the analysis. RESULTS: Type I OPHL revealed the best phonatory outcomes. Type II and type III OPHL showed similar and poor results, with a highly deteriorated voice quality. A significant difference in MTP was found for patients who had both arytenoids/cricoarytenoid units preserved. Age and time from surgery showed significant correlations with voice quality after OPHLs. CONCLUSIONS: Voice and communication outcomes after OPHLs are heterogeneous and might be influenced by several factors. Knowing variables with a substantial impact on phonatory outcomes may help clinicians in the preoperative decision-making process and the postoperative rehabilitative program.

Phonosurgical Injection Approaches for Voice Restoration After Open Partial Horizontal Laryngectomies: A Pilot Study.

OBJECTIVE: The aim of the present study is to evaluate the efficacy of phonosurgical corrective approaches based on injection laryngoplasties and pharyngoplasties followed by speech therapy for voice restoration after unsatisfactory phonatory results of open partial horizontal laryngectomies. METHODS: Ten patients with not satisfying phonatory results despite speech therapy after type II or type III open partial horizontal laryngectomies (OPHLs) were included. Each patient underwent a voice restoration program based on phonosurgery (injection laryngoplasty and/or injection pharyngoplasty) with hyaluronic acid and/or calcium hydroxyapatite, followed by post-surgical voice rehabilitation. Voices were recorded and analysed through spectrographic, aerodynamic, perceptual, laryngoscopic and self-assessment evaluations before the treatment (T0), after 1 month (T1) and after three months (T2). RESULTS: Significant improvements in the patients voices were found between T0, T1 and T2 concerning acoustic, perceptual, aerodynamic, laryngoscopic and self assessment evaluations. CONCLUSIONS: The results of the present study support phonosurgical injection procedures followed by speech therapy as an effective strategy for voice restoration after type II or type III OPHLs in selected patients.

Substitution Voice Rehabilitation After Open Partial Horizontal Laryngectomy Through the Proprioceptive Elastic Method (PROEL): A Preliminary Study.

OBJECTIVE: The aim was to investigate the efficacy of the Proprioceptive Elastic Method (PROEL) in the rehabilitation of the substitution voice after open partial horizontal laryngectomy (OPHL). STUDY DESIGN: Prospective outcome study. METHODS: Fifteen patients surgically treated by OPHL type II or type III for laryngeal cancer were recruited (experimental group). Each patient underwent a specific program of voice rehabilitation based on the PROEL method with the same speech and language pathologist. Acoustic-aerodynamic analysis: maximum phonation time (MPT); spectrographic classification (Titze's modified classification), perceptual analysis (INFVo rating scale) and self-assessments (SECEL questionnaire) were performed before the treatment (T0), after 3 months of rehabilitation (T1), and at the end of the 6-month rehabilitation program (T2). A control sample of other 15 patients who underwent OPHL type II or type III and who underwent a standard perioperative rehabilitation was randomly extracted from an historical database and compared to the experimental group. RESULTS: Significative voice improvements between T0-T1 and T2 were found for acoustic, aerodynamic, perceptual, and self-assessments analysis in the experimental group. Significative differences were found between the experimental group at T2 and the control sample for aerodynamic, self-assessment, and perceptual analysis. CONCLUSIONS: The results of the present study support PROEL method as an effective approach for substitution voice rehabilitation after OPHL type II and III. Randomized controlled trials on larger groups of patients are needed in future in order to compare PROEL with other rehabilitative approaches.

Lipofilling after total parotidectomy: a useful option to prevent functional and aesthetic sequelae.

Objective: Parotidectomy is the main treatment for parotid tumours, but its functional and aesthetic sequelae can be very disturbing for patients. Methods: 15 patients underwent total conservative parotidectomy, harvesting of a superficial musculoaponeurotic system (SMAS) flap and lipofilling between May 2014 and June 2020 for a benign parotid tumour. Aesthetic, functional sequelae and cosmetic results were assessed with the House-Brackmann scale, Luna-Ortiz's classification and a semiquantitative questionnaire. Lipofilling resorption was analysed by maxillofacial and neck MRI imaging at 2 years after surgery. The results were compared to a group of 21 patients who underwent total parotidectomy without harvesting a SMAS flap and lipofilling. Results: No complications were observed. No facial defects were seen during follow-up. Post-operative MRI showed fat resorption was less than 20% in 12 patients and from 20 to 30% in 3 patients. Cosmetic satisfaction was 100% in all cases. Only 1 patient (6%) complained of Frey's syndrome. Conclusions: Lipofilling is an excellent solution considering its efficacy, safety, simplicity, duration over time and economic costs. Donor site invasiveness is minimal, and reintervention is always possible. Face-lift incision and SMAS flap can improve aesthetic results and minimise the disfiguring impact of the surgical scar.

Impact of COVID-19 restrictions on hospitalisation and post-operative rehabilitation of head and neck cancer patients.

OBJECTIVE: The COVID-19 pandemic emergency forced the health system in Italy to implement an immediate reorganisation to support the care of tens of thousands of patients and to maintain the quality of care for patients with other pathologies, such as oncologic diseases. The main goal of this study was to evaluate the impact of COVID-19 restrictions on the hospitalisation and post-operative rehabilitation of head and neck oncologic patients and to determine whether the introduction of new technologies such as video-communication may be useful to mitigate social distancing by close family members. METHODS: Fifty-one consecutive patients underwent surgery for head and neck cancer during the period of lockdown caused by the COVID-19 pandemic. The data collected (post-operative pain, post-operative complications, duration of hospitalisation) were compared with those of 51 consecutive patients treated for head and neck cancer in the period immediately preceding lockdown. RESULTS: The average duration of hospitalisation was longer in patients operated on in the COVID-19 period, and, in particular, among patients who underwent a more demanding rehabilitation protocol. Despite this, our study did not show a significant difference in psychological aspects during hospitalisation. CONCLUSIONS: The greatest difficulties that occurred in the COVID-19 period were met by a greater commitment from medical staff, allowing the quality of life of head and neck cancer patients during post-operative rehabilitation to be maintained at a similar level to that before the pandemic. In the future, there will be a need for technological solutions to bring the patient closer to family members.

Preoperative prognostic factors for functional and clinical outcomes after open partial horizontal laryngectomies.

BACKGROUND: In minority of cases, the clinical recovery of the neolarynx after open partial horizontal laryngectomies (OPHLs) can be challenging, possibly affecting the final functional outcome. METHODS: One hundred and twenty-three patients who underwent OPHLs were selected. A series of clinical preoperative independent variables were considered. All patients were monitored for the following dependent outcome variables: sequelae; need for percutaneous endoscopic gastrostomy positioning; days before tracheal cannula removal and nasogastric tube removal; and length of hospital stay. Univariate and multivariate logistic regression analyses were performed to identify significant associations between preoperative clinical variables and outcomes variables. RESULTS: Multivariate analysis confirmed age, cT classification, body mass index, and smoking habits as significant prognostic factors for worse functional and clinical recovery outcomes. CONCLUSIONS: Knowing what variables are significantly associated with worse clinical and functional outcomes can guide clinicians in defining the best surgical choice not only from an oncological perspective, but also for a better postoperative recovery.

Aggregation is a Context-Dependent Constraint on Protein Evolution.

Solubility is a requirement for many cellular processes. Loss of solubility and aggregation can lead to the partial or complete abrogation of protein function. Thus, understanding the relationship between protein evolution and aggregation is an important goal. Here, we analysed two deep mutational scanning experiments to investigate the role of protein aggregation in molecular evolution. In one data set, mutants of a protein involved in RNA biogenesis and processing, human TAR DNA binding protein 43 (TDP-43), were expressed in S. cerevisiae. In the other data set, mutants of a bacterial enzyme that controls resistance to penicillins and cephalosporins, TEM-1 beta-lactamase, were expressed in E. coli under the selective pressure of an antibiotic treatment. We found that aggregation differentiates the effects of mutations in the two different cellular contexts. Specifically, aggregation was found to be associated with increased cell fitness in the case of TDP-43 mutations, as it protects the host from aberrant interactions. By contrast, in the case of TEM-1 beta-lactamase mutations, aggregation is linked to a decreased cell fitness due to inactivation of protein function. Our study shows that aggregation is an important context-dependent constraint of molecular evolution and opens up new avenues to investigate the role of aggregation in the cell.

Effect of sex hormones on human voice physiology: from childhood to senescence.

The aim of the present literature review is to describe the influence of sex hormones on the human voice in physiological conditions. As a secondary sexual organ, the larynx is affected by sex hormones and may change considerably over the lifespan. In the current review, sex hormone-related voice modifications occurring during childhood, puberty, the menstrual cycle, pregnancy and senescence are described. The roles of sex hormones (including gonadotropins, testosterone, estrogen, androstenedione, dehydroepiandrosterone, and dehydroepiandrosterone-sulfate) underlying physiological voice changes are discussed, the main differences between males and females are explained and clinical implications are taken into account.

Selection and Modelling of a New Single-Domain Intrabody Against TDP-43.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder associated to deteriorating motor and cognitive functions, and short survival. The disease is caused by neuronal death which results in progressive muscle wasting and weakness, ultimately leading to lethal respiratory failure. The misbehaviour of a specific protein, TDP-43, which aggregates and becomes toxic in ALS patient's neurons, is supposed to be one of the causes. TDP-43 is a DNA/RNA-binding protein involved in several functions related to nucleic acid metabolism. Sequestration of TDP-43 aggregates is a possible therapeutic strategy that could alleviate or block pathology. Here, we describe the selection and characterization of a new intracellular antibody (intrabody) against TDP-43 from a llama nanobody library. The structure of the selected intrabody was predicted in silico and the model was used to suggest mutations that enabled to improve its expression yield, facilitating its experimental validation. We showed how coupling experimental methodologies with in silico design may allow us to obtain an antibody able to recognize the RNA binding regions of TDP-43. Our findings illustrate a strategy for the mitigation of TDP-43 proteinopathy in ALS and provide a potential new tool for diagnostics.

VITOM-3D assisted neck dissection via a retroauricular approach (RAND-3D): a preclinical investigation in a cadaver lab.

OBJECTIVE: The recent introduction of 3D exoscopic surgery has allowed interesting technical improvements in head and neck surgery resulting in technical solutions that are also applicable to neck dissection. The aim is to replace robotic surgery while minimising the costs of the procedure. METHODS: Based on these considerations, we conducted a preclinical investigation in the cadaver lab focused on approaching conventional neck dissection using a retroauricular incision, and evalute the applications and usefulness of the Storz 3D Exoscopic System at different stages of the surgical procedure. The acronym RAND-3D (3D exoscopic surgery) was coined to describe the application of this optical tool in neck dissection. RESULTS: The current study in the cadaver lab indicates that RAND-3D is an acceptable alternative operating technique in performing neck dissection by a retroauricular approach. Technically feasible and safe, this technique assures a complete compartment-oriented dissection without damaging major vascular or nervous structures. CONCLUSIONS: This approach can be used in selected cases with a clear cosmetic benefit and represents a valid alternative to endoscopic- and robotic-assisted neck dissection.