Radiation Dose to Otologic Structures During Head and Neck Cancer Radiation Therapy

Background: Otologic structures are often contained within head and neck cancer radiation treatment ports. The dosimetry to otologic structures has not been routinely analyzed and radiation treatment planning does not currently attempt to specifically avoid the inner ear structures when dosimetry is calculated. Recent studies demonstrate that up to 30% of patients experience sensorineural hearing loss on multimodality therapy with cisplatin and radiation. Methods: In the current case series, radiation dosimetry to otologic structures was calculated from computed tomogram treatment plans on patients. Fifteen nasopharyngeal, oral cavity, oropharyngeal, and hypopharyngeal cancer patients were analyzed. Results: Between 8% and 102% of the total dose is delivered to the petrous bone/cochlea, with 4 of 15 patients getting more than 50% of the dose to at least one cochlea. The mastoid air cells received between 3% and 75% of the total dose, with higher doses being delivered to patients with bulky high neck metastases or nasopharyngeal tumors. The eustachian tubes received between 2% and 102% of the total dose, with 10 of 15 patients receiving more than 50% of the dose to this anatomic site. Conclusion: We conclude that the cochlea and eustachian tubes receive significant radiation during treatment, particularly in nasopharyngeal cancer patients. Careful design of radiation treatment ports may allow for the reduction of radiation to hearing structures.     

Characterization of the Sheep Round Window Membrane

Intratympanic injection is a clinically used approach to locally deliver therapeutic molecules to the inner ear. Drug diffusion, at least in part, is presumed to occur through the round window membrane (RWM), one of the two openings to the inner ear. Previous studies in human temporal bones have identified a three-layered structure of the RWM with a thickness of 70–100 μm. This is considerably thicker than the RWM in rodents, which are mostly used to model RWM permeability and assess drug uptake. The sheep has been suggested as a large animal model for inner ear research given the similarities in structure and frequency range for hearing. Here, we report the structure of the sheep RWM. The RWM is anchored within the round window niche (average vertical diameter of 2.1 ± 0.3 mm and horizontal diameter of 2.3 ± 0.4 mm) and has a curvature that leans towards the scala tympani. The centre of the RWM is the thinnest (55–71 μm), with increasing thickness towards the edges (< 171 μm), where the RWM forms tight attachments to the surrounding bony niche. The layered RWM structure, including an outer epithelial layer, middle connective tissue and inner epithelial layer, was identified with cellular features such as wavy fibre bundles, melanocytes and blood vessels. An attached “meshwork structure” which extends over the cochlear aqueduct was seen, as in humans. The striking anatomical similarities between sheep and human RWM suggest that sheep may be evaluated as a more appropriate system to predict RWM permeability and drug delivery in humans than rodent models.     

Head and Neck Cancer: The Importance of Oxygen

Objectives To use recently introduced polarographic technology to characterize the distribution of oxygenation in solid tumors, explore the differences between severe hypoxia and true necrosis, and evaluate the ability to predict treatment outcomes based on tumor oxygenation. Study Design Prospective, nonrandomized trial of patients with advanced head and neck cancer, conducted at an academic institution. Methods A total of 63 patients underwent polarographic oxygen measurements of their tumors. Experiment 1 was designed to determine whether a gradient of oxygenation exists within tumors by examining several series of measurements in each tumor. Experiment 2 was an analysis of the difference in data variance incurred when comparing oxygen measurements using oxygen electrodes of two different sizes. Experiment 3 compared the proportion of tumor necrosis to the proportion of very low (≤2.5 mm Hg) polarographic oxygen measurements. Experiment 4 was designed to explore the correlation between oxygenation and treatment outcomes after nonsurgical management. Results No gradient of oxygenation was found within cervical lymph node metastases from head and neck squamous cell carcinomas (P > .9). Tumor measurements achieved with larger (17 μm) electrodes displayed smaller variances than those obtained with smaller (12 μm) electrodes, although this difference failed to reach statistical significance (P = .60). There was no correlation between tumor necrosis and the proportion of very low (≤2.5 mm Hg) oxygen measurements. There was a nonsignificant trend toward poorer locoregional control and overall survival in hypoxic tumors. Conclusions Hypoxia exists within cervical lymph node metastases from head and neck squamous carcinomas, but the hypoxic regions are distributed essentially randomly. As expected, measurements of oxygen achieved with larger electrodes results in lowered variance, but with no change in overall tumor mean oxygen levels. Polarographic oxygen measurements are independent of tumor necrosis. Finally, oxygenation as an independent variable is incapable of predicting prognosis, probably reflecting the multifactorial nature of the biological behavior of head and neck cancers.     

Perilymph Kinetics of FITC-Dextran Reveals Homeostasis Dominated by the Cochlear Aqueduct and Cerebrospinal Fluid

Understanding how drugs are distributed in perilymph following local applications is important as local drug therapies are increasingly used to treat disorders of the inner ear. The potential contribution of cerebrospinal fluid (CSF) entry to perilymph homeostasis has been controversial for over half a century, largely due to artifactual contamination of collected perilymph samples with CSF. Measures of perilymph flow and of drug distribution following round window niche applications have both suggested a slow, apically directed flow occurs along scala tympani (ST) in the normal, sealed cochlea. In the present study, we have used fluorescein isothiocyanate-dextran as a marker to study perilymph kinetics in guinea pigs. Dextran is lost from perilymph more slowly than other substances so far quantified. Dextran solutions were injected from pipettes sealed into the lateral semicircular canal (SCC), the cochlear apex, or the basal turn of ST. After varying delays, sequential perilymph samples were taken from the cochlear apex or lateral SCC, allowing dextran distribution along the perilymphatic spaces to be quantified. Variability was low and findings were consistent with the injection procedure driving volume flow towards the cochlear aqueduct, and with volume flow during perilymph sampling driven by CSF entry at the aqueduct. The decline of dextran with time in the period between injection and sampling was consistent with both a slow volume influx of CSF (∼30 nL/min) entering the basal turn of ST at the cochlear aqueduct and a CSF-perilymph exchange driven by pressure-driven fluid oscillation across the cochlear aqueduct. Sample data also allowed contributions of other processes, such as communications with adjacent compartments, to be quantified. The study demonstrates that drug kinetics in the basal turn of ST is complex and is influenced by a considerable number of interacting processes.     

Guideline for the Surgical Management of Locally Invasive Differentiated Thyroid Cancer From the Korean Society of Head and Neck Surgery

The aim of this study was to develop evidence-based recommendations for determining the surgical extent in patients with locally invasive differentiated thyroid cancer (DTC). Locally invasive DTC with gross extrathyroidal extension invading surrounding anatomical structures may lead to several functional deficits and poor oncological outcomes. At present, the optimal extent of surgery in locally invasive DTC remains a matter of debate, and there are no adequate guidelines. On October 8, 2021, four experts searched the PubMed, Embase, and Cochrane Library databases; the identified papers were reviewed by 39 experts in thyroid and head and neck surgery. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess the quality of evidence, and to develop and report recommendations. The strength of a recommendation reflects the confidence of a guideline panel that the desirable effects of an intervention outweigh any undesirable effects, across all patients for whom the recommendation is applicable. After completing the draft guidelines, Delphi questionnaires were completed by members of the Korean Society of Head and Neck Surgery. Twenty-seven evidence-based recommendations were made for several factors, including the preoperative workup; surgical extent of thyroidectomy; surgery for cancer invading the strap muscles, recurrent laryngeal nerve, laryngeal framework, trachea, or esophagus; and surgery for patients with central and lateral cervical lymph node involvement. Evidence-based guidelines were devised to help clinicians make safer and more efficient clinical decisions for the optimal surgical treatment of patients with locally invasive DTC.     

Surgical anatomy and pathology of the round window

A study of the surgical anatomy and pathology of the round window was performed on a total of 292 serially sectioned temporal bones. The surgical approach to the round window is discussed with consideration of the anatomical findings. In the pathological study obliteration of the round window niche occurred as a congenital anomaly, in otosclerosis, chronic otitis media and as an end result in suppurative labyrinthitis. Clinical reports seem to indicate that obliteration of the window is associated with a significant hearing loss, contrary to the findings in experimental animals. In chronic otitis media the round window is a pathway for spread of infection to the labyrinth, but also the finding of perilymphatic precipitates adjacent to the window in some ears suggests that certain inflammatory products may enter the scala tympani through the round window and so lead to high tone sensorineural hearing loss.     

Comparative Evaluation of Chemoimmunoradiotherapy and Chemoradiotherapy in the Management of Advanced Head and Neck Cancer

50 patients of advanced squamous cell carcinoma of the head and neck were randomised cither to receive chemotherapy followed by radiation therapy or chemoimmunotherapy followed by radiotherapy. In the chemoimmunotherapy arm, the patients received recombinant interferon alpha 2b 3 M.U. subcutaneously, thrice a week on alterante days for 5 weeks from Day 1, Cisplatinum 70 mg/ m² on Day 1 and 21, and 5 — flurouracil 1000mg/m² on Day 1, 2, 3 and Day 21, 22, 23, followed by from Dav 36, radiotherapy'by Co bait 60 to a tumour dose of 65 Gy in 30 # over 6 weeks. In the control arm, patiens received Cisplatitnum 70 mg/ m² on Day 1 and Day 21, 5 flurouracil 1000 mg/ m² on Dav 1, 2, 3 and Day 21, 22, 23 followed by radiotherapy by Cobalt 60 to a tumour dose of 65 Gy in 30 # over 6 weeks from Day 36. Only Grade II and III toxicity was observed in the two arms which were manageable Patients treated with chemoimmunotherapy followed by radiotherapy showed 60% complete response, 20% partial response and 12% no change/ progressive disease; while the patients on the control arm treated with chemotherapy and radiotherapy showed 12% complete response 44% Partial response and 32% no change“ progressive disease. This trial concludes that chemoimmunotherapy followed by radiotherapy is an excellent alternative therapeutic strategy for the management of advanced head and neck cancers with manageable toxicity.     

The Use and Misuse of Level IA Dissection for Head and Neck Cancer

Bronchogenic cysts are rare congenital malformations of ventral foregut development. They are usually located in the mediastinum and intrapulmonary regions. Localization in the cervical area is unusual and the majority of cases reported have been found in the pediatric population: the literature reports few cases in adults. We describe a 57-year-old male who presented an asymptomatic right lateral neck mass. Diagnostic studies included chest X-ray, pharyngo-esophagus double-contrast X-ray, computed tomography (CT), and bronchoscopy. The mass was excised through a transverse right cervical skin incision. The right lateral neck mass of the patient was identified as a bronchogenic cyst. The embryology, the presentation, the pathological and radiological evaluation, treatment of the cyst and a review of the English literature are reported in this paper. Cervical bronchogenic cysts are usually diagnosed in the pediatric population; these lesions are rare in adults. We suggest that the clinical observation of an asymptomatic lateral neck mass in an adult should include the possibility of a bronchogenic cyst in the differential diagnosis. Surgical excision is the elective treatment for this tumor, in order to prevent complications including infection, compression symptoms, malignant transformation, and the rare but fatal air embolism.     

Round window membrane and labyrinthine pathological changes: an overview

The round window membrane is considered the most likely pathway from the middle to the inner ear. Various substances placed in the middle ear have been seen to pass through the round window membrane. Once toxic substances or inflammatory mediators such as cytokines and nitric oxide enter the inner ear, various inner ear sequelae such as labyrinthitis, endolymphatic hydrops, sensorineural hearing loss or more insidious diseases can occur.     

Animal Models of Cancer in the Head and Neck Region

Animal models that resemble the cancers of the head and neck region are of paramount importance in studying the carcinogenesis of these diseases. Although several methods for modeling cancer in the head and neck are available, none are fully satisfactory. Subcutaneous xenograft models of cancer in nude mice are often used in preclinical studies. However, these models are problematic in several aspects as they lack the specific interactions that exist between the tumor cells and their native environment. Establishment of tumors at the orthotopic sites restore these distinct patterns of interactions between the tumor and the host organs that are lost or altered when the tumors are established in ectopic sites. With regard to the transgenic model of cancer in the head and neck region, it should be kept in mind that the transgene used to drive the malignant transformation may not be representative of the carcinogenic process found in human tumors. Low penetrance of tumor formation also translates into high cost and time commitment in performing studies with transgenic models. In this review, we will discuss some of the commonly used methods for modeling cancer in the head and neck region including squamous cell carcinoma of the head and neck as well as thyroid carcinoma.     

Systematic Management of Osteoradionecrosis in the Head and Neck

Objectives: Osteoradionecrosis is one of the most serious and devastating complications of radiotherapy. The proper management of osteoradionecrosis is currently undetermined. The objective of this study is to evaluate the treatment results of a systematic approach to osteoradionecrosis. Study Design: A prospective study of a systematic approach to osteoradionecrosis in the head and neck area was undertaken. Methods: From July 1993 to June 1998, 33 cases of osteoradionecrosis in the head and neck area were treated using a systematic approach that combined sequestrectomy and hyperbaric oxygen therapy. Results: Seven (21%) had recurrent cancer. The control rate of the other 26 osteoradionecrosis cases was 77% (20/26). Conclusions: Persistent osteoradionecrosis, despite diligent radical treatment, raises the suspicion of recurrent cancer. Extensive osteoradionecrosis with a multiple discharging fistula, a large area of exposed necrotic bone, or a coexistent fracture should be treated primarily with radical sequestrectomy and microvascular free flap reconstruction. Surgery still plays a major role in controlling osteoradionecrosis, and hyperbaric oxygen therapy is adjuvant.     

Perilymph Pharmacokinetics of Markers and Dexamethasone Applied and Sampled at the Lateral Semi-Circular Canal

Perilymph pharmacokinetics was investigated by a novel approach, in which solutions containing drug or marker were injected from a pipette sealed into the perilymphatic space of the lateral semi-circular canal (LSCC). The cochlear aqueduct provides the outlet for fluid flow so this procedure allows almost the entire perilymph to be exchanged. After wait times of up to 4 h the injection pipette was removed and multiple, sequential samples of perilymph were collected from the LSCC. Fluid efflux at this site results from cerebrospinal fluid (CSF) entry into the basal turn of scala tympani (ST) so the samples allow drug levels from different locations in the ear to be defined. This method allows the rate of elimination of substances from the inner ear to be determined more reliably than with other delivery methods in which drug may only be applied to part of the ear. Results were compared for the markers trimethylphenylammonium (TMPA) and fluorescein and for the drug dexamethasone (Dex). For each substance, the concentration in fluid samples showed a progressive decrease as the delay time between injection and sampling was increased. This is consistent with the elimination of substance from the ear with time. The decline with time was slowest for fluorescein, was fastest for Dex, with TMPA at an intermediate rate. Simulations of the experiments showed that elimination occurred more rapidly from scala tympani (ST) than from scala vestibuli (SV). Calculated elimination half-times from ST averaged 54.1, 24.5 and 22.5 min for fluorescein, TMPA and Dex respectively and from SV 1730, 229 and 111 min respectively. The elimination of Dex from ST occurred considerably faster than previously appreciated. These pharmacokinetic parameters provide an important foundation for understanding of drug treatments of the inner ear.