Definitive Chemoradiotherapy with Docetaxel, Cisplatin, and 5-Fluorouracil for Advanced Cervical Esophageal Cancer: A Medium-Term Outcome.

BACKGROUND: Definitive chemoradiotherapy (dCRT) is widely considered as a treatment option for cervical esophageal squamous cell carcinoma (ESCC) toward preserving the larynx. We have reported favorable outcomes, including the treatment response rate and short-term survival of dCRT concomitant with docetaxel, cisplatin, and 5-fluorouracil (DCF-RT) for advanced cervical ESCC. The aim of this paper was to report the subsequent progress of the study. METHODS: We assessed 18 patients with advanced (clinical stage II-IV, including T4b and/or M1 lymph node) cervical ESCC at our department who received DCF-RT as the first-line treatment between December 2010 and June 2020. RESULTS: A total of 14 men and 4 women underwent the study regimen. The pretreatment clinical stage included stage II, stage III, stage IVA, and stage IVB cases (including 9 patients with T4b) [8 trachea and 2 thyroids] and 7 patients with the M1 lymph node. The complete response (CR) was achieved in 15 patients, stable disease in 2, and progressive disease in 1. Of 15 patients with CR, 7 experienced recurrence, and 8 had continued CR. Frequent cases of grade ≥3 adverse effects included leucopenia, neutropenia, febrile neutropenia, and pharyngeal pain. The 3-year overall survival rate, disease-free survival rate, and disease-specific survival rate were 44.2%, 47.7%, and 48.6%, respectively. CONCLUSION: DCF-RT for advanced cervical esophageal cancer could achieve a favorable prognosis with larynx preservation. Further observations are warranted to establish the long-term prognosis, late complications of radiotherapy, and the significance of salvage surgery.

The effect of galvanization and potassium iodide iontophoresis of the throat and larynx on thyroid parameters: a randomized controlled trial.

Few studies have assessed the application and side effects of potassium iodide (KI) iontophoresis. Using a double-blinded randomized controlled trial with a 1:1 parallel-group, we investigated the effect of galvanization and the KI iontophoresis in the throat and larynx on three thyroid parameters. A total of 50 healthy volunteers with normal TSH, FT3, and FT4 levels and lacking focal changes in the thyroid ultrasonography were subjected to 10 electrotherapy treatments. The TSH, FT3, and FT4 levels were determined prior to the 10 electrotherapeutic treatments (T1), 2-weeks after treatment (T2) and 6-months after treatment (T3). At T2 and T3, both groups had normal levels of TSH, FT3, and FT4. Regarding the change of TSH, FT3, and FT4 levels between T1 vs. T2 and T1 vs. T3, no significant differences between the galvanization and iontophoresis groups were found. However, both groups had lower levels of all three hormones at T3. Together, these data indicate that KI iontophoresis does not affect thyroid hormone levels in the short- nor long-term. Additional follow-up studies with larger groups are required to better confirm the safety of galvanization and iontophoresis procedures in the pharynx and larynx.Trial registration ClinicalTrials.gov (NCT04013308; URL: www.clinicaltrials.gov ). Day of first registration 09/07/2019.

Laryngeal Injury Due to Amikacin Inhalation for Refractory Mycobacterium avium Complex Infection.

Inhaled antibiotics have long been used for chronic lung infections, especially in patients with cystic fibrosis and increasingly for non-cystic fibrosis bronchiectasis. Amikacin liposome inhalation suspension (ALIS) has emerged as a promising treatment for Mycobacterium avium complex infection refractory to oral antibiotics. However, despite its efficacy, nearly one-half of patients in phase II and III trials experienced dysphonia as a treatment-associated adverse effect. Here, we describe a patient who experienced severe, acute-onset laryngitis while receiving ALIS for refractory M avium complex infection, prompting discontinuation of ALIS therapy. This is the first report directly describing vocal fold injury due to such therapy. Given the high frequency of dysphonia reported with ALIS, this case highlights the potential severity of laryngeal toxicity, the importance of coordination of care for patients receiving inhaled antibiotics for chronic pulmonary disease, and the need for better insight into mechanisms of toxicity.

Vocal fold injection material does not preclude interpretation of laryngeal electromyography.

INTRODUCTION/AIMS: Temporary vocal fold injection (VFI) is a common treatment for acute and subacute vocal fold paralysis (VFP). Laryngeal electromyography (LEMG) is useful for diagnosing neurogenic causes of VFP. This study evaluated whether the presence of VFI material prevents interpretation of LEMG in patients with acute and subacute VFP. METHODS: Patients with acute and subacute unilateral VFP (onset ≤6 mo) who underwent temporary VFI within 3 mo preceding LEMG were evaluated. A matched control group that did not undergo VFI was also studied. The LEMG team (laryngologist and electromyographer) performed and interpreted LEMG using a pre-specified protocol, including qualitative and quantitative motor unit analysis. RESULTS: Eighteen patients with VFI underwent LEMG successfully with interpretation of spontaneous activity and motor unit recruitment. Fourteen patients were seen in follow-up to determine accuracy of established LEMG prognosis. Seven of seven subjects with poor LEMG prognosis did not recover vocal fold motion. Five of seven subjects with fair LEMG prognosis recovered vocal fold motion. Findings were similar for the control group. DISCUSSION: VFI augmentation material did not prevent interpretation of meaningful LEMG data in patients with acute and subacute VFP, and accurate prognoses of vocal fold motion recovery were established.

The Effect of Antioxidant Agents on Cisplatin-Induced Laryngeal Histological Alterations in Rats.

The larynx-related adverse effects that depend on cisplatin decrease patient comfort and many antioxidants have been used to eliminate these side effects. We aimed to identify the laryngeal mucosal changes imposed by cisplatin and investigated whether antioxidants, and their healing effects on these changes, may help reduce laryngeal complications in patients resulting from adverse effects in the larynx. A rat model was designed to evaluate the effects of cisplatin on the larynx and the protective role of antioxidants. Single-dose cisplatin was given both intraperitoneally alone and additionally administered with p-coumaric acid, melatonin, resveratrol, vitamin D, and oleic acid over 5 days. Whole larynges were dissected and evaluated histologically, histochemically, and immunohistochemically. Varying degrees of mucosal changes cisplatin group, but neither erosion nor an ulcer was observed. Numerous variable histological effects of antioxidants were observed on cisplatin exposed laryngeal mucosa. The most obvious effects of cisplatin were edema. The results of the study showed that resveratrol was the most preventive antioxidant agent against cisplatin-dependent mucosal changes. The highest increase in the Ki67 index was in the oleic acid group. Vitamin D increased stromal cyclooxygenase-2 expression that may have an effect on increasing mucosal damage.

Routine restaging after primary non-surgical treatment of laryngeal squamous cell carcinoma-a review.

PURPOSE: Treatment of patients with laryngeal squamous cell carcinoma with radiotherapy or chemoradiation is an established alternative to laryngeal surgery in many cases, but particularly for advanced tumors without cartilage invasion. Imaging modalities face the challenge of distinguishing between posttherapeutic changes and residual disease in the complex anatomic subsite of the larynx. Guidelines concerning restaging of head and neck squamous cell carcinomas (HNSCC) are presented by the National Comprehensive Cancer Network (NCCN) and other national guidelines, but clearly defined recommendations for routine restaging particularly for laryngeal cancer are lacking. METHODS: A systematic search was carried out in PubMed to identify studies evaluating routine restaging methods after primary non-surgical treatment of laryngeal squamous cell carcinoma from 2009 to 2020. RESULTS: Only three studies were deemed eligible, as they included at least ≥50% patients with laryngeal squamous cell carcinoma and evaluated imaging modalities to detect residual cancer. The small number of studies in our review suggest restaging with fluoro-deoxy-glucose positron-emission tomography/computed tomography (FDG PET/CT) 3 months after initial treatment, followed by direct laryngoscopy with biopsy of the lesions identified by FDG PET/CT. CONCLUSION: Studies evaluating restaging methods after organ-preserving non-surgical treatment of laryngeal carcinoma are limited. As radiotherapy (RT), chemoradiotherapy (CRT), systemic therapy followed by RT and radioimmunotherapy are established alternatives to surgical treatment, particularly in advanced laryngeal cancers, further studies are needed to assess and compare different imaging modalities (e.g. PET/CT, MRI, CT, ultrasound) and clinical diagnostic tools (e.g., video laryngoscopy, direct laryngoscopy) to offer patients safe and efficient restaging strategies. PET or PET/CT 3 months after initial treatment followed by direct laryngoscopy with biopsy of the identified lesions has the potential to reduce the number of unnecessary laryngoscopies.

Prenatal developmental toxicity studies on fumes from bitumen in the rat.

The prenatal developmental toxicity of bitumen fume was tested by nose-only inhalation in the rat. The fumes for exposure were collected from the headspace of a storage tank filled with a bitumen corresponding in composition to an anticipated worst-case occupational exposure. The composition of these fumes was compared to actual paving site fumes to ensure its representativeness for workplace exposures. In a dose-range-finding study male and female rats were exposed to 0, 103, 480 or 1043 mg/m3 of fume (as total organic mass), for 6 h/day during 20 days post conception (p.c.). Dose-related effects on body weight and lungs were observed in the mid- and high-dose groups. In the main study, dams were exposed to 0, 52, 151 and 482 mg/m3 of fume, for 6 h/day during 19 days p.c. The maternal NOAEL was 52 mg/m³. In the high-dose group treatment-related effects on body weight (gain), food consumption, lung weights, and histopathological changes in lungs and larynx were observed. In the mid-dose group only histopathological changes in the larynx and lungs were found. The NOAEL for prenatal developmental toxicity was 151 mg/m³ based on reduced fetal weight in the high-dose group (482 mg/m³). However, these changes are most likely a consequence of the maternal toxicity, in particular the reduction of maternal body weight gain by 26 % as compared to control. Nose-only exposure to bitumen fumes in concentrations up to 482 mg/m³ from days 1-19 p.c. did not induce any significant fetal anomalies.

Reconstructive Options During Nonfunctional Laryngectomy.

OBJECTIVE: A paucity of data exists regarding surgical outcomes for patients undergoing total laryngectomy for a dysfunctional larynx. Herein, we present the largest study evaluating the method of closure on postoperative fistula rate and swallowing ability. METHOD: We performed a retrospective review of patients undergoing total laryngectomy for a dysfunctional larynx after primary radiation or chemoradiation therapy for laryngeal carcinoma from 1998 to 2020. Demographic information, operative details, length of hospitalization, fistula formation, method of fistula treatment, and need for enteral feeding 6 months after surgery were analyzed. RESULTS: A total of 268 patients were included. Flaps were performed in 140 (52.2%) patients, including radial forearm free flaps (RFFF), pectoralis flaps, and supraclavicular flaps. Sixty-four (23.9%) patients developed postoperative fistulas. There was no significant difference in the fistula rate between flap and primary closure methods (P = .06). However, among patients who had a flap, RFFF had a significantly lower fistula rate (P = .02). Significantly more patients who had initial closure with a pectoralis flap required an additional flap for fistula repair than those who underwent RFFF or primary closure (P < .05). Last, whereas 87 patients (32.5%) required an enteral feeding tube 6 months after surgery, significantly fewer patients who underwent RFFF were feeding tube-dependent (P = < .0001). CONCLUSION: Herein, we present the largest study of outcomes after total laryngectomy for dysfunctional larynx. Postoperative fistula rates are high, 23%; however, the majority of patients, 67%, will not require long-term enteral support. The RFFF is an excellent option demonstrating the lowest rates of postoperative fistula and enteral feeding tube dependence. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:E1510-E1513, 2021.

Evaluation of the effects of helmet continuous positive airway pressure on laryngeal size in dogs anesthetized with propofol and fentanyl using computed tomography.

OBJECTIVE: To evaluate the effect of 5 cm H2 O of continuous positive airway pressure (CPAP) on laryngeal size in spontaneously breathing anesthetized dogs via computed tomography (CT). DESIGN: Prospective, randomized, cross-over clinical study. SETTING: University teaching hospital and referral private practice. ANIMALS: Eight healthy client-owned dogs undergoing CT. INTERVENTIONS: Dogs were sedated with acepromazine 20 µg/kg IM and induced with fentanyl 2 µg/kg and propofol 3-5 mg/kg IV before being maintained on fentanyl (5 µg/kg/h) and propofol (0.3 mg/kg/min) constant rate infusion. Dogs received an air/oxygen mixture with (CPAP) and without (NO-CPAP) 5 cm H2 O of CPAP in a random order. Each study step lasted 15 minutes. MEASUREMENTS AND MAIN RESULTS: Ten minutes after the beginning of each study period, a CT scan of the laryngeal region was obtained at end-expiration. CT images were analyzed to determine the laryngeal cross-sectional area (CSA; cm2 ), total volume (VTOT ; cm3 ), and laterolateral and dorsoventral diameters (DLL and DDV , respectively; cm). Differences between the 2 treatments were analyzed with t-test for paired data (P < 0.05). Compared to the NO-CPAP, during CPAP the CSA increased by 53.3 ± 23.1% (ie, from 3.3 ± 0.8 to 5.1 ± 1.3 cm2 , P = 0.0004), VTOT increased by 52.4 ± 13.6% (from 6.2 ± 1.7 to 9.4 ± 2.4 cm3 , P < 0.0001), and DLL and DDV were 55.5 ± 13.3% (3.6 ± 0.8 vs 2.4 ± 0.5 cm, P = 0.006) and 20.3 ± 8.8% larger (3.2 ± 0.7 vs 2.7 ± 0.6 cm, P = 0.0002), respectively. CONCLUSIONS: Laryngeal volume and cross sectional area increased during the application of 5 cm H2 O of helmet CPAP in spontaneously breathing anesthetized dogs.

Laryngeal reflex responses in pediatric anesthesia.

Laryngeal and respiratory reflexes are vitally important defense mechanisms against foreign body aspiration, safeguarding airway patency, and ventilation. These highly preserved automatisms easily overrule external influences like willpower or (anesthetic) medication. Prevention and anticipation are, therefore, the essential strategies to avoid adverse events and damage, and treatment is most effective in the early stage of the reflex response. The physiology and pathophysiology of the various defensive reflexes as well as a comprehensive anesthetic approach to prevention and treatment are outlined in this review.

Liquiritin apioside attenuates laryngeal chemoreflex but not mechanoreflex in rat pups.

Liquiritin apioside (LA), a main flavonoid component of licorice, reportedly suppresses cough responses to inhalation of aerosolized capsaicin [CAP; a stimulant to transient receptor potential vanilloid 1 (TRPV1)] in conscious guinea pigs via acting on peripheral nerves. However, the evidence of LA having a direct effect on airway sensory fibers is lacking. Considering the important role laryngeal chemoreceptors and mechanoreceptors play in triggering apnea and cough, we studied whether LA suppressed the apneic responses to stimulation of these receptors via directly acting on the superior laryngeal nerve (SLN). Intralaryngeal delivery of chemical [CAP, HCl, and distilled water (DW)] and mechanical [an air-pulse (AP)] stimulations was applied in anesthetized rat pups to evoke the apnea. These stimuli were repeated after intralaryngeal LA treatment or peri-SLN LA treatment to determine the direct effect of LA on the SLN. Our results showed that all stimuli triggered an immediate apnea. Intralaryngeal LA treatment significantly attenuated the apneic response to chemical but not mechanical stimulations. The same attenuation was observed after peri-SLN LA treatment. Owing that TRPV1 receptors of laryngeal C fibers are responsible for the CAP-triggered apneas, the LA impact on the activity of laryngeal C neurons retrogradely traced by DiI was subsequently studied using a patch-clamp approach. LA pretreatment significantly altered the electrophysiological kinetics of CAP-induced currents in laryngeal C neurons by reducing their amplitudes, increasing the rise times, and prolonging the decay times. In conclusion, our results, for the first time, reveal that LA suppresses the laryngeal chemoreceptor-mediated apnea by directly acting on the SLN (TRPV1 receptors of laryngeal C fibers).

Laryngeal Demasculinization in Wild Cane Toads Varies with Land Use.

Anthropogenic factors, including the spread of endocrine-disrupting chemicals, have been linked to alterations in the reproductive physiology, morphology, and behavior of wildlife. Few studies of endocrine disruption, however, focus on secondary sexual traits that affect mating signals, despite their importance for reproductive success. The larynx of many anurans (frogs and toads), for example, is larger in males than in females and is crucial for producing mating calls. We aim to determine if wild populations of cane toads (Rhinella marina) near sugarcane fields in Florida have demasculinized larynges when compared to populations near urban areas. We find evidence of demasculinization in both primary and secondary sexual traits in male toads living near sugarcane. Relative to body size, the laryngeal mass, vocal cord length, and dilator muscle width are all reduced in males from sugarcane regions compared to their urban counterparts. Strong correlations between primary and secondary male sexual traits indicate that demasculinization occurs in concert both within and across diverse organs, including the testes, larynx, and skin. Our results show that anurans near sugarcane fields have demasculinized reproductive systems, that this disruption extends to secondary sexual traits like the larynx, and that it is likely due to anthropogenic causes.

Medications and the larynx.

PURPOSE OF REVIEW: The larynx is a complex organ that houses some of the most intricate structures of the human body. Owing to its delicate nature, the larynx is affected by different medications to varying degrees. Many of these effects manifest in subjective complaints in one's voice or swallow. This review article invokes the present available literature to describe the effects different medical agents have on the functionality of the laryngeal structures. RECENT FINDINGS: Multiple available studies explore the effects of inhaled corticosteroids on the larynx. While laryngeal candidiasis is a well known complication of chronic steroid use, other rarer fungal infections have also demonstrated themselves as risks. Among anesthetics, the literature suggests that sevoflurane in standard and high doses does not appear to significantly reduce the risk of laryngospasm. The use of topical and intravenous lidocaine appear to have conflicting evidence regarding their use in laryngospasm prevention, whereas postoperative sore throat, hoarseness, and cough may be prevented with preinduction nebulization of ketamine and magnesium sulfate or budesonide. SUMMARY: Further study is warranted to explore the effects that these and other classes of agents, such as antibiotics, have on the structure and function of the larynx.

Induction chemotherapy in head and neck cancers: Results and controversies.

Standard treatment for locally advanced head and neck squamous cell carcinoma (LAHNSCC) consists mainly of concurrent chemoradiation (CCR) but induction chemotherapy (IC) by docetaxel-cisplatin-fluorouracil (TPF), followed by CCR, is a strong option. Comparative trials suggest that IC and CCR are equivalent, and some trials suggest superiority of IC, whereas none shows inferiority. IC might have less interest in oropharyngeal cancer (more often linked to HPV infection). When functional laryngeal preservation is the patient's priority, essays strongly suggest that IC is the best treatment. There is little data about a less toxic regimen of IC, but several schemes are promising and need to be developed. An early selection of responders to IC by metabolic imaging must be considered. Intensification attempts with cetuximab were too toxic and unsafe, but trials with immunotherapy are ongoing to enhance TPF efficacy. After IC, CCR either with cetuximab or cisplatin seems to be equally effective.

Effects of chemical and mechanical stimulation on laryngeal motion during alfaxalone, thiopentone or propofol anaesthesia in healthy dogs.

OBJECTIVE: To compare the effect of chemical and mechanical stimulation on arytenoid cartilage motion during anaesthetic induction with alfaxalone, thiopentone or propofol. STUDY DESIGN: Masked, randomized, crossover study. ANIMALS: A group of eight adult Beagle dogs. METHODS: Anaesthesia was induced with thiopentone (7.5 mg kg-1), propofol (3 mg kg-1) or alfaxalone (1.5 mg kg-1) intravenously (IV), which were concurrently paired with either chemical (doxapram at 2.5 mg kg-1 IV) or mechanical (gentle pressure to the corniculate process of the right arytenoid cartilage using a cotton bud) stimulation for enhanced assessment of laryngeal motion, in random order, with a 1 week wash-out period between treatments. If deemed inadequately anaesthetized, supplemental boli of thiopentone (1.8 mg kg-1), propofol (0.75 mg kg-1) or alfaxalone (0.4 mg kg-1) were administered. Assessment of number of arytenoid motions and vital breaths, among others, was initiated immediately after induction. Chemical (doxapram) and mechanical stimulation were begun 2 minutes after anaesthetic induction. Data were collected at 2, 3 and 5 minutes after anaesthetic induction and the Friedman rank-sum or repeated-measures analysis of variance tests were used when applicable for statistical analysis. RESULTS: The duration of examination time was shorter among treatments combined with chemical stimulation (p=0.001). Examination time during induction was longer for alfaxalone-chemical (8.9 minutes) and -mechanical (10.9 minutes) compared to both induction with thiopentone-chemical (3.8 minutes) and propofol-chemical (4.0 minutes). The median number of arytenoid motions for both thiopentone (67) and propofol (59) induction combined with chemical stimulation was significantly higher in comparison to that of alfaxalone (1), thiopentone (2) and propofol (2), when combined with mechanical stimulation at 3 minutes after induction. CONCLUSION AND CLINICAL RELEVANCE: Among the regimens for assessing laryngeal motion assessed in the present study, combinations of thiopentone or propofol with doxapram are the most effective means of stimulating arytenoid motion and could improve the accuracy of diagnosis of laryngeal paralysis in dogs.

Engineering an immunomodulatory drug-eluting stent to treat laryngotracheal stenosis.

OBJECTIVE: Develop a drug-eluting stent construct with a reliable drug-release profile and adequate mechanically stability for a trial in a small animal model of laryngotracheal stenosis (LTS), a debilitating pathologic narrowing of the airway leading to significant shortness of breath. METHODS: Biodegradable, biocompatible stents containing 1.0% rapamycin made of PLLA-PCL (70% Poly-l-Lactide and 30% Polycaprolactone blend) and 50 : 50 PDLGA (Poly(dl-lactide-co-glycolide)) were compared. Mechanical strength testing and drug elution rates using high performance liquid chromatography analysis (HPLC) was assessed. Next, efficacy of stent elution on LTS derived scar fibroblasts. Finally, stents were placed in situ in an LTS mouse model. RESULTS: The PLLA-PCL stent construct exhibited greater mechanical strength compared to the PDLGA stent over a 4-week period (Young's Modulus (PLLA-PCL) = 13.82; Young's Modulus (PDLGA) = 4.015). Moreover, the PLLA-PCL stent showed a reliable rapamycin release profile for 6 weeks (30% elution for PLLA-PCL stents compared to <1% elution for PDLGA). Collagen 1 (p < 0.05) and fibroblast cell proliferation were decreased in vitro when treated with the rapamycin stent. In vivo, the rapamycin stent reduced lamina propria thickness (p < 0.05) and collagen 1(p < 0.05), collagen 3, TGF-B (p < 0.05) and a-SMA (p < 0.05). CONCLUSIONS: The PLLA-PCL construct demonstrated superior mechanical strength and greater drug elution compared to PDLGA stents. We demonstrated the feasibility of testing this drug-eluting stent in vivo, showing that the rapamycin-eluting stent treats fibrosis. To our knowledge this is the first study to deploy a drug-eluting stent to treat tracheal pathology in an animal model. Optimization of a rapamycin-eluting PLLA-PCL stent for translational investigation will lead to improved treatment strategies of LTS.