Treatment de-escalation for HPV-associated oropharyngeal squamous cell carcinoma with radiotherapy vs. trans-oral surgery (ORATOR2): study protocol for a randomized phase II trial.

BACKGROUND: Patients with human papillomavirus-positive (HPV+) oropharyngeal squamous cell carcinoma (OPC) have substantially better treatment response and overall survival (OS) than patients with HPV-negative disease. Treatment options for HPV+ OPC can involve either a primary radiotherapy (RT) approach (± concomitant chemotherapy) or a primary surgical approach (± adjuvant radiation) with transoral surgery (TOS). These two treatment paradigms have different spectrums of toxicity. The goals of this study are to assess the OS of two de-escalation approaches (primary radiotherapy and primary TOS) compared to historical control, and to compare survival, toxicity and quality of life (QOL) profiles between the two approaches. METHODS: This is a multicenter phase II study randomizing one hundred and forty patients with T1-2 N0-2 HPV+ OPC in a 1:1 ratio between de-escalated primary radiotherapy (60 Gy) ± concomitant chemotherapy and TOS ± de-escalated adjuvant radiotherapy (50-60 Gy based on risk factors). Patients will be stratified based on smoking status (< 10 vs. ≥ 10 pack-years). The primary endpoint is OS of each arm compared to historical control; we hypothesize that a 2-year OS of 85% or greater will be achieved. Secondary endpoints include progression free survival, QOL and toxicity. DISCUSSION: This study will provide an assessment of two de-escalation approaches to the treatment of HPV+ OPC on oncologic outcomes, QOL and toxicity. Results will inform the design of future definitive phase III trials. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT03210103. Date of registration: July 6, 2017, Current version: 1.3 on March 15, 2019.

Predictors of plate extrusion in oromandibular free flap reconstruction.

OBJECTIVES: Plate extrusions after free tissue transfer for mandibular reconstruction can be problematic and generally require revision surgery. Our objective was to assess the predictors of plate extrusion and compare outcomes between fibular free flaps (FFF), lateral border scapular flaps (LBSF), and scapular tip free flaps (STFF). METHODS: Retrospective review of consecutive patients who underwent osseous free tissue reconstruction of the mandible (2008-2014) at Victoria Hospital, London, Ontario. Patient demographics and treatment-related information were collected. RESULTS: We identified 134 procedures and 27 (20.2%) plate extrusions (21/61 FFF, 3/49 STFF, and 3/24 LBSF). Freedom from extrusion after 2 years was significantly associated with the use of FFF (P = .003, HR 6.09 1.82-20.44), performing 1 osteotomy (P = .03, HR 2.61 1.08-6.31), and anterior mandibular defects (P = .01, HR 2.66 1.25-5.66) in the univariate model. FFF's were employed more frequently in younger patients, with 2.4 mm plates, more anterior defects, and with a greater number of osteotomies (P < .001). However, after controlling for these variables in multivariate analyses the use of a FFF was the only significant predictor of extrusion at 2 years (P = .006, HR 3.68 1.46-9.28). CONCLUSIONS: At our institution, use of the STFF predicts mandibular defects that are less prone to developing plate extrusion and FFF tended to be used more frequently in anterior defects with osteotomies. However, after controlling for these factors use of the FFF appeared to have higher rates of extrusion than scapular flaps. Further prospective studies controlling for defect variables are needed to elucidate the risk factors for plate extrusion.

Swallowing Preparation and Execution: Insights from a Delayed-Response Functional Magnetic Resonance Imaging (fMRI) Study.

The present study sought to elucidate the functional contributions of sub-regions of the swallowing neural network in swallowing preparation and swallowing motor execution. Seven healthy volunteers participated in a delayed-response, go, no-go functional magnetic resonance imaging study involving four semi-randomly ordered activation tasks: (i) "prepare to swallow," (ii) "voluntary saliva swallow," (iii) "do not prepare to swallow," and (iv) "do not swallow." Results indicated that brain activation was significantly greater during swallowing preparation, than during swallowing execution, within the rostral and intermediate anterior cingulate cortex bilaterally, premotor cortex (left > right hemisphere), pericentral cortex (left > right hemisphere), and within several subcortical nuclei including the bilateral thalamus, caudate, and putamen. In contrast, activation within the bilateral insula and the left dorsolateral pericentral cortex was significantly greater in relation to swallowing execution, compared with swallowing preparation. Still other regions, including a more inferior ventrolateral pericentral area, and adjoining Brodmann area 43 bilaterally, and the supplementary motor area, were activated in relation to both swallowing preparation and execution. These findings support the view that the preparation, and subsequent execution, of swallowing are mediated by a cascading pattern of activity within the sub-regions of the bilateral swallowing neural network.

Occurrences of yawn and swallow are temporally related.

Yawning is a stereotyped motor behavior characterized by deep inhalation and associated dilation of the respiratory tract, pronounced jaw opening, and facial grimacing. The frequency of spontaneous yawning varies over the diurnal cycle, peaking after waking and before sleep. Yawning can also be elicited by seeing or hearing another yawn, or by thinking about yawning, a phenomenon known as "contagious yawning". Yawning is mediated by a distributed network of brainstem and supratentorial brain regions, the components of which are shared with other airway behaviors including respiration, swallowing, and mastication. Nevertheless, the possibility of behavioral coordination between yawning and other brainstem-mediated functions has not been examined. Here we show, with a double-blind methodology, a greater-than-fivefold increase in rest (saliva) swallowing rate during the 10-s period immediately following contagious yawning elicited in 14 adult humans through the viewing of videotaped yawn stimuli. Sixty-five percent of yawns were followed by a swallow within 10 s and swallows accounted for 26 % of all behaviors produced during this post-yawn period. This novel finding of a tight temporal coupling between yawning and swallowing provides preliminary evidence that yawning and swallowing are physiologically related, thus extending current models of upper airway physiology and neurophysiology. Moreover, our finding suggests the possibility that yawning plays a role in eliciting rest swallowing, a view not considered in previous theories of yawning. As such, the present demonstration of a temporal association between yawning and swallowing motivates a re-examination of the longstanding question, "Why do we yawn?".

Randomized Trial of Radiotherapy Versus Transoral Robotic Surgery for Oropharyngeal Squamous Cell Carcinoma: Long-Term Results of the ORATOR Trial.

PURPOSE: The incidence of oropharyngeal squamous cell carcinoma (OPSCC) has risen rapidly, because of an epidemic of human papillomavirus infection. The optimal management of early-stage OPSCC with surgery or radiation continues to be a clinical controversy. Long-term randomized data comparing these paradigms are lacking. METHODS: We randomly assigned patients with T1-T2, N0-2 (≤ 4 cm) OPSCC to radiotherapy (RT) (with chemotherapy if N1-2) versus transoral robotic surgery plus neck dissection (TORS + ND) (with or without adjuvant therapy). The primary end point was swallowing quality of life (QOL) at 1-year using the MD Anderson Dysphagia Inventory. Secondary end points included adverse events, other QOL outcomes, overall survival, and progression-free survival. All analyses were intention-to-treat. Herein, we present long-term outcomes from the trial. RESULTS: Sixty-eight patients were randomly assigned (n = 34 per arm) between August 10, 2012, and June 9, 2017. Median follow-up was 45 months. Longitudinal MD Anderson Dysphagia Inventory analyses demonstrated statistical superiority of RT arm over time (P = .049), although the differences beyond 1 year were of smaller magnitude than at the 1-year timepoint (year 2: 86.0 ± 13.5 in the RT arm v 84.8 ± 12.5 in the TORS + ND arm, P = .74; year 3: 88.9 ± 11.3 v 83.3 ± 13.9, P = .12). These differences did not meet the threshold to qualify as a clinically meaningful change at any timepoint. Certain differences in QOL concerns including more pain and dental concerns in the TORS + ND arm seen at 1 year resolved at 2 and 3 years; however, TORS patients started to use more nutritional supplements at 3 years (P = .015). Dry mouth scores were higher in RT patients over time (P = .041). CONCLUSION: On longitudinal analysis, the swallowing QOL difference between primary RT and TORS + ND approaches persists but decreases over time. Patients with OPSCC should be informed about the pros and cons of both treatment options (ClinicalTrials.gov identifier: NCT01590355).

Effects of oropharyngeal air-pulse stimulation on swallowing in healthy older adults.

While previous research has shown that air-pulse stimulation of the oropharynx facilitates saliva swallowing in young adults, the effects of air pulses in older adults have not been examined. Responses to air-pulse stimulation may differ in young and older adults given age-related changes in sensation, swallowing physiology, and swallow-related brain activation. Therefore, this study sought to determine the effects of oropharyngeal air-pulse stimulation on saliva swallowing rates in 18 healthy older adults. Saliva swallowing rates were monitored across six conditions: baseline without mouthpiece, baseline with mouthpiece in situ, unilateral right oropharyngeal stimulation, unilateral left oropharyngeal stimulation, bilateral oropharyngeal stimulation, and sham stimulation. Results indicated that bilateral oropharyngeal air-pulse stimulation was associated with a statistically significant increase in mean saliva swallowing rate compared to baseline without mouthpiece, baseline with mouthpiece in situ, and sham stimulation. In previous studies, young adults reported an irrepressible urge to swallow in response to oropharyngeal air-pulse delivery, but the older adults in the current study did not perceive the air-pulse stimulation as being associated with swallowing or other behaviors. These findings indicate that oropharyngeal air-pulse stimulation facilitates the elicitation of saliva swallowing in older adults.

Comparison of fibular and scapular osseous free flaps for oromandibular reconstruction: a patient-centered approach to flap selection.

IMPORTANCE: Provides an approach to osseous free flap selection for reconstruction of segmental mandible defects that takes into consideration general medical status of the patient and reconstruction requirements; demonstrates the complementary qualities of fibular and subscapular system free flaps; and describes the different surgical indications for lateral border scapular and scapular tip free flaps. OBJECTIVES: To review our experience with osseous mandible reconstruction comparing the fibular and subscapular system free flaps, determine reconstruction-specific and general health variables that may differ between these patient groups, and present our approach to oromandibular reconstruction. DESIGN: Retrospective study. SETTING: Academic tertiary care medical center. PARTICIPANTS: A total of 110 patients (68 male, 42 female) undergoing single-stage oromandibular reconstructions with free-tissue transfers between May 1, 2006, and May 30, 2012. INTERVENTION: Single-stage oromandibular reconstruction with free-tissue transfer. MAIN OUTCOME MEASURES: Differences in patient demographics, bone and soft-tissue aspects of the reconstruction, operative time, flap outcomes, and major postoperative complications between fibular, lateral scapular border, and scapular tip free flaps. RESULTS: A total of 110 patients underwent 113 reconstructions, including 58 fibular free flaps (FFFs) (51.3%) and 55 subscapular system flaps (48.7%). Of the subscapular system free flaps, 27 flaps (49%) were scapular tip free flaps (STFFs) based on the angular artery branch of the thoracodorsal pedicle; the remaining 28 cases were lateral scapular border flaps (LSBFs). Patients undergoing reconstruction with FFFs were significantly younger than their subscapular system flap counterparts (56 vs 70 years, P < .001). Mean mandible defect lengths were similar for patients undergoing FFF and LSBF reconstruction (7.8 and 7.7 cm, respectively); STFFs were used to reconstruct significantly shorter defects (mean, 6.0 cm, P < .001). The FFFs were more commonly used for anterior mandible defects in which multiple osteotomies and limited soft tissue were required, while subscapular flaps were more commonly used for linear mandible defects with complex soft-tissue requirements. A single complete flap loss occurred in a patient who underwent reconstruction with an STFF; other complication rates were similar between groups. CONCLUSIONS AND RELEVANCE: The FFFs and subscapular flaps are complementary options for oromandibular reconstruction. The FFF is ideal for younger patients, extended defects, multiple osteotomies, and limited soft-tissue requirements. The subscapular system free flaps (LSBF and STFF) are excellent options for (1) elderly patients; (2) those with significant comorbidities, such as peripheral vascular disease; and (3) mandible defects associated with complex soft-tissue requirements. Furthermore, the STFF offers a reliable option to reconstruct short-segment defects, in particular, defects involving the angle of the mandible.

Oropharyngeal stimulation with air-pulse trains increases swallowing frequency in healthy adults.

This study sought to determine whether air-pulse trains delivered to the peritonsillar area would facilitate swallowing in healthy subjects. Trains of unilateral or bilateral air pulses were delivered to the peritonsillar area via tubing embedded in a dental splint, while swallows were simultaneously identified from their associated laryngeal and respiratory movements. Results from four subjects indicated that oropharyngeal air-pulse stimulation evoked an irrepressible urge to swallow, followed by an overt swallow as verified by laryngeal and respiratory movements. Moreover, air-pulse stimulation was associated with a significant increase in swallowing frequency. Mean latency of swallowing following bilateral stimulation tended to be less than the latency of swallowing following unilateral stimulation. These findings in healthy adults suggest the possibility that oropharyngeal air-pulse stimulation may have clinical utility in dysphagic individuals.