Abrasion and blunt tissue trauma study of a novel flexible robotic system in the porcine model.

OBJECTIVES: The objective of this study was to determine if a flexible robotic system caused increased tissue reaction when accessing the oropharynx and hypopharynx compared to intubation controls in only 2 scenarios: high speed tissue impact and multiple unit insertions and retractions. The data obtained were submitted as part of the entirety of information submitted for FDA approval. METHODS: This study consisted of 5 groups of Yorkshire pigs (2 animals per group). On Day 0, all animals were intubated. For group 1 (control), a second endotracheal tube was advanced to just above the vocal cords. In abrasion groups 2 and 3, the flexible robotic system was advanced against the oropharyngeal and hypopharyngeal tissues, respectively. In blunt trauma groups 4 and 5, the flexible robotic system was advanced at maximum speed (22mm/s) to collide with oropharyngeal and hypopharyngeal tissues, respectively. Pre- and post-procedure endoscopic assessments of tissue reaction were performed daily for 4 days. An independent reviewer graded tissue reaction using a 0-3 point scale. RESULTS: Tissue reaction scores at each observation time point for all test groups were less than or equal to control scores except for one instance of moderate scoring (2 out of 3) on Day 2 for an animal in the blunt trauma group where reaction was likely intubation-related rather than device impact related. Otherwise, all flexible robotic system-treated animal scores were less than 1 by Day 4. CONCLUSIONS: In this limited study, the flexrobotic system afforded surgical access to the oropharynx and hypopharynx without an increased level of abrasion or tissue trauma when compared to intubation alone.

The Global Experience of Laryngeal Transplantation: Series of Eleven Patients in Three Continents.

BACKGROUND: The loss of laryngeal function affects breathing, swallowing, and voice, thus severely compromises quality of life. Laryngeal transplantation has long been suggested as a solution for selected highly affected patients with complete laryngeal function loss. OBJECTIVE: To obtain insights regarding the advantages, weaknesses, and limitations of this procedure and facilitate future advances, we collected uniform data from all known laryngeal transplants reported internationally. METHODOLOGY: A case series. Patients were enrolled retrospectively by each institutional hospital or clinic. Eleven patients with complete loss of laryngeal function undergoing total laryngeal transplantation between 1998 and 2018 were recruited. RESULTS: After a minimum of 24 months follow-up, three patients had died (27%), and there were two graft explants in survivors, one total and one partial, due to chronic rejection. In the remaining cases, voice was functional in 62.5% and 50% achieved decannulation. Swallowing was initially restricted, but only one patient was gastrostomy-dependent by 6 months and all had normal or near-normal swallowing by the end of year two after transplantation. Median follow-up was 73 months. Functional (voice, swallowing, airway) recovery peaked between 12 and 24 months. CONCLUSIONS: Laryngeal transplantation is a complex procedure with significant morbidity. Significant improvements in quality of life are possible for highly selected individuals with end-stage laryngeal disorders, including laryngeal neoplasia, but further technical and pharmacological developments are required if the technique is to be more widely applicable. An international registry should be created to provide better quality pooled data for analysis of outcomes of any future laryngeal transplants. LEVEL OF EVIDENCE: IV Laryngoscope, 2024.

A Heterotopic Mouse Model for Studying Laryngeal Transplantation.

Laryngeal heterotopic transplantation, although a technically challenging procedure, offers more scientific analysis and cost benefits compared to other animal models. Although first described by Shipchandler et al. in 2009, this technique is not widely used, possibly due to the difficulties in learning the microsurgical technique and time required to master it. This paper describes the surgical steps in detail, as well as potential pitfalls to avoid, in order to encourage effective use of this technique. In this model, the bilateral carotid arteries of the donor larynx are anastomosed to the recipient carotid artery and external jugular vein, allowing for blood flow through the graft. Blood flow can be confirmed intraoperatively by the visualization of blood filling in the graft bilateral carotid arteries, reddening of the thyroid glands of the graft, and bleeding from micro vessels in the graft. The crucial elements for success include delicate preservation of the graft vessels, making the correct size arteriotomy and venotomy, and using the appropriate number of sutures on the arterial-arterial and arterial-venous anastomoses to secure vessels without leakage and prevent occlusion. Anyone can become proficient in this model with sufficient training and perform the procedure in approximately 3 h. If performed successfully, this model allows for immunologic studies to be performed with ease and at low cost.

Ten-month laryngeal allograft survival with use of pulsed everolimus and anti-alphabeta T-cell receptor antibody immunosuppression.

OBJECTIVES: The risks of daily immunosuppression limit the use of laryngeal transplantation as a reconstructive option. Pulsed immunosuppressive dosing can lessen these risks. The study objective was to develop a long-term pulsing regimen that minimizes exposure to immunosuppressive agents. METHODS: Rat laryngeal transplantation was performed. Everolimus (1 mg/kg per day) and anti-c41 T-cell receptor (TCR) antibodies (250 microg) were given for 7 days beginning 1 day before transplantation and for 5 days beginning on day 90 after transplantation. On day 180, group 1 (n = 5) received the initial regimen for 3 days, and group 2 (n = 5) received everolimus (1 mg/kg per day) until euthanization, which occurred when parathyroid hormone (PTH) levels dropped to less than 11 pg/mL or at 300 days. RESULTS: Four of the 5 rats in group 1 had normal PTH levels at 300 days. The PTH level for 1 rat was less than 11 pg/ mL at 270 days. In group 2, none of the 5 rats had normal PTH levels at 300 days. Two had PTH levels below 11 pg/mL at 270 days, and 3 had PTH levels below 11 pg/mL at 300 days. The allografts that survived beyond 300 days had an essentially normal histologic appearance. CONCLUSIONS: Pulsed immunosuppression prevented allograft rejection for 10 months and was more effective than daily everolimus. Short-term perioperative therapy followed by pulsed, tapered dosing is a viable alternative to traditional regimens and may decrease associated risks.

Safety and Feasibility of a Novel Esophageal Balloon for Circumferential Cytologic Sampling.

OBJECTIVES: A prior publication introduced the Strome-Blitzer balloon's ability to obtain circumferential esophageal cytologic sampling. This GLP study was requisite for FDA approval to determine if equivalent cell capture and cellularity was observed with the balloon compared to surface sampling brushes and to determine the balloon's usability for naive otolaryngologists. METHODS: Three naïve users tested the Hobbs brush and Strome-Blitzer balloon on 4 Yorkshire swine. Four anatomical sites were sampled, beginning distally and ending proximally. In 2 animals, the balloon was used first distally and in the remaining 2, 4 new Hobbs brushes were used distally first. Moving proximally, the balloon and brushes were sequentially alternated. In follow-the-leader fashion, the balloon was introduced trans-orally followed by an endoscope to the desired site. The balloon was inflated exposing the abrasive strips to contact the esophageal mucosa. Moving the balloon 1 to 2 cm superiorly and inferiorly effected circumferential cell capture. The balloon was collapsed and removed, preserving the cellularity. The Hobbs brush was passed through the scope's channel. Four brushes, 1 per quadrant, obtained the samples at an anatomical site. The balloon was rated as pass/fail on the following: delivery, kinking, usability, and malfunction. A blinded veterinary pathologist evaluated the cytology. RESULTS: There was no device malfunction, mucosal trauma, or difficulty with device use. Balloon cytologic samples were comparable in cellularity and quality to the brush. CONCLUSION: A single balloon sampling was comparable to 4 brushes in capturing diagnostically relevant cellular volumes and architecture. Naïve users easily performed the procedures after reading the guidelines. LEVEL OF EVIDENCE: 3.

Validation of the use of a fluorescent PARP1 inhibitor for the detection of oral, oropharyngeal and oesophageal epithelial cancers.

For oral, oropharyngeal and oesophageal cancer, the early detection of tumours and of residual tumour after surgery are prognostic factors of recurrence rates and patient survival. Here, we report the validation, in animal models and a human, of the use of a previously described fluorescently labelled small-molecule inhibitor of the DNA repair enzyme poly(ADP-ribose) polymerase 1 (PARP1) for the detection of cancers of the oral cavity, pharynx and oesophagus. We show that the fluorescent contrast agent can be used to quantify the expression levels of PARP1 and to detect oral, oropharyngeal and oesophageal tumours in mice, pigs and fresh human biospecimens when delivered topically or intravenously. The fluorescent PARP1 inhibitor can also detect oral carcinoma in a patient when applied as a mouthwash, and discriminate between fresh biopsied samples of the oral tumour and the surgical resection margin with more than 95% sensitivity and specificity. The PARP1 inhibitor could serve as the basis of a rapid and sensitive assay for the early detection and for the surgical-margin assessment of epithelial cancers of the upper intestinal tract.

New mouse model for studying laryngeal transplantation.

OBJECTIVES: Laryngeal transplantation research has been studied in various animal models. For in-depth, immunology-based transplantation research, however, a thoroughly studied animal model must exist. The purpose of this study was to develop a reliable surgical technique in mice to serve as a model for further study of laryngeal transplantation. METHODS: Heterotopic laryngeal transplantation was attempted in 15 immunocompetent mice by use of modifications of previously described techniques established in rats. RESULTS: Various microvascular techniques were used that led to 8 successful transplants (of 15) with patent vascularity at the time of sacrifice. The first 7 attempts at transplantation were unsuccessful because of technical difficulties related to vessel size, soft tissue traumatic injury, and venous congestion. Subsequently, 8 transplantation procedures were successfully performed after modifications of the surgical technique. CONCLUSIONS: This pilot study describes the reproducible surgical techniques performed in using mice for studying laryngeal transplantation. Mice are cost-effective and immunologically well studied, and are thus ideal for further laryngeal transplantation research.

Ansa cervicalis-to-recurrent laryngeal nerve anastomosis for unilateral vocal fold paralysis: experience of a single institution.

OBJECTIVES: One treatment option for unilateral vocal fold paralysis (UVFP) is ansa cervicalis-to-recurrent laryngeal nerve (ansa-RLN) anastomosis to provide reinnervation to the affected vocal fold. The advantages of this treatment approach are that it 1) provides vocal fold tone, bulk, and tension, 2) is technically simple, and 3) does not preclude other medialization procedures. We present all patients who have undergone ansa-RLN anastomosis for UVFP at our institution. METHODS: An Institutional Review Board-approved retrospective chart review was performed to include all patients who had undergone an ansa-RLN anastomosis procedure for UVFP at our institution. Data from clinical and endoscopic laryngoscopy with stroboscopy were recorded. Statistical analysis was performed on visual and perceptual vocal data. RESULTS: A total of 46 patients were included in the study. Stroboscopic analysis and perceptual vocal evaluation was performed in a blinded fashion on the 21 patients who had preoperative and postoperative stroboscopy. Severity, roughness, breathiness, and strain all improved significantly over time. Glottic closure, vocal fold edge, and supraglottic effort all significantly improved after operation. Of the 38 patients with at least 3 months of follow-up, all except 1 demonstrated evidence of reinnervation. CONCLUSIONS: This technique for treating UVFP results in significant improvements in patients' voice and on visual examination.

Induction with T-cell receptor antibody leads to long-term laryngeal allograft function.

PURPOSE: The use of induction therapy with alphabeta T-cell receptor (alphabetaTCR) monoclonal antibody in association with tacrolimus in an allogeneic rat laryngeal transplant model permits rigorous long-term evaluation of potential short-term synergism offered by these agents. MATERIALS AND METHODS: The allogeneic model consisted of 19 Brown Norway larynges transplanted to Lewis recipients. Treatment consisted of tacrolimus (1.2 mg/kg per day) alone and in combination with 7 days of alphabetaTCR (0.5 mL/d). Control groups consisted of untreated animals, as well as a semiallogeneic model with Lewis-Brown Norway larynges transplanted to Lewis recipients and treated with tacrolimus monotherapy. Each group consisted of 6 to 11 rats. The median duration of engraftment was 44 days (range, 14-106 days). Graft histopathology was graded according to an established 31-point scale in a blinded fashion. Long-term grafts (>75 days) were followed with serum parathyroid hormone levels. RESULTS: Untreated controls experienced almost complete rejection (mean score, 27; SD, 0). Allogeneic transplants treated with tacrolimus monotherapy experienced near-complete rejection (mean score, 25.2; SD, 2.1). Allogeneic transplants treated with combination therapy and followed for a median duration of 100 days demonstrated significantly better rejection scores than controls (mean score, 11.1; SD, 1.7; P = .003). Combination therapy was also significantly more effective in preventing acute rejection than monotherapy with tacrolimus in a semiallogeneic model (mean score, 22.1; SD, 4.6; P < .04). CONCLUSIONS: Induction therapy with tacrolimus and alphabetaTCR prevents rejection in an allogeneic model for up to 100 days. This regimen was associated with significantly better histopathologic rejection scores than untreated controls, or monotherapy with tacrolimus in allogeneic or semiallogeneic models.

Donor bone marrow in laryngeal transplantation: results of a rat study.

INTRODUCTION: The concept of donor bone marrow transplantation has been successfully used in human solid organ transplantation to increase recipient chimerism. The development of recipient chimerism is associated with a decreased need for immunosuppression and even donor-specific tolerance. In this study, we attempted to augment recipient chimerism by the transfer of donor bone marrow at the time of rat laryngeal transplant. STUDY DESIGN: Experimental study in rats. METHODS: The study used a well-established semiallogeneic rat laryngeal transplant model with partial major histocompatibility complex (MHC)-mismatched Lewis-Brown-Norway donors and Lewis recipients. Donor bone marrow was introduced at transplantation via (1) intravascular injection and (2) transfer of a vascularized femoral bone graft. Recipients were treated with an established immunosuppressive regimen consisting of everolimus and anti-alphabetaTCR monoclonal antibody for a 7-day perioperative course. Animals received a 5-day boost of the same regimen at 90 days posttransplantation. Parathyroid hormone levels and histological examination were used for rejection surveillance and scoring. RESULTS: Animals treated with intravenous bone marrow injection followed by perioperative and pulsed immunosuppression commonly demonstrated early rejection (90%). Animals receiving transfer of vascularized donor femur had an average rejection score of 2.9 (scale, 1-6) at 180 days posttransplantation. Mixed-lymphocyte reaction did not demonstrate donor-specific tolerance in the latter group, and chimerism was less than 1%. CONCLUSIONS: In the rat laryngeal transplant model, donor bone marrow does not consistently lead to augmentation of peripheral chimerism using our established pulsed immunosuppression protocol. In many cases, rejection occurred earlier than animals not receiving bone marrow. This may be due to several different factors including (1) an element of graft-vs-host disease, (2) inability to establish bone marrow engraftment due to our short-term perioperative immunosuppression regimen, or (3) preferential rejection of donor bone marrow cells.

Transoral robot-assisted CO2 laser supraglottic laryngectomy: experimental and clinical data.

BACKGROUND: Transoral CO2 laser surgery for selected supraglottic tumors results in improved postoperative function and decreased morbidity, with comparable survival to open surgery. Recently, robot-assisted techniques have been reported for the management of supraglottic lesions. There are no reports in the English literature of robotic technology coupled with CO2 laser technology. Our objective was to report the use of such technology. STUDY DESIGN: Experimental resection of the supraglottis in a cadaver and a dog model using a commercially available surgical robot coupled with CO2 laser technology. Initial human experience with such technology is reported. METHODS: With use of a hollow core fiber that allows the transmission of CO2 laser energy linked to the daVinci Surgical Robot, a supraglottic laryngectomy was performed in an edentulous female cadaver. The FK Laryngo-Pharyngoscope was used for exposure. In a second experiment, a supraglottic partial laryngectomy was performed in an 80 pound dog. On the basis of our experimental experience, a CO2 laser robotic-assisted supraglottic laryngectomy was attempted in three patients. RESULTS: Removal of the supraglottic larynx in both a cadaver and canine experimental models was believed to be satisfactory using this technology. Bleeding was easily controlled in the live canine model. A 74-year-old woman with a large supraglottic mass for which she had been offered a total laryngectomy was resected successfully with this technology. The FK Laryngo-Pharyngoscope provided excellent exposure. The patient was able to swallow without difficulty on postoperative day 5. Follow-up endoscopic examination at 1 month showed no evidence of residual laryngeal tumor. Robot-assisted procedures were attempted in two additional patients, but adequate exposure could not be achieved, and more traditional techniques were performed. CONCLUSIONS: The use of the daVinci Surgical robot coupled with CO2 laser technology is feasible, as demonstrated by our experimental and clinical data. Although further development of the robotic technology is required at present, the use of robotics coupled with CO2 laser technology may have important implications in the management of supraglottic laryngeal cancer in the future.

Postallograft donor and recipient dendritic cell trafficking in the rat larynx.

OBJECTIVES/HYPOTHESIS: Dendritic cells (DC) are potent antigen-presenting cells that instigate allograft rejection. Their migration kinetics vary depending on the type of organ transplanted. The timing of donor and recipient DC trafficking in laryngeal transplants is unknown. STUDY DESIGN: Prospective animal model. METHODS: Lewis to Brown Norway (BN) rat laryngeal allografts and BN to BN isografts were performed without immunosuppression. Recipient animals were sacrificed at seven posttransplant time points. Total DC, as well as recipient and donor DC (in allograft recipients), were enumerated in situ in the airway epithelium and subepithelium using monoclonal antibodies, immunofluorescence, confocal microscopy, and image analysis software. RESULTS: Total DC densities in both laryngeal allografts and isografts decreased to approximately 10% of their initial values in the first 3 days and then rose beyond their starting values. In allografts, there was a net efflux of donor DC, reaching a nadir by 3 to 5 days; they were identified in recipient cervical lymph nodes from 12 hours to 5 days. Recipient DC infiltrated the laryngeal allograft, reaching a maximal density by day 7. CONCLUSION: The paradigm of donor DC efflux and recipient DC influx has been confirmed in a rat laryngeal transplant model, and the allograft-specific timing of these events has been elucidated. Similarities in total DC migration between allografts and isografts suggest that this phenomenon may not be driven entirely by major histocompatibility mismatch. Further understanding of trafficking may help with the goal of manipulating DC to induce allograft tolerance in the absence of generalized immunosuppression.

Swallowing outcomes after microvascular head and neck reconstruction: a prospective review of 191 cases.

BACKGROUND: The use of microvascular free tissue flaps tailored specifically to the ablative surgical defects has allowed precise anatomic reconstructions to be performed and, in turn, has improved patient outcomes. We report here the postoperative swallowing outcomes of patients undergoing microvascular reconstructions for a range of head and neck defects at the Cleveland Clinic. METHODS: The study includes 191 consecutive reconstructions for varied defects. All patients were reconstructed with four specific microvascular flaps based on their surgical defect, and postoperative swallowing outcomes were evaluated and recorded on a prospectively maintained database. Pre- and postoperative swallowing was graded on an ordinal scale. Data were simultaneously collected on the precise anatomic ablative defect in each patient, subdividing the head and neck into 16 subsites. The data were analyzed using a multivariate analysis accounting for comorbid factors, type of flap used, and subsite of defect. RESULTS: The findings are summarized as follows. There were no flap failures. The percent of patients who were able to swallow and maintain an exclusively oral diet postoperatively was 78.5%. Only 16.8% were unable to have an oral diet (NPO) and dependent on a gastric tube (G-tube) for feeding. The factors that predicted an inability to swallow include tongue resection, preoperative radiation therapy, and hypopharyngeal defects. In contrast, floor of mouth, mandibular, and pharyngeal defects, regardless of size, had excellent long-term swallowing outcomes. Most patients with these defects were able to tolerate at least a soft solid diet. CONCLUSIONS: In summary, we report excellent postoperative swallowing outcomes after microvascular reconstructions at our institution that compare favorably with outcomes with pedicled flaps and historic controls. The type of flap used and the size of defect had minimal effects on swallowing outcomes. The most difficult subsites to reconstruct were tongue defects, which strongly correlated with poor swallowing outcomes. The other factor that strongly impacted outcomes was preoperative radiation treatment. We believe these results highlight the utility of free flaps in recreating the precise anatomy required to maintain swallowing function. These data will hopefully support numerous previous studies that have established the use of microvascular reconstruction as standard of care for ablative surgical defects in the head and neck.

Ability of positron emission tomography to detect residual neck node disease in patients with head and neck squamous cell carcinoma after definitive chemoradiotherapy.

OBJECTIVE: To report our experience using the neck examination, computed tomography (CT), and positron emission tomography (PET) to clinically evaluate node-positive patients with head and neck squamous cell cancer for residual neck node disease after definitive chemoradiotherapy. DESIGN: Retrospective review of all Cleveland Clinic patients with head and neck squamous cell cancer and N2 or N3 neck node involvement at presentation who were treated with definitive concurrent chemoradiotherapy and who underwent clinical restaging after treatment using the neck examination, CT, and PET. SETTING: Tertiary care referral institution. PATIENTS: Forty-eight patients with 72 positive necks at diagnosis were followed up for a median of 20 months. MAIN OUTCOME MEASURES: Palpable nodes on examination, nodes larger than 1 cm, nodes with central necrosis on CT, or any hypermetabolic lymph nodes on PET were considered clinical evidence of residual nodal disease. The true rate of pathologic involvement was determined by histologic examination after planned neck dissection or if regional recurrence developed. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were calculated for all 3 clinical assessment tools. RESULTS: Planned neck dissection was performed in 33 necks and was positive for residual neck node disease in 5 necks. A delayed neck dissection was performed in 5 necks and was positive in 3 necks. The positive predictive value was low for all 3 clinical assessment tools. The addition of PET did not significantly improve the negative predictive value or positive predictive value of CT and the clinical examination. CONCLUSIONS: Residual neck node disease after definitive chemoradiotherapy was infrequent and was not well predicted by PET. A positive PET finding in this setting is of little utility. Although a negative PET finding was highly predictive for control of neck disease after chemoradiotherapy, it added little to the clinical neck examination and CT.

Quantitative analysis of OX62-positive dendritic cell distribution in the rat laryngeal complex.

OBJECTIVES: Dendritic cells (DCs) are key instigators of rejection after transplantation. Their distribution has not been systematically characterized in all locations of the larynx and its surrounding tissues. METHODS: Rat larynges were stained with monoclonal antibodies identifying DCs. These cells were then enumerated by a new combination of techniques including immunofluorescence, confocal microscopy, and imaging software. RESULTS: The vast majority of DCs were located in the epithelium and subepithelium of the airway; the mean DC density ranged from 9 cells per square millimeter (0.2% of cells) to 645 cells per square millimeter (10.3% of cells). Their density in the epithelium was 3 to 11 times higher than that in the subepithelium. Non-airway sites (thyroid, parathyroid, muscle, fat) had mean DC densities varying from 3 cells per square millimeter (0.2%) to 57 cells per square millimeter (0.8%). No DCs were detected in cartilage. CONCLUSIONS: Dendritic cells are concentrated in the laryngotracheal epithelium and subepithelium and represent a much smaller proportion in the other sites studied. A baseline for laryngeal DC population studies has been established, and a computerized model for consistent quantitation using confocal microscopy has been developed. This unique method will serve as a foundation for investigating DC trafficking after rat laryngeal transplantation.

Directed balloon cytology of the esophagus: A novel device for obtaining circumferential cytologic sampling.

OBJECTIVE: Current methods of obtaining esophageal cytology include brush biopsy and blind balloon sampling, among others. These methods can be time-consuming if performed in accordance with acknowledged standards. Further, exact site localization can prove to be difficult. We describe a novel device for esophageal sampling using an esophageal balloon with debriding strips contained within the pleats of the balloon. Inflation brings the latter in contact with the surface to be sampled. Cell capture was compared with the commonly used brush technique in a pig model. METHODS: Separate balloon and standard brush cytology samples were collected from a pig model. Smear and cell pellet preparations were compared regarding cell density and total volume. RESULTS: Adequate samples were obtained with both the brush and balloon. On the cell smear preparations, the cell density was greater when obtained with balloon sampling. Further, the cell pellet volume was significantly greater with the latter as well. The intact morphology of individual rafts of squamous epithelial cells also was comparable between the two methods. In addition, the balloon provided precise mapping of the cytology sites in contrast to the standard brush technique. CONCLUSION: We present an innovative new balloon technology for esophageal sampling, which demonstrated a decreased sampling time interval, precise mapping, and increased cellular volume when compared to a commonly used brush technique. LEVEL OF EVIDENCE: NA. Laryngoscope, 127:1032-1035, 2017.

Metformin Prevents the Progression of Dysplastic Mucosa of the Head and Neck to Carcinoma in Nondiabetic Patients.

OBJECTIVE: Metformin is an oral anti-hyperglycemic agent used to treat type 2 diabetes mellitus (DM). In vitro and animal models have shown that metformin can prevent the progression of oral lesions to carcinoma; however, there is conflicting data in the clinical literature regarding risk reduction for malignancy in head and neck cancer (HNC). STUDY DESIGN: Case series. METHODS: We present 3 cases in which adjuvant metformin therapy was used to treat recurrent and multifocal dysplastic lesions in previously treated nondiabetic HNC patients. RESULTS: Patients included 1 with a history of oral cavity squamous cell carcinoma (SCC) and 2 with a history of laryngeal SCC. Follow-up time ranged between 3 and 33 months. All 3 patients showed complete or partial regression of the remaining mucosal lesions and did not require any additional surgeries. CONCLUSION: We present 3 cases of nondiabetic HNC patients with field cancerization who showed a good response to adjuvant therapy with metformin. The nondiabetic population is not affected by confounding factors such as increased risk of malignancy and decreased overall survival that is itself associated with abnormal glucose metabolism and is therefore an excellent cohort in which to study the use of adjuvant metformin therapy in HNC patients.

Vocal fold healing after laser cordectomy with adjuvant cryotherapy.

OBJECTIVES: To understand the effect of adjuvant cryotherapy on glottic wound healing after endoscopic CO2 laser cordectomy. STUDY DESIGN: Canine acute injury model with videolaryngostroboscopic and histopathologic outcomes analysis. METHODS: Twelve adult male dogs underwent bilateral endoscopic CO2 laser transmuscular cordectomy followed by randomized unilateral endoscopic glottic cryotherapy. The animals were randomly divided into four groups and underwent videolaryngostroboscopy followed by sacrifice at 0, 2, 6, and 12 weeks postoperatively. Three untreated male dogs served as controls. Histopathologic sections were prepared with Alcian blue, Giemsa, hematoxylin-eosin, movat's, Masson's trichrome, and picrosirius stains. RESULTS: Videostroboscopy demonstrated an earlier restoration of glottic volume and a return of mucosal waves among vocal folds treated with combined therapy by 6 weeks posttreatment. The mean depth of inflammatory reaction in the vocal cords treated with combined therapy was 1.07 mm versus 1.15 mm in vocal cords treated with CO2 laser therapy alone. At 2 and 6 weeks postoperatively, combined treatment was associated with a decreased volume of collagen. At 12 weeks postoperatively, combined treatment was associated with greater collagen organization, normalized collagen histoarchitecture, and decreased keratinization. CONCLUSIONS: Adjuvant cryotherapy appears to alter glottis-specific wound healing, leading to decreased and more organized collagen formation and decreased keratinization with a resultant improvement in glottic function, when compared with CO2 laser surgery alone, in an acute canine injury model. Studies in humans are ongoing to further evaluate the clinical potential of cryotherapy on glottic wound healing.

Everolimus (RAD) inhibits in vivo growth of murine squamous cell carcinoma (SCC VII).

OBJECTIVE: Everolimus (RAD) is an mTOR inhibitor closely related to rapamycin. A potent immunosuppressive agent, it has also shown evidence of antineoplastic properties. SCC VII is a spontaneously arising murine squamous cell carcinoma line. This study examines the effect of everolimus on SCC VII proliferation. The data may provide support for the use of everolimus in transplant recipients with a history of malignancy. METHODS: A dose efficacy study was conducted that used a murine model of intradermal tumor growth and pulmonary metastases. The development of intradermal tumors and pulmonary metastases were studied. Of 80 total mice, 40 received intradermal injection of 1 x 10 SCC VII cells and 40 received intravenous injection of 1 x 10 cells to establish pulmonary metastases. Within each group, animals were subdivided into four subgroups that received 1) 1 mg/kg everolimus twice a day, 2) 0.5 mg/kg everolimus twice a day, 3) 7.5 mg/kg cyclosporine per day, and 4) no treatment. Intradermal tumors were measured three times per week. Animals receiving an intravenous tumor injection were killed after 17 days and pulmonary metastases were quantified. Medication trough levels were measured in all treated animals. RESULTS: Everolimus showed statistically significant tumor inhibition at 1.0 mg/kg twice a day and 0.5 mg/kg twice a day when compared with animals treated with cyclosporine and with untreated animals (P < .0001). Tumor inhibition was evident in both models studied (intradermal tumors and pulmonary metastasis generation). CONCLUSIONS: Everolimus provides potent tumor inhibition in animals inoculated with SCC VII cells. Inhibition of both local and distant spread of disease is evident. Although most immunosuppressives are known to potentiate neoplastic disease, this study supports the use of everolimus immunosuppression in the face of prior malignancy. This data has significant implication for laryngeal transplantation after laryngectomy.

Association between development of hypothyroidism and improved survival in patients with head and neck cancer.

OBJECTIVE: To determine if the development of hypothyroidism has an effect on the outcome of advanced-stage head and neck squamous cell carcinoma. DESIGN: Retrospective database analysis. SETTING: Tertiary care center. PATIENTS: The study population comprised 155 patients with advanced-stage head and neck squamous cell carcinoma. INTERVENTIONS: Patients underwent radiation therapy alone or in combination with chemotherapy and surgery when indicated. MAIN OUTCOME MEASURES: Kaplan-Meier analysis was used to assess survival, not adjusting for timing of the detection of hypothyroidism. The following 2 analyses were then performed to adjust for the timing of detection: (1) hypothyroidism was assessed as a time-varying covariate in a Cox proportional hazards model and (2) a landmark analysis was conducted at 9, 12, 15, 18, 21, and 24 months using the Kaplan-Meier method. RESULTS: Of the 155 patients, 59 developed hypothyroidism, defined as a thyrotropin level greater than 5.5 mIU/L (institutional value). An unadjusted Kaplan-Meier analysis indicated that patients who develop hypothyroidism have significantly better survival than patients who do not (P<.001, log-rank test). After adjusting for the timing of hypothyroidism, a Cox proportional hazards analysis indicated that survival was better, but not statistically significant, for patients who developed hypothyroidism (hazard ratio, 0.62; P=.12); results from a landmark analysis supported this finding (P values ranged from .11 to .19). CONCLUSIONS: Development of hypothyroidism may be associated with improved survival and increased recurrence-free survival. Larger, prospective studies appear warranted to test the beneficial effect of hypothyroidism.