Indications for sentinel lymph node biopsy in node-negative oral cancers.

BACKGROUND: We aimed to define the indications for sentinel lymph node biopsy (SLNB), the third option for cervical treatment in oral cancer with negative cervical lymph nodes. METHODS: The greatest depth of invasion (DOI) and long diameter (LD) of the primary site were used as exposures. SLN metastasis was considered the outcome. RESULTS: In three trials conducted between 2009 and 2016, 158 patients were eligible and reassigned to this study group. The scatterplot based on the respective values of DOI and LD would eventually be divided into three sections. In cases of sections T1, T2, and T3, the proportions of SLN metastasis positivity were 21.3%, 35.3%, and 51.2%, respectively. In certain cases of T1 with 2 mm < DOI ≤ 5 mm and 8 mm < LD ≤ 20 mm, the proportion of SLN metastasis positivity was 40.9%. CONCLUSIONS: SLNB-navigated or assisted neck dissection can be added as an effective procedure for N0 neck control.

The value of serum p53 antibody as a biomarker in oral and pharyngeal squamous cell carcinoma.

BACKGROUND: The development of more sensitive biomarkers for the detection of early-stage head and neck squamous cell carcinoma is needed. AIMS/OBJECTIVES: This study was performed to assess the value of serum p53 antibody (s-p53-Ab) as a biomarker for oral and pharyngeal carcinoma. MATERIAL AND METHODS: Pre-treatment serum was collected for 71 patients with oral and pharyngeal carcinoma and 117 healthy volunteers as controls and analyzed s-p53-Ab using enzyme-linked immunosorbent assay (ELISA). RESULTS: Using 1.3 U/mL as the cut-off value, 14 of 71 patients (sensitivity 19.7%), and 12 of 117 control cases were positive for s-p53-Ab (specificity 89.7%). Excluding 12 cases of p16-positive oropharyngeal and nasopharyngeal cancer which were all negative for s-p53-Ab, the sensitivity in early-stage 1-2 cases was 30.0%, which was higher than conventional tumor markers. CONCLUSIONS AND SIGNIFICANCE: The s-p53-Ab was not detected in any cases of virus-related cancer in which p53 gene mutations were not involved in carcinogenesis. Since the s-p53-Ab sensitivity was high even in early-stage disease, s-p53-Ab measurement may be useful as an early diagnostic biomarker in patients with oral, p16- oropharyngeal, and hypopharyngeal cancer.

Evaluation of chronological changes in videofluorographic findings after transoral videolaryngoscopic surgery to reveal mechanism of dysphagia.

OBJECTIVES: Transoral surgery preserves good swallowing function in most cases, however, postoperative dysphagia sometimes leads to fatal complication such as aspiration pneumonia. We investigated the chronological changes in swallowing function have not been revealed relationship with dysphagia. The primary aim of this study was to reveal the mechanism of dysphagia following transoral surgery by analyzing chronological videofluorography (VF) findings. Moreover, the secondary aim of this study was to evaluate the relationship between mechanism of dysphagia and risk factors of patients to clarify the risk for dysphagia lead to prevention of postoperative complications. METHODS: 22 patients who underwent transoral videolaryngoscopic surgery (TOVS) for either supraglottic or hypopharyngeal cancer were evaluated swallowing function. We performed VF during the preoperative, postoperative acute, and stable phases and investigated the chronological changes in the VF findings. The following parameters were evaluated by VF: horizontal distance of laryngeal movement, vertical distance of laryngeal elevation, laryngeal elevation delay time (LEDT), Bolus Residue Scale (BRS) scores, and Penetration Aspiration Scale (PAS) scores. Additionally, we evaluated risk factors for postoperative aspiration by investigating relationships between preoperative VF parameters, age of patients, history of radiation therapy, resection area, tumor (T) stage, postoperative Numeric Rating Scale (NRS), and PAS and BRS scores. RESULTS: The median time at which oral feeding was resumed in this study was 9 (2-200) days. The patients who had postoperative acute PAS scores of 4 and above exhibited delays in resuming oral ingestion after surgery. TOVS did not impair laryngeal elevation and LEDT; however, the BRS and PAS scores temporarily worsened in the acute phase compared to the preoperative scores. These scores almost recovered to their preoperative states in the stable phase, and both the BRS and PAS scores worsened and recovered concurrently. Patients who exhibited poor vertical distance in laryngeal elevation as observed via preoperative VF or who had histories of radiation therapy had worse PAS scores in postoperative acute phase VF. Patients with broad resection areas had worse BRS scores in postoperative acute phase VF. CONCLUSION: TOVS didn't impair the function of laryngeal elevation and elicitation of the swallowing reflex whereas pharyngeal bolus clearance, laryngeal penetration, and aspiration temporarily deteriorated concurrently but eventually almost recovered to their baseline values. Patients with histories of radiotherapy, poor laryngeal elevation, and broad resection areas are at the risk of postoperative dysphagia after TOVS. Patients with these risk factors need appropriate evaluation before resuming postoperative oral intake.

Frequent occurrence of postbreakfast syncope due to carotid sinus syndrome after surgery for hypopharyngeal cancer: A case report.

RATIONALE: Syncope often occurs in patients with advanced head and neck cancers due to the stimulation of the autonomic nervous system by the tumor. Here, we describe a case of frequent syncopal episodes after laryngopharyngectomy for hypopharyngeal cancer. As all syncopal episodes were observed during the forenoon, we also evaluated the heart rate variability using ambulatory electrocardiography to determine why the syncopal episodes occurred during a specified period of the day. PATIENT CONCERNS: A 73-year-old Japanese man who underwent laryngopharyngectomy for recurrent hypopharyngeal cancer started experiencing frequent episodes of loss of consciousness that occurred during the same time period (10:00-12:00). He had never experienced syncopal episodes before the operation. From 23 to 41 days postoperatively, he experienced 9 syncopal episodes that occurred regardless of his posture. DIAGNOSES: Pharyngo-esophagoscopy revealed an anastomotic stricture between the free jejunum graft and the upper esophagus. Swallowing videofluoroscopy confirmed the dilatation of the jejunal autograft and a foreign body stuck on the oral side of the anastomosis. Contrast-enhanced computed tomography revealed that the carotid artery was slightly compressed by the edematous free jejunum. The patient was diagnosed with carotid sinus syndrome (CSS) as the free jejunum was dilated when consuming breakfast, which may have caused carotid sinus hypersensitivity and induced a medullary reflex. INTERVENTIONS: Administration of disopyramide was effective in preventing syncope. Heart rate variability analysis using ambulatory electrocardiography showed that parasympathetic dominancy shifted to sympathetic dominancy during 10:00 to 12:00. The significant time regularity of the syncopal episodes may have been affected by modified diurnal variation in autonomic tone activity. OUTCOMES: After the surgical release and re-anastomosis of the pharyngoesophageal stenosis via an open-neck approach, no recurrent episodes of syncope were reported. LESSONS: We reported a case of frequent syncopal episodes limited to the forenoon due to CSS after surgery for hypopharyngeal carcinoma. The patient was treated with anticholinergics followed by the release and re-anastomosis of the pharyngoesophageal stenosis. When syncope occurs after surgery for head and neck lesions, CSS due to postoperative structural changes should be considered as a differential diagnosis of syncope.

TrkA inhibitor promotes motor functional regeneration of recurrent laryngeal nerve by suppression of sensory nerve regeneration.

Recurrent laryngeal nerve (RLN) injury, in which hoarseness and dysphagia arise as a result of impaired vocal fold movement, is a serious complication. Misdirected regeneration is an issue for functional regeneration. In this study, we demonstrated the effect of TrkA inhibitors, which blocks the NGF-TrkA pathway that acts on the sensory/automatic nerves thus preventing misdirected regeneration among motor and sensory nerves, and thereby promoting the regeneration of motor neurons to achieve functional recovery. RLN axotomy rat models were used in this study, in which cut ends of the nerve were bridged with polyglycolic acid-collagen tube with and without TrkA inhibitor (TrkAi) infiltration. Our study revealed significant improvement in motor nerve fiber regeneration and function, in assessment of vocal fold movement, myelinated nerve regeneration, compound muscle action potential, and prevention of laryngeal muscle atrophy. Retrograde labeling demonstrated fewer labeled neurons in the vagus ganglion, which confirmed reduced misdirected regeneration among motor and sensory fibers, and a change in distribution of the labeled neurons in the nucleus ambiguus. Our study demonstrated that TrkAi have a strong potential for clinical application in the treatment of RLN injury.

Scar contracture prevention with local steroid injections in transoral videolaryngoscopic surgery.

OBJECTIVE: The aim of this study was to evaluate the efficacy and safety of local steroid injections to prevent scar contracture after transoral videolaryngoscopic surgery (TOVS) in hypopharyngeal cancer patients. METHODS: Patients were enrolled in this study if they had received a local steroid injection during TOVS and had attended an outpatient clinic after at least three months. All patients were being treated for hypopharyngeal cancer and received a single session of triamcinolone acetonide, injected using a 21-gage needle. Retrospective chart reviews were performed, and the degree of scar contracture, pharyngeal stenosis, vocal fold movements, and adverse events were evaluated. Scar contracture was assessed using a scoring system, which compared the endoscopic findings of treatment and matched pair control groups. RESULTS: A total of 20 patients received local steroid injections during TOVS and were enrolled in the treatment. Scar contracture was seen in 14 patients (70%); however, the degree of scar contracture was significantly decreased when compared to control cases. Vocal fold immobility was observed in five patients, but no pharyngeal stenosis was noted. Adverse effects, such as postoperative laryngeal chondritis or cervical spondylitis, were seen in three patients who had previously been treated with resection to the muscularis propria or definitive irradiation. CONCLUSION: Local steroid injection during TOVS significantly reduced the degree of postoperative scar contracture. However, caution should be used when treating with local steroid injection during TOVS, as this may complicate wound healing in patients who have already received treatment.

Transoral videolaryngoscopic surgery for laryngeal and hypopharyngeal cancer - Technical updates and long-term results.

OBJECTIVE: Transoral videolaryngoscopic surgery (TOVS) was developed as a non-robotic procedure for en bloc laryngo-hypopharyngeal cancer resection. Straight devices had been used for this procedure, however, some cases had difficulty to reach the lesions especially in hypopharyngeal area. To overcome this problem, technical updates to facilitate transoral manipulation were developed and long term oncological and functional results were analyzed. METHODS: Surgical indications were Tis, T1, T2 and selected T3 cases. In advanced T3 or T4 lesions, neoadjuvant chemotherapy was performed before surgery. Radiation failure cases (rT1 and rT2) were also indicated for TOVS. Resectable nodal involvement can be managed by combination of neck dissection. Ninety hypopharyngeal and 25 supraglottic cancer cases were retrospectively reviewed for survival analyses. In fresh hypopharyngeal cancer, 51 Stage 0-II disease and 32 Stage III-IV disease were included. In supraglottic cancer, 11 Stage I-II disease and 9 Stage III-IV disease were included. Twelve radiation failure cases were analyzed separately. As new devices, malleable forceps and malleable suction coagulator were introduced to reach the whole laryngo-hypopharynx. New curved blades for the FKWO retractor were developed and these were applied for difficult hypopharyngeal exposure cases by conventional blades. Swallowing functional outcome and risk factors for postoperative dysphagia were evaluated by univariate analysis. RESULTS: The 5-year overall survival, disease-specific survival and larynx preservation rate of fresh hypopharyngeal cancer cases were 83.2%, 94.3% and 94.6%, respectively. Those of supraglottic cancer cases were 80%, 95% and 94.7%, respectively. Those of salvage cases were 87.5%, 87.5% and 82.5%, respectively. Those of T3 and T4 hypopharyngeal cancer treated by neoadjuvant chemotherapy with TOVS were 75.0%, 82.5% and 100% respectively. Surgical complication included bleeding (2.6%) and emergency tracheostomy (3.4%). Oral intake was maintained in 94.8% cases. By univariate analysis, patient's age (especially 80 years of age or older), larger resected area, arytenoid resection and tracheostomy were regarded as risk factors for postoperative dysphagia. Among 31 recent cases, 5 cases had difficulty in exposing hypopharyngeal lesions by conventional blades. These exposure problems were solved by curved blades. CONCLUSION: Using malleable devices and new curved blades for the FKWO retractor, exposure problems in the hypopharynx could be solved and TOVS could be applied in more cases. Although oncological outcomes and functional outcomes were good, patients with risk factors for dysphagia should be carefully indicated.

Minimally invasive surgery for laryngopharyngeal cancer: Multicenter feasibility study of a combination strategy involving transoral surgery and real-time indocyanine green fluorescence-navigated sentinel node navigation surgery.

BACKGROUND: Sentinel node navigation surgery using indocyanine green (ICG-SNNS) can be performed in the operation room. The combination of minimally invasive transoral surgery (TOS) with ICG-SNNS can provide functional preservation options for both primary lesions and lymph node (LN) metastasis. This multicenter feasibility study of this strategy was conducted in Japan. METHODS: Patients with clinical T1 or T2, N0 oropharyngeal, hypopharyngeal, or supraglottic cancer were enrolled. The identification rate of sentinel nodes, delayed cervical LN metastasis in 2 years, and survival rate were assessed. RESULTS: Twenty-two patients (10 oropharynx, 8 hypopharynx, 4 supraglottic cancer) were enrolled. The identification rate was 100%. One case had delayed nodal metastasis. The accuracy was 95.5%, sensitivity was 75%, and specificity was 100%. The 5-year disease-specific survival was 100%, overall survival was 72.3%, and disease-free survival was 60.5%. CONCLUSIONS: The combination of TOS with ICG-SNNS is feasible as a minimally invasive strategy and has favorable oncological outcomes.

Sentinel Lymph Node-Targeted Therapy by Oncolytic Sendai Virus Suppresses Micrometastasis of Head and Neck Squamous Cell Carcinoma in an Orthotopic Nude Mouse Model.

In clinical N0 (cN0) cases with head and neck squamous cell carcinoma (HNSCC), a treatment selection is still controversial: elective neck dissection or watchful waiting. We focused on sentinel lymph node (SLN)-targeted therapy using the urokinase-type plasminogen activator (uPA)-dependent oncolytic Sendai virus "BioKnife." The objectives of this study were to investigate BioKnife migration into SLNs and elucidate its antitumor effect on lymph node metastases (LNM). We established an orthotopic nude mouse model of HNSCC, with LNM being frequently induced. We inoculated HSC-3-M3, human highly metastatic tongue squamous cell carcinoma cells, in the tongue of the nude mice, and after 2 weeks, we injected BioKnife into the primary tumor. We tracked BioKnife migration into the SLNs by immunostaining, RT-PCR, and an in vivo imaging system. We also examined its antitumor effects and mechanisms through serial section analysis of lymph nodes. GFP reporter expression was clearly visible in the lymph nodes of virus groups, which corresponded to SLNs. Relative GFP mRNA was significantly increased in both the tongues and lymph nodes in the virus groups compared with that in the control group (P < 0.05). Serial section analysis showed that BioKnife infected cancer cells and exhibited significant antitumor effect against LNM compared with the control groups (P < 0.05). We detected apoptosis in LNM infected by BioKnife. BioKnife migrated into SLNs after its injection into the primary tumor and effectively suppressed LNM, suggesting that SLN-targeted therapy using BioKnife has great potential to provide a novel and promising alternative to elective neck dissection in cN0 patients with HNSCC.

Induction of cell fusion/apoptosis in anaplastic thyroid carcinoma in orthotopic mouse model by urokinase-specific oncolytic Sendai virus.

BACKGROUND: This study was designed to assess the therapeutic effect of urokinase-targeted recombinant oncolytic Sendai virus, termed "BioKnife," on anaplastic thyroid carcinoma (ATC). METHODS: Urokinase activity was investigated in human ATC cell lines, and BioKnife cytotoxicity against the cell lines was evaluated in vitro. Orthotopic mouse models of ATC were treated with three intratumoral injections of BioKnife, control virus, or phosphate-buffered saline (PBS) and were observed daily until >20% weight loss occurred. RESULTS: All three ATC cell lines showed a high level of urokinase activity. BioKnife induced urokinase-dependent cell fusion and cytotoxicity in all cell lines. Orthotopic models treated with BioKnife showed significantly prolonged survival compared with models treated with control virus or PBS (BioKnife 41.6 ± 15.0, control virus 17.0 ± 2.9, PBS 17.7 ± 6.3 days). CONCLUSIONS: BioKnife exerted therapeutic effects in orthotopic ATC mouse models. Thus, BioKnife represents a possible treatment option for ATC.

Feasibility of transnasal flexible carbon dioxide laser surgery for laryngopharyngeal lesions.

OBJECTIVE: The fiber-guided carbon dioxide (CO2) laser is a useful device for laryngopharyngeal surgery. The flexible CO2 wave-guide laser has been developed and commercially available for several years. However, the transnasal use of CO2 flexible wave-guided laser surgery through the instrument channel of a flexible endoscope (CO2 TNFLS) is not permitted in Japan. This feasibility study aimed to assess the value and the safety of an in-office CO2 TNFLS procedure. METHODS: Patients with small laryngopharyngeal diseases were enrolled from June 2015. Eligible patients had indications with lesions generally localized superficial lesions such as the benign tumor, leukoplakia, and premalignant lesion-like carcinoma in situ (CIS). Patients were locally well anesthetized using xylocaine. After removing as much of the lesion(s) as possible with flexible forceps, the remainder of the lesions were evaporated using CO2 TNFLS through the instrument channel of a flexible endoscope under local anesthesia. RESULTS: Eighteen surgeries involving 13 patients, including 9 papilloma (7 recurrent respiratory papilloma [RRP]), 2 carcinoma in situ, 1 leukoplakia, and 1 large epiglottic cyst), were performed. Four patients with RRP required multiple surgeries. Except for 3 patients with RRP, all patients achieved disease control without additional intervention. All procedures were completed with no severe adverse events. CONCLUSION: Office-based CO2 TNFLS is safe and feasible for patients with laryngopharyngeal pathologies. It is especially valuable for RRP patients with small lesions to avoid surgery under general anesthesia.

Oncolytic Sendai virus-induced tumor-specific immunoresponses suppress "simulated metastasis" of squamous cell carcinoma in an immunocompetent mouse model.

BACKGROUND: The objectives of this study were to demonstrate anti-metastatic effect of BioKnife, uPA activity-dependent oncolytic Sendai virus, after BioKnife treatment for primary tumor, and analyze its mechanisms in a simulated metastasis mouse model of head and neck squamous cell carcinoma (HNSCC). METHODS: We established a simulated metastasis mouse model using a murine HNSCC cell line "SCCVII." We assessed a tumor size and an induction of tumor-specific immunoresponses using cytotoxic T-lymphocyte (CTL) assay, flow cytometry (FCM) in spleen and immunohistochemistry (IHC) in secondary tumor. RESULTS: Secondary tumors were significantly smaller in BioKnife-treated group. CTL activities were significantly improved in BioKnife group. FCM revealed that induction of dendritic cells and CD4+ /CD8+ lymphocytes was significantly higher in BioKnife group. IHC showed that CD8+ lymphocytes invaded secondary tumor. CONCLUSION: Tumor-specific immunoresponses induced by BioKnife has great potential to be a novel, safe, and less invasive option for control and prevention of metastasis.

Gene Therapy for Recurrent Laryngeal Nerve Injury.

Recurrent laryngeal nerve (RLN) injury has considerable clinical implications, including voice and swallowing dysfunction, which may considerably impair the patient’s quality of life. Recovery of vocal fold movement is an essential novel treatment option for RLN injury. The potential of gene therapy for addressing this issue is highly promising. The target sites for RLN gene therapy are the central nervous system, nerve fibers, laryngeal muscles, and vocal cord mucosa. Gene transduction has been reported in each site using viral or non-viral methods. The major issues ensuing after RLN injury are loss of motoneurons in the nucleus ambiguus, degeneration and poor regeneration of nerve fibers and motor end plates, and laryngeal muscle atrophy. Gene therapy using neurotrophic factors has been assessed for most of these issues, and its efficacy has been reported. Another important matter for functional vocal fold movement recovery is misdirected regeneration, in which the wrong neurons may innervate other laryngeal muscles, where even if innervation is reestablished, proper motor function is not restored. Novel strategies involving gene therapy bear promise for overcoming this issue and further investigations are underway.

Vocal function after transoral videolaryngoscopic surgery (TOVS) for hypopharyngeal and supraglottic cancer.

CONCLUSION: The resection of the medial and lateral pyriform sinus was associated with post-operative voice impairment after TOVS. Scar contracture around the cricoarytenoid joint lead to arytenoid fixation toward lateral position, and this wound healing process caused insufficient glottis closure. Although oncological and functional outcomes of TOVS was satisfactory, surgeons should mention the risk of post-operative voice impairment in pre-operative counseling. OBJECTIVES: Transoral surgery is a minimally invasive treatment option for hypopharyngeal and supraglottic cancer. Post-operative vocal function was satisfactory in most cases, but in some cases vocal cord was fixed and occasionally voice impairment persists. METHODS: Vocal function of 55 patients who underwent transoral videolaryngoscopic surgery (TOVS) for hypopharyngeal and supraglottic cancers was evaluated by the GRBAS perceptive scale, aerodynamic tests and acoustic analyses, and the Voice Handicap Index questionnaire. The risk factors for voice impairment were identified. RESULTS: Voice impairment (G score ≧2) was found in 16 cases (29.1%). Univariate analysis revealed that the resection of medial and lateral pyriform sinus (p = .0018) and neck dissection (p = .0421) were associated with post-operative voice impairment. Multivariate analysis revealed that the resection of medial and lateral pyriform sinus (p = .0021) was associated with post-operative voice impairment.

Clinical features and treatment outcomes of Japanese head and neck cancer patients with a second primary cancer.

AIM: It has been well established that patients with head and neck cancer (HNC) have an elevated risk of developing a second primary cancer (SPC), owing to the common carcinogenic risk factors, including tobacco and alcohol consumption, and inactive aldehyde dehydrogenase-2 genotype. Here we investigated the current state of SPC in Japanese HNC patients. METHODS: We retrospectively investigated the incidence and treatment outcomes of synchronous and metachronous SPCs among 434 newly diagnosed HNC patients. Moreover, the associations between various carcinogenic risk factors and SPC were also assessed. RESULTS: Fifty-two (12.0%) and 104 patients (24.0%) had synchronous and metachronous SPCs, respectively. The cases with SPC were associated with high rates of smoking and alcohol histories (81.1% and 74.6%, respectively). Immunohistochemical analysis revealed that 47.5% of all oropharyngeal cancer cases showed positive p16 expression, and there was no significant difference between p16-positive and -negative cases in terms of the proportions of patients with SPC. The 3-year overall survival rates were 78.8%, 75.3% and 75.9% in patients without, with synchronous, and with metachronous SPC, respectively (P = 0.4048). CONCLUSION: Given the distinct features of the carcinogenic risk factors for HNC in Japan, care should be taken not to underestimate the frequency of SPC, even for human papillomavirus-related oropharyngeal cancer patients. Considering the high incidence of SPC associated with HNC, the appropriate diagnostic strategy to allow for early detection of SPC and a treatment strategy aimed at avoiding unnecessary radiotherapy for the index tumor would contribute to improving the prognosis for HNC.

Salvage Transoral Videolaryngoscopic Surgery for radiorecurrent hypopharyngeal and supraglottic cancer.

OBJECTIVE: To evaluate the feasibility of Transoral Videolaryngoscopic Surgery (TOVS) for radiorecurrent supraglottic and hypopharyngeal cancer, and to compare survival and complications between primary and radiorecurrent cases. METHODS: Twelve cases of salvage TOVS for radiorecurrent cancer and 53 cases of TOVS as an initial treatment (primary cases) were evaluated. Days to resume soft diet, Functional Outcomes of Swallowing Scale (FOSS), postoperative complications, epithelization days and survival outcomes were assessed by retrospective chart review. RESULTS: FOSS score was significantly worse in salvage cases compared with primary cases. Bleeding and airway compromise was slightly greater in salvage cases than in primary cases; however, this was not statistically significant. Wound healing was significantly delayed in salvage cases compared with primary cases (P<0.001). In primary cases, wounds were re-epithelized within 60 days in 83% of patients and within 90 days in almost all patients, while in salvage cases 42% of patients required more than 90 days for wound healing. In salvage cases, the 5-year overall survival, disease specific survival rate, local control rate, and laryngeal preservation rate was 85.7%, 85.7%, 62.5%, and 78.0%, respectively, and 85.7%, 98.0%, 91.3%, and 97.8%, respectively, for primary cases. Local control rate was significantly better in primary cases than in salvage cases. CONCLUSION: Salvage TOVS was feasible in highly selected cases. After serial transoral surgery, the final laryngeal preservation rate was satisfactory. Swallowing function in salvage cases tended to be worse than in primary cases, and a significantly longer time was required for wound healing.