The risk of pocket infection or bloodstream infection following central venous port placement for the patients with Cetuximab therapy.

OBJECTIVE: Cetuximab is a molecular targeted drug that targets epithelial growth factor receptors. The skin toxicity of cetuximab arising from epithelial growth factor inhibition is well known. Some patients with cetuximab therapy decided to make central venous port during the long-term intravenous treatments. Therefore, the author hypothesized that cetuximab administration might increase the risk of central venous port-related infection due to damage to skin barrier function. The main aim of the present study was to investigate the relationship between cetuximab administration and central venous port-related infection. METHODS: A total of 83 patients had a central venous port placed from 2016 through 2021. We analyzed, retrospectively, the relationship between cetuximab therapy and the incidence of central venous port-related infection involving central line-associated bloodstream infection and pocket infection. Additionally, the risk factors of central venous port-related infection were examined in the population undergoing cetuximab therapy. RESULTS: In total populations (83 cases), central line-associated bloodstream infection happened in five patients (6%) and pocket infection happened in six patients (7%) after central venous port placement. In the cetuximab therapy group (45 cases), there were four patients with central line-associated bloodstream infection (9%) and six with pocket infection (13%). The pocket infection happened more frequently in the cetuximab group than the other group with significant differences. Additionally, in the cetuximab group, the patients who had an interval of less than seven days between central venous port placement and cetuximab dosing, or central venous port placement preceded by cetuximab dosing had more pocket infection with significant differences. CONCLUSION: Skin complications after the central venous port placement were related to cetuximab administration and the timing of cetuximab therapy.

Prognostic values of systemic inflammation and nutrition-based prognostic indices in oropharyngeal carcinoma.

Objective: Pretreatment systemic inflammation and nutrition-based prognostic indices (SINBPI) have demonstrated significance. This study investigated the prognostic value of pretreatment SINBPI for patients with oropharyngeal cancer and identified unfavorable prognostic markers. Methods: We retrospectively reviewed the data of 124 patients with oropharyngeal squamous cell carcinoma (OPSCC) who received definitive treatment between January 2010 and December 2018. The prognostic utility of the neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), prognostic nutritional index, and high-sensitivity modified Glasgow prognostic score (HS-mGPS) was assessed for disease-free survival (DFS), disease-specific survival (DSS), and overall survival (OS) using univariate and multivariate analyses. Results: Multivariate analyses revealed that human papillomavirus (HPV) status and HS-mGPS were significantly associated with DFS, DSS, and OS. Patients with a HS-mGPS of 2 had a significantly higher rate of treatment-related deaths than those with a HS-mGPS of 0 or 1. The combination of the HS-mGPS and PLR had more accurate predictive ability in DFS and OS compared with the HS-mGPS alone, and the combination of the HS-mGPS and LMR had more accurate predictive ability in DSS and OS. Conclusion: Our results indicated that the HS-mGPS was a useful prognostic marker for patients with OPSCC, and combined markers consisting of the HS-mGPS and PLR or LMR may provide more accurate prognostic predictions.Level of Evidence: 3.

Long-term outcomes of basic fibroblast growth factor treatments in patients with vocal fold scarring, aged vocal fold, and sulcus vocalis.

OBJECTIVE: Fibrotic changes in the vocal fold mucosa have been observed in patients with vocal fold scarring, aged vocal fold, and sulcus vocalis, which often lead to severe voice disorders. Previous research suggests that the basic fibroblast growth factor (b FGF) improves variations in vocal fold properties [1,2]. Although clinical studies on b FGF treatments have been conducted [3,4,5], these studies only demonstrated the efficacy of this drug over a short period. The present study is the first to investigate the long-term efficacy of b FGF treatment. METHODS: b FGF injections were performed in six patients from January of 2016 to December of 2017 at our institution. Patient follow-up continued for at least two years after the last injection. Three patients had vocal fold scarring, two had aged vocal fold atrophy, and one patient had sulcus vocalis. Each vocal fold was injected with 10 µg of b FGF four times. Voice and stroboscopic examinations were performed after surgery (at one month, three months, six months, one year, two years). Fundamental frequency, maximum phonation time (MPT), mean flow rate (MFR), amplitude perturbation quotient (APQ), pitch perturbation quotient (PPQ), and noise-to-harmonic ratio (NHR), and voice handicap index-10 (VHI-10) were examined and compared statistically between the pretreatment time and at each posttreatment time point. RESULTS: The speaking F0 had an obvious decreasing tendency, with significant differences suggesting the increase in volume in the vocal folds. Aerodynamic parameters also showed small improvements. The most remarkable improvement was observed in the acoustic parameters, indicating that the treatment could improve the vocal fold to make vibrations symmetrically and regularly for a long period. Achievement of symmetry and regularity on vocal fold vibrations suggested the property changes had happened in the vocal folds. Consequently, the score of VHI-10 had improved, indicating high patient satisfaction with this treatment. CONCLUSION: b FGF injections could be a reliable treatment option for diseases that deteriorate the property of vocal fold.

A Comparison of the Localization of Integral Membrane Proteins in Human and Rabbit Vocal Folds.

OBJECTIVES: This study's objective was to identify and compare the localization of Aquaporin (AQP) 1, 4, 7, Na+/K + -ATPase, E-cadherin, zona occludin (ZO)-1, and occludin in human and rabbit vocal folds (VF)s to inform the design of future studies to explore the function of these proteins in the regulation of VF homeostasis. METHODS: Four human larynges and five New Zealand white rabbit larynges were used. Samples were immunolabeled for primary antibodies against AQP1, AQP4, AQP7, the alpha subunit of Na+/K + -ATPase, E-cadherin, and ZO-1 and occludin and then captured digitally using a Nikon Eclipse 90i microscope and Hamamatsu C10600 Camera. Two raters familiar with human and rabbit VF histology identified positive labeling in tissue structures, including the apical epithelium, basal epithelium/basement membrane, and lamina propria (LP). RESULTS: Samples from both species showed positive labeling for AQP1 in the basal epithelium/basement membrane, superficial LP, and deep/intermediate LP. Aquaporin 4, Aquaporin 7, Na+/K + -ATPase, and E-cadherin were primarily localized to the epithelium of both species. Zona occludin-1 was primarily localized apical epithelium and the superficial LP of both species. Occludin was primarily present in the apical epithelium in rabbit samples but not human. CONCLUSION: These data provide evidence of the presence of key ion transport channels and cell adhesion proteins in human and rabbit VFs. Aquaporin 1, 4, 7, Na+/K + -ATPase, E-cadherin, and ZO-1 were similarly localized in both species. These findings will be useful to investigators interested in the exploration of VF homeostasis and barrier integrity in future studies. LEVEL OF EVIDENCE: N/A Laryngoscope, 131:E1265-E1271, 2021.

Endoscopic Sealing With a Polyglycolic Acid Sheet for Restoration of Vocal Fold Mucosa in Dogs.

OBJECTIVES/HYPOTHESIS: Voice outcomes of cordectomy for early glottic cancer are often poor due to vocal fold scarring and tissue defects. Improvements in this aspect could make cordectomy a more acceptable treatment option than radiotherapy. We hypothesized that a polyglycolic acid (PGA) sheet could be used to cover vocal fold defects. The present study aimed to prevent vocal fold scarring after cordectomy using the PGA sheet. STUDY DESIGN: Animal experiment. METHODS: Nine male beagles were divided into three groups including a control group (n = 3). Following cordectomy, the vocal fold defect was covered with the PGA sheet plus fibrin glue (PGA group; n = 3) or with the PGA sheet plus fibrin glue containing basic fibroblast growth factor (bFGF; the PGA-bFGF group, n = 3). Vocal folds were chronologically observed, and larynges were removed 6 months after surgery. Mucosal amplitude was measured using a high-speed camera, and histological analysis was performed. RESULTS: The re-epithelialization process was delayed in the PGA and PGA-bFGF groups compared with the control group. The mucosal amplitude was significantly more normalized and the thickness ratio significantly higher in the PGA and PGA-bFGF groups compared with the control group. The PGA-bFGF group had the highest elastic fiber density, followed by the PGA group and then the control group, with a significant difference between the PGA-bFGF and control groups. CONCLUSIONS: The PGA sheet plus fibrin glue could serve as an effective regenerative scaffold for reconstructing vocal fold morphology and function after cordectomy, with the potential benefit of establishing an endoscopic sealing method for vocal fold defects. LEVEL OF EVIDENCE: NA Laryngoscope, 130:E436-E443, 2020.

Pathological mechanisms of laryngeal papillomatosis based on laryngeal epithelial characteristics.

OBJECTIVES: Human papillomavirus (HPV) infects basal cells of the stratified squamous epithelium through micro epithelial trauma. However, laryngeal papillomatosis commonly appears in any site on the laryngeal mucosa not covered by stratified squamous epithelium. The purpose of this study is to clarify pathological mechanisms of laryngeal papillomatosis based on the characteristics of the laryngeal epithelium. STUDY DESIGN: Morphological and immunohistochemical study. METHODS: Larynges from one newborn and two adults were used. Morphological differences in the laryngeal squamo-ciliary junction (lSCJ) were compared to those in the cervical squamo-columnar junction (cSCJ) in a resected cervix uterus. Morphological characteristics of laryngeal epithelial distribution were also compared between the newborn and adult larynges. Immunohistochemical evaluations were performed using p63 (an epithelial stem-cell marker) and integrin-α6 (a cellular HPV receptor). RESULTS: Morphological differences were noted between the lSCJ and the cSCJ. The lSCJ was present in the adult, but not the newborn supraglottis. Goblet cells in the pseudostratified ciliated columnar epithelium were also found in the adult but not the newborn larynx. In addition, basal cells of the stratified squamous epithelium as well as the pseudostratified ciliated columnar epithelium expressed p63 and integrin-α6 in both newborn and adult larynges. CONCLUSIONS: HPV can infect any immature laryngeal epithelium with or without the lSCJ. Squamous metaplasia of pseudostratified ciliated columnar epithelium with a latent HPV infection can also cause tumorigenesis. LEVEL OF EVIDENCE: N/A.

Stable Tracheal Regeneration Using Organotypically Cultured Tissue Composed of Autologous Chondrocytes and Epithelial Cells in Beagles.

OBJECTIVES: In tracheal regeneration, the slow process of epithelialization is often a barrier to the stability and safety of the transplanted trachea. The aim of this study was to examine a new tracheal regeneration technique using organotypically cultured tissue composed of autologous cells. METHODS: Nine beagles were prepared. Chondrocytes from auricular cartilage and epithelial cells from buccal mucosa were isolated and cultured. Tissue-engineered cartilages were fabricated with chondrocytes at a density of 1 × 107 cells/mL (high-density group) and 1 × 106 cells/mL (low-density group). A fabricated epithelial cell sheet was laid on a poly(lactic-co-glycolic acid) block in atelocollagen gel containing the chondrocytes, and the organotypically cultured tissues were transplanted into a partially resected trachea. The control group had only the block transplanted. RESULTS: The tissue-engineered cartilages in the high-density group contained many viable chondrocytes and many cartilage matrices. The low-density group had abundant collagen fibers and no chondrocytes. Tracheal endoscopy revealed no deformation or atrophy at the transplant site in the high-density group. Histologically, partially hyaline cartilages covered with epithelium and lamina propria were found in the high-density group but not in the low-density and control groups. CONCLUSIONS: Stable tracheal regeneration was achieved using organotypically cultured tissue fabricated with autologous high-density chondrocytes and epithelial cells.

Endoscopic surgical technique for benign fibrotic strictures of the upper esophageal sphincter.

A 43-year-old man with complaints of increased difficulty swallowing and weight loss underwent videofluorographic examination of swallowing, which revealed severely reduced cricopharyngeal opening. Endoscopic cricopharyngeal myotomy was carried out using a modified technique (mECPM). A benign fibrotic stricture of the upper esophageal sphincter (UES) was identified under visualization of a distending operating laryngoscope. A vertical midline incision in the strictured mucosa and submucosal resection of the cricopharyngeal muscle were done using a CO2 laser. The initial vertical mucosal incision was tightly sutured in the horizontal direction with absorbable surgical sutures. Histopathological examination of the cricopharyngeal muscle revealed infiltration of inflammatory cells. The patient started oral intake on postoperative day 7. He has been symptom free for 2 years with an improved body mass index, and postoperative laryngoscopy revealed no salivary retention in the piriform sinuses. The technique presented here provides sufficient opening of the UES by eliminating the problem of restenosis. mECPM will be useful for treating benign fibrotic strictures of the UES.

Recurrent laryngeal nerve regeneration using an oriented collagen scaffold containing Schwann cells.

OBJECTIVES/HYPOTHESIS: Regeneration of the recurrent laryngeal nerve (RLN), which innervates the intrinsic laryngeal muscles such that they can perform complex functions, is particularly difficult to achieve. Synkinesis after RLN neogenesis leads to uncoordinated movement of laryngeal muscles. Recently, some basic research studies have used cultured Schwann cells (SCs) to repair peripheral nerve injuries. This study aimed to regenerate the RLN using an oriented collagen scaffold containing cultured SCs. STUDY DESIGN: Preliminary animal experiment. METHODS: A 10-mm-long autologous canine cervical ansa was harvested. The nerve tissue was scattered and subcultured on oriented collagen sheets in reduced serum medium. After verifying that the smaller cultivated cells with high nucleus-cytoplasm ratios were SCs, collagen sheets with longitudinally oriented cells were rolled and inserted into a 20-mm collagen conduit. The fabricated scaffolds containing SCs were autotransplanted to a 20-mm deficient RLN, and vocal fold movements and histological characteristics were observed. RESULTS: Scaffolds containing cultured SCs were successfully fabricated. Immunocytochemical examination revealed that these isolated and cultured cells, identified as SCs, expressed S-100 protein and GFAP but not vimentin. The orientation of SCs matched that of the oriented collagen sheet. Two months after successful transplantation, laryngeal endoscopy revealed coordinated movement of the bilateral vocal folds by external stimulation under light general anesthesia. Hematoxylin and eosin staining showed that the regenerated RLN lacked epineurium surrounding the nerve fibers and was interspersed with collagen fibers. Myelin protein zero was expressed around many axons. CONCLUSIONS: Partial regeneration of RLN was achieved through the use of oriented collagen scaffolding. LEVEL OF EVIDENCE: NA Laryngoscope, 127:1622-1627, 2017.

A case of peritoneal metastasis during treatment for hypopharyngeal squamous cell carcinoma.

BACKGROUND: Advanced head and neck squamous cell carcinomas frequently develop distant metastases to limited organs, including the lungs, bone, mediastinal lymph nodes, brain, and liver. Peritoneal carcinomatosis as an initial distant metastasis from hypopharyngeal squamous cell carcinoma is quite rare. CASE PRESENTATION: A 75-year-old man diagnosed with hypopharyngeal squamous cell carcinoma and his clinical stage was determined as T2N2cM0. Notably, the right retropharyngeal lymph node surrounded more than half of the right internal carotid artery. Concomitant conformal radiation therapy was administered for the primary hypopharyngeal lesion, and the whole neck and tumor response was evaluated at this point according to our algorithm-based chemoradioselection protocol. As the tumor responses at both the primary and lymph nodes were poor, with the right retropharyngeal lymph node in particular demonstrating mild enlargement, we performed a radical surgery: pharyngolaryngectomy, bilateral neck dissection, and reconstruction of the cervical esophagus with a free jejunal flap. Then, postoperative CRT was performed. During these therapies, the patient developed a fever and mild abdominal pain, which was associated with an increased C-reactive protein level. Contrast-enhanced computed tomography from the neck to the pelvis demonstrated mild peritoneal hypertrophy and ascites with no evidence of recurrent and/or metastatic tumor formation. We initially diagnosed acute abdomen symptoms as postoperative ileus. However, cytological examination of the refractory ascites resulted in a diagnosis of peritoneal carcinomatosis. Owing to rapid disease progress, the patient died 1.5 months after abdominal symptom onset. CONCLUSIONS: The present case is the second reported case of head and neck squamous cell carcinoma with peritoneal carcinomatosis as an incipient distant metastasis. Therefore, peritoneal carcinomatosis should be considered a differential diagnosis when acute abdomen is noted during treatment for head and neck cancers.

Histoanatomical characteristics to increase the success in transoral surgery for hypopharyngeal cancer.

OBJECTIVES/HYPOTHESIS: Transoral laser microsurgery (TLM) for hypopharyngeal cancer results in a lower incidence of complications than conventional open surgery. However, additional knowledge regarding the histoanatomical characteristics of the hypopharynx is necessary to prevent severe complications during TLM. The purpose of this study is to investigate the histoanatomical characteristics of the hypopharynx for TLM. STUDY DESIGN: Histoanatomical study. METHODS: Whole organ serial sections of three hypopharynges and larynges from autopsy cases were subjected to hematoxylin & eosin and Elastica van Gieson staining. Surgical histoanatomy of the hypopharynx was observed with each section, and the histoanatomical characteristics directly related to TLM performance were examined microscopically. RESULTS: The histological structures of muscle layers showed obvious differences between each hypopharyngeal subsite. The posterolateral wall had two kinds of pharyngeal elevator muscles. These fasciae were connected to the perichondrium of the thyroid cartilage. The anterolateral wall between the superior horn and the lamina of the thyroid cartilage had no muscle layer. The superior laryngeal artery and the internal branch of the superior laryngeal nerve run into the larynx and hypopharynx at that site. The inner perichondrium of the thyroid cartilage was present beneath the mucosa. The dihedral angle of the anterior piriform fossa had a deep propria mucosa and paraglottic space. The postcricoid wall consisted of a multilayered structure, including cricoid cartilage covered with laryngeal muscles and mucosa. CONCLUSION: A precise understanding of the histoanatomical characteristics of the hypopharynx increases the success of TLM, decreases complication rates, and improves laryngeal preservation. LEVEL OF EVIDENCE: N/A. Laryngoscope, 126:1783-1789, 2016.

Regeneration of Vocal Fold Mucosa Using Tissue-Engineered Structures with Oral Mucosal Cells.

OBJECTIVES: Scarred vocal folds result in irregular vibrations during phonation due to stiffness of the vocal fold mucosa. To date, a completely satisfactory corrective procedure has yet to be achieved. We hypothesize that a potential treatment option for this disease is to replace scarred vocal folds with organotypic mucosa. The purpose of this study is to regenerate vocal fold mucosa using a tissue-engineered structure with autologous oral mucosal cells. STUDY DESIGN: Animal experiment using eight beagles (including three controls). METHODS: A 3 mm by 3 mm specimen of canine oral mucosa was surgically excised and divided into epithelial and subepithelial tissues. Epithelial cells and fibroblasts were isolated and cultured separately. The proliferated epithelial cells were co-cultured on oriented collagen gels containing the proliferated fibroblasts for an additional two weeks. The organotypic cultured tissues were transplanted to the mucosa-deficient vocal folds. Two months after transplantation, vocal fold vibrations and morphological characteristics were observed. RESULTS: A tissue-engineered vocal fold mucosa, consisting of stratified epithelium and lamina propria, was successfully fabricated to closely resemble the normal layered vocal fold mucosa. Laryngeal stroboscopy revealed regular but slightly small mucosal waves at the transplanted site. Immunohistochemically, stratified epithelium expressed cytokeratin, and the distributed cells in the lamina propria expressed vimentin. Elastic Van Gieson staining revealed a decreased number of elastic fibers in the lamina propria of the transplanted site. CONCLUSION: The fabricated mucosa with autologous oral mucosal cells successfully restored the vocal fold mucosa. This reconstruction technique could offer substantial clinical advantages for treating intractable diseases such as scarring of the vocal folds.

Origin of Vocal Fold Stellate Cells in the Human Macula Flava.

OBJECTIVES: There is growing evidence that vocal fold stellate cells (VFSCs) in the human maculae flavae are tissue stem cells of the human vocal fold and that the maculae flavae are a stem cell niche. The origin of the cells in the human maculae flavae (CHMF) and the relationship with bone marrow-derived cells were investigated. METHODS: Five human adult vocal fold mucosae were investigated. The CHMF were subcultured and morphological features were assessed. Immunoreactivity to antibodies directed to cytokeratin, desmin, GFAP, vimentin, CD34, CD45, and collagen type I was investigated. RESULTS: Cultured CHMF formed a colony-forming unit, indicating they are mesenchymal stem cells or stromal stem cells in the bone marrow. The CHMF expressed hematopoietic markers (CD34, CD45) and collagen type I, which are the major makers for bone marrow-derived circulating fibrocytes. The cultured CHMF expressed epithelium-associated, muscle-associated, neural-associated, and mesenchymal cell-associated proteins, indicating the CHMF are undifferentiated and express proteins of all 3 germ layers. CONCLUSIONS: The CHMF are undifferentiated cells derived from the differentiation of bone marrow cells. The results of this study are consistent with the hypothesis that the VFSCs are tissue stem cells or progenitor cells of the human vocal fold mucosa.

Analysis of passive motion of para- and retropharyngeal structures during swallowing using dynamic magnetic resonance imaging.

The purpose of this study was to analyze passive motion of the para- and retropharyngeal space (PRS) during swallowing using dynamic magnetic resonance imaging (MRI). We conducted a preliminary study involving 30 healthy volunteers who underwent dynamic MRI. Consecutive MRI axial images were obtained by examining the plane parallel to the hard palate at the level of the anterior inferior corner of C2. Anterior displacement of the posterior pharyngeal wall (PPW) was measured as a motion index of pharyngeal contraction. The displacement and internal angle of the bilateral external and internal carotid arteries (ECA and ICA) and the bilateral centroids of the PRS area, as well as the increase in PRS area, were calculated at rest and at maximum pharyngeal contraction. In most participants, the bilateral ECA, ICA, and centroids were anterointernally displaced by pharyngeal contraction. The normalized ECA displacement (r = 0.64, r (2) = 0.41), normalized ICA displacement (r = 0.60, r (2) = 0.37), and normalized centroid displacement (r = 0.43, r (2) = 0.19) were more than moderately positively correlated with the normalized PPW displacement. The normalized PRS area increase (r = 0.35, r (2) = 0.12) was weakly positively correlated with the normalized PPW displacement. These results revealed that PRS area increased as the ECA and ICA were drawn anterointernally via its passive motion by pharyngeal contraction.

[Repeated syncope episodes caused by intractable hiccups; a case report].

A 66-year-old man visited our hospital with a chief complaint of a sore throat. On examination, the pharyngeal and laryngeal mucosa was reddish and localized mucosal erosion was present on the left side. Based on an initial diagnosis of acute pharyngitis caused by bacteriological infection or mycotic infection, treatment with antibacterial and antimycotic agents was initiated. However, the patient's sore throat gradually worsened and he developed intractable hiccups. Intravenous steroids were given for the treatment of the severe sore throat, and this symptom was gradually alleviated. However, the intractable hiccups persisted. In addition, the patient began to have convulsive syncope episodes and was subsequently admitted to our hospital. Further examination revealed that the syncope episodes were linked to the hiccups. To treat the hiccups, baclofen and Chinese medicine were prescribed, and the convulsive syncope episodes disappeared immediately. The patient's hiccups also improved and disappeared six days thereafter. Based on this clinical evidence, we concluded that the hiccups were caused by pharyngitis, resulting in the stimulation of the glossopharyngeal nerve, while the convulsive syncope episodes were a type of situational syncope related to hiccups.