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.

The expression of programed death ligand-1 could be related with unfavorable prognosis in salivary duct carcinoma.

BACKGROUND: Salivary duct carcinoma (SDC) is a rare tumor occurring in the salivary gland. SDC is a highly aggressive tumor and its prognosis is extremely poor. Effective treatments in advanced SDC have not yet been established. Recently, immune checkpoint inhibitors have paved the way for the treatment of various malignancies. We examined the expressions of programed death ligand (PD-L) 1/PD-L2 and programed death (PD-1), and the correlation of clinicopathological findings. METHODS: We examined 18 cases of SDC and conducted immunohistochemical staining using formalin-fixed paraffin-embedded full-face sections. RESULTS: The expression of PD-L1 and PD-L2 in tumor cells was observed in nine cases (50%) and 14 cases (78%), respectively. Cases with a high expression of PD-L1 and PD-L2 were found in four (22%) and seven cases (39%), respectively. The cases with a high expression of PD-L1 showed significantly shorter overall survival compared to those with low PD-L1 expression and null expression. We also examined the expression of PD-L1/PD-L2 and PD-1 of tumor-infiltrating mononuclear cells (TIMC) in stroma. The expressions of PD-L1 in tumor cells and stroma had a significant correlation. Association between the expressions of PD-L1 in tumor cells and those of PD-1 in stroma was significant. However, PD-L2 expression in the tumor had no significant correlation with expression in TIMCs. PD-L1, PD-L2 and PD-1 expressions in stroma were not associated with patient prognosis. CONCLUSIONS: High PD-L1 expression in SDC was strongly associated with unfavorable prognosis, indicating that PD-1/PD-L1 inhibitors could be effective in SDC.

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.

Mechanical regulation of human vocal fold stellate cells.

OBJECTIVE: It is generally accepted that tensile and compressive strains have direct effects on cell morphology and structure, including changes in cytoskeletal structure and organization. Cytoskeletons play the role of mechanoreceptor of the cells. Vocal fold stellate cells (VFSCs) in the human maculae flavae (MFe) are inferred to be involved in the metabolism of extracellular matrices essential for the viscoelasticity of the vocal fold mucosa. Our previous studies have supported the hypothesis that the tension caused by phonation (vocal fold vibration) regulates the behavior of the VFSCs. The microstructure of the intermediate filaments and the expression of their proteins were investigated in VFSCs in the MFe, which had remained unphonated since birth. METHODS: Three adult vocal fold mucosae that had remained unphonated since birth were investigated by immunohistochemistry and electron microscopy. RESULTS: The intermediate filaments of the VFSCs were fewer in number. The expression of their characteristic proteins (vimentin, desmin, and glial fibrillary acidic protein) was also reduced. CONCLUSION: Vocal fold vibration seems to affect VFSC morphology and structure, such as cytoskeletal structure and organization. This supports the hypothesis that vocal fold vibration regulates VFSC behavior in the human MFe. In addition to chemical factors, mechanical factors also appear to modulate VFSC behavior.

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.

[Laryngeal Papillomatosis: A Statistical Analysis of 60 Cases].

Laryngeal papillomatosis is the most common benign neoplasm of the larynx. Juvenile onset laryngeal papillomatosis tends to recur. In patients with adult onset laryngeal papillomatosis, laryngeal cancer rarely develops. This paper reports a clinical analysis of 60 patients with laryngeal papillomatosis who were treated at our clinic between January 1971 and September 2009. We analyzed the sex ratio, age at the onset of papilloma, type of developing papilloma (single or multiple type), site of developing papilloma, recurrence rate, and therapeutic modalities. Furthermore, the clinical characteristics of the patients with malignant transformation were examined. The patients were classified according to their age at the onset of the papilloma and the type of developing papilloma. The patients were grouped into a juvenile-onset group and an adult-onset group according to their age at the onset of the papilloma. They were also classified into single-type or multiple-type according to whether the initial papilloma appeared singly or multiply. The male to female sex ratios were 1.2 in the juvenile-onset group and 5.1 in the adult-onset group. Among the patients who developed papilloma at an age of under 10 years old, most of the juvenile cases had experienced onset by 4 years of age. Furthermore, the frequency of multiple-type papilloma was significantly higher in the juvenile-onset group, compared with the adult-onset group. The vocal fold was the most frequent site of the papilloma. The recurrence rate in the juvenile-onset group was significantly higher than that of the adult-onset group. A stratified analysis according to the type of papilloma occurrence, however, showed no significant difference in recurrences between the juvenile-onset and adult-onset groups. A stratified analysis according to the age at the onset of papilloma showed that the recurrence rate of multiple-type papilloma was significantly higher than that of single-type papilloma in the adult-onset group. Among multiple therapeutic modalities, vaporization by carbon dioxide laser was the most frequently used. Adjuvant therapy was performed in 6 cases who suffered from multiple relapses. The injection of interferon was performed in 5 cases, and the local injection of cidofovir was performed in 1 case. Malignant transformation of the papilloma was confirmed in 3 cases. The periods between the onset of papilloma and the malignant transformation were 40 years, 14 years, and 3 years. The present study indicates that patients with laryngeal papilloma developing at multiple sites have a significantly higher rate of relapse, even in the adult-onset group. There was no tendency in the period observed between the onset of papilloma and malignant transformation. From the standpoint of recurrence and malignant transformation, patients with papillomatosis should be carefully followed up for a long period of time.

[Surgical approach of lateral temporal bone resection for treatment of head and neck cancer with invasion surrounding the jugular foramen].

We herein present a review of the surgical approach of lateral temporal bone resection (LTBR) in the treatment of 5 cases of head and neck cancers invading the jugular foramen between 2008 to 2013. The patients comprised 3 males and 2 females with ages ranging from 25 to 76 and observation times were between 13 and 22 months. In this study we reviewed the method of operation and treatment. Four patients are alive, but one patient died from the primary disease. Complications occurred including postoperative facial nerve palsy and hearing loss. Although the LTBR with jugular foramen approach can cause postoperative facial nerve palsy and hearing loss, this method would be recommended as a safe surgical procedure for its wide surgical field. We therefore propose that this LTBR technique is useful for patients with head and neck cancer extending to the jugular foramen.

Pathogenesis of Reinke's Edema of the Vocal Fold.

OBJECTIVES: The most frequent etiologic factor of Reinke's edema (RE) is considered to be smoking. However, the mechanism for the onset and development of the disease remains unclear. Hypoxia-inducible factor-1α (HIF-1α) is an oxygen-dependent transcriptional activator which plays crucial roles in angiogenesis in hypoxic microenvironments. HIF-1α induces the expression of vascular endothelial growth factor (VEGF) which involves angiogenesis and enhances vascular permeability. This study investigated the roles of HIF-1α in the pathogenesis of RE. METHODS: Surgical specimens of RE from patients who underwent endolaryngeal microsurgery were used. Normal vocal folds were used as a control group. Expression of HIF-1α and VEGF was analyzed by immunohistochemistry. Three-dimensional fine structures of the vessels in RE were investigated using correlative light and electron microscopy (CLEM) technique. RESULTS: HIF-1α and VEGF were broadly expressed in the stromal, inflammatory, and endothelial cells in the lamina propria of the vocal fold of RE. The expression of HIF-1α and VEGF of RE were significantly higher than in the lamina propria of the normal vocal fold mucosa. CLEM showed vascularization and telangiectasia and there were many dilated capillaries with thin endothelium not covered with pericytes indicating the vessels were fragile. CONCLUSION: Transcription factor HIF-1α and induced VEGF likely play roles in the pathogenesis of RE. And increased vascular permeability with fragile vessels in angiogenesis is likely to be an etiology of RE. Transcription factor HIF-1α and induced VEGF are potential therapeutic targets for RE. LEVEL OF EVIDENCE: NA Laryngoscope, 134:1785-1791, 2024.

Growth and development of epiglottis and preepiglottic space of larynx as it acquires vocal tract.

Objectives: The growth and development of the epiglottis and preepiglottic space (PES) of the human larynx as it acquires the vocal tract were investigated. Methods: Three newborns, one infant, four children (2, 7, 8, and 12 years old), and two adult normal larynges were investigated and compared using the whole organ serial section technique. Results: The newborn PES occupied a small area just anterior to the epiglottis. It was composed of immature adipose tissue and areolar tissue. The epiglottis lay on a somewhat horizontal axis and is partially obscured behind the hyoid bone. The hyoid bone overlapped the thyroid cartilage, partially obscuring the superior thyroid notch. The newborn epiglottic cartilage was immature elastic cartilage, and the elastic fiber component was sparse. In the first 8 years of life, as the PES grew, the PES was located not only anterior to but also posterolateral and inferolateral to the epiglottic cartilage and thyroepiglottic ligament. Meanwhile, the epiglottic cartilage matured. Conclusions: In order to develop the vocal tract for speech production, it is reported that the human larynx descends as the child grows in the first 9 years of life. This study showed that the PES, occupying a small area just anterior to the epiglottis, grew and existed astride the epiglottis as the larynx descended and the vocal tract developed. Consequently, its distribution allows the epiglottis to more effectively play the role of retroflection during swallowing in order to prevent aspiration. The human speech faculty likely develops in conjunction with swallowing physiology.

Relationship between Swallowing Pressure and Saliva Residue on Endoscopic Evaluation in Pharyngeal Dysphagia.

OBJECTIVE: In pharyngeal dysphagia, poor pharyngeal contraction and upper esophageal sphincter (UES) dysfunction result in post-swallow saliva residue (SR). This study aimed to clarify the relationship between swallowing pressure and SR in the valleculae and piriform sinuses on flexible endoscopic evaluation of swallowing (FEES). METHODS: Pharyngeal dysphagia patients with Wallenberg syndrome were included. Amounts of post-swallow SR in the valleculae and piriform sinuses were classified into four grades using SR scores based on FEES. The Hyodo score was also calculated to evaluate swallowing function. High-resolution manometric data in the nasopharyngeal, oropharyngeal, hypopharyngeal, oro-hypopharyngeal, and UES zones on swallowing were obtained for comparison with SR and Hyodo scores. RESULTS: Of the 31 recruited, data from 26 patients who successfully underwent FEES and manometry were analyzed. Vallecular SR scores were strongly negatively correlated with a maximum pressure of the oropharynx (r = -0.52, p = 0.006), distal contractile integrals (DCI) of the oropharynx (r = -0.52, p = 0.007), and DCI of the oro-hypopharynx (r = -0.55, p = 0.004). Hyodo scores for parameters 1 and 4 (corresponding to salivary pooling and pharyngeal clearance, respectively) were strongly negatively correlated with a maximum hypopharyngeal pressure (r = -0.57, p = 0.002) and strongly positively correlated with peristaltic velocity (r = 0.53, p = 0.007), respectively. SR scores and Hyodo scores related to SR were not correlated with pressure data of the UES. CONCLUSION: Manometric analysis of our SR scoring method using FEES revealed that a higher amount of SR in the valleculae, but not in the piriform sinuses, is associated with weaker pharyngeal pressure in pharyngeal dysphagia, especially at the oropharyngeal level. LEVEL OF EVIDENCE: 4 Laryngoscope, 134:3519-3526, 2024.

Effectiveness and feasibility of selective intra-arterial low dose of cisplatin infusion and concomitant radiotherapy for patients with advanced laryngeal cancer with impaired renal function: A retrospective cohort study.

BACKGROUND: Chemoradiation therapy with high-dose cisplatin is the standard regimen against advanced squamous cell carcinoma of the larynx (SCC-L). However, patients with renal dysfunction are ineligible for this regimen. We investigated the effectiveness and feasibility of selective intra-arterial low-dose cisplatin infusion and radiotherapy (modified [m]-RADPLAT) for patients with impaired renal function. METHODS: We retrospectively reviewed the data of 77 patients with SCC-L who received m-RADPLAT. RESULTS: Fourteen and 63 patients had creatinine clearance (CrCl) values of 30 ≤ CrCl < 60 mL/min and ≥60 mL/min, respectively. The m-RADPLAT regimen led to no significant changes in serum creatinine or CrCl values post-treatment. The 5-year local control, overall survival, and laryngectomy-free survival rates of the CrCl < 60 and ≥60 groups were 90.0% and 90.5%, 100% and 81.8%, and 100% and 79.0%, respectively. Grade 3 or higher toxicity rates were not significantly different between the groups. CONCLUSIONS: The m-RADPLAT regimen yielded favorable survival rates and clinical outcomes in patients with impaired renal function.

Clinical, genomic and immune microenvironmental determinants of nivolumab response in head and neck squamous cell carcinoma.

Background: In view of improving biomarkers predicting the efficacy of immunotherapy for head and neck squamous cell carcinoma (R/M HNSCC), this multicenter retrospective study aimed to identify clinical, tumor microenvironmental, and genomic factors that are related to therapeutic response to the anti- Programmed cell death protein 1 (PD-1) antibody, nivolumab, in patients with R/M HNSCC. Methods: The study compared 53 responders and 47 non-responders, analyzing formalin-fixed paraffin-embedded samples using 14-marker multiplex immunohistochemistry and targeted gene sequencing. Results: Of 100 patients included, responders had significantly lower smoking and alcohol index, higher incidence of immune related adverse events, and higher PD-1 ligand (PD-L1) expression in immune cells as well as PD-L1 combined positive score (CPS) than non-responders. The frequency of natural killer cells was associated with nivolumab response in patients with prior cetuximab use, but not in cetuximab-naïve status. Age-stratified analysis showed nivolumab response was linked to high CPS and lymphoid-inflamed profiles in patients aged ≥ 65. In contrast, lower NLR in peripheral blood counts was associated with response in patients aged < 65. Notably, TP53 mutation-positive group had lower CPS and T cell densities, suggesting an immune-excluded microenvironment. Patients with altered tumor suppressor gene pathways, including TP53, CDKN2A, and SMAD4 mutations, had lower CPS, higher smoking index, and were associated with poor responses. Conclusion: Nivolumab treatment efficacy in HNSCC is influenced by a combination of clinical factors, age, prior treatment, immune environmental characteristics, and gene mutation profiles.

Distribution of Label-Retaining Cells and their Properties in the Newborn Vocal Fold Mucosa.

OBJECTIVES: There is growing evidence that the cells in the maculae flavae (MFe) are candidates for tissue stem cells of the vocal fold mucosa and the MFe are a stem cell niche. Distribution of label-retaining cells and their properties in the postnatal vocal fold mucosa were investigated. METHODS: Oral administration of bromodeoxyuridine (BrdU) was given to pregnant Sprague-Dawley rats and the label-retaining cells in the postnatal vocal fold mucosa were observed by immunohistochemistry. Immunoreactivity to antibodies directed to Ki-67 was studied to investigate the cell cycle. RESULTS: At day 1 after birth, BrdU positive cells were identified in the MFe (60.1 ± 1.7%), epithelium (58.7 ± 10.6%) and lamina propria (52.4 ± 7.8%) of the vocal fold mucosa. At day 56 after birth, the number of BrdU positive cells in the epithelium (4.8 ± 2.2%) and lamina propria (32.3 ± 16.5%) were significantly lower compared to day 1 after birth (P < 0.05). However, the number of BrdU positive cells remaining in the MFe was still high (56.2 ± 2.5%). The label-retaining cells were distributed throughout the MFe. Few Ki-67 positive cells were identified in the MFe indicating they were resting cells. CONCLUSIONS: The results of this study are consistent with the hypothesis that the cells in the postnatal MFe are candidates for tissue stem cells. At birth, these cells are already present in the MFe of the newborn vocal fold and they are likely ready to start the growth and development of the vocal fold mucosa.

Vascularity in the macula flava of human vocal fold as a stem cell niche.

OBJECTIVES: There is growing evidence that the maculae flavae of the human vocal fold are a stem cell niche, which is a microenvironment nurturing tissue stem cells. This study investigated the microenvironment, especially vascularity, in the maculae flavae of the human vocal fold. METHODS: Three normal human adult, three normal newborn vocal folds obtained from autopsy cases and three surgical specimens of glottic carcinoma were investigated using light and electron microscopy. For scanning electron microscopy, a chemical digestion method (modified sodium hydroxide maceration method) was used to observe the inner 3-dimensional structure of the macula flava. RESULTS: Capillaries ran around the anterior and posterior maculae flavae in adults and newborns. However, there was no vascularity in the maculae flavae of the vocal fold. The inner 3-dimensional electron microscopic structure of the macula flava showed there were no blood vessels in the maculae flavae of the vocal fold. Glottic carcinoma (squamous cell carcinoma) surrounded and was in contact with the macula flava, however, the carcinoma did not invade the macula flava indicating there was no vascular supply into the macula flava from the surrounding tissue. CONCLUSIONS: There was no vascularity in the anterior and posterior maculae flavae in the human adult and newborn vocal folds. The present study is consistent with the hypothesis that the hypoxic microenvironment in the maculae flavae of the adult and newborn vocal fold as a stem cell niche is likely favorable to maintaining the stemness and undifferentiated states of the tissue stem cells in the stem cell system.

Comparative Histoanatomy of the Epiglottis and Pre-epiglottic Space of the Chimpanzee Larynx.

OBJECTIVES: Understanding of the evolution of the larynx clarifies the physiology and functional histoanatomy of the present-day human organ. Comparative histoanatomy of the epiglottis and pre-epiglottic space of the chimpanzee larynx (a hominid, phyletic closest relative of humans) was investigated. METHODS: Two normal adult chimpanzee larynges obtained from natural deaths were investigated. The whole organ serial section technique was employed. RESULTS: The histoanatomical structures of the chimpanzees' epiglottis and pre-epiglottic space were considerably similar to those of human adults. The chimpanzees' epiglottic cartilage was relatively thin and composed of elastic cartilage. These histologic findings of epiglottis indicate that the chimpanzee's epiglottis is flexible and plays the role of retroflection. The chimpanzees' larynges had a pre-epiglottic space composed of adipose tissue and loose connective tissue. Epiglottic cartilage was connected to the thyroid cartilage anteroinferiorly with an intervening thyroepiglottic ligament and to the hyoid bone anteriorly with an intervening hyoepiglottic ligament. These histoanatomical structures of the epiglottis and pre-epiglottic space reflect the fact that chimpanzees have a descended larynx and acquire the pharyngeal space of the vocal tract. CONCLUSION: The results of this study are consistent with the hypothesis that, in the process of evolution, the histoanatomical structures of the epiglottis and pre-epiglottic space change and allow the larynx to descend and lengthen the pharyngeal space of the vocal tract which facilitates speech production in humans. Moreover, the distribution of the human pre-epiglottic space likely allows the epiglottis to more effectively play the role of retroflection during swallowing in order to prevent aspiration.

Glycolytic Metabolism of the Tissue Stem Cells in the Maculae Flavae of the Human Vocal Fold.

OBJECTIVES: Metabolic programs in the stem cells are essential for maintaining homeostasis and protecting against stem cell aging. There is growing evidence that the tissue stem cells reside in the anterior and posterior maculae flavae of the human vocal fold mucosa. Our previous studies observed that the glycolysis of the cell in the human maculae flavae seems to rely more on anaerobic glycolysis for energy supply in comparison with oxidative phosphorylation. However, previous studies showed only the metabolic enzymes of glycolysis and functional morphology of the mitochondria, therefore, it has not yet been determined whether anaerobic glycolysis actually took place. The purpose of this study is to investigate the glycolytic metabolites of the cells in the maculae flavae of the human vocal fold in vitro. METHODS: Four normal human vocal folds were used. After extraction of the anterior maculae flavae, cells in the maculae flavae were cultured and proliferated. Glucose transporter-1 was assessed using immunocytochemistry and metabolites of glycolysis (lactate and NADPH) were measured. RESULTS: The cells in the maculae flavae expressed glucose transporter-1 in the cytoplasm and the cell membranes. In addition, the cultured cells produced lactate (metabolites of anaerobic glycolysis) and NADPH (metabolites of the pentose phosphate pathway). CONCLUSIONS: The cells in the maculae flavae of the human vocal folds were found to undergo anaerobic glycolysis via the pentose phosphate pathway. This suggests that the cells in the maculae flavae of the human vocal fold have a metabolism that favors the maintenance of stemness and undifferentiated states.

Small Cell Neuroendocrine Carcinoma of the Parotid Gland: An Uncommon Example of Incompletely Encapsulated Tumor Including S100 Protein-Positive Clear Cells.

Small cell carcinoma is rare in salivary glands and has recently been termed small cell neuroendocrine carcinoma. We herein describe an uncommon example arising in the parotid gland. The patient was a 75 yearold Japanese male who had swelling in the right parotid area. He underwent a superficial lobectomy and, after a histological diagnosis was made, a total parotidectomy. Histologically, the tumor had a thick hyalinized capsule that was incomplete, beyond which the tumor invaded into the surrounding parotid parenchyma. The tumor consisted of typical small basophilic cells intermingled with bland clear cells, between which a gradual transition was observed both inside and outside the capsule. Small basophilic cells were immunoreactive for chromograninA as well as synaptophysin, while clear cells were positive for S100 protein. The Ki-67 labeling rate reached 30-40% at the high points of small basophilic cells, but clear cells were minimally labelled. The present case was considered a dedifferentiated carcinoma of the parotid gland, possibly with acinic cell carcinoma as a precursor. This tumor could also be considered a "mixed exocrine-endocrine carcinoma," which may explain the histogenesis of neuroendocrine carcinomas in non-endocrine organs that are not included in the diffuse (dispersed) neuroendocrine system, such as the parotid gland.

Case Report: A case of complete response to entrectinib in NTRK fusion gene-positive parotid gland cancer.

Introduction: Expression of the NTRK gene is rare in solid tumors but is highly prevalent in salivary gland secretory carcinomas. Here, we report a case of a complete response to entrectinib in a patient with NTRK fusion gene-positive parotid carcinoma. Case description: The patient was a 44-year-old man who underwent total left parotidectomy and left cervical lymph node dissection for a left parotid tumor at 24 years of age. The histopathological diagnosis was mammary analog secretory carcinoma. Postoperatively, the patient received only radiation therapy. Sixteen years after the surgery, the patient became aware of a mass in the left parotid region. A close examination revealed local recurrence and multiple cervical lymph node metastases. S-1 monotherapy was started as chemotherapy but was discontinued 3 years later because of disease progression. As there was no standard treatment, a comprehensive genomic profiling test using a next-generation sequencer was performed, and the ETV6-NTRK3 fusion gene was identified. Entrectinib, an NTRK inhibitor, was immediately administered at a dose of 600 mg/day. The local recurrence rapidly shrank grossly from the beginning of treatment, and a complete response was observed 6 months later. However, creatinine levels exhibited an increase at week 68 of treatment; consequently, entrectinib dosage was lowered to 400 mg/day, leading to an immediate improvement in creatinine levels. Entrectinib was associated with additional side effects, including dysgeusia, fatigue, dizziness, and weight gain, all of which were also alleviated by the reduction in entrectinib dose. Thirty months after treatment initiation, the patient maintained a complete response and continued to receive entrectinib. Conclusion: The NTRK fusion gene should always be checked in the presence of salivary gland secretory carcinoma.

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.

Vocal fold stem cells and their niche in the human vocal fold.

OBJECTIVES: Vocal fold stellate cells (VFSCs) in the maculae flavae have many morphological differences from conventional fibroblasts in the human vocal fold mucosa. It is uncertain whether the VFSCs are derived from the same embryonic source as conventional fibroblasts. The purpose of this study was to investigate the stemness of the VFSCs and whether the pericellular matrices in the maculae flavae are a hyaluronan-rich matrix, which is required for a stem cell niche. METHODS: Paraffin-embedded specimens were stained with Alcian blue (pH 2.5) for a hyaluronidase digestion study. Immunoreactivity to antibodies directed to CD44, CD133, Oct-4, Ki67, and telomerase was investigated in 5 human adult vocal fold mucosae. RESULTS: The VFSCs were resting cells (G0-phase) and expressed a mesenchymal stem cell marker. The VFSCs did not express hematopoietic or embryonic stem cell markers. Telomerase resided in the VFSCs. The hyaluronan concentration in the maculae flavae was high and the VFSCs expressed hyaluronan receptors, indicating that maculae flavae are characterized by a certain criterion of hyaluronan-rich matrix. CONCLUSIONS: There is growing evidence that the VFSCs in the human maculae flavae are somatic (mesenchymal) stem cells of the vocal fold, and that the maculae flavae may be a candidate for a stem cell niche that is a microenvironment nurturing a pool of VFSCs.