What prognostic factors have impacted the efficacy of immune checkpoint inhibitors in patients with recurrent or metastatic oral cancer?

BACKGROUND: Immune checkpoint inhibitors (ICIs) are widely adapted for recurrent or metastatic head and neck cancer (RM-HNC), and various studies on its prognostic factors have been reported. We aimed to elucidate the prognostic factors of ICI treatment for RM oral cancer (RM-OC) in a retrospective study. METHODS: We retrospectively reviewed patients with RM-OC treated with ICIs (nivolumab and pembrolizumab) at our department from May 2017 to February 2023. The objective response rate (ORR) for ICI treatment and the relationship between several potential prognostic factors, progression-free survival (PFS), and overall survival (OS) were analyzed statistically. RESULTS: The investigation enrolled 31 patients, 16 with nivolumab and 15 with pembrolizumab. There were no significant differences in the ORR or disease control rate between the nivolumab and pembrolizumab groups (p = 0.4578 and 0.2524). In multivariate analysis, the prognostic nutritional index (PNI) and C-reactive protein to albumin ratio (CAR) exhibited statistical correlations with PFS, whereas the use of antibiotics and proton pump inhibitors (PPIs), neutrophil to lymphocyte ratio (NLR), and PNI demonstrated statistical associations with OS. CONCLUSION: Our findings imply that the use of antibiotics and PPIs, which can modify the gut microbiota, may also serve as a prognostic determinant for ICI treatment in RM-OC, consistent with previous studies. Additionally, PNI may be essential in affecting the survival rates of both PFS and OS and could be an exceedingly valuable inflammatory biomarker for RM-OC.

Improvement of the temporomandibular joint symptoms due to the condylar position change following modified L-shaped intraoral vertico-sagittal ramus osteotomy: a single-center, retrospective study.

PURPOSE: Intraoral vertico-sagittal ramus osteotomy (IVSRO) was first reported by Choung in 1992 as a surgical procedure to decrease postoperative condylar dislocation. In 2017, Iwanaga et al. developed modified L-shaped IVSRO (mIVSRO) to reduce postoperative nerve dysfunction and achieved favorable outcomes. This study aimed to clarify the effect of mIVSRO on changes in temporomandibular joint (TMJ) symptoms and three-dimensional condylar position. METHODS: We conducted a retrospective study of thirty sides in fifteen Japanese adults diagnosed with jaw deformities who underwent mIVSRO and sagittal split ramus osteotomy (SSRO). TMJ symptoms were assessed chronologically, and the condylar long axis and the condylar position were analyzed two- and three-dimensionally using axial cephalograms and cone-beam computed tomography. RESULTS: Postoperative TMJ symptoms improved by 90% (9/10 sides) in the mIVSRO group and by 50% (7/14 sides) in the SSRO group. The mIVSRO group exhibited outward rotation of the condylar long axis, while the SSRO group exhibited inward rotation. Moreover, mIVSRO induced residual anteromedial-inferior deviation of the condyle. The inclination angle of the condylar process was not significantly different between the two procedures pre- and postoperatively. CONCLUSION: These results clearly demonstrated the effect of mIVSRO on symptomatic TMJ. Residual changes in the position of the condyle following mIVSRO may not affect jaw function.

Pulmonary Tuberculosis Following Immune Checkpoint Inhibitor Treatment for Recurrent Maxillary Squamous Cell Carcinoma.

Immune checkpoint inhibitors (ICIs) like nivolumab and pembrolizumab are effective treatments for recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). However, they can lead to immune-related adverse events (irAEs) and tuberculosis (TB) reactivation. We present a case of a 79-year-old male with recurrent maxillary squamous cell carcinoma treated with pembrolizumab, cisplatin, and 5-fluorouracil. The patient developed a fever, and pulmonary TB development was confirmed. Prolonged TB treatment was required, and ICI treatment was discontinued. The patient ultimately opted for palliative care due to aggressive tumor growth. TB development during ICI treatment is a rare but important concern, especially in TB-endemic areas. Vigilant monitoring and screening might be essential to manage this risk in cancer patients with R/M SCCHN receiving ICIs.

Prognostic effect of programmed cell death ligand 1/programmed cell death 1 expression in cancer stem cells of human oral squamous cell carcinoma.

The relationship between cancer stem cells (CSCs) in oral squamous cell carcinoma (OSCC) and programmed cell death ligand 1 (PD-L1)/programmed cell death 1 (PD-1) remains unclear. Therefore, the present study aimed to clarify the association between the CD44v3high/CD24low immunophenotype of CSCs in OSCC and PD-L1/PD-1 co-expression, and to assess the prognostic effect of CSCs in terms of immune checkpoint molecules. Formalin-fixed, paraffin-embedded tissue samples and clinicopathological data from 168 patients with OSCC were retrospectively retrieved. Immunohistochemical staining and reverse transcription quantitative polymerase chain reaction were applied to a tissue microarray of the invasive front of each case. Semi-automated cell counting was used to assess CD44v3, CD24, PD-L1 and PD-1 expression by immunohistochemistry (IHC) using a digital image analysis program. Associations between immunological markers and clinicopathological variables were estimated. Patients with the CSC immunophenotype CD44v3high/CD24low, and patients with a high PD-L1/PD-1-positive cell density in the tumor parenchyma and stroma had significantly lower survival rates. Furthermore, patients with the CSC immunophenotype (CD44v3high/CD24low) and high PD-L1/PD-1 co-expression had even lower survival rates (P<0.01, log-rank test). Notably, there was a positive correlation between CD44v3 and PD-L1 expression (τ=0.1096, P=0.0366, Kendall rank correlation coefficient) and a negative correlation between CD24 and PD-1 expression (τ=-0.1387, P=0.0089, Kendall rank correlation coefficient). Additionally, the high CD44v3 expression group, as determined by IHC, exhibited significantly decreased expression of U2 small nuclear RNA auxiliary factor 1 (U2AF1) at the mRNA level compared with that in the low CD44v3 expression group (P<0.001, Mann-Whitney U test), and U2AF1 and PD-L1 mRNA expression exhibited a significant negative correlation (τ=-0.3948, P<0.001, Kendall rank correlation coefficient). In conclusion, CSCs in OSCC may evade host immune mechanisms and maintain CSC stemness via PD-L1/PD-1 co-expression, resulting in unfavorable clinical outcomes.

Gingival Squamous Cell Carcinoma Predicted to Originate From the Gingival Sulcular Epithelium in a Young Female: A Report of a Rare Case.

Oral cancer is a disease primarily in older adults and extremely rare in young adults. Risk factors for oral cancer are irritants such as tobacco smoke and alcohol and chronic mechanical irritants but mechanisms involved in carcinogenesis in young adults are unclear because of less exposure to their risk factors. Herein, we report a rare case of gingival squamous cell carcinoma in a 19-year-old female patient, in whom the tumor predictably originated in the gingival sulcular epithelium. Histopathological examination of the resected tissue showed a cancer cell nest invading from the gingival sulcular epithelium without a breakdown of the basement membrane of the marginal gingival epithelium. Six years after the surgery, no recurrence or metastasis has been detected.

An Isolated Laminar Osteoma Arising in the Maxillary Sinus.

BACKGROUND Osteomas are benign tumors characterized by proliferation of dense or trabecular bone. Most osteomas of the head and neck occur in the mandible, they rarely occur in the maxillary sinus, and free osteomas are extremely rare. While usually detected incidentally on plain radiographs, symptoms appear when the osteoma obstructs the sinus orifice or invades the adjacent orbit or intracranial structures. Herein, we report a case of a patient with an isolated laminar osteoma arising in the maxillary sinus. CASE REPORT A 52-year-old man presented to our hospital with a radiopaque mass in the right maxillary sinus. An oval mass of size 2.7×2.3 cm was observed in the right maxillary sinus on computed tomography, and no sinusitis was present. Under general anesthesia, the mass was removed orally via the modified Caldwell-Luc method. Histopathologic examination revealed layered compact bony tissue covered by the sinus membrane. The mass was free from the inferior wall of the right maxillary sinus, and a part of the mass was covered by the sinus membrane. The postoperative course was uneventful, and no recurrence was noted after 5 years. CONCLUSIONS We experienced a case of an extremely rare osteoma in the maxillary sinus. The osteoma was solitary and free within the maxillary sinus. The treatment performed was surgical excision using the modified Caldwell-Luc method. The cause of the free osteoma was thought to be odontogenic maxillary sinusitis caused by apical periodontitis of the nearby tooth.

Anatomical Study of the Communication Between the Mental Nerve and Marginal Mandibular Branch of the Facial Nerve.

Background Trigeminal-facial nerve communications have been recognized for over 100 years. More specifically, the mental nerve (MN) and marginal mandibular branch of the facial nerve (MMb) communication have been studied but the termination of these branches remains unclear. Therefore, we aim to classify the anatomical communication between the MN and MMb by its course. Methods Sixty sides from thirty adult cadaveric heads were dissected. The communicating branches were dissected and observed anatomically and histologically. Results Communication between the MN and MMb was found on all sides. Based on the course, the communication was classified into two types, superior and anterior. For the superior type, a small branch of the MN and MMb join and travel superiorly to reach the lower lip area. The communication was observed at the level of the mental foramen or above it. For the anterior type, a small branch of the MN and MMb join and travel anteriorly to reach the chin area. The termination was either in the subcutaneous tissue of the chin or in the mentalis. This communication was observed below the mental foramen. Histological observation revealed that these communications contained two or more perineuria. Conclusions Although the function of such neural communications is still unclear, this study helps better understand the anatomical variants of these unions and provides a novel classification system.

Mesoscopic structural analysis via deep learning processing, with a special reference to in vitro alteration in collagen fibre induced by a gap junction inhibitor.

Dense connective tissue, including the ligament, tendon, fascia and cornea, is formed by regularly arranged collagen fibres synthesized by fibroblasts (Fbs). The mechanism by which fibre orientation is determined remains unclear. Periodontal ligament Fbs consistently communicate with their surroundings via gap junctions (GJs), leading to the formation of a wide cellular network. A method to culture Fb-synthesized collagen fibres was previously reported by Schafer et al. ('Ascorbic acid deficiency in cultured human fibroblasts'. J. Cell Biol. 34: 83-95, 1967). This method has been applied to investigate the ability and activity of Fb collagen synthesis/phagocytosis using conventional electron microscopy (EM). However, the three-dimensional mesoscopic architecture of collagen fibres and the influence of GJ inhibitors on collagen fibre formation in vitro are poorly understood. In this study, three-dimensional mesoscopic analysis was used to elucidate the mechanism of directional fibre formation. We investigated the influence of GJ inhibitors on collagen formation driven by periodontal ligament Fbs in vitro, histomorphometrically, and the structural properties of in vitro collagen fibre on a mesoscale quantitatively, using correlative light and EM optimized for picrosirius red staining and focused ion beam-scanning EM tomography. Our results indicate that under culture conditions, in the presence of a GJ inhibitor, the orientation of collagen fibres becomes more disordered than that in the control group. This suggests that the GJ might be involved in determining fibre orientation during collagen fibre formation. Elucidation of this mechanism may help develop novel treatment strategies for connective tissue orientation disorders. Graphical Abstract.

Multicenter retrospective study of nivolumab for recurrent/metastatic oral squamous cell carcinoma.

OBJECTIVES: Immunotherapy with nivolumab for patients with recurrent/metastatic oral squamous cell carcinoma has not been evaluated. Here, we aimed to examine the efficacy, safety, and prognostic factors of nivolumab in these patients. MATERIALS AND METHODS: This multicenter retrospective observational study involved patients who received nivolumab between April 2017 and June 2019. The patient characteristics were evaluated for association with progression-free and overall survival. Progression-free and overall survival rates were calculated; parameters that were significant in the univariate analysis were used as explanatory variables. Independent factors for progression-free and overall survival were identified using multivariate analysis. RESULTS: Totally, 143 patients were included. The overall response and disease control rates were 27.3% and 46.2%, respectively. The median, 1- and 2-year progression-free survival rates were 2.7 months, 25.4%, and 19.2%, respectively; those for overall survival were 11.2 months, 47.3%, and 33.6%, respectively. The independent factors affecting progression-free survival were performance status and immune-related adverse event occurrence, whereas those affecting overall survival were performance status, target disease, and number of previous lines of systemic cancer therapy. Eight patients reported grade ≥3 immune-related adverse events. CONCLUSION: Nivolumab was effective for recurrent/metastatic oral squamous cell carcinoma treatment and was well tolerated by patients.

Squamous cell carcinoma of the tongue: subtypes and morphological features affecting prognosis.

Squamous cell carcinoma (SCC) is the most common histological type of mobile tongue carcinoma. The incidence of mobile tongue carcinoma is decreasing in some countries owing to decreasing exposure to risk factors, but it has been reported to be increasing in younger people. The majority of mobile tongue cancers are conventional SCCs. Pathological diagnosis of conventional SCC is relatively easy. However, mobile tongue SCCs involve several subtypes that have distinct pathological features and biological behaviors. Some subtypes are relatively rare, and the pathological subtype influences treatment decision-making. Therefore, the recognition of SCC subtypes is crucial for proper treatment. In this review, we summarize nine SCC subtypes, including conventional SCC and highlight their pathological characteristics. We also report some morphological factors, such as the pattern of invasion, budding, desmoplastic reaction, lymphovascular invasion, and perineural invasion, which could be predictive of prognosis. As some morphological factors are closely associated with prognosis, pathologists may need to evaluate additional factors in pathological reports of near features. In summary, we highlight the basic knowledge of mobile tongue SCC with an emphasis on pathological subtypes, morphological features, and their relationship. We provide information to further elucidate SCC in the oral region.

Protocol for a multicentre, prospective observational study of elective neck dissection for clinically node-negative oral tongue squamous cell carcinoma (END-TC study).

INTRODUCTION: In early-stage oral tongue squamous cell carcinoma (OTSCC), elective neck dissection (END) is recommended when occult lymph node metastasis is suspected; however, there is no unanimous consensus on the risks and benefits of END in such cases. The management of clinically node-negative (cN0) OTSCC remains controversial. This study, therefore, aimed to evaluate the efficacy of END and its impact on the quality of life (QoL) of patients with cN0 OTSCC. METHODS AND ANALYSIS: This is a prospective, multicentre, nonrandomised observational study. The choice of whether to perform END at the same time as resection of the primary tumour is based on institutional policy and patient preference. The primary endpoint of this study is 3-year overall survival. The secondary endpoints are 3-year disease-specific survival, 3-year relapse-free survival and the impact on patient QoL. Propensity score-matching analysis will be performed to reduce selection bias. ETHICS AND DISSEMINATION: This study was approved by the Clinical Research Review Board of the Nagasaki University. The protocol of this study was registered at the University Hospital Medical Information Network Clinical Trials Registry. The datasets generated during the current study will be available from the corresponding author on reasonable request. The results will be disseminated internationally, through scientific and professional conferences and in peer-reviewed medical journals. TRIAL REGISTRATION NUMBER: UMIN000027875.

Cutaneous branch of the nerve to the mylohyoid muscle: Potential cause of postoperative sensory alteration in the submental area.

BACKGROUND: Previous studies suggest that the nerve to the mylohyoid muscle could have a cutaneous branch. However, its clinical relevance has rarely been discussed because there is insufficient evidence for it. Our aim in this study was to investigate the anatomy of the cutaneous branch of the nerve to the mylohyoid muscle and extend the discussion to surgical management. METHODS: Twenty sides from ten embalmed cadaveric heads were dissected to identify the cutaneous branch of the nerve to the mylohyoid muscle. The cutaneous branch was traced up to its termination. RESULTS: The cutaneous branch was observed in 90% and classified into types I and II. In type I, the terminal trunk reached the anterior belly of the digastric muscle. In type II there were two types of terminal trunks, superior and inferior branches, which were identified on all sides. The number of the terminal trunk was one in 23.1% (type I; 6/26) and two in 76.9% (type II; 20/26). The terminal points of the cutaneous branch were all located within a 3 cm × 2 cm rectangular segment in the center of the submental area. CONCLUSIONS: We propose a new dermatome including the nerve to the mylohyoid muscle in the center. Understanding the cutaneous branch of the nerve could help surgeons to prevent iatrogenic sensory loss of the submental area.

Three-dimensional ultrastructure and histomorphology of mouse circumvallate papillary taste buds before and after birth using focused ion beam-scanning electron microscope tomography.

Early taste buds are formed from placode cells. Placode cells differentiate into Type I-Ⅲ cells at birth; however, the ultrastructure of these first taste cells remain elusive. Here, we used focused ion beam-scanning electron microscopy (FIB-SEM) to analyze taste buds on the dorsal surface of the circumvallate papilla on embryonic day (E) 18.5 and postnatal day (P) 1.5. The taste buds on E18.5 existed as a mass of immature cells. One of the immature cells extended the cell process to the surface of the epithelium from the taste bud mass. Cytoplasm of this cell contained many mitochondria and vesicles in the apical region. The taste buds at P1.5 had small taste pores and had an onion-shaped structure. Most of the cells in the taste buds extended toward the taste pores. Some of the cells in the taste buds were Type II-like cells with glycogen in their cytoplasm. In this study, it was shown in three dimensions that immature cells extend to the surface of epithelium before the formation of the taste pore. Subsequently, the formation of taste pores and maturation of taste buds progress simultaneously.

Expression and significance of laminin receptor in squamous cell carcinoma of the tongue.

BACKGROUND: Laminin receptor is a non-integrin cell-surface receptor that binds laminin present on the basement membrane. It has been reported to be associated with infiltration and metastasis of various malignant tumors. However, no studies regarding tongue cancer have been reported. This study aimed to clarify the role of laminin receptor in squamous cell carcinoma of the tongue. METHODS: We performed immunohistochemical staining of specimens from 66 patients with squamous cell carcinoma of the tongue and assessed laminin receptor expression and clinicopathological factors. As epithelial-mesenchymal transition has been shown to be associated with infiltration and metastasis of malignant tumors, staining for E-cadherin, vimentin, and N-cadherin were also performed. RESULTS: Of 20 patients with postoperative recurrence, 14 exhibited high laminin receptor expression (p = 0.0025). Kaplan-Meier analysis revealed a significantly shorter time to postoperative recurrence for the high laminin receptor expression group than that for the low laminin receptor expression group (p = 0.0008). Based on multivariate analyses for postoperative recurrence, high laminin receptor expression was associated with poor prognosis (high expression vs. low expression; HR =3.19, 95% CI =0.92-11.08; p = 0.0682). There was a correlation between laminin receptor and N-cadherin (p = 0.0089) but not between laminin receptor and E-cadherin (p = 0.369) or vimentin (p = 0.4221). CONCLUSION: These results suggest that high laminin receptor expression is a useful prognostic factor for postoperative recurrence and may be a target for molecular therapy to treat squamous cell carcinoma of the tongue.

Mast cells can produce transforming growth factor ß1 and promote tissue fibrosis during the development of Sjögren's syndrome-related sialadenitis.

OBJECTIVES: This study investigated the associations of mast cells with immune-mediated inflammation and fibrosis in patients with primary Sjögren's syndrome (pSS); it also explored the underlying pathophysiology of pSS-related sialadenitis. METHODS: Twenty-two patients with pSS and 10 patients with sicca (control individuals) underwent labial salivary gland biopsies. Sections were subjected to staining and immunofluorescence analyses. HMC-1 human mast cells were cocultured with fibroblasts in vitro; fibroblasts were also grown in HMC-1 conditioned medium. mRNA levels of collagen Type I (Col1a) and transforming growth factor (TGF)ß1 were analysed in cultured cells. RESULTS: Mast cell numbers in labial salivary glands were significantly greater in patients with pSS than in control individuals. In salivary glands from patients with pSS, mast cell number was significantly correlated with fibrosis extent; moreover, mast cells were located near fibrous tissue and expressed TGFß1. Col1a and TGFß1 mRNAs were upregulated in cocultured fibroblasts and HMC-1 cells, respectively. Fibroblasts cultured in HMC-1 conditioned medium exhibited upregulation of Col1a mRNA; this was abrogated by TGFß1 neutralizing antibodies. CONCLUSIONS: Mast cell numbers were elevated in patients with pSS-related sialadenitis; these cells were located near fibroblasts and expressed TGFß1. TGFß1 could induce collagen synthesis in fibroblasts, which might contribute to fibrosis.

The potential for facial artery injury during mandibular third molar extraction. An anatomical study using contrast-enhanced computed tomography.

The purpose of this study was to evaluate the risk of injury to the facial (FA) and related arteries during mandibular third molar (MTM) extraction using contrast-enhanced computed tomography (CE-CT). CE-CT images of the MTM region were retrospectively reviewed. The area of the MTM was equally divided into three zones in the coronal images from mesial to distal, that is, zone 1, zone 2, and zone 3. The FA, submental artery (SMA), and sublingual artery (SLA) were identified. The distance from the mandible to FA, SMA, and SLA and the diameter of the FA, SMA, and SLA was measured in three zones, respectively. The thickness of the facial soft tissues and width of the mandible were measured at their maximum. The mean distance from the FA to the buccal cortical bone in zone 1, zone 2 and zone 3 was 2.24 mm, 2.39 mm and 1.67 mm, respectively. The SMA and SLA were found to be distal to the mandible. The mean diameter of the FA was 1.26 mm in males and 1.04 mm in females, respectively (p < 0.0001). The distance between the FA and buccal cortical bone of the mandible, and the patients' weight showed moderate correlation in zones 1 and 2. Based on our findings, the FA can be damaged if the surgical invasion reaches the facial soft tissues during MTM surgery. The patients' weight might be a good predictor for FA injury when CE-CT is not available.

An anatomical and histological study of mental nerve branches to the inferior labial glands.

PURPOSE: In this study, we aimed to reveal the detailed anatomy of mental nerve branches to the inferior labial glands. METHODS: Embalmed cadaveric heads were used in this study and the mental nerve branches to the inferior labial glands were dissected. Branches to the glands were then excised for histological observation. RESULTS: On all sides, the inferior labial glands were innervated by small branches arising from mental nerve branches that innervated the lower lip. No nerve branches to the inferior labial gland crossed the midline. Histological observation found that the tissue to the inferior labial gland were composed primarily of nerve fibers with a small number of surrounding vessels. Histological findings in examined specimens were consistent. CONCLUSION: The inferior labial glands were innervated by small branches of the mental nerve to the lower lip.

Solitary Neurofibroma of the Hard Palate: A Case Report and Literature Review.

BACKGROUND Neurofibromas are benign tumors of neurological origin caused by the proliferation of Schwann cells and fibroblasts; they often occur in the skin and nerves as a symptom of von Recklinghausen disease. Solitary neurofibromas are also known to occur on their own, but solitary development in the hard palate is extremely rare and difficult to distinguish from schwannomas. The neural origin of solitary neurofibromas is also difficult to determine intraoperatively, and there have been no reports that clearly identify the neural origin of neurofibromas in the hard palate. CASE REPORT We report a case of a solitary neurofibroma originating in the hard palate in a 24-year-old woman. She presented to our department with a 1.2×0.8-cm dome-shaped left palate mass. After identification of the nerve at the source, the tumor was resected under general anesthesia. Histopathology was positive for S-100 and CD34 immunostaining, as well as for Alcian blue. Eventually, the mass was diagnosed as a neurofibroma. CONCLUSIONS Solitary neurofibromas originating in the hard palate are difficult to differentiate from other neoplastic lesions, especially schwannomas, based on clinical findings alone. Therefore, it is important to perform a biopsy and immunostaining of the biopsied specimens for S-100 and CD34. In neurofibromas, tumor cells are loose and delicate, often with wavy or serpentine nuclei, and S-100 protein-positive cells are sparser than in schwannomas. An overall pathological diagnosis should be made with regard to CD34, taking into account that schwannomas are CD34-negative and neurofibromas are CD34-positive.

Comprehensive review of lower third molar management: A guide for improved informed consent.

Lower third molar removal is the most commonly performed dental surgical procedure. Nevertheless, it is difficult to ensure that all the informed consent forms given to patients are based on the best evidence as many newer publications could change the conclusions of previous research. Therefore, the goal of this review article is to cover existing meta-analyses, randomized control trials, and related articles in order to collect data for improved and more current informed consent.