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.

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.

Radiotherapy Plus Cetuximab for Squamous Cell Carcinoma of the Oral Cavity: A Multicenter Retrospective Study of 79 Patients in Japan.

There are a few reports that focus on radiotherapy (RT) and cetuximab (CET) therapy exclusively for oral cancer. This retrospective study aimed to investigate the efficacy and safety of RT and CET therapy for locally advanced (LA) or recurrent/metastatic (R/M) oral squamous cell carcinoma (OSCC). Seventy-nine patients from 13 hospitals who underwent RT and CET therapy for LA or R/M OSCC between January 2013 and May 2015 were enrolled in the study. Response, overall survival (OS), disease-specific survival (DSS), and adverse events were investigated. The completion rate was 62/79 (78.5%). The response rates in patients with LA and R/M OSCC were 69% and 37.8%, respectively. When only completed cases were examined, the response rates were 72.2% and 62.9%, respectively. The 1- and 2-year OS were 51.5% and 27.8%, respectively (median, 14 months), for patients with LA OSCC, and 41.5% and 11.9% (median, 10 months) for patients with R/M OSCC. The 1- and 2-year DSS were 61.8% and 33.4%, respectively (median, 17 months), for patients with LA OSCC, and 76.6% and 20.4% (median, 12 months) for patients with R/M OSCC. The most common adverse event was oral mucositis (60.8%), followed by dermatitis, acneiform rash, and paronychia. The completion rate was 85.7% in LA patients and 70.3% in R/M patients. The most common reason for noncompletion was an inadequate radiation dose due to worsening general conditions in R/M patients. Although the standard treatment for LA or R/M oral cancer is concomitant RT with high-dose cisplatin (CCRT) and the efficacy of RT and CET therapy for oral cancer is not considered to be as high as that for other head and neck cancers, it was thought that RT and CET therapy could be possible treatments for patients who cannot use high-dose cisplatin.

Clinical Application of the IllumiScan Fluorescence Visualization Device in Detecting Oral Mucosal Lesions.

OBJECTIVE: Fluorescence visualization devices are screening devices that can be used to examine lesions of the oral mucosa non-invasively. We observed oral squamous cell carcinoma (OSCC) and leukoplakia using the IllumiScan (Shofu, Kyoto, Japan) fluorescence visualization device and examined its usefulness and characteristics. METHODS: We investigated 31 OSCC and nine leukoplakia in patients who were examined using the IllumiScan and treated in our department from January 2017 to February 2018. Images taken with the IllumiScan were analyzed using image analysis software. We also examined the lesions using narrowband imaging (NBI). Additionally, the IllumiScan and NBI images and the non-stained areas of iodine staining method (IOM) were visually evaluated. RESULTS: The average luminance of OSCC in the keratinized mucosa was significantly lower than that of OSCC in non-keratinized mucosa. The average luminance of OSCC was significantly lower than that of leukoplakia. Even in keratinized mucosa where IOM is impossible to use, the OSCC lesion exhibited fluorescence visualization loss. CONCLUSION: The application of the fluorescence visualization device to the oral mucosa may be useful for distinguishing between cancer and normal areas and can be used to detect OSCC in the keratinized mucosa. The use of the IllumiScan in combination with other conventional screening methods may lead to a better diagnosis.

The retromolar canals and foramina: radiographic observation and application to oral surgery.

PURPOSE: The retromolar canal (RMC) and foramen (RMF) are anatomic variants in the retromolar area of the mandible. The purpose of this study was to clarify the relationship between the RMC and RMF and related complications, and to reveal how the RMC could impact the mandibular anatomy using cone-beam computed tomography (CBCT) and panoramic images (PAN). MATERIALS AND METHODS: CBCT and PAN images of 50 patients were retrospectively analyzed to investigate the morphology of the RMC and RMF, and their impact on impacted third molar surgery and orthognathic surgery. RESULTS: In PAN images, neither the RMC nor RMF was detected. In CBCT images, the RMCs were detected in 26% (13/50) of the patients. A double RMC was detected on one side of one patient. The diameter of the RMC ranged from 0.8 to 2.9 mm (mean; 1.5 ± 0.6 mm), and the RMF ranged from 0.6 to 2.3 mm (mean; 1.1 ± 0.5 mm). No patients experienced unexpected bleeding. Unilateral postoperative hypoesthesia of the buccal gingiva in the molar region was reported in 6.7% of patients with the RMC. CONCLUSIONS: Hypoesthesia of the buccal gingiva in the lower molar region may be the main complication when the RMC is damaged.

Aortic arch origin of the left vertebral artery: An Anatomical and Radiological Study with Significance for Avoiding Complications with Anterior Approaches to the Cervical Spine.

Complications from anterior approaches to the cervical spine are uncommon with normal anatomy. However, variant anatomy might predispose one to an increased incidence of injury during such procedures. We hypothesized that left vertebral arteries that arise from the aortic arch instead of the subclavian artery might take a more medial path in their ascent making them more susceptible to iatrogenic injury. Fifty human adult cadavers were examined for left vertebral arteries having an aortic arch origin and these were dissected along their entire cervical course. Additionally, two radiological databases of CTA and arteriography procedures were retrospectively examined for cases of aberrant left vertebral artery origin from the aortic arch over a two-year period. Two cadaveric specimens (4%) were found to have a left vertebral artery arising from the aortic arch. The retrospective radiological database analysis identified 13 cases (0.87%) of left vertebral artery origin from the aortic arch. Of all cases, vertebral arteries that arose from the aortic arch were much more likely to not only have a more medial course (especially their preforaminal segment) over the cervical vertebral bodies but also to enter a transverse foramen that was more cranially located than the normal C6 entrance of the vertebral artery. Spine surgeons who approach the anterior cervical spine should be aware that an aortic origin of the left vertebral artery is likely to be closer to the midline and less protected above the C6 vertebral level. Clin. Anat. 30:811-816, 2017. © 2017Wiley Periodicals, Inc.

Communicating branches between lingual and hypoglossal nerve: observation using Sihler's staining technique.

PURPOSE: Many dental procedures are at risk of injuring the lingual nerve. We performed this study to better elucidate the microanatomy that exists between the ipsilateral lingual and hypoglossal nerves so that iatrogenic injury can be avoided. METHODS: Adult human cadaveric tongues (ten sides) underwent Sihler's staining to identify the microanatomy between the lingual and hypoglossal nerves. RESULTS: The lingual nerve entered the middle part of the anterior two-thirds of the tongue from its lateral side and divided into two to four thick branches. These branches were then disseminated to the anterior, middle, and posterior parts of the anterior two-thirds of the tongue via 7-14 thin nerve bundles as terminal branches. The hypoglossal nerve entered the tongue at the posterior border of its anterior two-thirds and traveled forward to the apex of the tongue on all sides. All specimens were found to have communicating branches between the lingual and hypoglossal nerves at its anterior, middle, and posterior thirds. CONCLUSIONS: Our results indicate that the ipsilateral lingual and hypoglossal nerves constantly have three connections on each side between them. This knowledge might aid the dentist in minimizing iatrogenic nerve injury.

Diagnostic dilemma of IgG4-related primary localized cervical lymphadenopathy associated with aberrant IL-6 expression level.

BACKGROUND: Immunoglobulin G4-related disease (IgG4-RD) is a recently recognized inflammatory condition with single- or multi-organ involvement. The disease is characterized by tumefactive lesions with dense IgG4 plasmacytic infiltration (an elevated IgG4(+)/IgG(+) cell ratio of > 40 %), storiform fibrosis, and obliterative phlebitis, with or without elevated serum IgG4 levels. The diagnostic criteria for IgG4-RD, proposed in 2011, were quite comprehensive and practical; however, it is important to remember that other diseases, such as hyper-interleukin (IL)-6 syndromes, may have common histopathological findings. Therefore, the histopathology of suspected IgG4-RD is occasionally not diagnostic. Here, we report a case of IgG4-related primary localized cervical lymphadenopathy without any other organ involvement. To our knowledge, there have been no previous reports of this. Additionally, the disease was associated with a 20-fold increase in IL-6 levels compared to that of the normal range. CASE PRESENTATION: We report the case of a 52-year-old Japanese man who presented with a painless, somewhat diffuse swelling in the left submandibular region. Although the case fulfilled diagnostic criteria for IgG4-RD, the diagnosis was not straightforward due to abnormally high levels of serum IL-6. After systematic evaluation of the patient, a final diagnosis of IgG4-RD was established. Since then, a specialist in connective tissue disorders has evaluated the patient on a regular basis. Two years after his initial visit, no disease progress or systemic involvement has been noted. CONCLUSION: We present a case of an IgG4-related primary localized cervical lymphadenopathy mimicking hyper-IL-6 syndrome. This case can serve as an excellent reminder that the definitive diagnosis of IgG4-RD should be established using a systematic approach, in particular when it appears as an atypical manifestation.

The clinical anatomy of accessory mental nerves and foramina.

Since three-dimensional computed tomography was developed, many researchers have described accessory mental foramina. The anatomical and radiological findings have been discussed, but details of accessory mental nerves (AMNs) have only been researched in a small number of anatomical and clinical cases. For this article, we reviewed the literature relating to accessory mental foramina (AMFs) and nerves to clarify aspects important for clinical situations. The review showed that the distribution pattern of the AMN can differ according to the position of the accessory mental foramen, and the reported incidence of AMFs differs among observation methods. A review of clinical cases also revealed that injury to large AMF can result in paresthesia. This investigation did not reveal all aspects of AMNs and AMFs, but will be useful for diagnosis and treatment by many dentists and oral and maxillofacial surgeons.

An immunohistochemistry-based study on aquaporin (AQP)-1, 3, 4, 5 and 8 in the parotid glands, submandibular glands and sublingual glands of Sjögren's syndrome mouse models chronically administered cevimeline.

Cevimeline is a muscarinic agonist that promotes saliva secretion and is used to treat Sjögren's syndrome (SS), an autoimmune disorder in which the exocrine glands that produce saliva are destroyed. Cevimeline is thought to affect the composition of saliva in part by regulating the localization of aquaporins (AQPs). In this study, we investigated the effects of chronic Cevimeline administration in the salivary glands of SS mice on the immunohistochemical localization of aquaporin (AQP)-1, 3, 4, 5 and 8. We used Cevimeline-untreated SS mice, treated SS mice, discontinued SS mice and untreated normal mice. AQP-5 was found in the apical and lateral membranes of acinar cells in the parotid and submandibular glands of cevimeline-treated SS mice and untreated normal mice. Saliva secretion and AQP-5 localization were sustained in SS mice who were chronically administered Cevimeline and at four weeks after discontinuation. Unlike AQP-5, the localization of AQP-1, 3, 4 and 8 were not affected by Cevimeline administration. Our findings demonstrated that administration of Cevimeline maintains the proper localization of AQP-5 in the acinar cells of the salivary gland, which may promote salivation in chronically treated SS mice. Clinically, this suggests that chronic Cevimeline administration may be useful therapeutically for SS patients suffering from a decrease in saliva secretion by improving the disordered AQP-5 localization.

Influence of a fabella in the gastrocnemius muscle on the common fibular nerve in Japanese subjects.

The fabella is a sesamoid bone located in the proximal tendon of the gastrocnemius muscle. In rare cases, its presence may lead to a variety of clinical problems, including fabella syndrome and common fibular (CF) nerve palsy. The purpose of this study was to analyze the morphology of the fabella and CF nerve and discuss the influence of any existing fabellae on the size of the CF nerve. The morphology of the fabella and CF nerve in the popliteal region of the lateral head of the gastrocnemius muscle was investigated in 102 knees of 51 Japanese cadavers. The maximum circumference of the thigh, knee, and calf and the frequency, position, and size of the fabella were measured. In addition, the CF nerve width and thickness were measured proximal to the fabellar region and again as the CF nerve passed posterior, lateral, or medial to the region. A fabella was observed in 70 knees (68.6%). The CF nerve adjacent to the fabella was significantly wider and thinner than in the region proximal to the fabella (P < 0.001). In cases in which a bony fabella was present, there was a significant relationship between the thickness of the CF nerve and the circumference of the thigh and knee. The following factors were observed to contribute to the presence of a fabella causing alterations in the size of the CF nerve: a bony fabella, a CF nerve path posterior or lateral to the fabella, and subjects with a thin physique and bony fabella.

Anatomical Research of the Three-dimensional Route of the Thoracodorsal Nerve, Artery, and Veins in Latissimus Dorsi Muscle.

BACKGROUND: The latissimus dorsi (LD) muscle flap has been widely used in facial reanimation surgery. However, there are no standards to what degree the muscle flap may be safely thinned because the three-dimensional positional relationship of thoracodorsal artery, vein, and nerve inside the LD muscle is poorly understood. METHODS: From 18 formalin-fixed cadavers, we made 36 transparent specimens of LD muscles using a newly developed decoloration technique. In 26 specimens, nerve staining (Sihler's staining method) and silicone rubber (Microfil) injection to the thoracodorsal artery were performed, and the relationship of the artery and the vein was examined in 10 specimens. RESULTS: The thoracodorsal artery and vein always ran parallel in a deeper layer compared to the nerve. The thoracodorsal nerve constantly existed in a deeper layer than half (50%) of the muscle in the range of use of the muscle flap in facial reanimation surgery. CONCLUSIONS: The thoracodorsal nerves ran in a shallower layer, and the depth to the nerve in the muscle flap in actual facial reanimation surgery is safe enough to avoid damage to the nerves. The LD muscle may be thinned to half its original thickness safely.

Relationship between masseter muscle form and occlusal supports of remaining teeth.

To chew, it is necessary to maintain harmony between the masseter muscle and other organs. Various studies have been conducted on the masseter muscle, but none has examined the relationships among masseter muscle form, occlusal support of remaining teeth, and maxillofacial morphology. Thus, we conducted the present study using cadavers donated to anatomy practice. After the masseter muscle was extracted, its length, width, thickness, and volume were measured; histological observations were conducted; and the muscle fiber cross-sectional area and muscle density were calculated. In addition, denture use and non-use were examined. The results showed that when regional support loss occurs, muscle fiber thickness and density decrease. This in turn causes masseter muscle thickness and volume to decrease, resulting in muscle atrophy. Furthermore, excluding Eichner class A cases (all regions intact), the thickness of the masseter muscle is greatest when the premolar support region remains. The premolar support region was shown to have the most impact on masseter muscle morphology. These results suggest that atrophy of the masseter muscle can be arrested or improved with the use of dentures in the case of tooth loss.

[Retrospective investigation and analysis of dental injuries during endotracheal intubation].

BACKGROUND: The objective of this study is to clarify the causes of dental injuries (DIs) developed during the direct laryngoscopy for the endotracheal intubation (EI) in our hospital. METHODS: Subjects are 4173 patients who had the EI from April 1, 2006 to March 31, 2007. Mallampati's classification and Miller's classification were used for the evaluation of difficult airway and the dental unsteadiness, respectively. RESULTS: There was no case between 10 and 40 years of age. Twelve cases (0.3%) had the DIs during the observation period. In 8 out of 12 cases (67%), EI was carried out by the residents with less than 3 months of the training period. Three cases (25%) were classified to the II or III grade. The dissociation of the evaluations by a dental anesthesiologist and medical anesthesiologists were found in two cases. Eight cases received temporary treatment by a dental anesthesiologist. CONCLUSIONS: Temporary treatment in the operating room was carried out by a dental anesthesiologist. Careful inquiry is needed for the proper preoperative teeth evaluation, especially in the schoolchild with milk teeth and elderly patients. A precise educational system for the residents is required for the prevention of DIs during the EI.