Role of Stromal Fibroblast-Induced WNT7A Associated with Cancer Cell Migration Through the AKT/CLDN1 Signaling Axis in Oral Squamous Cell Carcinoma.

Wnt signaling plays a crucial role in the progression of various cancers, including oral squamous cell carcinoma (OSCC). However, the tumor microenvironment (TME) regulating Wnt signaling has not yet been fully elucidated. In this study, we investigated whether cancer-associated fibroblasts (CAFs), the primary components of the TME, activate Wnt signaling and promote tumor progression in OSCC. We conducted a Transwell coculture assay using human OSCC cell lines and normal human dermal fibroblasts (NHDFs). NHDFs stimulated WNT7A expression in several OSCC cell lines, especially HO-1-N-1 and HSC-5. An immunohistochemical study using 122 human OSCC samples indicated that high WNT7A expression in tumor cells was significantly associated with invasion depth and poor prognosis. Moreover, WNT7A expression in OSCC cells was positively correlated with α-smooth muscle actin expression in CAFs. WNT7A knockdown in OSCC cells demonstrated that OSCC cells cocultured with NHDFs significantly promoted tumor cell migration and invasion, which was dependent on WNT7A expression in OSCC cells. We also isolated HSC-5 cells from the coculture and conducted microarray analysis to investigate the factors that promote tumor progression induced by WNT7A. Among the various differentially expressed genes, we identified a downregulated gene encoding CLDN1 and confirmed that WNT7A negatively regulated CLDN1 expression in OSCC cells and CLDN1 knockdown in OSCC cells promoted their migration. Phosphokinase array analysis showed that WNT7A activates protein kinase B (AKT) phosphorylation. Activating AKT signaling using the SC79 agonist induced CLDN1 downregulation in OSCC cells. In the coculture assay, the AKT inhibitor MK2206 significantly recovered CLDN1 expression downregulated by WNT7A, resulting in OSCC cell migration suppression. These results suggest that CAFs stimulate OSCC cells to produce WNT7A, following CLDN1 expression downregulation by activating AKT signaling, promoting cancer cell migration. These findings highlight the importance of molecular therapies targeting the TME in OSCC.

Salivary gland polymorphous adenocarcinoma: Clinicopathological features and gene alterations in 36 Japanese patients.

BACKGROUND: Polymorphous adenocarcinoma is a common intraoral minor salivary gland carcinoma in Western countries but is extremely rare in Japan. The current study aimed to characterize the clinicopathological features and status of molecular alterations of polymorphous adenocarcinoma-associated genes, such as PRKD1/2/3, ARID1A, and DDX3X, in a large cohort of Japanese patients with polymorphous adenocarcinoma. METHODS: We examined the cases of 36 Japanese patients with salivary gland polymorphous adenocarcinoma and 26 cases involving histopathological mimics. To detect gene splits, fluorescence in situ hybridization was carried out for polymorphous adenocarcinoma-associated genes. Additionally, we applied a SNaPshot multiplex assay to identify PRKD1 hotspot mutations. RESULTS: This study revealed the indolent clinical course of polymorphous adenocarcinoma with a high 10-year overall survival rate (92.9%), accompanied by occasional local recurrences and cervical lymph node metastasis (23.3%). Twenty cases (55.6%) of polymorphous adenocarcinoma (but none of the mimics) exhibited alterations in at least one polymorphous adenocarcinoma-associated gene. Rearrangement of polymorphous adenocarcinoma-associated genes and PRKD1 E710D were identified in 17 (47.2%) and 4 (11.1%) cases, respectively; one case showed coexisting PRKD3 split and PRKD1 E710D. In the multivariate analysis, high clinical stage (p = 0.0005), the presence of prominent nucleoli (p = 0.0003), and ARID1A split positivity (p = 0.004) were independent risk factors for disease-free survival. CONCLUSION: Japanese patients with polymorphous adenocarcinoma showed clinicopathological features similar to those reported in Western countries. This study disclosed that polymorphous adenocarcinoma-associated genetic alterations were common and specific findings in polymorphous adenocarcinomas. The diagnostic role and possible prognostic significance of polymorphous adenocarcinoma-associated genetic alterations in polymorphous adenocarcinomas were suggested.

Clinical manifestations of diffuse large B-cell lymphoma that exhibits initial symptoms in the maxilla and mandible: a single-center retrospective study.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphatic tumor; however, extranodal DLBCLs that exhibit initial symptoms in the maxilla and mandible are rare. Moreover, DLBCL is clinically classified as a moderate to highly malignant lymphatic tumor that can progress rapidly; therefore, early diagnosis is crucial. However, diagnosis is difficult as the disease causes a diverse range of clinical symptoms with no characteristic imaging findings. We conducted a clinical investigation to clarify the clinical characteristics of DLBCL that exhibits initial manifestation in the maxilla and mandible. METHODS: Of the 2748 patients with malignant tumors of the oral and maxillofacial region examined at our hospital during a period of 11 years between January 2006 and December 2016, 27 primary cases diagnosed with DLBCL based on the chief complaint of symptoms in the gingiva and bone of the maxilla and mandible were enrolled in this study. Evaluations were based on sex, age, whether treatment was provided by a previous physician, symptoms, duration of disease until treatment was sought, clinical diagnosis, laboratory findings, and imaging results. RESULTS: There were 15 cases that involved the maxilla and 12 that involved the mandible. The median duration of disease until treatment was sought was 60 d (3-450 d). All cases exhibited a tumor or a mass, and hypoesthesia of the chin was confirmed in eight cases wherein the mandible was involved. The clinical stages were stage I in eight cases, stage II in ten cases, and stage IV in nine cases. Serum lactate dehydrogenase (LDH) levels were elevated in 13 of 22 patients. The overall survival rate was 63%. CONCLUSIONS: Symptoms associated with nontender swelling and numbness of the lip or chin in the absence of other findings such as dental infections should raise suspicions about DLBCL. Patients should be provided appropriate imaging and accurate biopsy assessments to improve prognosis.

Malignant transformation of oral lichen planus: a retrospective study of 565 Japanese patients.

BACKGROUND: Oral lichen planus (OLP) is a chronic inflammatory oral mucosa disease that is recognized as an oral potentially malignant disorder. However, the potentially malignant nature of OLP remains unclear. METHODS: We designed this study to examine the demographic and clinical characteristics of patients with OLP and evaluate the associated malignant transformation rate. A total of 565 patients with a clinical and histopathological diagnosis of OLP who presented at our department between 2001 and 2017 were retrospectively studied. Patients who had clinical and histopathological features of oral lichenoid lesions (OLLs) classified as oral lichenoid contact lesions, oral lichenoid drug reactions and oral lichenoid lesions of graft-versus-host disease were excluded. RESULTS: The study population included 123 men and 442 women aged 21-93 years (mean ± standard deviation, 60.5 ± 11.8). The 565 patients were followed up for a duration of 55.9 ± 45.3 months, during which 4 (0.7%) patients developed squamous cell carcinoma (SCC). In three of these 4 patients who developed SCC, the clinical type of OLP was the red type. CONCLUSIONS: Our results suggested that OLP was associated with a low risk of malignant transformation. We recommend regular follow-up for OLP patients and clear differentiation of oral epithelial dysplasia and OLLs to enable early detection of malignant transformation. Further investigation of the clinical risk factors associated with malignant transformation is necessary.

Histopathological evaluation of minor salivary gland papillary-cystic tumours: focus on genetic alterations in sialadenoma papilliferum and intraductal papillary mucinous neoplasm.

AIMS: Minor salivary gland tumours showing a predominant papillary-cystic structure are rare, and constitute a mixture of various types of neoplasm; thus, the histopathological assessment of these tumours poses a significant diagnostic challenge. We aimed to delineate the histological characteristics of these tumours and further mutational aspects with a particular focus on sialadenoma papilliferum (SP) and intraductal papillary mucinous neoplasm (IPMN). METHODS AND RESULTS: We retrieved 28 papillary-cystic tumours of the minor salivary glands, and performed histological re-evaluation and mutation analyses of several key oncogenes. The histological classifications were as follows: SP (n = 10), SP-like intraductal papillary tumour (SP-IPT) (n = 2), IPMN (n = 9), intraductal papilloma, cystadenoma, and cystadenocarcinoma (two, three and two respectively). Whereas SP typically consisted of a combination of exophytic squamous epithelium and endophytic intraductal papillary infoldings, SP-IPT lacked the exophytic component. SP and SP-IPT frequently harboured BRAF V600E mutations (75.0%), which were identified in both squamous and ductal components. IPMN was characterised by a well-demarcated cystic lesion filled exclusively with a papillary proliferation of mucinous cells and a high rate of AKT1 E17K mutations (88.9%). Intraductal papillomas were unilocular cystic lesions with intraluminal papillary growth of bland columnar cells. In contrast, both cystadenomas and cystadenocarcinomas showed a multicystic appearance with a papillary configuration. Cystadenocarcinomas invaded the surrounding tissue and were composed of markedly atypical tumour cells. CONCLUSION: The appropriate interpretation of histological findings and specific genetic alterations (e.g. BRAF V600E and AKT1 E17K in SP and IPMN) would be useful for the correct diagnosis of minor salivary gland papillary-cystic tumours.

Buccinator and Mandibular Node Metastases in Oral Squamous Cell Carcinoma.

PURPOSE: The buccinator and mandibular nodes belong to the facial lymph node group, and metastasis of oral cancer to these nodes is extremely rare. The purpose of this study was to examine particularly rare metastatic cases in which treatment was administered for the buccinator or mandibular nodes. PATIENTS AND METHODS: The authors identified 1,479 cases of oral squamous cell carcinoma treated at their hospital from April 2001 to December 2016. After excluding cases with distant metastasis at initial treatment, perioperative mortality, and lack of follow-up data, the final study population consisted of 1,406 cases. RESULTS: Six patients were identified who had pathologic metastasis to the buccinator or mandibular node (3 men and 3 women; age range, 45 to 72 yr; average age, 59.3 yr). The primary sites were the lower gingiva in 2 cases and the buccal mucosa in 4 cases. There were 2 cases of metastasis to the buccinator nodes and 4 cases of metastasis to the mandibular nodes. There were no cases of metastasis to the buccinator and mandibular nodes. Each case also involved submandibular node metastasis. The outcomes were disease-free survival in 4 cases and death from cancer in 2 cases; the cumulative disease-specific 5-year survival rate was 62.5%. CONCLUSIONS: The possibility of metastasis to the buccinator and mandibular nodes should be considered in oral cancer when primary tumor invasion reaches the buccinator muscle with submandibular node metastasis.

The high expression of FOXA1 is correlated with a favourable prognosis in salivary duct carcinomas: a study of 142 cases.

AIMS: Salivary duct carcinoma (SDC) is an uncommon, aggressive tumour that, histologically, resembles high-grade mammary ductal carcinoma, and is characterised by the expression of androgen receptor (AR). The androgen signalling pathway, a potential therapeutic target, can be regulated by FOXA1. This study aimed to evaluate the clinicopathological implications of FOXA1 in SDC. METHODS AND RESULTS: We examined the relationship between the immunoexpression of FOXA1 and FOXA1 mutations and clinicopathological factors, including the biomarker status and clinical outcome, in 142 SDCs. FOXA1 was expressed in 128 SDCs (90.1%); the immunoexpression was heterogeneous. SDCs with a higher FOXA1 labelling index (LI) (≥20%) more frequently showed less advanced tumors on T classification (P = 0.002). FOXA1 LI was correlated positively with the AR expression value (r = 0.430, P < 0.001). PI3K and p-mTOR positivity, and intact-PTEN, were associated with a higher FOXA1 LI. Twenty-two of 121 SDCs (18.2%) harboured FOXA1 gene mutations at the flanking regions in and around the forkhead DNA binding domain; however, the given gene mutation and the expression of FOXA1 were not significantly correlated. A multivariate analysis revealed that SDCs with a higher FOXA1 LI were associated with longer overall survival and progression-free survival (P = 0.029 and 0.016, respectively). CONCLUSIONS: In SDC, FOXA1, which may biologically interact with the AR and PI3K signalling pathways, is a putative biomarker that may be associated with a favourable prognosis. Further studies are needed to apply the findings to the development of targeted personalised therapy for patients with SDC.

Clinical Course of Oral Squamous Cell Carcinoma in Patients on Immunosuppressant and Glucocorticoid Therapy.

PURPOSE: Depressed immune function is a serious adverse effect of long-term immunosuppressant or steroid administration at doses that exceed the physiologically required amount. The purpose of this study was to determine the effects of immunosuppression on carcinogenesis, particularly malignant tumor development, in patients with oral squamous cell carcinoma who had immunosuppression because of immunosuppressant therapy with or without steroid therapy administered for different underlying diseases. MATERIALS AND METHODS: In this retrospective chart review, 886 patients with oral squamous cell carcinoma who received treatment at the authors' department from April 2001 through December 2011 were included. Their clinical characteristics; tumor, node, and metastasis (TNM) stage; initial treatment for the primary cancer; mode of cervical lymph node metastasis; incidence rate of distant metastases; white blood cell, neutrophil, and lymphocyte counts on initial examination; and therapeutic outcomes were evaluated and compared between patients on and those not on immunosuppressant therapy with or without steroid therapy. Survival rates were calculated using the Kaplan-Meier method. RESULTS: Fourteen eligible patients (5 men, 9 women; mean age, 65.2 yr) were identified who were on immunosuppressant therapy with or without steroid therapy. They exhibited considerably more metastases, extracapsular spread, and distant metastases, and the number of metastases and extracapsular spread were statistically significant (P = .0213, P = .042, respectively). In 9 patients, total lymphocyte count in the peripheral blood was no higher than 1,500/µL, indicating the lower limit of the normal range. One patient died of recurrence of the primary tumor. Another patient died of cervical lymph node recurrence. Distant metastases occurred in 2 patients. The cumulative disease-specific 5-year survival rate of patients receiving immunosuppressive therapy was 62.3% and that of patients with cervical lymph node metastasis was 25%. CONCLUSION: The results of this study suggest that patients with oral squamous cell carcinoma on immunosuppression therapy show progression of cervical lymph node metastasis and extracapsular spread and are at high risk of developing distant metastases.

Oral Focal Mucinosis of the Tongue: Case Report and Review of the Literature.

Oral focal mucinosis (OFM) is an oral mucosal lesion characterized by focal mucosal accumulation that rarely occurs on the tongue. This report describes a rare case of OFM on the right side of the tongue in a 71-year-old female patient. The clinical features of OFM have not been well defined, making it difficult to differentiate it from other lesions based solely on clinical manifestations; therefore, histopathological examinations are necessary. Although OFM on the tongue is rare and has a good prognosis with resection, it should be considered as differential for painless mass lesions in the oral cavity.

Treatment strategies for patients over 80 years of age with oral squamous cell carcinoma.

OBJECTIVE: To analyze the clinical characteristics of patients with oral squamous cell carcinoma aged ≥80 years, focusing on surgical treatments. STUDY DESIGN: We reviewed patients with oral squamous cell carcinoma aged ≥80 years who underwent surgery between 2005 and 2018. Basic information, comorbidities, multiple primary cancers, initial treatment, complications, and outcomes were evaluated. RESULTS: Of 197 patients aged ≥80 years, 119 patients underwent surgery (50 males, 69 females; mean age: 83.5 years). The gingiva was the most common primary tumor site (63 patients, 52.9 %). The stage classification was stage I in 35 patients (29.4 %), stage II in 44 (37 %), stage III in 16 (13.4 %), stage IVA in 22 (18.5 %), and stage IVB in 2 (1.7 %). Comorbidities were identified in 112 patients (94.1 %). Surgery was the initial treatment in 111 patients (93.3 %). Eight (6.7 %) patients received postoperative adjuvant chemotherapy/radiotherapy; 20 patients (16.8 %) underwent free tissue transplantation. Perioperative complications were observed in 36 patients (30.3 %). The cumulative 5-year and 10-year overall survival rates were 82 % and 68.3 %, respectively; the disease-specific survival rates were 90 %. CONCLUSION: Good treatment outcomes were obtained with radical surgery. Surgery should be the first choice if quality of life is assured and there are no issues with surgical tolerance, regardless of age.

Efficacy and safety of GH treatment in Japanese children with short stature due to SHOX deficiency: a randomized phase 3 study.

We conducted a randomized phase 3 study to investigate the efficacy and safety of GH treatment in prepubertal Japanese patients with short stature due to SHOX deficiency. The patients were randomly allocated to the GH-GH group (n = 10), in which the patients were treated with GH (0.35 mg/kg/wk) subcutaneously once daily for 24 mo, or the no-treatment (NT)-GH group (n = 9), in which the patients were untreated for the first 12 mo and then administered the same dosage of GH for the next 12 mo. At month 12, the ∆height standard deviation score (SDS) for chronological age (CA) and serum IGF-1 level were significantly higher in the GH-GH group than those in the NT-GH group. In contrast, bone age (BA) and ΔBA/ΔCA were numerically higher in the GH-GH group but were not statistically significant. At month 24, these parameters were comparable between the two groups. The height velocity was significantly larger in the GH-GH group during the first year and in the NT-GH group during the second year. No serious adverse drug reactions were observed; however, one patient in the GH-GH group exhibited increased insulin resistance at month 24. These results indicated that GH is a promising treatment option for short stature in patients with SHOX deficiency.

Clinicopathological analysis of 134 patients with squamous cell carcinoma of the mandibular gingiva.

Objective: The accurate assessment of the involvement of mandibular gingival squamous cell carcinoma (SCC) is essential for determining the extent of resection and is also useful for predicting lymph node metastasis and prognosis. The purpose of this study was to investigate the factors for predicting the prognosis. Study design: We reviewed 134 patients with mandibular gingival SCC treated between 2008 and 2017. The clinical findings, TN stage, relationship between radiographical type and histological pattern, and factors affecting the survival rate were investigated. Results: The moth-eaten radiographic type was significantly associated with histologically infiltrative pattern. For all 134 cases, the 5-year OS was 89.5 %, and 5-year DSS was 93.9 %. The 5-year DSS was 95.0 % for cN0 and/or pN0 cases and 90.3 % for pN (+) cases, with a significant difference. The significant risk factors for lymph node metastasis were teeth extractions by previous physicians and moth-eaten radiographic type. Conclusion: The risk factor for poor prognosis was lymph node metastasis. In addition, teeth extractions by previous physicians and moth-eaten radiographic type were the risk factors for lymph node metastasis. It is recommended that these cases be treated considering the possibility of cervical lymph node metastasis.

PD-L1 expression as a predictive biomarker in patients with recurrent or metastatic salivary gland carcinoma treated with pembrolizumab.

Although immune checkpoint inhibitors (ICIs) are effective in some patients with salivary gland carcinoma (SGC), biomarkers which predict the efficacy and prognosis of SGC patients treated with pembrolizumab have not been identified. We conducted a multi-institutional retrospective cohort study to evaluate the efficacy and safety of pembrolizumab monotherapy in patients with recurrent and/or metastatic SGC and to determine optimal cut-off values of the combined positive score (CPS) and tumor proportion score (TPS) as numerical expression levels of programmed death-ligand 1 (PD-L1), which predict the efficacy of pembrolizumab. Furthermore, we investigated the association of patient characteristics and hematological markers with clinical outcomes, including overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). From 2016 to 2021, 27 patients were included in the analysis. ORR of SGC was 25.9%. Optimal cut-off values of CPS and TPS were 15 and 25%, respectively. ORRs of CPS-high and TPS-high were 55.6 and 75.0%, respectively, and significantly higher than those of CPS-low and TPS-low. Furthermore, patients with a low platelet-lymphocyte ratio (PLR) had a significantly longer PFS. No grade 4 or greater adverse events were observed. This study demonstrated the efficacy and safety of pembrolizumab monotherapy and identified optimal cut-off values of CPS and TPS.

The clinicopathological and prognostic significance of autonomic nerves in salivary duct carcinoma.

Many researchers have focused on the role of the autonomic nervous system in the tumor microenvironment. Autonomic nerves include the sympathetic and parasympathetic nerves, which are known to induce cancer growth and metastasis. However, in salivary duct carcinoma (SDC), a rare and highly malignant tumor, the issue should be investigated from both biological and therapeutic perspectives. We explored the clinicopathological and prognostic implications of the autonomic nerves in 129 SDCs. Immunohistochemistry was performed to determine the nature of each nerve using antibodies against S100, tyrosine hydroxylase (TH) as a sympathetic marker, and vesicular acetylcholine transporter (VAChT) as a parasympathetic marker. The area of each marker-positive nerve was digitized and evaluated quantitatively. Double immunofluorescence for TH and VAChT was performed in selected cases. The expression of the secreted neurotrophins was also examined. S100-positive nerves were present in the cancer tissue in 94 of 129 cases (72.9%). Among them, TH-positive sympathetic nerves and/or VAChT-positive parasympathetic nerves were identified in 92 cases (97.9%), and 59 cases (62.8%) had TH/VAChT-co-expressing nerves. Double immunofluorescence revealed a mosaic pattern of sympathetic and parasympathetic fibers in co-expressing nerve bundles. The presence of autonomic nerves, regardless of their area, was significantly associated with aggressive histological features, advanced T/N classification, and a poor prognosis, with shorter disease-free and overall survival. There was an association between some tumor immune microenvironment-related markers and the autonomic nerve status, but not the latter and the secreted neurotrophin expression. This study suggests that autonomic nerves might play a role in the progression of SDC.

A rare case of solitary intraoral superficial angiomyxoma arising in the soft palate.

Superficial angiomyxomas are myxoid mesenchymal tumors, and intraoral superficial angiomyxoma is extremely rare. This paper reports a novel case of a 41-year-old Japanese male patient with a 32 × 22 mm superficial angiomyxoma in the right soft palate. Tumor resection was performed and a polyglycolic acid sheet was attached. Over a 28-month follow-up, there was no evidence of disease recurrence. This paper also reviewed 11 cases of intraoral superficial angiomyxomas reported in previous literature. The condition was more common among middle-aged men. Surgical resection was the most common treatment, and local recurrence was observed in only one case.

Buccinator muscle invasion is a risk factor for cervical lymph node metastasis in squamous cell carcinoma of the buccal mucosa: A retrospective study.

The present study aimed to determine the risk factors associated with cervical lymph node metastasis (CLNM) in patients with buccal mucosa squamous cell carcinoma (BMSCC). This retrospective study included patients with primary BMSCC who underwent surgery at the Department of Oral and Maxillofacial Surgical Oncology of Tokyo Medical and Dental University (Tokyo, Japan) between January 2008 and December 2017. The following data were collected and analyzed: Sex, age, primary lesion subsite, tumor/node/metastasis stage, clinical growth patterns, tumor differentiation, lymphovascular and perineural invasion, mode of invasion, pathological depth of invasion, extent of tumor invasion, and clinical outcome of patients with BMSCC. Multivariate analysis was performed to identify the possible risk factors for CLNM. A total of 75 patients were included in the present study, among whom 30 (40%) were found to have histological CLNM. Of the 33 patients with buccinator muscle infiltration by the tumor, 24 (72.7%) had CLNM. Multiple logistic regression analysis revealed that buccinator muscle invasion was the most significant predictive risk factor for CLNM in BMSCC. The present study found that tumor invasion of the buccinator muscle was the most significant predictive risk factor for CLNM in BMSCC. Therefore, elective neck dissection should be performed if buccinator muscle invasion is identified in patients with BMSCC.

Free-flap volume correlates with body mass index in patients with tongue squamous cell carcinoma.

Objectives: This study aimed to investigate the relationship between postoperative reconstructed tongue flap volume (RTFV) and body mass index (BMI) and identify factors affecting the flap volume in patients with tongue squamous cell carcinoma. Methods: Thirty-two patients were evaluated for RTFV from computed tomography images and BMI. The first and second evaluations were done at 6 months and 1.5 years after surgery respectively. RTFV rate changes and BMI differences from the first and second evaluations were calculated. The correlation between RTFV rate change and BMI difference was assessed using Spearman's rank correlation coefficient. Multiple regression analysis evaluated the relationship between the flap volume rate change and age, sex, flap type, and BMI difference to identify influencing factors. Results: The flap volume rate change and BMI difference correlated significantly (r = .594, p < .05). BMI difference and flap type were independent factors that affected reconstructed flap volume rate change in multiple regression analysis (p < .05). Conclusion: The flap volume of patients with tongue squamous cell carcinoma correlates with the BMI change in the chronic phase. Patients after tongue reconstruction need to be well nourished to maintain BMI and thus postoperative tongue volume to maintain the quality of life. Level of Evidence: Level 3.

Invasion of the bucco-mandibular space by oral squamous cell carcinoma: histopathological analysis of invasion pattern.

Background: This study aimed to determine the patterns of invasion of oral squamous cell carcinoma (OSCC) into the bucco-mandibular space (BMS) using detailed histopathological analysis and to assess clinical outcomes. Methods: Patients with OSCC who underwent segmental mandibulectomy or hemi-mandibulectomy combined with resection of the BMS between 2012 and 2021 were included. The invasions of the BMS were classified into three patterns. Pattern A was defined as a horizontal invasion, Pattern B as a vertical invasion, and Pattern C as an expansive invasion. Results: In total, 109 patients were reviewed. Of these 109 patients, the primary tumor affected the lower gingiva in 78 patients, the buccal mucosa in 18 patients, and was a primary intraosseous carcinoma of the mandible in 13 patients. Invasion of the BMS was significantly associated with a higher pathological T stage, positive/close margins, and lower disease-free survival (DFS) rates. The DFS rates were 86.7% and 66.0% in the BMS non-invasion and invasion groups, respectively. The DFS rates for each type of invasion were 82.1% for Pattern A, 67.4% for Pattern B, and 48.0% for Pattern C (P=0.277). Conclusion: Patients with BMS invasion have a poorer prognosis than those without invasion of the BMS. Therefore, adjuvant therapy is necessary, especially in Patterns B and C. Evaluation of preoperative BMS invasion patterns is important for predicting the prognosis of OSCC.

Neutrophil-to-lymphocyte ratio as an early marker of outcomes in patients with recurrent oral squamous cell carcinoma treated with nivolumab.

The immune checkpoint inhibitor (ICI), nivolumab, has revolutionised the treatment of recurrent and metastatic oral cancer. However, the response rate to ICIs remains low, and identifying predictors of nivolumab response is critical. Although the neutrophil-to-lymphocyte ratio (NLR) has been suggested as a predictive marker of nivolumab response in patients with various types of cancer, its utility in oral squamous cell carcinoma (OSCC) has not been elucidated. In this retrospective multicentre cohort study, we evaluated the association between NLR and outcome of nivolumab treatment in 64 patients with OSCC treated between 2017 and 2020. The objective response and disease control rates were 25.1% and 32.9%, respectively. The rates for complete and partial responses were 15.7% (10/64) and 9.4% (6/64), respectively; stable and progressive disease rates were 7.8% (5/64) and 67.1% (43/64), respectively. Complete and partial responses were classified as responders, and stable and progressive diseases were classified as non-responders. The median (range) pre-treatment NLR among responders was 4.3 (2.8-8.0), which decreased to 4.0 (2.6-6.3) after nivolumab treatment, and the median (range) pre-treatment NLR among non-responders was 5.1 (2.7-7.9), which increased to 6.4 (4.0-14.0) with tumour growth. Moreover, overall survival was significantly worse in the group with a higher post-treatment NLR (≥5) than in the group with a lower NLR (<5). Patients with a post-treatment NLR of ≥6 had worse outcomes for salvage chemotherapy following nivolumab treatment. Thus, post-treatment NLR could be a useful marker for predicting the response to nivolumab treatment or salvage chemotherapy in patients with OSCC.

Prognostic value and clinicopathological roles of the tumor immune microenvironment in salivary duct carcinoma.

Salivary duct carcinoma (SDC) is an aggressive type of salivary gland carcinoma. Recently, immunotherapies targeting immune checkpoints, including PD1, PD-L1, CTLA4, and LAG3, have had a considerable prognostic impact on various malignant tumors. The implementation of such immune checkpoint inhibitor (ICI) therapies has also been attempted in cases of salivary gland carcinoma. The tumor immune microenvironment (TIME) is implicated in tumorigenesis and tumor progression and is closely associated with the response to ICI therapies. However, the TIME in SDC has not been fully explored. We examined the immunohistochemical expression of CD8, FOXP3, PD1, PD-L1, CTLA4, LAG3, and mismatch repair (MMR) proteins, tumor-infiltrating lymphocytes (TILs), and microsatellite instability (MSI) status in 175 cases of SDC. The associations between these TIME-related markers and the clinicopathological factors and prognosis were evaluated. An elevated expression of CD8, FOXP3, PD1, CTLA4, and LAG3 was associated with more aggressive histological features and an advanced N and/or M classification, elevated Ki-67 index, and poor prognosis. Furthermore, cases with a high PD-L1 expression exhibited more aggressive histological features and adverse clinical outcomes than those with a low expression. Alternatively, there was no significant correlation between TILs and clinicopathological factors. No SDC cases with an MSI-high status or MMR deficiency were found. The coexistence of both an immunostimulatory and immunosuppressive TIME in aggressive SDC might play a role in the presence of T-cell exhaustion. The contribution of multiple immune escape pathways, including regulatory T cells and immune checkpoints, may provide a rationale for ICI therapy, including combined PD1/CTLA4 blockade therapy.