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.

18F-FDG PET/CT imaging of IgG4-producing MALT lymphoma with multiple site involvement.

18F-FDG PET/CT is regarded as a modality utilized for the purpose of lesion localization, staging and assessment of treatment response in patients with lymphoma. However, it is difficult that we diagnose among multifocal lymphoma, IgG4-related disease (IgG4-RD), or a combination of both conditions when confronted with multiple sites of 18F-FDG uptake with heightened serum IgG4 levels. We present a case of a 72-year-old male who was suspected of Sjögren's syndrome based on symptoms of xerostomia accompanied by swelling of the bilateral upper eyelid and salivary glands. Following a diagnostic biopsy that revealed mucosa-associated lymphoid tissue (MALT) lymphoma as a possible finding, 18F-FDG PET/CT was conducted, which demonstrated multiple sites of 18F-FDG accumulation. While multifocal MALT lymphoma was initially suspected, the coexistence of IgG4-RD could not be definitively ruled out due to the elevated serum IgG4 levels. Subsequent histopathological and immunohistochemical examinations confirmed the diagnosis of IgG4-producing MALT lymphoma. After receiving systemic therapy with rituximab, the swelling of the bilateral upper eyelid and parotid glands resolved upon visual examination, and the serum IgG4 levels returned to within the normal range in a few months. No new lesions were detected during the subsequent follow-up examinations conducted over a period of 3 years.

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.

A histological study of the adult ligamentum arteriosum: Novel findings with application to a patent ductus arteriosus.

The ligamentum arteriosum (LA) is the vestigial fibrous remnant of the ductus arteriosus (DA), a fetal vessel arising from the left dorsal segment of the sixth aortic arch that connects the left pulmonary artery to the aortic arch. Incomplete obliteration of the DA results in a patent ductus arteriosus (PDA), causing the shunting of oxygen-rich blood to recirculate to the lungs, which can lead to pulmonary hypertension. The current study aims to further elucidate the structural characteristics of the LA via histological analysis with data gathered from adult cadaveric specimens. The LA was harvested and histologically observed with Hematoxylin and Eosin, van Gieson, and Masson's trichrome staining. Fibrous and muscle tissues were observed in all 25 specimens. The LA was categorized into three types based on the morphological features of the LA. Type I (vessel-like structure), type II (fibrotic tissue with duct-like structure), and type III (no duct-like structure) were found in 4.0%, 80.0%, and 16.0%, respectively. Finally, the remnant of a valve in the LA was also observed at the junction between the AA and LA. We suggest that this valve be called the "pulmonary-aortic valve." In the majority of the adult LAs, a duct-like structure was still present. These data could better elucidate our understanding of the pathology and etiology of a PDA.

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.

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.

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.

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.

Prognostic Value of Tumor Proportion Score in Salivary Gland Carcinoma.

OBJECTIVE: Limited information is available regarding the role of programmed death ligand 1 (PD-L1) expression and CD8+ tumor-infiltrating lymphocyte (TIL) density in the tumor immune microenvironment (TIM) of patients with salivary gland carcinoma (SGC). This study aimed to assess the association between the prognosis of SGC patients and the probability of PD-L1 expression in tumor and/or immune cells using the tumor proportion score (TPS), mononuclear immune cell density score (MIDS), combined positive score (CPS), and CD8+ TIL density in the TIM. STUDY DESIGN: Retrospective cohort study. METHODS: We retrospectively reviewed 73 SGC patients treated with definitive surgery between 2000 and 2015. Immunohistochemical analysis was used to assess TPS, MIDS, CPS, and CD8+ TIL density, followed by prognostic evaluation of these immune-related parameters. RESULTS: Histological grade was associated with TPS, MIDS, and CPS based on PD-L1 expression, and these scores exhibited a significant association with CD8+ TIL density. Patients with positive TPS had an unfavorable disease-free survival and overall survival. Multivariate analyses indicated that the TPS was a significant and independent prognostic factor. CONCLUSION: Our results suggest that TPS might be a useful prognostic biomarker in SGC patients receiving definitive surgery. Laryngoscope, 131:E1481-E1488, 2021.

Involvement of cholinergic neurons in orexin-induced contraction of guinea pig ileum.

The mechanism underlying orexin-induced contraction was examined in isolated preparations of guinea pig ileum, in relation to cholinergic transmission. Orexin-A caused contraction of ileal strips in a concentration-dependent manner. 1-(2-Methylbenzoxazol-6-yl)-3-[1,5]napthyridin-4-yl-urea hydrochloride (SB-334867-A) antagonized the orexin-A-induced contraction, with no effects on the acetylcholine-induced contraction and twitch contractions. The orexin-A-induced contraction was inhibited by tetrodotoxin and atropine, but not by hexamethonium, an antagonist of vasoactive intestinal peptide and a mixture of 5-hydroxytryptamine receptor antagonists. Orexin-A evoked an outflow of [3H]acetylcholine from the ileal strips preincubated with [3H]choline, in a concentration-dependent manner, and the orexin-A-evoked outflow was inhibited by tetrodotoxin, indicating that the outflow of [3H]acetylcholine originates from the nerve terminals. The orexin-A-evoked outflow of [3H]acetylcholine was antagonized by SB-334867-A. Thus, orexin-A evokes the release of acetylcholine from the enteric cholinergic neurons due to stimulation of the orexin-1 receptors and then causes contractions of guinea pig ileum.

HLA class I distribution in Japanese patients with schizophrenia.

Several Caucasian studies and one Japanese study have observed associations between human leukocyte antigen (HLA) class I specificities, including A24 (9) and A26 (10) and schizophrenia. Most of those studies were conducted in 1970s and early 1980s, when the typing technique of HLA was not adequately reliable. Also, an operational diagnostic system was not employed in many of the studies. The present study investigated frequencies of HLA-A specificities in schizophrenia patients (ICD-10 and DSM-III-R, n=98) and sex-matched healthy controls (n=392) from population in the southwestern part of Japan. HLA-B and -C specificities were studied in addition. Frequencies of subjects possessing A24 and A26 were not different between the patients and controls (54% and 24% in the patients and 62% and 24% in the controls, respectively). No significant difference was found in frequencies of other class I (A, B, and C) specificities between the patients and the controls. Thus, the present study provided no evidence for an association between the HLA class I specificities, including A24, A26, and others, and schizophrenia in the Japanese population.