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.

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.

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.