[A Case of Severe Skin Disorder during Pembrolizumab Treatment for Recurrent Maxillary Gingival Carcinoma].

Immune checkpoint inhibitors are known to produce immune-related adverse events(irAE)that require medical management. Herein, we report a case of a patient treated with pembrolizumab who experienced a Grade 3 interrupted skin disorder. The patient is a 67-year-old female diagnosed with right maxillary gingival squamous cell carcinoma(cT4aN0M0, Stage ⅣA)and underwent partial right maxillectomy, right extended supra-omohyoid neck dissection, and maxillary reconstruction using a forearm flap. Six months postoperatively, late lymph node metastases with extracapsular spread was found in the right buccal lymph node and the left neck, and the patient underwent right buccal lymphadenectomy and left modified radical neck dissection. After postoperative combined chemoradiotherapy(cisplatin plus IMRT)followed by 13 courses of cetuximab plus paclitaxel, a recurrent lesion was found in the right buccal region. After 8 courses of pembrolizumab, a skin rash appeared on the forearm, chest, and back, which was diagnosed as Grade 3 irAE, requiring hospitalization. The patient was re-instituted after waiting for improvement of the skin disorder. The pembrolizumab at 75% reduction dose was re-administrated, and the patient has been followed up so far.

Cancer-nerve interplay in cancer progression and cancer-induced bone pain.

INTRODUCTION: Cancer-induced bone pain (CIBP) is one of the most common and debilitating complications associated with bone metastasis. Although our understanding of the precise mechanism is limited, it has been known that bone is densely innervated, and that CIBP is elicited as a consequence of increased neurogenesis, reprogramming, and axonogenesis in conjunction with sensitization and excitation of sensory nerves (SNs) in response to the noxious stimuli that are derived from the tumor microenvironment developed in bone. Recent studies have shown that the sensitized and excited nerves innervating the tumor establish intimate communications with cancer cells by releasing various tumor-stimulating factors for tumor progression. APPROACHES: In this review, the role of the interactions of cancer cells and SNs in bone in the pathophysiology of CIBP will be discussed with a special focus on the role of the noxious acidic tumor microenvironment, considering that bone is in nature hypoxic, which facilitates the generation of acidic conditions by cancer. Subsequently, the role of SNs in the regulation of cancer progression in the bone will be discussed together with our recent experimental findings. CONCLUSION: It is suggested that SNs may be a newly-recognized important component of the bone microenvironment that contribute to not only in the pathophysiology of CIBP but also cancer progression in bone and dissemination from bone. Suppression of the activity of bone-innervating SNs, thus, may provide unique opportunities in the treatment of cancer progression and dissemination, as well as CIBP.

Oral Dysfunction in Patients with Oral Cancer Could Occur Before Treatment and Require Early Nutritional Improvement: A Cross-Sectional Study.

Patients with oral cancer have poor nutritional status before treatment. However, there have been no reports of the detailed evaluation of preoperative oral function in patients with oral squamous cell carcinoma (OSCC). Therefore, this study aimed to evaluate the preoperative oral function of patients with OSCC and examine the relationship with nutritional status. Oral function measurements (microorganisms, oral dryness, occlusal force, tongue pressure, masticatory function, Eating Assessment Tool, and Postoperative Oral Dysfunction Scale) and Mini Nutritional Assessment-Short Form (MNA-SF) data were collected from 51 patients with OSCC (men: 37, women: 14, mean age: 72.1 years) who visited the Shimane University Hospital, Department of Oral and Maxillofacial Surgery, from September 2019 to September 2021. The tongue was the most prevalent primary gingiva site [22 patients (43.1%)], and 36 patients (70.6%) had advanced cancer. Comparisons between nutritional status and each related factor revealed significant differences in the number of individuals in the household, cancer stage, presence of pulmonary disease, number of teeth, microorganisms (grade), and masticatory function (mg/dL) (p < 0.05). Multiple regression analysis using the total MNA-SF score as the dependent variable with adjustment for confounding factors showed significant association between oral dryness and tongue pressure (p < 0.05). No significant association was found for the Eating Assessment Tool or Postoperative Oral Dysfunction scale. Patients with OSCC may have decreased oral function because of the tumor at the time of diagnosis, which causes a decline in nutritional status. Preoperative interventions are necessary to improve nutrition based on the state of oral function.

Preservation of the Nerve to the Mylohyoid Muscle During Submental Island Flaps: An Anatomic Feasibility Study for Facial Nerve Reanimation Procedures.

The submental island flap is an axial pattern pedicle flap widely used in head and neck surgery because of its ease and success. Indications of the submental island flap range from reconstruction for the malignant tumor resection to loss of temporal bone and facial skin due to trauma. Whereas, intraoperative facial nerve injury is not uncommon. We verified whether it was possible to localize the nerve to the mylohyoid muscle and reanimate the facial nerve during submental island flap procedures by preserving the mylohyoid muscle using human fresh cadaveric specimens. Six cadaveric heads were dissected and the position of the nerve to the mylohyoid muscle identified to the mylohyoid triangle documented. We identified the nerve to the mylohyoid muscle on all sides within the mylohyoid triangle and were able to separate the nerve from the submental island flap completely. Our results suggest that facial nerve reanimation using the nerve to the mylohyoid muscle can be used while reconstructing with a submental island flap in cases of intraoperative facial nerve injury.

The Role of Hedgehog Signaling in the Melanoma Tumor Bone Microenvironment.

A crucial regulator in melanoma progression and treatment resistance is tumor microenvironments, and Hedgehog (Hh) signals activated in a tumor bone microenvironment are a potential new therapeutic target. The mechanism of bone destruction by melanomas involving Hh/Gli signaling in such a tumor microenvironment is unknown. Here, we analyzed surgically resected oral malignant melanoma specimens and observed that Sonic Hedgehog, Gli1, and Gli2 were highly expressed in tumor cells, vasculatures, and osteoclasts. We established a tumor bone destruction mouse model by inoculating B16 cells into the bone marrow space of the right tibial metaphysis of 5-week-old female C57BL mice. An intraperitoneal administration of GANT61 (40 mg/kg), a small-molecule inhibitor of Gli1 and Gli2, resulted in significant inhibition of cortical bone destruction, TRAP-positive osteoclasts within the cortical bone, and endomucin-positive tumor vessels. The gene set enrichment analysis suggested that genes involved in apoptosis, angiogenesis, and the PD-L1 expression pathway in cancer were significantly altered by the GANT61 treatment. A flow cytometry analysis revealed that PD-L1 expression was significantly decreased in cells in which late apoptosis was induced by the GANT61 treatment. These results suggest that molecular targeting of Gli1 and Gli2 may release immunosuppression of the tumor bone microenvironment through normalization of abnormal angiogenesis and bone remodeling in advanced melanoma with jaw bone invasion.

[Case of Tongue Cancer That Was Considered to Be a Metachronous Double Cancer with Parotid Gland Cancer].

In Japan, the incidence of double cancers is increasing due to the rise in cancer prevalence in the super-aging society, and the frequency is particularly high among patients with head and neck cancer. To the best of our knowledge, there has been only 1 reported case of metachronous double cancer with parotid gland cancer and tongue squamous cell carcinoma, and herein we report the outline of this case. The patient was a 70-year-old male with a smoking history. In 2017, a total parotidectomy and neck dissection for adenocarcinoma of the right parotid gland were performed at the otolaryngology department, followed by concurrent chemoradiotherapy as postoperative therapy. Pathological examination revealed adenocarcinoma NOS(pT4aN2bM0, Stage ⅣA). There was no recurrence or metastasis, and the patient was recovering well. However, in October 2022, the patient presented to the hospital with a chief complaint of pain at the right margin of the tongue. At the initial consultation, an ulcerative lesion with a slightly unclear boundary and maximum diameter of approximately 15 mm was observed on the right margin of the tongue. Since epithelialization was observed in some regions, it was diagnosed as intractable stomatitis and the patient was put under observation for the time being. With no signs of healing during the follow- up examination a month later and considering the possibility of malignant tumors, a total excision of tongue lesion was performed. Pathological examination revealed well-differentiated squamous cell carcinoma(pT1N0M0, Stage Ⅰ). Going forward, we plan to conduct careful follow-up observations with the possibility of further metachronous double cancer occurrences in mind.

[A Case of Reconstruction of the Osteoradionecrosis of the Jaw Using the Patient-Specific Custom-Made Cutting Guide and Mandibular Reconstruction Plate].

Multidisciplinary treatment, combining ablative surgery and reconstruction, radiotherapy, and chemotherapy, is used to treat advanced oral cancers. In this study, we report a case of extensive osteoradionecrosis of the mandible following multidisciplinary treatment for tongue cancer, in which a computer-assisted, patient-specific custom-made cutting guide and reconstruction plate(TruMatch® )were used to improve the patient's facial morphology and oral-maxillofacial functioning. A 70-year-old man received multidisciplinary treatment for squamous cell carcinoma of the left side of the tongue (cT3N2bM0, cStage ⅣA)at a previous hospital. Seven years postoperatively, bilateral osteoradionecrosis of the mandible developed, and the patient was referred to our department for further treatment. Since the lesions were extensive, we planned reconstructive surgery using the TruMatch® system in collaboration with the plastic surgery department of our hospital. Surgery was performed precisely and accurately according to the preoperative simulation. Postoperatively, the patient's recovery was uneventful. The TruMatch® system enables us to achieve good morphological and comprehensive functional oral-maxillofacial reconstruction.

[A Case of Recurrent Tongue Cancer in a Patient of AYA Generation Who Underwent Salvage Surgery and Oral-Maxillofacial Reconstruction after Super-Selective Intra-Arterial Chemoradiotherapy].

Radical tumor resection for oral cancer can cause morphological and esthetic disorders and oral and maxillofacial dysfunction and maintaining a social life could become challenging, especially in the adolescents and young adults(AYA)generation. Conversely, chemoradiotherapy for young patients may cause adverse reactions such as impaired fertility and late side effects of radiation. Therefore, treatment should be performed cautiously. We report a case of AYA generation patient who underwent salvage surgery and maxillofacial reconstruction for recurrent tongue cancer after super-selective intra-arterial chemoradiotherapy. The patient was a 30-year-old woman who was 20 weeks pregnant. She was diagnosed with Stage Ⅲ squamous cell carcinoma of the right tongue, cT3N0M0. After abortion, the patient underwent super-selective intra-arterial chemoradiotherapy and achieved a complete response. However, 13 years later, a recurrence of Stage ⅣA tongue cancer, r- cT4aN2bM0, was reported. Additionally, the patient had osteoradionecrosis. We performed radical tumor resection(bilateral neck dissection plus subtotal glossectomy plus segmental mandibulectomy)and maxillofacial reconstruction with a fibula flap. Subsequently, we performed occlusal reconstruction treatment using dental implants. Three years postoperatively, no tumor recurrence was observed, and the patient was satisfied with the restored morpho-aesthetic and maxillo-oral functions.

[Two Cases of Advanced Lower Gingival Carcinoma Treated Surgically Using a Novel Patient-Specific Full Custom- Made Mandibular Reconstruction Plate System].

The treatment of advanced lower gingival carcinoma requires postoperative chemoradiotherapy; therefore, simultaneous hard-tissue reconstruction may not be indicated. In these cases, mandibular reconstruction is performed using a temporal reconstruction plate and various skin flaps. Herein, we reported 2 cases of advanced lower gingival carcinoma treated with a novel computer-assisted patient-specific, fully custom-made mandibular reconstruction plate system(Cosmofix®)in combination with a pedicle/free flap. In case 1, an 80-year-old female patient was diagnosed with right lower gingival carcinoma( cT4aN3bM0, Stage ⅣB). Under general anesthesia, she underwent tracheostomy, bilateral neck dissection, segmental mandibulectomy, and mandibular reconstruction using Cosmofix® in combination with an ulnar forearm free flap. In case 2, an 81-year-old male patient was diagnosed with right lower gingival carcinoma(cT4aN2bM0, Stage ⅣA). The patient underwent maintenance dialysis and required minimally invasive surgery using a pedicle flap. Under general anesthesia, the patient underwent tracheostomy, right modified radical neck dissection, segmental mandibulectomy, and mandibular reconstruction using Cosmofix® in combination with a pectoralis major myocutaneous flap. Postoperative facial morphology, occlusion, eating, swallowing, articulation, and other dysfunctions were minimal in both the cases. Adjuvant chemoradiotherapy was recommended. In conclusion, the utilization of the Cosmofix® system enabled both esthetic and functional reconstruction following segmental mandibulectomy for advanced lower gingival carcinoma.

[Effect of the Hyoid Bone Suspension Technique on the Preservation of Swallowing Function after Total Glossectomy and Pectoralis Major Musculocutaneous Flap Reconstruction for Locally Advanced Tongue Cancer].

Dysphagia is a major postoperative complication in patients with locally advanced oral cancer. In this case report, we describe the effect of the hyoid bone suspension technique on the preservation of swallowing function after total glossectomy and pectoralis major musculocutaneous flap reconstruction for locally advanced tongue cancer. Case: A 72-year-old Japanese male was diagnosed with advanced squamous cell carcinoma on the left side of his tongue(cT4aN2cM0, cStage ⅣA). Under general anesthesia, the patient underwent a tracheotomy, bilateral modified radical neck dissection type Ⅲ, total glossectomy, and reconstruction with a left pectoralis major musculocutaneous flap(PMMC flap). Intraoperatively, the PMMC flap was designed to have a heart shape of 11×6 cm and was elevated. Subsequently, holes were made at the lower edge of the mandible, and the hyoid bone was suspended and fixed to the mandibular border using 2-0 nylon sutures. The postoperative course was uneventful; the flap was completely engrafted and was in good condition. The hyoid bone suspension technique can reproduce the pharyngeal phase of swallowing, and the palatal augmentation prosthesis helps to improve food mass feeding and preserve the swallowing function.

Reproduction of the Antitumor Effect of Cisplatin and Cetuximab Using a Three-dimensional Spheroid Model in Oral Cancer.

Background/Aim: Cancer research has been conducted using cultured cells as part of drug discovery testing, but conventional two-dimensional culture methods are unable to reflect the complex tumor microenvironment. On the other hand, three-dimensional cultures have recently been attracting attention as in vitro models that more closely resemble the in vivo physiological environment. The purpose of this study was to establish a 3D culture method for oral cancer and to verify its practicality. Materials and Methods: Three-dimensional cultures were performed using several oral cancer cell lines. Western blotting was used for protein expression analysis of the collected cell masses (spheroids), and H-E staining was used for structural observation. The cultures were exposed to cisplatin and cetuximab and the morphological changes of spheroids over time and the expression changes of target proteins were compared. Results: Each cell line formed spheroidal cell aggregates and showed enhancement of cell adhesion molecules over time. H-E staining showed tumor tissue-like structures specific to each cell line. Cisplatin showed concentration-dependent antitumor effects due to loss of cell adhesion and spheroid disruption in each cell line, while cetuximab exhibited antitumor effects that correlated with EGFR expression in each cell line. Conclusion: Spheroids made from oral cancer cell lines appeared to have tumor-like characteristics that may reflect their clinical significance. In the future, it may become possible to produce tumor spheroids from tissue samples of oral cancer patients, and then apply them to drug screening and to develop individualized diagnostic and treatment methods.

[Surgical Treatment of Maxillary Gingival Carcinoma with Mental Retardation-A Case Report].

Many patients with mental retardation have a limited awareness of abnormalities in the oral cavity, making early detection of oral cancer difficult. Moreover, during examination and treatment, these patients may not understand well-intentioned verbal explanations and may express their anxiety through nonverbal communication. Herein we discuss a case in which favorable results were obtained when surgical treatment was performed on a maxillary gingival carcinoma patient with mental retardation. The patient was a 61-year-old man who was admitted to our hospital with maxillary gingival pain. A biopsy revealed well-differentiated oral squamous cell carcinoma(cT4aN0M0, Stage ⅣA). Hemi-maxillectomy was performed and postoperative recovery was uneventful. A maxillary prosthesis was provided for oral rehabilitation. At the 5-year follow-up, there were no signs of recurrence or metastasis. This case illustrates the importance of collaboration between oral maxillofacial surgeons and specialists from related departments for the comprehensive management of patients with mental retardation.

[A Case of Cavernous Sinus Metastasis following of the Postoperative Maxillary Gingival Carcinoma].

We report a case of cavernous sinus metastasis following postoperative maxillary gingival squamous cell carcinoma. An 83-year-old man was referred to our hospital due to pain in the left maxillary gingiva. Contrast-enhanced computed tomography imaging showed a mass lesion with bone destruction in the left maxillary gingiva. Biopsy indicated the presence of squamous cell carcinoma(T4bN1M0, Stage ⅣB), and the tumor was resected under general anesthesia. Four months after surgery, the patient experienced headache, and orbital pain, failing vision, and movement disorder of the left eye appeared. Magnetic resonance imaging revealed a tumor invading the cavernous sinus and orbit. The lesion was clinically diagnosed as metastatic cavernous sinus following postoperative left maxillary gingival carcinoma. Although the patient underwent chemotherapy, he died from multiple organ failure about 5 months after surgery.

[A Case of Lower Gingival Carcinoma Treated Surgically Using Computer-Assisted Patient-Specific Cutting Guide and Mandibular Reconstruction Plate].

We report a case of advanced lower gingival carcinoma treated with a computer-assisted custom-made surgical guide and reconstruction plate system(TruMatch®)in combination with a pectoralis major myocutaneous flap. In a 74-year-old male patient, a neoplastic lesion with a 30×30 mm periapical induration was observed around an extraction socket of left mandibular third molar. After various examinations, we diagnosed lower gingival carcinoma(cT4aN2bM0, Stage ⅣA). The patient was a paraplegic with a spinal cord injury, and reconstruction of mandible with free flap was not indicated, requiring minimally invasive surgery. Therefore, a surgical guide and reconstruction plate were prepared preoperatively using the Tru- Match® system. Under general anesthesia, the patient underwent tracheostomy, left modified radical neck dissection, segmental mandibulectomy, and reconstruction of the mandible using this system in combination with a pectoralis major myocutaneous flap. Postoperatively, the patient had minimal dysfunction. Currently, at 18 months follow up postoperatively, good prognosis was observed. In conclusion, this is a useful surgical system with accurate and less invasive surgery for segmental mandibulectomy of advanced lower gingival carcinoma.

[Oral Function Restoration via Two-Stage Reconstructive Treatment of an Extensive Maxillary Defect Following Maxillectomy].

Recently, the number of survivors that had oral cancer has increased, but deterioration in the quality of life of patients concerning oral function and cosmetic appearance has become problematic. Prosthodontic dentures usefully treat jaw defects after maxillary resection for cancer, but advances in microsurgery have rendered the possibility to reconstruct maxillary defect and oral cavity using a microvascular flap. Here, we describe 2-stage treatment after 35 years postoperatively. We restored the maxillofacial function using microvascular flaps and partial denture. The patient was a 59-year-old woman who underwent left lateral maxillectomy 35 years previously to treat an advanced left maxilla gingival carcinoma. A maxillary prosthesis was applied, requiring repeated adjustments and refabrications. The patient visited to obtain improvements for oral and maxillofacial functions and long-term quality of life. The left maxillary bone defect was 45×50 mm in area. Collaborating with the Department of Plastic and Reconstructive Surgery, the patient underwent reconstructive treatment using a microvascular forearm flap and partial denture. The patient's progress was excellent; eating, swallowing, and articulation improved. For 1 year postoperatively, the patient was satisfied with the results.

[A Case of Tongue Carcinoma with Malignant Transformation Caused by the Pandemic].

In April 2020, a state of emergency was declared because of the pandemic, and the public was instructed to refrain from leaving their homes. Consequently, this stirred up anxiety about visiting medical institutions. Here, we describe a case of tongue carcinoma that developed from an oral precancerous lesion into a malignant transformation owing to the effects of refraining from medical examinations caused by the pandemic. The patient was a 62-year-old woman. In March 2020, the patient became aware of a mass at the tongue's margin and was referred to our department. An excisional biopsy was performed, and a diagnosis of inflammatory change was made. The following month, a white ulcerative lesion was found, and another excisional biopsy was performed; therefore, a diagnosis of left tongue leukoplakia without epithelial dysplasia was made. The patient was scheduled for surgery; however, refused treatment and consultation because of the pandemic. In September 2021, the patient revisited our department on her own volition because an ulcerative lesion with indistinct borders and induration was found at the left lingual margin. Upon close examination, a diagnosis of left tongue squamous cell carcinoma(cT2N2bM0, Stage ⅣA)was made. In October 2021, radical tumor resection and reconstruction were performed. After 8 months postoperatively, the patient is currently well.

Expression of SARS-CoV-2 entry factors in human oral tissue.

The distribution of cells expressing SARS-CoV-2 entry factor angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) in human oral tissues were tested. The investigation was conducted with normal flesh tissue and paraffin-embedded specimens. The ACE2 and TMPRSS2 expression was detected with all subjects in the normal mucosa of the keratinized stratified squamous epithelia of the tongue and non-keratinized stratified squamous epithelia of the lip and cheek. It was found that ACE2 is expressed in the cytoplasm and on the cell membrane mainly in the stratum granulosum of the epithelia while the TMPRSS2 is strongly expressed on the cell membrane mainly in the stratum granulosum and stratum spinosum, but not in the stratum basale. Antibodies' reactions for ACE2 and TMPRSS2 were not observed in the nuclei or keratin layer. The expression of ACE2 and TMPRSS2 in the oral epithelia appears to be general, and the expression was also observed in the mucous and serous acini of the labial glands. The SARS-CoV-2 may transiently attach to the oral mucosa and the minor salivary glands which are present under all of the oral mucosa. The oral cavity can be considered an important organ for SARS-CoV-2 attachment and may provide a preventive medical avenue to guard against COVID-19 by preventing saliva from scattering.

A rare anatomical variation of the submental artery.

The submental artery usually runs anteriorly on the inferior surface of the mylohyoid muscle, giving branches to that muscle and to the anterior belly of the digastric muscle, finally supplying the submental skin. Branches of it often perforate the mylohyoid muscle and enter the sublingual space. During a routine anatomy dissection, we encountered a case in which the main trunk of the submental artery perforated the mylohyoid muscle, where the sublingual artery usually runs. No branches coursed anteriorly to supply the submental skin. To our knowledge, this submental artery variation has not been reported in the English literature. Any surgical procedure in the submandibular area, such as the axial pattern submental local flap, requires knowledge of such arterial variations.

[Functional Recovery following Incisional Cheiloplasty for Lower Labial Edema That Developed after Bilateral Neck Dissection and Postoperative Chemoradiotherapy-A Case Report].

We report a case of functional recovery following incisional cheiloplasty for the management of lower labial edema that developed after bilateral neck dissection with preservation of the one-side internal jugular vein and postoperative chemoradiotherapy. An 81-year-old woman underwent partial maxillectomy for the treatment of maxillary gingival cancer(squamous cell carcinoma, cT1N0M0, Stage Ⅰ)in April 2013. In July 2013, she underwent bilateral neck dissection(right, modified; left, radical)for bilateral cervical lymph node recurrence with an extra-nodal spread and received postoperative chemoradiotherapy( CDDP 75 mg/m2×3 course and total radiotherapy dosage of 66 Gy). Thereafter, the patient's condition progressed without recurrence or metastasis; however, the lower labium became edematous, and severe labial dysfunction was observed. Therefore, lower labial incisional cheiloplasty was performed under local anesthesia in October 2020. An excision area of 160×14 mm was determined on the inner side of the lower labium, and excision was performed with a steel blade scalpel. Lip closure became possible one week after the operation. Seven months after the operation, the patient recovered labial function and was satisfied with the outcome.

[A Case of Recurrent Squamous Cell Carcinoma of the Mandibular Gingiva Around a Mandibular Dental Implant].

Extensive bimaxillary bone support devices(hereafter referred to as a dental implant)are useful for morphological and functional reconstruction after resection of oral cancer. However, tumor recurrence due to peri-implantitis may occur. In this report, we describe a case of squamous cell carcinoma(SqCC)recurrence around a mandibular dental implant. An 80-year- old female patient underwent tumor resection and stratification for SqCC extending from the left lingual margin to the gingiva of the left lower molar in 2013. In 2014, 2 dental implants were placed in the bilateral mandibular canine region and a prosthetic device of implant-overdenture was installed. Six years after the primary tumor resection, a mass lesion was found in the peri-implant area of the left mandibular canine. Upon examination, the patient was diagnosed with SqCC recurrence and underwent radical tumor resection and immediate reconstruction using a submental flap and a reconstruction plate. Additional dental implants were concurrently placed in the remaining mandible. There was no evidence of recurrence, and the patient remains under careful observation so far.