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Temporomandibular joint herniation (TJH) is a rare condition in which the contents of the temporomandibular joint herniate into the external auditory canal (EAC). The foramen of Huschke (FH), also known as the foramen tympanicum, is an anatomical defect in the anteroinferior aspect of the EAC bone, and persisting FH is thought to be one of the causes of TJH. We report a case of spontaneous TJH along with a review of the literature. A 42-year-old man with aural fullness visited our department for the examination of the temporomandibular joint and a potentially neoplastic lesion in March 2020. Computed tomography performed previously showed a soft tissue density with a bone defect in the anterior wall of the left EAC. Otoscopic examination revealed a dome-shaped raised mass in the anterosuperior wall of the left side of the EAC. The mass protruded when the mouth was closed and disappeared when the mouth was opened. The patient was diagnosed with left TJH based on the clinical and imaging findings. Due to the lack of clinical symptoms, we decided not to perform aggressive surgical treatment for TJH, but to follow up carefully with regular imaging examinations. Fifteen months have passed since the first visit, and the symptoms have not worsened. This case report shows that TJH presents with characteristic clinical and imaging findings. Therefore, understanding the pathophysiology of this disease is essential for oral and maxillofacial surgeons who deal with temporomandibular joint diseases on a daily basis.

A mucoepidermoid carcinoma (MEC) is the most common malignant tumor of the salivary gland. It frequently occurs in the parotid and minor salivary glands, but rarely originates from the sublingual gland. We report a case of a low-grade MEC arising from the sublingual gland with a MAML2 gene split on fluorescence in situ hybridization (FISH). In May 2017, a 57-year-old woman visited our hospital with left-sided tongue numbness and swelling of the floor of the mouth. We performed a biopsy, but the lesion was indistinguishable from malignant tumors such as MEC, or atypical epithelium associated with inflammation. Subsequently, an MEC was suspected based on computed tomography findings of invasion into the bone marrow and destruction of the outer margin of the mandibular cortex. In July 2017, tracheostomy, bilateral supraomohyoid neck dissection, combined resection of the floor of the mouth and reconstruction of the free peroneal composite flap with a vascular handle were performed under general anesthesia. Although perineural and mandibular invasion was observed, the tumor was considered a low-grade malignancy based on histopathological findings. Furthermore, a split signal in the MAML2 gene was detected on detailed molecular analysis using FISH. No recurrence was observed more than three years after definitive surgery. The presence of the MAML2 fusion gene is useful for the accurate diagnosis of an MEC. Overall, we report a rare case of an MEC in the sublingual gland with mandibular invasion where MAML2 fusion was confirmed.

Supplementary Figure legends for Supplementary Fig.1 and Fig. 2

Inactivation of methylcytosine dioxygenase, ten-eleven translocation (TET) is known to be associated with aberrant DNA methylation in cancers. Tumors with a CpG island methylator phenotype (CIMP), a distinct subgroup with extensive DNA methylation, show characteristic features in the case of colorectal cancer. The relationship between TET inactivation and CIMP in colorectal cancers is not well understood. The expression level of TET family genes was compared between CIMP-positive (CIMP-P) and CIMP-negative (CIMP-N) colorectal cancers. Furthermore, DNA methylation profiling, including assessment of the TET1 gene, was assessed in colorectal cancers, as well as colon polyps. The TET1 was silenced by DNA methylation in a subset of colorectal cancers as well as cell lines, expression of which was reactivated by demethylating agent. TET1 methylation was more frequent in CIMP-P (23/55, 42%) than CIMP-N (2/113, 2%, P < 0.0001) colorectal cancers. This trend was also observed in colon polyps (CIMP-P, 16/40, 40%; CIMP-N, 2/24, 8%; P = 0.002), suggesting that TET1 methylation is an early event in CIMP tumorigenesis. TET1 methylation was significantly associated with BRAF mutation but not with hMLH1 methylation in the CIMP-P colorectal cancers. Colorectal cancers with TET1 methylation have a significantly greater number of DNA methylated genes and less pathological metastasis compared to those without TET1 methylation (P = 0.007 and 0.045, respectively). Our data suggest that TET1 methylation may contribute to the establishment of a unique pathway in respect to CIMP-mediated tumorigenesis, which may be incidental to hMLH1 methylation. In addition, our findings provide evidence that TET1 methylation may be a good biomarker for the prediction of metastasis in colorectal cancer. Cancer Prev Res; 8(8); 702–11. ©2015 AACR.

Supplementary Table 2. Primer sets for pyrosequencing methylation analysis, mutation analysis, and RT-PCR

Supplementary Fig. 2. Genetic and epigenetic alterations in CIMP-P CRCs

Supplementary Fig. 1. DNA methylation and expression analyses in TET1

Supplementary Table 4. Relationship between TET1 methylation and Clinical features in CIMP-P CRCs (TCGA data set)

Supplementary Table 3. Relationship between TET1 methylation and other mutation and methylation markers in CIMP-P CRCs (in our cohort)

COVID-19 is pandemic since 2020 and further information is necessary on the risk factors associated with the infection of SARS-CoV-2. As an entry mechanism, SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) as receptor and transmembrane serine protease 2 (TMPRSS2) to activate fusion with host plasma membrane. Because dysgeusia is an early symptom of COVID-19, we here studied the expression of ACE2 and TMPRSS2 in the tongue and the associated tissues of mice and humans with immunohistochemistry and immunoblot analysis. ACE2 expression was low in the human tongue but was observed in the squamous epithelium, perineurium, arterial wall, salivary glands as well as taste buds. In contrast, mice showed high expression. In sharp contrast, TMPRSS2 expression was high in all the cells mentioned above in humans but relatively low in mice except for salivary glands. We then performed semi-quantitation of immunohistochemistry data of human ACE2 and TMPRSS2 and analyzed for age, sex, alcohol intake, and smoking habit with logistic regression analysis. We found that alcohol intake and female gender were the significant risk factors for increasing TMPRSS2 expression. In conclusion, TMPRSS2 is an important factor to be considered regarding SARS-CoV-2 entry and amplification in the oral cavity, which is promoted through drinking habit.

Lingual artery (LA) aneurysms are particularly rare, and pseudoaneurysms are associated with trauma, infection, and surgical intervention. LA aneurysms can be fatal if not recognised or treated; however, only a few cases of idiopathic LA aneurysms have been reported in the literature, all of which have been described as pseudoaneurysms. To address this knowledge gap in reporting a true LA aneurysm, here, we describe a 55-year-old woman with an idiopathic aneurysm of the lingual artery. The lesion was detected by another department on a computed tomographic angiography of the neck, which was performed as a post-aneurysmectomy evaluation of the right internal carotid artery. The embolisation failed twice, after which we performed an aneurysmectomy of the left atrium. A histopathological examination of the excised aneurysms revealed fibromuscular dysplasia (FMD). Thus, we believe that FMD may be a cause of external LA aneurysms. Our findings will be relevant for oral surgeons and physicians who may consider FMD as a differential diagnosis when treating multiple LA aneurysms.

Ossifying fibroma is a fibro-osseous lesion of the jaw and usually occurs as a single lesion. Little is known about ossifying fibromas, which occur as a manifestation of hyperparathyroidism-jaw tumor syndrome (HPT-JT), an autosomal dominant disorder. We experienced a patient with HPT-JT who had ossifying fibromas on both sides of the mandible. A 32-year-old female was referred to our department because of swelling on the right side of the mandible. She had a history of parathyroid adenomas and endometrial hyperplasia; however, there was no family history of parathyroid, mandibular, or renal lesions. She was diagnosed with recurrent parathyroid adenoma close to the time of her visit to our department. A biopsy revealed that the jaw lesion was an ossifying fibroma, and genetic testing revealed HPT-JT. She underwent surgery for the parathyroid and mandibular lesions and is currently undergoing follow-up. Accurate diagnosis of HPT-JT is important because it is an inherited condition and is associated with a high incidence of parathyroid carcinoma. This case indicates that cooperation among multiple medical care departments is essential for proper diagnosis and treatment of HPT-JT.

Post-transplant lymphoproliferative disorders (PTLDs) are lesions that proliferate lymphocytes or plasma cells and are caused by immunosuppression after organ transplantation or hepatopoietic stem cell transplantation. According to the 2016 WHO classification, PTLDs are classified into four types: early lesions, polymorphic PTLDs, monomorphic PTLDs, and classical Hodgkin lymphoma-type PTLDs. We report a case of PTLD that first occurred in the oral and maxillofacial area more than ten years after living renal transplantation. A sixty-one-year-old man visited our department in the middle of August 2013 because of right parotid gland swelling. We consulted with an otorhinolaryngologist and prescribed antibiotics to determine whether the swelling was parotitis or a tumor; however, the swelling did not improve. At the end of September 2013, a tumor was found in the right palatine tonsil; consequently, a biopsy was performed. After the biopsy, the lesion was diagnosed as monomorphic PTLD (diffuse large B-cell lymphoma), and the patient was admitted to the hematology and oncology ward. Immunosuppressants were interrupted or reduced. However, the tumor continued to swell, and R-CHOP treatment was started. The therapeutic value was PR, and the patient’s general condition was good; therefore, in mid-February, he discharged. However, at the end of April 2014, the patient experienced septic shock due to pneumonia and passed away the next day. As this case shows, it is important for oral and maxillofacial surgeons to consider the possibility of PTLD in the oral and maxillofacial area.

Maffucci syndrome, first described in 1881, is a rare, non-hereditary skeletal disorder characterized by multiple enchondromas in combination with soft tissue hemangiomas. Recent studies have implicated somatic mutations in IDH1/2 contributing to the pathogenesis of Maffucci syndrome. This study describes the first case of Maffucci syndrome harboring a mutation in IDH1, which was associated with a hemangioma in the oral mucosa. A 32-year-old man, who was diagnosed with Maffucci syndrome during childhood, was referred to our department in April 2020 due to a mass in the left buccal mucosa. The mass was soft, dome-shaped, had dark red protrusions and well-defined borders, and the dimensions were approximately 15 × 10 mm. Magnetic resonance imaging revealed a mass with a dimension of 13 × 10 mm, which appeared hyperintense on T2-weighted images. The vascular lesion was surgically resected under local anesthesia owing to hemangioma diagnosis. We then analyzed the IDH1/2 sequences using DNA extracted from the excised tumor tissue and peripheral blood. The analysis revealed the presence of a heterozygous mutation in IDH1 in the tumor tissue, corresponding to an R132C substitution. The mutation was not present in peripheral blood DNA. After over one year of resection, the patient is presently free from tumor recurrence and is under follow-up for the early detection of recurrent hemangioma.

Objective Members of the Notch family are frequently dysregulated in various types of cancers, and these alterations can lead to oncogenesis or tumor suppression depending on the context. The aim of this study was to elucidate the relationship between members of the Notch family and oral squamous cell carcinoma (OSCC) tumorigenesis, with a focus on epigenetic alteration, especially DNA methylation. Material and methods We analyzed the expression and DNA methylation of members of the Notch family in six OSCC cell lines. Additionally, we evaluated the DNA methylation level and the frequency of Notch3 methylation in clinical samples and compared the results between tumor and normal tissues using The Cancer Genome Atlas (TCGA) dataset. Further, we comprehensively evaluated DNA methylation and gene mutation of Notch3 in tumor tissues. Results Notch1, Notch2, and Notch4 were substantially expressed in all the OSCC cells, whereas Notch3 expression was not detected; moreover, Notch3 was highly methylated at the promoter region in one of the six cell lines. In the OSCC clinical samples, Notch3 methylation was significantly higher in tumor than in normal tissues (P = 0.04). Intriguingly, DNA methylation and loss of function mutation of Notch3 tended to be mutually exclusive. Conclusion Our data indicate that Notch3 is downregulated by multiple mechanisms during OSCC tumorigenesis, mainly due to DNA methylation.

Chemotherapy is a mainstay of treatment for solid tumors. However, little is known about how therapy-induced immune cell infiltration may affect therapy response. We found substantial CD45+ immune cell density adjacent to E-selectin expressing inflamed vessels in doxorubicin (DOX)-treated residual human breast tumors. While CD45 level was significantly elevated in DOX-treated wildtype mice, it remained unchanged in DOX-treated tumors from E-selectin null mice. Similarly, intravenous administration of anti-E-selectin aptamer (ESTA) resulted in a significant reduction in CD45+ immune cell density in DOX-treated residual tumors, which coincided with a delay in tumor growth and lung metastasis in MMTV-pyMT mice. Additionally, both tumor infiltrating T-lymphocytes and tumor associated-macrophages were skewed towards TH2 in DOX-treated residual breast tumors, however, ESTA suppressed these changes. This study suggests that DOX treatment instigates de novo intratumoral infiltration of immune cells through E-selectin, and functional blockade of E-selectin may reduce residual tumor burden as well as metastasis through suppression of TH2 shift.

Inactivation of methylcytosine dioxygenase, ten-eleven translocation (TET) is known to be associated with aberrant DNA methylation in cancers. Tumors with a CpG island methylator phenotype (CIMP), a distinct subgroup with extensive DNA methylation, show characteristic features in the case of colorectal cancer. The relationship between TET inactivation and CIMP in colorectal cancers is not well understood. The expression level of TET family genes was compared between CIMP-positive (CIMP-P) and CIMP-negative (CIMP-N) colorectal cancers. Furthermore, DNA methylation profiling, including assessment of the TET1 gene, was assessed in colorectal cancers, as well as colon polyps. The TET1 was silenced by DNA methylation in a subset of colorectal cancers as well as cell lines, expression of which was reactivated by demethylating agent. TET1 methylation was more frequent in CIMP-P (23/55, 42%) than CIMP-N (2/113, 2%, P < 0.0001) colorectal cancers. This trend was also observed in colon polyps (CIMP-P, 16/40, 40%; CIMP-N, 2/24, 8%; P = 0.002), suggesting that TET1 methylation is an early event in CIMP tumorigenesis. TET1 methylation was significantly associated with BRAF mutation but not with hMLH1 methylation in the CIMP-P colorectal cancers. Colorectal cancers with TET1 methylation have a significantly greater number of DNA methylated genes and less pathological metastasis compared to those without TET1 methylation (P = 0.007 and 0.045, respectively). Our data suggest that TET1 methylation may contribute to the establishment of a unique pathway in respect to CIMP-mediated tumorigenesis, which may be incidental to hMLH1 methylation. In addition, our findings provide evidence that TET1 methylation may be a good biomarker for the prediction of metastasis in colorectal cancer. Cancer Prev Res; 8(8); 702–11. ©2015 AACR.

Despite the clinical advancement, pancreatic cancer remains one of the most deadly cancers. Pancreatic cancers are often difficult to diagnose and there is no reliable screening biomarker for early detection of this cancer. Epigenetic alterations have emerged as a common hallmark of many types of human cancers as well as pancreatic cancers. Studies have shown that epigenetic dysregulation is associated with multiple steps during carcinogenesis. Therefore, detection of aberrant DNA methylation from blood samples may be a promising diagnostic tool for pancreatic cancers. First, we analyzed KRAS mutation status of 100 samples obtained by Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA), which is a safe and accurate technique to perform the pancreatic tissue biopsy, and found that more than 80% of the cells in the samples harbors KRAS mutation indicating high amount of cancer cells in the specimens. Next, we performed genome-wide DNA methylation analysis of 38 EUS-FNA specimens using Illumina Infinium HumanMethylation450 BeadChip. We further analyzed the deposited DNA methylation profiles of other tumor types in the public databases, such as TCGA, and identified 8 marker genes with high frequency and specificity of DNA methylation in pancreatic cancers. We validated the DNA methylation status of these genes by bisulfite pyrosequencing and quantitative methylation specific PCR. These markers were frequently methylated in EUS-FNA samples (95% of samples are methylation positive in at least one marker gene). Now we are analyzing the DNA methylation status in pancreatic cancers and corresponding blood samples in order to identify the most effective set of markers for diagnose pancreatic cancers. Our results suggest that analysis of DNA methylation in the circulating free DNA might be a safe and potent tool for evaluating and staging pancreatic cancers. Citation Format: Keiko Shinjo, Fumiharu Ohka, Keisuke Katsushima, Akira Hatanaka, Norihisa Ichimura, Zhao Juan, Kenji Yamao, Yutaka Kondo. DNA methylation in circulating free DNA as a new biomarker for pancreatic cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1069. doi:10.1158/1538-7445.AM2015-1069

Recent comprehensive genome analyses revealed the accumulation of genetic alterations in colorectal cancers (CRCs). However, it is still unknown which genetic alterations are closely associated with certain phenotype of CRCs, such as tumors with highly invasive character regardless of its small size. Here we examined the small invasive CRCs using high-throughput sequencing in order to clarify the common molecular features in those CRCs. Seven small invasive CRCs (types 0-IIa+IIc or 0-Is+IIc, less than 20mm in diameter and with submucosal massive invasion) were examined by exon sequencing. Seven thousands six variants (SNVs and indels) were detected. Among them, PTPRK was frequently mutated (3 cases, 43%; 1 nonsense and 2 missense mutations). We further examined public database (TCGA and COSMIC) and found that 50 of 617 (8.17%) CRCs contain PTPRK mutation. Those cases are frequent in proximal colon, extensively methylated (CIMP-H), microsatellite instability-high (MSI-H) and pathologically mucinous type. Consistent with clinical behavior, invasion assay in CRC cell lines revealed that CRCs with PTPRK domain D1 mutation showed high invasiveness via WNT signaling activity. These data indicate that PTPRK domain D1 mutation contributes to the invasiveness and progression of proximal CRCs, especially CIMP-H and MSI-H cases. Citation Format: Masayuki Tojo, Kazuo Konishi, Keiko Shinjo, Fumiharu Ohka, Keisuke Katushima, Akira Hatanaka, Norihisa Ichimura, Hisako Nozawa, Tomoe Shimazaki, Hitoshi Yoshida, Yutaka Kondo. Mutation in protein tyrosine phosphatase receptor type K (PTPRK) enhances progression of colon cancer through WNT signaling. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5278. doi:10.1158/1538-7445.AM2015-5278

Inactivation of methylcytosine dioxygenase, ten-eleven translocation (TET) is known to be associated with aberrant DNA methylation in cancers. Tumors with a CpG island methylator phenotype (CIMP), a distinct subgroup with extensive DNA methylation, show characteristic features in the case of colorectal cancer (CRC). The relationship between TET inactivation and CIMP in CRCs is not well understood. The expression level of TET family genes was compared between CIMP-positive (CIMP-P) and CIMP-negative (CIMP-N) CRCs. Furthermore, DNA methylation profiling, including assessment of the TET1 gene, was assessed in CRCs, as well as colon polyps. The TET1 was silenced by DNA methylation in a subset of CRCs as well as cell lines, expression of which was reactivated by demethylating agent. TET1 methylation was more frequent in CIMP-P (24/55, 44%) than CIMP-N (3/113, 3%, P Citation Format: Norihisa Ichimura, Keiko Shinjo, Fumiharu Ohka, Keisuke Katsushima, Akira Hatanaka, Masayuki Tojo, Yasuhiro Shimizu, Eiichiro Yamamoto, Hiromu Suzuki, Yutaka Kondo. Aberrant TET1 methylation closely associated with CpG island methylator phenotype in colorectal cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1054. doi:10.1158/1538-7445.AM2015-1054