Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

Secretory carcinoma (SC) is a recently described salivary gland tumor reported in the fourth edition of World Health Organization classification of head and neck tumors. SC is characterized by strong S-100 protein, mammaglobin, and vimentin immunoexpression, and harbors a t(12;15)(p13;q25) translocation which leads to ETV6-NTRK3 fusion product. Histologically, SC displays a lobulated growth pattern and is often composed of microcystic, tubular, and solid structures with abundant eosinophilic homogenous or bubbly secretion. SC is generally recognized as low-grade malignancy with low-grade histopathologic features, and metastasis is relatively uncommon. In this case, we described a SC of hard palate that underwent high grade transformation and metastasis to the cervical lymph node in a 54-year-old patient. In addition, this case showed different histological findings between primary lesion and metastasis lesion. Therefore, the diagnosis was confirmed by the presence of ETV6 translocation. Here, we report a case that occurred SC with high-grade transformation in the palate, and a review of the relevant literature is also presented.

DOI： 10.3390/reports3020006

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Language：English   Publishing type：Research paper (scientific journal)  

The stroma affects the properties and dynamics of the tumor. Previous studies have demonstrated that bone marrow-derived cells (BMDCs) possess the capability of differentiating into stromal cells. However, the characteristics and roles of BMDCs in oral squamous cell carcinoma remain unclear. The current study therefore investigated their locations and features by tracing green fluorescent protein (GFP)-labeled BMDCs in a transplantation mouse model. After irradiation, BALB-c nu-nu mice were injected with bone marrow cells from C57BL/6-BALB-C-nu/nu-GFP transgenic mice. These recipient mice were then injected subcutaneously in the head with human squamous cell carcinoma-2 cells. Immunohistochemistry for GFP, Vimentin, CD11b, CD31 and α-smooth muscle actin (SMA), and double-fluorescent immunohistochemistry for GFP-Vimentin, GFP-CD11b, GFP-CD31 and GFP-α-SMA was subsequently performed. Many round-shaped GFP-positive cells were observed in the cancer stroma, which indicated that BMDCs served a predominant role in tumorigenesis. Vimentin(+) GFP(+) cells may also be a member of the cancer-associated stroma, originating from bone marrow. Round or spindle-shaped CD11b(+) GFP(+) cells identified in the present study may be macrophages derived from bone marrow. CD31(+)GFP(+) cells exhibited a high tendency towards bone marrow-derived angioblasts. The results also indicated that spindle-shaped α-SMA(+) GFP(+) cells were not likely to represent bone marrow-derived cancer-associated fibroblasts. BMDCs gathering within the tumor microenvironment exhibited multilineage potency and participated in several important processes, such as tumorigenesis, tumor invasion and angiogenesis.

DOI： 10.3892/ol.2019.11045

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Language：English   Publishing type：Research paper (scientific journal)  

Sonic hedgehog (SHH) and its signaling have been identified in several human cancers, and increased levels of SHH expression appear to correlate with cancer progression. However, the role of SHH in the tumor microenvironment (TME) of oral squamous cell carcinoma (OSCC) is still unclear. No studies have compared the expression of SHH in different subtypes of OSCC and focused on the relationship between the tumor parenchyma and stroma. In this study, we analyzed SHH and expression of its receptor, Patched-1 (PTCH), in the TME of different subtypes of OSCC. Fifteen endophytic-type cases (ED type) and 15 exophytic-type cases (EX type) of OSCC were used. H&E staining, immunohistochemistry (IHC), double IHC, and double-fluorescent IHC were performed on these samples. ED-type parenchyma more strongly expressed both SHH and PTCH than EX-type parenchyma. In OSCC stroma, CD31-positive cancer blood vessels, CD68- and CD11b-positive macrophages, and α-smooth muscle actin-positive cancer-associated fibroblasts partially expressed PTCH. On the other hand, in EX-type stroma, almost no double-positive cells were observed. These results suggest that autocrine effects of SHH induce cancer invasion, and paracrine effects of SHH govern parenchyma-stromal interactions of OSCC. The role of the SHH pathway is to promote growth and invasion.

DOI： 10.3390/ijms20225779

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Language：English   Publisher：硬組織再生生物学会  

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Language：English   Publisher：硬組織再生生物学会  

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Language：English   Publishing type：Research paper (scientific journal)  

CXCR4 is a chemokine receptor crucial in tumor progression, although the angiogenic role of CXCR4 in oral squamous cell carcinoma (OSCC) has not been investigated. Here we show that CXCR4 is crucial for tumor angiogenesis, thereby supporting tumor survival in OSCC. Immunohistochemistry on human clinical specimens revealed that CXCR4 and a tumor vasculature marker CD34 were co-distributed in tumor vessels in human OSCC specimens. To uncover the effects of CXCR4 inhibition, we treated the OSCC-xenografted mice with AMD3100, so-called plerixafor, an antagonist of CXCR4. Notably, we found a unique pathophysiological structure defined as tumor angiogenic inhibition triggered necrosis (TAITN), which was induced by the CXCR4 antagonism. Treatment with AMD3100 increased necrotic areas with the induction of hypoxia-inducible factor-1α in the xenografted tumors, suggesting that AMD3100-induced TAITN was involved in hypoxia and ischemia. Taken together, we demonstrated that CXCR4 plays a crucial role in tumor angiogenesis required for OSCC progression, whereas TAITN induced by CXCR4 antagonism could be an effective anti-angiogenic therapeutic strategy in OSCC treatment.

DOI： 10.3390/cells8070761

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Language：Japanese   Publisher：克誠堂出版(株)  

2016年10月〜2017年12月に頭頸部癌に対し遊離皮弁で再建手術を行った60例(男39例、女21例、平均年齢65.8歳)を対象に、患者背景因子および移植遊離皮弁の種類、CT画像の頸部動脈石灰化所見について、吻合動脈の病理組織学的動脈硬化の程度との相関性を後方視的に評価した。背景因子のうち年齢と糖尿病が皮弁栄養動脈の動脈硬化と正の相関を示した。移植遊離皮弁別では空腸(22/23例)と腓骨皮弁(5/5例)はほぼ全例で栄養動脈に硬化を認めた。また腓骨皮弁では2/5例に皮弁栄養動脈内の石灰化を認めた。移植床動脈の動脈硬化は年齢と動脈硬化が正の相関を示した。Agatston石灰化スコアを参考に頸部動脈の石灰化値を計算した結果、動脈硬化がなかった症例は平均8.3、動脈硬化があった症例は平均18.6であった。

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Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2019&ichushi_jid=J00398&link_issn=&doc_id=20190704190010&doc_link_id=%2Fad3ksgke%2F2019%2F006207%2F014%2F0780-0787%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fad3ksgke%2F2019%2F006207%2F014%2F0780-0787%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：English   Publishing type：Research paper (scientific journal)  

Histopathological findings of oral neoplasm cell differentiation and metaplasia suggest that tumor cells induce their own dedifferentiation and re-differentiation and may lead to the formation of tumor-specific histological features. Notch signaling is involved in the maintenance of tissue stem cell nature and regulation of differentiation and is responsible for the cytological regulation of cell fate, morphogenesis, and/or development. In our previous study, immunohistochemistry was used to examine Notch expression using cases of odontogenic tumors and pleomorphic adenoma as oral neoplasms. According to our results, Notch signaling was specifically associated with tumor cell differentiation and metaplastic cells of developmental tissues. Notch signaling was involved in the differentiation of the ductal epithelial cells of salivary gland tumors and ameloblast-like cells of odontogenic tumors. However, Notch signaling was also involved in squamous metaplasia, irrespective of the type of developmental tissue. In odontogenic tumors, Notch signaling was involved in epithelial-mesenchymal interactions and may be related to tumor development and tumorigenesis. This signaling may also be associated with the malignant transformation of ameloblastomas. Overall, Notch signaling appears to play a major role in the formation of the characteristic cellular composition and histological features of oral neoplasms, and this involvement has been reviewed here.

DOI： 10.3390/ijms20081973

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Factors involved in neck lymph node metastasis (NLM) and prognosis of early tongue squamous cell carcinoma (SCC) remain unknown. METHODS: We analyzed disease-specific survival (DSS) and NLM including tumor budding grade (TBG) among 64 patients with cT1/2N0 tongue SCC. RESULTS: Univariate analysis of DSS of primary lesions uncovered significant differences in new cT, pT, new pT, pDiameter, venous infiltration, and TBG. Multivariate analysis selected only TBG3 as a predictor of NLM (odds ratio, 9.55; 95% confidence interval [CI], 1.80-50.8; P = .008), and a prognostic factor for DSS (hazard ratio, 4.41; 95% CI, 1.34-14.5; P = .02). CONCLUSION: The sole predictor of NLM and the prognosis of early tongue SCC was TBG, indicating that it might help to select overwhelming risk patients.

DOI： 10.1002/hed.25614

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Aims: Immunohistochemistry of PD-L1 has been recently established as a surrogate method to predict if immunotherapy targeting PD-L1/PD-1 has a significant effect on suppression of cancers such as lung non-small cell carcinoma, melanoma, and renal cell carcinoma. Here we performed immunohistochemistry for PD-L1 expression in squamous cell carcinoma (SCC) of the tongue to investigate the potential correlation between PD-L1 expression and clinicopathological factors and whether PD-L1 expression would be associated with prognosis. Methods: Tissue microarray cores of paraffin-embedded blocks from 135 cases with surgically resected tongue SCC were immunohistochemically analysed for PD-L1 expression. Results: We observed a positive correlation between PD-L1 expression and tongue SCC pT1 and pT2 tumours, but a negative correlation with pT2, pT3 and pT4 tumours. We also observed a positive correlation with lymph node metastasis. However, no positive correlation was demonstrated between PD-L1 expression and overall survival. Conclusions: PD-L1 tends to be overexpressed at the early stage of tongue SCC, showing a close correlation with initial development of tongue. However, PD-L1 expression may not affect prognosis.

DOI： 10.7150/ijms.27860

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Language：English   Publishing type：Research paper (scientific journal)  

RATIONALE: Malignant melanoma (MM) arising in ovarian cystic teratoma (OCT) is a rare disease with poor prognosis. Recently, immune checkpoint inhibitors of cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) and programmed death 1 (PD-1) have shown promising results in MM. Herein we report a case of MM arising in OCT. PATIENT CONCERNS: A 63-year-old Japanese primigravida had lower abdominal pain. Magnetic resonance imaging revealed the presence of an 85-mm mass at the right ovary. DIAGNOSES: The patient underwent right salpingo-oophorectomy for right ovarian tumor, and histopathological examinations revealed MM arising in OCT. On immunohistochemical analysis, the tumor cells were positive for HMB-45, Melan A, and S-100 protein, and negative for programmed death-ligand 1 (PD-L1). BRAF gene mutations were not detected by the Real-Time PCR. Two months after surgery, liver metastasis was detected. INTERVENTIONS: The patient underwent immune checkpoint inhibitors of CTLA4 (ipilimumab) and PD-1 (pembrolizumab and nivolumab). She had interstitial pneumonia associated with ipilimumab, but she safely underwent the immune checkpoint inhibitors therapy along with oral prednisolone. Pembrolizumab, ipilimumab, and nivolumab therapies had poor effect on the tumor. OUTCOMES: Now, the present case has had tumor-bearing survival for 14 months since the initial diagnosis and 12 months since the detection of liver metastasis. LESSONS: This is the first case of MM arising in OCT treated by immune checkpoint inhibitors, with information of PD-L1 immunohistochemical expression and adverse events. The present case is the longest survivor following the detection of recurrence among all the previous reports. The long survival and slow-growing tumor in the present case may be associated with no PD-L1 expressions.

DOI： 10.1097/MD.0000000000012937

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Language：English   Publisher：硬組織再生生物学会  

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Language：English   Publisher：硬組織再生生物学会  

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A number of biomaterials have been developed, some of which already enjoy widespread clinic use. We have devised a new honeycomb tricalcium phosphate (TCP) containing through-and-through holes of various diameters to control cartilage and bone formation. However, the way in which the geometric structure of the honeycomb TCP controls cartilage and bone tissue formation separately remains unknown. In addition, an association has been reported between bone formation and angiogenesis. Therefore, in the present study, we investigated the relationship between angiogenesis and various hole diameters in our honeycomb TCP over time in a rat ectopic hard tissue formation model. Honeycomb TCPs with hole diameters of 75, 300, and 500 μm were implanted into rat femoral muscle. Next, ectopic hard tissue formation in the holes of the honeycomb TCP was assessed histologically at postoperative weeks 1, 2, and 3, and CD34 immunostaining was performed to evaluate angiogenesis. The results showed that cartilage formation accompanied by thin and poor blood vessel formation, bone marrow-like tissue with a branching network of vessels, and vigorous bone formation with thick linear blood vessels occurred in the TCPs with 75-μm, 300-μm, and 500-μm hole diameters, respectively. These results indicated that the geometrical structure of the honeycomb TCP affected cartilage and bone tissue formation separately owing to the induced angiogenesis and altered oxygen partial pressure within the holes.

DOI： 10.7150/ijms.28452

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Language：English   Publisher：硬組織再生生物学会  

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Language：Japanese   Publisher：(一社)日本病理学会  

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