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Background: Fulminant myocarditis presentation (FMP) is a rare and severe presentation of myocarditis. The natural history of FMP and its clinical features associated with poor outcomes are incompletely understood because there is a lack of generalizable evidence. Methods: This multicenter retrospective cohort study included patients hospitalized with histologically proven myocarditis who underwent catecholamine or mechanical support from 235 cardiovascular training hospitals across Japan between April 2012 and March 2017. Clinical features and the prognostic predictors of death or heart transplantation within 90 days on the basis of clinical and pathologic findings were determined using the Kaplan-Meier method, log-rank test, and Cox regression analysis. Results: This study included 344 patients with histologically proven FMP (median age, 54 years; 40% female). The median follow-up was 600 days (interquartile range, 36 to 1599 days) and the cumulative risk of death or heart transplantation at 90 days was 29% (n=98). Results from multivariable Cox regression analysis showed that older age, nonsinus rhythm, low left ventricular wall motion ( Conclusions: The results from analyses of data from this multicenter registry demonstrated that patients with FMP are at a higher risk of death or heart transplantation in real-world settings. These observations inform which clinical and pathologic findings may be useful for prognostication in FMP. Registration: URL: https://www.umin.ac.jp/ctr ; Unique identifier: UMIN000039763.

Odontogenic gingival epithelial hamartoma (OGEH) is a rare odontogenic epitheliallesion. Distinguishing OGEH from peripheral ameloblastoma can pose a differential diagnostic challenge. We report a case of OGEH affecting the lower gingiva in a 78-year-old male patient. The lesion presented as a large, painless, pedunculated mass with a pleomorphic histological appearance. A diagnosis of OGEH was made after the exclusion of peripheral ameloblastoma and peripheral adenomatoid odontogenic tumour. Previous studies have reported differences in sex and age between patients with OGEH and peripheral ameloblastoma; this suggests that peripheral ameloblastoma is not derived from OGEH. Histological findings suggest that the lesions are independent entities.

Lymphomatoid papulosis (LyP) is one of primary cutaneous CD30-positive large T-cell lymphoproliferative disorders (CD30 + PCLPD) that seldom arises in the oral region. We report here an extremely rare case of LyP arising on the lip. A 25-year-old female developed a painless mass on her right upper lip, which gradually grew and became painful. She visited her dermatologist who diagnosed it as herpes labialis and administered valacyclovir, but the lesion was unchanged. Then, she was referred to our department. At first visit, the mass was elastic, slightly hard, scarlet in color, and 15 mm in diameter. As T-cell lymphoma was initially diagnosed following incisional biopsy, we referred her to the Departments of Hematology and also Dermatology at our hospital. Bone marrow examination showed no neoplastic changes, and positron emission tomography-computed tomography revealed no other lesion except on the lip. Although new lesions appeared on her upper lip during the examinations, the lesions spontaneously disappeared without further treatment after the biopsy. The final diagnosis was CD30 + PCLPD pathologically and LyP clinically. No recurrence was found during the 10-month follow-up period.

Periosteal fasciitis (PF), a subtype of nodular fasciitis, is an uncommon benign soft-tissue mass that originates from the periosteum or tissues adjacent to bones. PF has rarely seen in children, especially involving in the mandible. This case report presents a rare case of PF originating from the periosteum of the mandible in an 11-year-old girl. She was referred to our hospital with fast-growing painless swelling in her left mandible. Computed tomography revealed an exophytic juxtacortical mass eroding the lower part of the left mandible and lower mandibular cortex with a periosteal reaction. The mass showed low signal intensity on T1-weighted magnetic resonance imaging (MRI) and high signal intensity on T2-weighted MRI. The apparent diffusion coefficient (ADC) of the lesion found to be moderate. Dynamic contrast-enhanced MRI revealed a gradual increment pattern in the central region of the mass. On 18F-fluorodeoxyglucose (FDG) positron-emission tomography/computed tomography (PET/CT), relatively high 18F-FDG uptake was observed on the early scan and the 18F-FDG uptake was declined on the delayed scan. The clinical and conventional radiological findings of the mass were suggestive of malignancy. However, the findings of ADC and dynamic MRI and dual-time-point FDG-PET/CT favored benign etiology over malignant etiology. Histological and immunohistochemical findings along with reactive ossification of the periosteum confirmed the diagnosis of PF. Currently, comprehensive examinations, such as clinical, imaging, and histopathological examinations, are recommended for the definitive diagnosis of PF, while MRI and dual-time-point FDG-PET/CT could have a potential usefulness to differentiate from malignancy.

We previously reported that dickkopf WNT signaling inhibitor 3 (DKK3) would modulate malignant potential of oral squamous cell carcinoma (OSCC) via activating Akt. Recently, cytoskeleton associated protein 4 (CKAP4) functions as receptor of DKK3, which activates Akt in esophageal squamous cell carcinoma, but its expression and function in OSCC were unclear.We studied DKK3 and CKAP4 protein expression in OSCC tissue and investigated the correlation between protein expression and clinical data. We also investigated whether antibodies (Ab) for DKK3 or CKAP4 could suppress malignant potential of the cancer cells.DKK3/CKAP4 protein expression was observed in majority of OSCC cases and was associated with significantly higher T-stage and TNM stage. Multivariate analysis revealed that DKK3 and CKAP4 were independent prognostic biomarkers for overall survival (OS) and disease-free survival (DFS), respectively. Survival analyses revealed that DKK3-positive cases and CKAP4-positive cases showed significantly shorter OS and DFS, respectively, and that DKK3/CKAP4 double-negative cases showed significantly favorable prognosis. Both anti-DKK3Ab and anti-CKAP4Ab could suppress cancer cell proliferation, migration, and invasion.DKK3/CKAP4 axis is thought to be important in OSCC, and it would be a promising therapeutic target.

Myositis ossificans (MO) is a benign soft-tissue lesion characterized by the heterotopic formation of the bone in skeletal muscles, usually due to trauma. MO is occasionally difficult to diagnose because of its clinical and radiological similarities with malignancy. We report a case of traumatic MO (TMO) in the masseter and brachial muscles of a 37-year-old man who presented with painless swelling in the left cheek and severe trismus. Due to the absence of a traumatic history at the first consultation and identification of a tumorous lesion in the left masseter muscle by magnetic resonance imaging (MRI), the lesion was suspected to be a malignant tumor. Subsequently, 18F-fluorodeoxyglucose positron-emission tomography/computed tomography (FDG-PET/CT) showed multiple regions of high FDG uptake across the whole body, suggestive of multiple metastases or other systemic diseases. However, intramuscular calcifications were also observed in the left masseter and brachial muscles, overlapping the areas with high FDG uptake. Moreover, multiple fractures were seen in the rib and lumbar spine, also overlapping the areas with high FDG uptake. Based on these imaging findings, along with a history of jet-ski trauma, TMO was suspected. The left cheek mass was surgically excised and histologically diagnosed as TMO. In this case report, FDG-PET/CT could detect multiple TMOs across the whole body. To the best of our knowledge, cases of multiple TMOs located far apart in different muscles are rare, and this may be the first report.

Background Cancer arises from cumulative genetic or epigenetic aberrations, or the destabilization of central signaling pathways that regulate cell proliferation, differentiation, cell cycle, gene transcription, migration, angiogenesis and apoptosis. Investigating the cancer-specific genetic background is important to get deeper apprehension of cancer biology. In this review, we aimed to identify head and neck squamous cell carcinoma (HNSCC)-specific genes and identified DKK3 gene as a candidate. Highlight DKK3 belongs to the DKK family (DKK1, DKK2, DKK3 and DKK4), which codes for an evolutionally conserved secreted glycoprotein that is characterized by two distinct cysteine rich domains and functions as an antagonist of the oncogenic Wnt signaling pathway. It has been reported that DKK3 expression is decreased in many kinds of cancers, and it is thus thought to be a tumor suppressor gene. However, our investigations have demonstrated unique expression and function of DKK3 in HNSCC. DKK3 protein expression is predominantly positive in HNSCC, and DKK3-positive patients show significantly shorter disease-free survival rates, whereas DKK3-negative cases do not show metastasis. Molecular biological analyses demonstrated that DKK3 over expression significantly increased HNSCC cell proliferation, migration, and invasion via increased phosphorylation of AKT. Moreover, DKK3 knockdown in HNSCC cells significantly decreased these malignant potentials through decreased AKT phosphorylation. Conclusion Our previously published data, alongside those from other reports, indicate that DKK3 may have an additional oncogenic function other than tumor suppression.

Background: Head and neck squamous cell carcinoma (HNSCC) is the most common malignant tumor of the head and neck. We identified cancer‑specific genes in HNSCC and focused on DKK3 expression. DKK3 gene codes two iso‑forms of proteins (secreted and non‑secreted) with two distinct cysteine rich domains (CRDs). It is reported that DKK3 functions as a negative regulator of oncogenic Wnt signaling and, is therefore, considered to be a tumor suppressor gene. However, our series of studies have demonstrated that DKK3 expression is specifically high in HNSCC tissues and cells, and that DKK3 might determine the malignant potentials of HNSCC cells via the activation of Akt. Further analyses strongly suggested that both secreted DKK3 and non‑secreted DKK3 could activate Akt signaling in discrete ways, and consequently exert tumor promoting effects. We hypothesized that DKK3 might be a specific druggable target, and it is necessary to establish a DKK3 inhibitor that can inhibit both secreted and non‑secreted isoforms of DKK3. Methods: Using inverse polymerase chain reaction, we generated mutant expression plasmids that express DKK3 without CRD1, CRD2, or both CRD1 and CRD2 (DKK3ΔC1, DKK3ΔC2, and DKK3ΔC1ΔC2, respectively). These plasmids were then transfected into HNSCC‑derived cells to determine the domain responsible for DKK3‑mediated Akt activation. We designed antisense peptides using the MIMETEC program, targeting DKK3‑specific amino acid sequences within CRD1 and CRD2. The structural models for peptides and DKK3 were generated using Raptor X, and then a docking simulation was performed using CluPro2. Afterward, the best set of the peptides was applied into HNSCC‑derived cells, and the effects on Akt phosphorylation, cellular proliferation, invasion, and migration were assessed. We also investigated the therapeutic effects of the peptides in the xenograft models. Results: Transfection of mutant expression plasmids and subsequent functional analyses revealed that it is necessary to delete both CRD1 and CRD2 to inhibit Akt activation and inhibition of proliferation, migration, and invasion. The inhibitory peptides for CRD1 and CRD2 of DKK3 significantly reduced the phosphorylation of Akt, and consequently suppressed cellular proliferation, migration, invasion and in vivo tumor growth at very low doses. Conclusions: This inhibitory peptide represents a promising new therapeutic strategy for HNSCC treatment., Cancer Cell International, 22(1), art. no. 352; 2022

Cardiac sarcoidosis (CS) causes lethal arrhythmia and heart failure and has a poor prognosis; therefore, early detection and early stage treatment are important. However, diagnosis of isolated CS may be difficult in some cases owing to the low sensitivity of myocardial biopsy. Herein, we describe the case of a patient with isolated CS, showing change from negative to positive fluorine‐18 fluorodeoxyglucose (18F‐FDG) positron emission tomography (PET) uptake results within 9 months. The patient showed rapid reduction in left ventricular systolic function with sustained ventricular tachycardia. The diagnosis of isolated CS is often under‐recognized in clinical practice because it commonly requires the diagnosis of extracardiac disease in the absence of a positive endomyocardial biopsy. The Japanese Circulation Society recently published guidelines for CS diagnosis stating that isolated CS can be clinically diagnosed with positive 18F‐FDG PET or 67Gallium result. In this case, serial follow‐up 18F‐FDG PET was useful for diagnosing isolated CS.

Severe ventricular arrhythmias such as high-grade atrioventricular block and ventricular tachycardia may cause lethal conditions or sudden death in patients with cardiac sarcoidosis (CS). Physicians should examine patients carefully for these conditions and treat them appropriately. As arrhythmias are being better diagnosed and treated, physicians are increasingly aware of atrial arrhythmias, which have not been focused upon as CS-related conditions, in patients with CS. This article reports a case of atrial flutter in sarcoidosis, and discusses literature findings on atrial arrhythmias and atrial involvement of CS. It is highly likely that atrial arrhythmia and supraventricular conduction disorder associated with or caused by CS are more common than previously thought. Physicians should pay careful attention for these conditions in the diagnosis and treatment of CS.

We herein report a woman diagnosed with cardiac sarcoidosis (CS) based on the presence of epithelioid granulomas in non-cardiac organs and clinical findings including sustained ventricular tachycardia (VT) and cardiac dysfunction. She stopped oral corticosteroid after 4 years of treatment, and an abnormal myocardial uptake of fluorine-18 fluorodeoxyglucose and sustained VT recurred 3.5 years later. There is no consensus concerning whether or not corticosteroid therapy should be discontinued in the treatment of CS. As a relapse of sarcoidosis-related inflammation may be associated with life-threatening arrhythmia, some patients should continue corticosteroid therapy, even at low doses.

Objective Most malignant tumors require remodeling extracellular matrices (ECMs) for invasive growth and metastasis. Cancer cells and stromal cells remodel ECM. We investigated the relationship between regional lymph node (LN) metastasis and expression of ECM-remodeling factors in oral squamous cell carcinoma (OSCC). Methods Using primary OSCC and cervical LNs obtained surgically, we performed immunohistochemical evaluation of the ECM-remodeling factors, lysyl oxidase (LOX), MT1-MMP, S100A8, and TIMP-1 in primary tumor and marginal sinus histiocytosis (MSH) in LNs, and determined the statistical significance of the positive rates between metastatic and metastasis-free groups. Results Marginal sinus histiocytosis was more frequently formed in the metastatic group compared to the metastasis-free group. Lymphatic metastasis correlated with the immunopositivity rates of tumor cells expressing LOX, MT1-MMP, and TIMP-1, and of stromal cells expressing TIMP-1. The case rates of MSH containing macrophages positive for LOX and MT1-MMP in the metastasis group were significantly higher than in the metastasis-free group. ECM-remodeling-associated macrophages accumulate in marginal sinus in conjunction with lymphatic metastasis. Conclusion Expression of LOX, MT1-MMP, and TIMP-1 in the parenchyma, and stromal expression of TIMP-1 in primary tumor may predict lymphatic metastasis. LOX and MT1-MMP have a possibility to participate in formation of pre-metastatic niche in LNs.

Patient: Male, 46 Final Diagnosis: Eosinophilic granulomatosis with polyangiitis Symptoms: Chest pain Medication: — Clinical Procedure: Skin biopsy Specialty: Cardiology Objective: Rare co-existance of disease or pathology Background: Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare systemic vasculitis of unknown cause accompanied by prominent eosinophilia. Intracardiac thrombosis is one of the major cardiac complications in EGPA that may cause thromboembolism. Case Report: A 46-year-old male presenting with intermittent chest pain and numbness of the lower extremities was admitted to our center. His case was complicated by multiple brain infarcts and endocardial thrombosis in the left ventricle. A condition of restrictive cardiomyopathy was also found. After a thorough workup, he was diagnosed with antineutrophil cytoplasmic antibody (ANCA) positive EGPA. Interestingly, the thrombus was accompanied by a pressure gradient producing mid-ventricular obstruction. The patient improved reasonably with immunosuppression and anticoagulation treatment, in addition to heart failure treatment, and had a concomitant regression of the thrombus and reduction of the pressure gradient. Conclusions: For an EGPA patient complicated by intraventricular obstruction caused by endocardial thrombosis, which could accelerate the release of the thrombus into the systemic circulation resulting in a life-threating condition, timely and aggressive measures against cardioembolic complications should be considered.

A 74-year-old man was admitted for preoperative screening of aortic stenosis. Five months before this admission, he was found to have elevated serum immunoglobulin G4 (IgG4; 2,010 mg/dL). Computed tomography (CT) showed a soft tissue mass surrounding the abdominal aorta, suggestive of IgG4-related periaortitis. CT coronary angiography showed perivascular thickening of the right coronary artery, and subsequent coronary angiography showed a multi-vessel disease. The patient underwent aortic valve replacement and coronary bypass surgery. Immunohistochemical analysis showed IgG4-positive plasmacytic infiltration in specimens from the aortic valve, epicardium, and aortic adventitia, suggestive of the possible role of IgG4-related immune inflammation for the pathogenesis.

Fluorine-18 fluorodeoxygluose (18F-FDG) positron emission tomography (PET) is a useful tool for evaluating disease activity in sarcoidosis including cardiac involvement. A 67-year-old patient who developed atrioventricular block requiring permanent pacemaker implantation was diagnosed with cardiac sarcoidosis. The patient did not undergo steroid or immunosuppressive therapy but underwent serial 18F-FDG PET examination, which showed spontaneous reduction in the myocardial FDG uptake, indicating the remission of immune-inflammatory activity. Although the global systolic function remained preserved, thinning of the septal wall emerged during the clinical course of follow-up, which is characteristic for cardiac sarcoidosis.

DKK3, a member of the dickkopf Wnt signaling pathway inhibitor family, is believed to be a tumor suppressor because of its reduced expression in cancer cells. However, our previous studies have revealed that DKK3 expression is predominantly observed in head and neck/oral squamous cell carcinoma (HNSCC/OSCC). Interestingly, HNSCC/OSCC patients with DKK3 expression showed a high rate of metastasis and poorer survival, and siRNA-mediated knockdown of DKK3 in HNSCC-derived cancer cell lines resulted in reduced cellular migration and invasion. From these data, it was hypothesized that DKK3 might exert an oncogenic function specific to HNSCC. In the present research, the DKK3 overexpression model was established, and its influences were investigated, together with molecular mechanism studies. The DKK3 expression profile in cancer cell lines was investigated, including HNSCC/OSCC, esophageal, gastric, colorectal, pancreatic, prostatic, and lung cancers. DKK3 overexpression was performed in HNSCC-derived cells by transfection of expression plasmid. The effects of DKK3 overexpression were assessed on cellular proliferation, migration, invasion, and in vivo tumor growth. The molecular mechanism of DKK3 overexpression was investigated by Western blotting and microarray analysis. DKK3 overexpression significantly elevated cellular proliferation, migration, and invasion, as well as increased mRNA expression of cyclin D1 and c-myc. However, reporter assays did not show TCF/LEF activation, suggesting that the increased malignant property of cancer cells was not driven by the Wnt/β-catenin pathway. For the investigation of the pathways/molecules in DKK3-mediated signals, the Western blot analyses revealed that phosphorylation of Akt (S473) and c-Jun (Ser63) was elevated. The application of a PI3K kinase inhibitor, LY294002, on HSC-3 DKK3 cells significantly decreased tumor cell proliferation, migration, and invasion. From these results, we demonstrated that DKK3 might contribute to cellular proliferation, invasion, migration, and tumor cell survival in HNSCC cells through a mechanism other than the canonical Wnt signaling pathway, which might be attributed to PI3K‐Akt signaling.

Background Fibroblast growth factor 23 (FGF23) induces cardiac remodeling. We investigated the changes in serum FGF23 levels in patients diagnosed with acute myocardial infarction (AMI).Methods and Results:A total of 44 patients diagnosed with AMI were included in the current study. All patients underwent emergency percutaneous coronary intervention (PCI). The median of peak creatine kinase (CK) and CKMB values was 1,816 U/L and 159 U/L, respectively. Serum levels of FGF23, calcium, and inorganic phosphate (iP) were measured before PCI, and on days 1, 3, 5, 7 after PCI. Serum FGF23 levels showed a slight, but significant decrease on days 1 and 3 after PCI, and a 1.5- and 2.0-fold increase on days 5 and 7, respectively, after PCI. As compared with propensity score-matched patients without AMI, serum FGF23 was significantly lower among the current cohort of AMI patients. In 22 subjects who underwent a follow-up echocardiographic examination at 6 months after the onset of AMI, the log-transformed relative increase in FGF23 on day 7 significantly and negatively correlated with changes between LVEF on admission and that at 6 months afterward. Conclusions After a slight decrease on days 1 and 3 after admission, serum FGF23 increased significantly on days 5 and 7. The underlying mechanism and potential clinical importance of these observations require further investigation.

Several studies have shown that subjects with higher serum bilirubin may have a lower risk of cardiovascular disorders. We herein investigated whether serum bilirubin concentration is associated with lower extremity ischemia among cardiology patients. In total, 935 patients without a history of angioplasty or bypass surgery of the lower limb arteries and who had bilateral ankle-brachial index measurements were included in the study. Peripheral arterial disease (PAD) was defined to be present when ABI of either or both sides was

Epithelial-mesenchymal transition (EMT) is a significant process in the invasion and metastasis of cancers including oral squamous cell carcinoma (OSCC), and the cadherin switch has been identified as one of the hallmarks of EMT. The aim of the present study was to evaluate the significance of the cadherin switch in the prognosis of OSCC and generate a model for prognostic predictions. Seventy-six biopsy and/or initial surgical specimens from OSCC patients were immunohistochemically analyzed for the expression of E-cadherin and N-cadherin in either overall OSCC cells in tumor nests or in OSCC cells at the invasive front. Among 76 OSCC cases, overall OSCC cells in tumor nests were negative for the expression of E-cadherin in 10 cases and positive for that of N-cadherin in 53 cases. Among 10 cases negative for the expression of E-cadherin, 4 cases were positive for that of N-cadherin. In OSCC cells at the invasive front, the expression of E-cadherin was negative in 62 cases, while that of N-cadherin was positive in 39 cases. Among 62 cases negative for the expression of E-cadherin, 33 cases were positive for that of N-cadherin. A logistic regression analysis showed that a model using the evaluation of N-cadherin expression in overall OSCC cells in tumor nests with a cut-off point of 70 years old was the best fit model. These results suggest that N-cadherin has significant value in prognostic predictions for OSCC patients.

Background: Circulating soluble urokinase-type plasminogen activator receptor (suPAR), which can reflect immune activation and low-grade inflammation, may be a novel biomarker of cardiovascular disease. Methods: We investigated the potential association between suPAR and the prevalence of atrial fibrillation (AF) by analyzing patients with either sinus rhythm, paroxysmal atrial fibrillation (PAF), or non-paroxysmal atrial fibrillation (NPAF), which indicates either permanent or persistent AF. Results: Among 426 patients enrolled (mean age 71.4±9.2 years; 110 (25.8%) female), 310, 62, and 54 were diagnosed with sinus rhythm, PAF, and NPAF, respectively. NPAF was >10-fold more prevalent in the highest suPAR quartile (>3534 pg/mL; 32 (30.2%) of 106 patients) than in the lowest suPAR quartile (

A novel system auxiliary to the Union for International Cancer Control classification may allow the prognosis of patients with malignant tumors at similar stages to be predicted, as currently this is challenging. The present study generated a novel system to predict populations at low risk among patients with stage III/IV oral squamous cell carcinoma (OSCC). A total of 41 patients who were diagnosed at stages III/IV OSCC and underwent surgical tumor resection were analyzed. Band-like or follicular lymphocyte infiltration, intraepithelial micro-abscess formation and natural killer (NK) cell infiltration were histopathologically evaluated. Cox's proportional hazards regression model was used to identify prognostic factors, and a set of factors was selected from a combination of those prognostic factors to create a logic covariate model. A logic regression analysis for 41 patients with OSCC revealed that the presence of intraepithelial micro-abscesses and a lower density of NK cells were significantly associated with a favorable prognosis among patients with stage III/IV OSCC. These results suggested that the host innate immune responses, including neutrophil and NK cell infiltrations, are useful for prognostic prediction in patients with advanced malignant tumors.

Spindle cell carcinoma (SpCC), which predominantly arises in the oral, pharyngeal and laryngeal mucosal tissues, is composed of a mixture of squamous and sarcomatoid components. The present study describes the case of a 62-year-old woman with SpCC recurrence 4 years after an initial surgery to remove a well-differentiated primary squamous cell carcinoma (SCC) of the tongue. The recurrent tumor was spherical and located deep within the tongue tissue, which differs from the typical manifestation of ulcerated masses of the mucosa. The majority of cases of recurrence involving SpCC are associated with radiotherapeutic treatment of the primary malignancy; however, the patient in the present study had not received postoperative radiotherapy for SCC. Furthermore, the recurrent tumor in the present case exhibited marked anaplasia and sarcomatoid features, and the absence of SCC elements upon biopsy rendered histological diagnosis difficult. In summary, the present findings suggest that immunohistochemical examination and identification of SCC components are essential for ensuring the accuracy of the histological diagnosis of recurrent SpCC following a primary epithelial malignancy.

Serum levels of the soluble urokinase-type plasminogen activator receptor (suPAR) reflect immune and inflammatory activation, and are shown to be associated with cardiovascular outcomes. We herein investigated the potential association between suPAR and left ventricular diastolic dysfunction among patients with preserved left ventricular ejection fraction (LVEF) and sinus rhythm. Among 291 patients who had sinus rhythm and an LVEF of ≥50% enrolled in the study, 26 (8.9%) were considered to have diastolic dysfunction. Patients with diastolic dysfunction had lower estimated glomerular filtration rate (eGFR), and higher systolic blood pressure (BPs), BNP, C-reactive protein, and suPAR than those without diastolic dysfunction. As compared with the first suPAR quartile, the fourth suPAR quartile was significantly associated with both diastolic dysfunction with an odds ratio of 8.95 [95% confidence interval (CI), 1.04-77.0, P

Purpose Cytokine or chemokine networks involve lymphatic and distant metastasis of various malignancies, including oral squamous cell carcinoma (OSCC). Immunohistochemical analysis was used to investigate the contribution of the axis of the CC chemokine receptor-2 (CCR2) and the CC chemokine receptor-2 ligand (CCL2) to lymphatic metastasis, particularly the relation between primary OSCC and marginal sinus histiocytosis in regional lymph nodes. Materials and Methods Thirteen metastasis-free cases, 15 metastatic cases at resection of primary tumor resection, and 13 postresection metastasis cases were examined. No patient was treated with radiotherapy or chemotherapy before neck dissection. Samples were fixed in formalin, embedded in paraffin, and subjected to immunohistochemical analysis using antibodies against CCL2, CCR2, podoplanin, and α-smooth muscle actin (α-SMA). Results Marginal sinus histiocytosis was frequently observed in metastatic cases. CCL2 was expressed in tumor-associated neutrophils (TANs) and moderately or poorly differentiated SCC was detected at primary tumor sites. TANs expressing CCL2 flowed into the marginal sinus in the lymph nodes. CCR2-positive macrophages and mesenchymal cells infiltrated the tumor stroma and were seen within the carcinoma nests. They were predominantly present in the marginal sinus of metastatic cases. In small metastatic foci, α-SMA–positive spindle cells resembling carcinoma-associated fibroblasts (CAFs) were observed adjacent to the macrophages. Conclusion The CCL2-CCR2 axis is associated with lymphatic metastasis. To clarify the mechanism of lymphatic metastasis from OSCC, further functional analyses of the CCL2-positive TANs, CCR2-positive macrophages, and CAF-like cells detected in this study are recommended.

Mean serum uric acid (SUA) levels are higher in men than women. In addition, recent studies have suggested that the SUA threshold at which the cardiovascular risk might increase may vary between women and men. In the current retrospective study, by analyzing the data from 219 female and 519 male patients who were free from uric acid-lowering medication, we investigated whether SUA is associated with left ventricular mass index (LVMI), left ventricular ejection fraction (LVEF), and plasma levels of B-type natriuretic peptide (BNP) independent of confounding factors, such as serum calcium, inorganic phosphate, and fibroblast growth factor 23 (FGF23), in a gender-specific manner.In multivariate stepwise linear regression analysis in which age, blood pressure, eGFR, corrected calcium, inorganic phosphate, and FGF23 were entered as potential covariates, SUA was selected as a factor significantly associated with LVEF, LVMI, and plasma levels of BNP in both genders. On the other hand, however, after adding diuretic use as a potential covariate, the association between SUA and LVEF lost statistical significance in both genders, and that between SUA and BNP lost significance among female patients. These findings suggest that diuretic use is a non-negligible confounder in understanding the observed association between SUA and cardiac dysfunction and heart failure.In summary, SUA is associated with left ventricular hypertrophy independent of confounding factors including FGF23 and diuretic use in female and male patients. Whether lowering SUA can influence the progression of cardiac remodeling awaits further investigation.

Background Heart failure (HF) is an epidemic in healthcare worldwide including Asia. It appears that HF will become more serious with aging of the population. The patients with heart failure and preserved ejection fraction (HFpEF) were older, more often female, and frequently have comorbidities including hypertension. However, lower systolic blood pressure (SBP) on admission is associated with poor outcomes in patients with HF. It remains unclear whether this association is similar in very elderly patients with HFpEF. Purpose To investigate clinical features and prognosis in octogenarian HFpEF subjects. Methods We analyzed 87 consecutive subjects aged 80 years or older who were hospitalized for acute decompensated HF with left ventricular ejection fraction (LVEF) ≥50% between 2015 and 2017. Clinical characteristics and a composite event of cardiac death and HF hospitalization were compared in two groups according to SBP cut-off of 140 mmHg on admission. Results The prevalence of lower SBP subjects (mean BP = 118 mmHg) and higher SBP (mean BP = 166 mmHg) subjects were 41.4% and 58.6%, respectively. Lower SBP subjects were more comorbid with atrial fibrillation (72.2 vs. 45.1%, p=0.01). In the lower SBP group, diuretics, mineralocorticoid receptor antagonists (MRA), beta-blockers and ACE inhibitors/ARBs were more commonly used than higher SBP group (Table). During the observational period (median = 1.0 year), lower SBP on admission was associated with a 2.65-fold [95% confidence interval (CI): 1.29–5.55, p=0.009] greater likelihood of experiencing the composite events of cardiac death and rehospitalization for HF (Figure). This observation was still consistent even after adjusting clinical demographics and comorbidity [hazard ratio = 2.95, 95% CI: 1.30–6.87, p=0.01]. Table 1 Lower SBP group (n=36) Higher SBP group (n=51) P-value Atrial fibrillation (%) 72.2 0.01 0.01 Loop diuretic (%) 97.1 83.7 0.08 MRA (%) 47.1 24.5 0.04 Beta-blocker (%) 52.9 44.9 0.51 ACE inhibitor/ARB (%) 59.2 29.4 0.01 Figure 1 Conclusions In octogenarian patients with acute decompensated HF and preserved LVEF, SBP on admission less than 140 mmHg is significantly associated with poor outcomes. Future studies need to prospectively evaluate optimal SBP treatment goals in very elderly patients with HFpEF.

Treatment involving the insertion of an implantable cardioverter defibrillator and cardiac resynchronization therapy devices has markedly improved the prognosis of cardiac sarcoidosis. However, the prognosis remains poor in patients with advanced cardiac dysfunction or heart failure. We herein report the clinical course and histopathological findings of the autopsied heart of a patient with cardiac sarcoidosis with long-term refractory heart failure.

A case of tophaceous pseudogout (i.e., calcium pyrophosphate dihydrate crystal deposition disease) in the temporomandibular joint (TMJ) extending into the cranium is reported. A 59-year-old woman was referred to hospital with swelling and pain in the left cheek, and with trismus. Computed tomography imaging revealed a large, granular, calcified mass surrounding the left condylar head, partly destroying the cortex of the condylar head, and extending into the cranium by destroying the glenoid fossa. Magnetic resonance imaging revealed that the soft-tissue mass was of low-signal intensity on T1- and T2-weighted images, and was enhanced after intravenous injection of gadolinium. The mass was clinically and radiographically suspected to be a neoplastic lesion or a synovial osteochodromatosis. However, histological analysis demonstrated that the mass contained granulomatous lesion due to multiple nodular deposits of numerous rod-shaped and rhomboid crystals, which verified the diagnosis of tophaceous pseudogout. The lesion was excised surgically using a preauricular approach. Neither radiographic nor clinical examination demonstrated any signs of mass recurrence in the long-term 8- and 14-year postoperative recall examinations. Tophaceous pseudogout is a rare benign arthropathy that presents with clinical and radiographic features mimicking neoplastic conditions of the TMJ. Therefore, it is recommended that tophaceous pseudogout is considered in the differential diagnosis when a calcified mass lesion of the TMJ is encountered.

Severe ventricular arrhythmias such as high-grade atrioventricular block and ventricular tachycardia may cause lethal conditions or sudden death in patients with cardiac sarcoidosis (CS). Physicians should examine patients carefully for these conditions and treat them appropriately. As arrhythmias are being better diagnosed and treated, physicians are increasingly aware of atrial arrhythmias, which have not been focused upon as CS-related conditions, in patients with CS. This article reports a case of atrial flutter in sarcoidosis, and discusses literature findings on atrial arrhythmias and atrial involvement of CS. It is highly likely that atrial arrhythmia and supraventricular conduction disorder associated with or caused by CS are more common than previously thought. Physicians should pay careful attention for these conditions in the diagnosis and treatment of CS.

BackgroundInfluenza virus infection (IVI) was reported to be associated with minor cardiac changes, mostly those detected on electrocardiogram with and without elevated blood markers of myocardial injury; however, the characteristics of myocardial involvement in association with IVI are poorly understood. This study used echocardiographic tissue imaging (tissue Doppler, strain, and strain rate) to evaluate changes in left atrial (LA) and left ventricular (LV) myocardial function after IVI.Methods and resultsWe examined 20 adult individuals (mean age, 43 years) at 2 and 4 weeks after diagnosis of IVI. For myocardial functional variables, we obtained LV global longitudinal strain (GLS), LV early diastolic strain rate (e'sr), LA strain, and LA stiffness (E/e'/LA strain), in addition to data on tissue Doppler (s', e', and a') and myocardial performance index. Blood markers of myocardial injury were also examined. During follow-up, there were no significant changes in global chamber function such as LV ejection fraction, E/e', and LA volume. However, significant changes in myocardial function were observed, namely, in s' (8.0 ± 1.6 cm/s to 9.3 ± 1.5 cm/s; p = 0.01), e' (10.2 ± 2.8 cm/s to 11.4 ± 3.0 cm/s; p < 0.001), e'sr (1.43 ± 0.44 1/s to 1.59 ± 0.43 1/s; p = 0.005), and LA strain (35 ± 8% to 40 ± 12%; p = 0.025), and the myocardial performance index (0.52 ± 0.20 to 0.38 ± 0.09; p = 0.009), but not in a', LA stiffness, or GLS. Cardiac troponin T and creatinine kinase isoenzyme MB were not elevated significantly at any examination.ConclusionsMyocardial dysfunction during IVI recovery appeared to be transient particularly in the absence of myocardial injury. Echocardiographic tissue imaging may be useful to detect subclinical cardiac changes in association with IVI.

Dickkopf‑related protein 3 (DKK3), which is a member of the Dickkopf WNT signaling pathway inhibitor family, is considered to be a tumor suppressor, due to its reduced expression in cancer cells and its ability to induce apoptosis when overexpressed by adenovirus. However, our previous study demonstrated alternative functions for DKK3 in head and neck squamous cell carcinoma (HNSCC). Our study reported that DKK3 expression was predominantly upregulated in HNSCC cell lines and tissue samples, and its expression was significantly correlated with poor prognosis. Furthermore, DKK3 overexpression in HNSCC cells significantly increased cancer cell proliferation, migration, invasion and in vivo tumor growth. These data have led to the hypothesis that DKK3 may exert oncogenic functions and may increase the malignant properties of HNSCC. The present study established a stable DKK3 knockdown cell line (HSC‑3 shDKK3) using lentivirus‑mediated short hairpin RNA, and assessed its effects on cancer cell behavior using MTT, migration and invasion assays. In addition, its effects on in vivo tumor growth were assessed using a xenograft model. Furthermore, the molecular mechanisms underlying the effects of DKK3 knockdown were investigated by microarray analysis, pathway analysis and western blotting. Compared with control cells, HSC‑3 shDKK3 cells exhibited significantly reduced proliferation, migration and invasion, and formed significantly smaller tumor masses when subcutaneously transplanted into nude mice. In addition, in HSC‑3 shDKK3 cells, the expression levels of phosphorylated (p)‑protein kinase B (Akt) (Ser473), p‑phosphoinositide 3‑kinase (PI3K) p85 (Tyr467), p‑PI3K p55 (Try199), p‑3‑phosphoinositide‑dependent protein kinase‑1 (PDK1) (Ser241) and total p38 mitogen‑activated protein kinase (MAPK) were reduced. Furthermore, phosphorylation of mechanistic target of rapamycin (mTOR) (Ser2448) was slightly decreased in HSC‑3 shDKK3 cells, which may be due to the increased expression of DEP domain‑containing mTOR‑interacting protein. Conversely, DKK3 overexpression in HSC‑3 shDKK3 cells rescued cellular proliferation, migration and invasion. With regards to expression levels, p‑PI3K and p‑PDK1 expression was not altered, whereas mTOR and p‑p38 MAPK expression was elevated. These data supported the hypothesis and indicated that DKK3 may contribute to the malignant phenotype of HNSCC cells via the PI3K/Akt/mTOR and MAPK signaling pathways.

A 38-year-old woman had developed an abdominal distention, lower extremity edema, and dyspnea. Imaging examination revealed a large mass in the right atrium which was connected to lesions within the inferior vena cava. Although complete resection of the mass was not possible, partial surgical tumor resection was performed to avoid pulmonary embolization and circulatory collapse. Leiomyosarcoma was diagnosed histologically, and chemotherapy (doxorubicin) followed by radiotherapy was started. By reviewing papers published in the past 10 years that included 322 patients, we also discuss the clinical presentations and prognosis of leiomyosarcoma in the inferior vena cava.

To consider the biologic behaviors of keratocystic odontogenic tumors (KCOTs) and ameloblastomas and dentigerous cysts.A 63-year-old Japanese man presented with swelling and discomfort in the left cheek during jaw movement. Examination revealed a multilocular lesion within the mandible extending from the left second premolar to the left mandibular ramus and coronoid process; the lesion contained a deviated impacted tooth. The tumor had expanded beyond the bone and was invading the masseter and medial pterygoid muscles. Marginal mandibulectomy with a free iliac bone graft was performed.No recurrence was observed during a 7-year follow-up.The histopathological diagnosis of the lesion showed it was a KCOT. These tumors usually grow within the bone, causing bone expansion. However, this tumor had expanded beyond the bone and invaded surrounding muscles. Thus, KCOTs can, in rare cases, manifest themselves as described here. Evaluating preoperative images and histopathological findings is important to determine the optimal treatment strategy.

Neurofibromatosis?Noonan syndrome (NFNS) is an uncommon chromosomal disorder showing features of both neurofibromatosis (NF-1) and Noonan syndrome (NS). We encountered a case of NFNS with keratocystic odontogenic tumor and dentigerous cysts. A 19-year-old Japanese girl was referred to our hospital with a chief complaint of swelling in the left side of the mandible. The patient showed symptoms of both NF-1, in the form of cafe-au-lait spots and neurofibromatosis, and NS, in the form of short stature, intellectual disturbance, webbed neck, and hypertelorism. Panoramic radiography showed three cystic lesions, one on each side of the mandible and one on the left side of the maxilla. All cysts were removed surgically under general anesthesia. Histopathological examination revealed that both mandibular cysts were dentigerous cysts, while the maxillary cyst was a keratocystic odontogenic tumor. No recurrence has been seen as of 5 years postoperatively. Multiple jaw cysts might be added as a potential finding in NFNS., Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology, 28(1), pp.51-54; 2016

Serum inorganic phosphate level is associated with fibroblast growth factor 23 among cardiac patients with preserved renal function

Background Takotsubo cardiomyopathy is characterized by the basal hypercontractility and apical ballooning of the left ventriculum and T-wave inversion in the electrocardiogram. It has been suggested that Takotsubo cardiomyopathy might underlie the pathogenesis of persistent cardiac dysfunction; however, few reports are present demonstrating the advent of Takotsubo cardiomyopathy in patients with idiopathic cardiomyopathy. Case presentation A 64-year-old women was admitted due to dyspnea on effort and lower extremity edema. She had been diagnosed with idiopathic dilated cardiomyopathy 2.5 years before owing to the reduced left ventricular ejection fraction (24%), normal coronary artery, and interstitial fibrosis of the myocardial samples. On admission, her electrocardiogram showed giant negative T wave in II, III, aVF, and precordial leads. Echocardiography showed dyskinesis of the left ventricular apex and hypercontraction of the basal wall, which had not been observed in the previous examinations. Coronary angiography showed normal coronary arteries, and apical ballooning and basal hypercontractility was confirmed by left ventriculography. On day 15 of admission, contraction of apical wall was recovered, and basal hypercontraction was disappeared. Conclusion The present case is the first report demonstrating appearance the transient basal wall hypercontraction along with the advent of Takotsubo cardiomyopathy in a patient diagnosed with dilated cardiomyopathy. Whether such findings are indicative of fair prognosis and have the utility of understanding the pathogenesis of dilated cardiomyopathy needs further investigation.

The aim of the present study was to elucidate the associations between the expression of the vascular endothelial growth factor-C (VEGF-C)/VEGF receptor-3 (VEGFR-3) axis and lymphangiogenesis, regional lymph node metastasis and clinicopathological factors in oral tongue squamous cell carcinoma (OTSCC) using immunohistochemistry. The expression of VEGF-C, VEGFR-3 and podoplanin was immunohistochemically evaluated in specimens obtained from 65 patients with OTSCC (T1-2, N0) who had undergone radical surgery alone. The associations between the expression of VEGF-C, VEGFR-3 and podoplanin, and lymphangiogenesis, regional lymph node metastasis and clinocopathological factors were determined by immunohistochemical analysis. VEGF-C, VEGFR-3 and combined VEGF-C/VEGFR-3 expression was significantly higher in cases with regional recurrence compared with those without lymph node involvement (P, Oncology Letters, 10(4), pp.2027-2034; 2015

Serum uric acid (SUA) is associated with the severity and prognosis of systolic heart failure. We investigated the potential association between SUA and cardiac diastolic dysfunction among total of 744 cardiac patients (202 women and 542 men) who had preserved left ventricular ejection fraction. Presence of diastolic dysfunction was assessed by echocardiographic data, plasma B-type natriuretic peptide concentration, and left ventricular hypertrophy. Univariate analysis showed that the prevalence of diastolic dysfunction increased with increasing SUA value in women, but not in men. When sex-nonspecific SUA quartiles were used, multivariate logistic regression analysis, among female patients who were not taking uric acid lowering medication, showed that the third (SUA, 5.7–6.4 mg) and the fourth (SUA, ≥6.5 mg/dl) SUA quartiles were associated with diastolic dysfunction with an odds ratio of 3.25 ( P < 0.05) and 8.06 ( P < 0.001), respectively, when compared with the first SUA quartile (≤4.7 mg/dl). When sex-specific SUA quartiles were used among these population, multivariate logistic regression analysis showed that the fourth SUA quartile (≥5.7 mg/dl) was associated with diastolic dysfunction with an odds ratio of 5.34 ( P < 0.05) when compared with the first SUA quartile (≤4.1 mg/dl). By contrast, the relationship between SUA and diastolic dysfunction was not significant in men, irrespective of which of the sex-nonspecific or sex-specific SUA quartiles were used. These data indicated that among cardiac patients with preserved ejection fraction, SUA was significantly associated with diastolic dysfunction in women but not in men.

Malignant melanoma of the oral cavity is a rare disease. Here, we present an extremely rare case of simultaneous triple primary malignant melanomas occurring in the buccal mucosa, upper gingiva, and tongue. A 97-year-old male was referred because of tumors of the right buccal mucosa and left upper gingiva. Macroscopically, neither the tumors nor the adjacent mucosae exhibited melanin pigmentation. Biopsies of the two lesions showed that both were malignant melanomas. The patient underwent resection of the two tumors and right neck dissection. A histological examination of the surgical specimens demonstrated primary malignant melanomas and a metastatic lymph node. Most of the tumor cells were amelanotic, but displayed positive reactions for S100 or HMB45. One month after surgery, a small amelanotic nodule appeared on the dorsum of the patient's tongue. An excisional biopsy demonstrated that this was also a primary malignant melanoma. The patient is well at 6 months after the initial surgical procedure.

Central odontogenic fibromas (COFs) are benign odontogenic tumors derived from the dental mesenchymal tissues. They are rare tumors that account for 0.1–12.8% of all odontogenic tumors [1–8]. The location of COFs and the tumor incidence with respect to sex and age distributions are not well understood. Clinical features of the tumor include an asymptomatic expansion of the cortical plate of the mandible or maxilla and unilocular or multilocular radiolucency. Here, we describe a case of COF in the posterior region of the left mandible in a 3-year-old girl. The mandible was segmentally resected with the tumor and reconstructed with a parietal bone graft. No signs of recurrence or postoperative complications including occlusion were found. The esthetic outcome was satisfactory.