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Knowledge of risk factors for development of pancreatic ductal adenocarcinoma (PDAC) is limited. To clarify the background condition of the pancreas for the development of PDAC, we analyzed pancreatic histological changes in noncancerous lesion specimens after pancreatectomy in PDAC patients.Seventy-six patients with PDAC were enrolled in this study. The PDAC was in the pancreatic head in 37 patients, in the body in 31, and in the tail in 8. No patients had a history of clinical chronic pancreatitis. As controls, 98 patients without PDAC were enrolled. The following parameters were examined: fibrosis, fatty degeneration, and inflammatory cell infiltration. More than 5% of fatty degeneration in the specimen, more than 10% of fibrosis, and more than 5% of inflammatory cell infiltration were considered positive changes.Pancreatectomy specimens showed a higher ratio of positive change in fibrosis (86% vs 42%), fatty degeneration (72% vs 44%), and inflammatory cell infiltration (14% vs 3%) than control samples. Multivariate analyses demonstrated that each histological change was a significant, independent determinant for PDAC.Our study demonstrated that cryptogenic pancreatic inflammation with fatty changes represents an important predisposing factor for PDAC. Screening for subclinical chronic pancreatitis in healthy populations may enable the detection of PDAC at an early stage.

The health-promoting effects of antioxidant vitamins C and E supplementation are unclear. This study investigated the effects of vitamins C and E on the activities of reactive oxygen species (ROS)-scavenging enzymes and protein and lipid peroxidation statuses under resting and exercise-induced conditions. Thirteen healthy, previously untrained males (age 20–21 years) participated in this study. Seven subjects performed physical exercise using a cycle ergometer, and six performed a 6-min walk test (6MWT) prior to vitamin administration and after 1-week oral administration of vitamin C (1000 mg/day) and vitamin E (300 IU/day). Venous blood samples were collected before and after exercise. Plasma vitamin C concentration, superoxide dismutase (SOD) activity, glutathione peroxidase (GPx) activity, and protein carbonyl and thiobarbituric acid-reactive substance (TBARS) contents were measured. Antioxidant supplementation increased vitamin C concentration by 34% (p

We present a case of malignant mesothelioma of the peritoneum with massive direct invasion to the liver in a 58-year-old Japanese woman. She had no history of asbestos exposure or other malignancies. Abdominal computed tomography revealed one 8-cm intrahepatic mass adjacent to the abdominal wall with peritoneal thickening, multiple smaller nodules in the peritoneal cavity, and intra-abdominal lymphadenopathy. Liver biopsy showed a small cluster of atypical cells similar to epithelial neoplasm, which formed a tubulopapillary structure. The tumor cells were positive for calretinin with strong nuclear and cytoplasmic expression together with podoplanin (D2-40) and some cytokeratins, but were negative for hepatocyte paraffin 1 and other adenocarcinoma markers. We confirmed a diffuse peritoneal mesothelioma with direct invasion to the liver. Liver masses with other peritoneal nodules are mostly encountered as metastatic diseases. However, the possibility of mesothelioma should be considered, even in women without an apparent history of asbestos exposure.

Background: Factors correlating with the technical difficulty of endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) are still unclear. EGC coexisting with fibrosis inside lesions has been a common therapeutic indication for ESD. The aim of this study was to clarify the most important factor related to difficult ESD for EGC. Patients and Methods: Fifty-six patients (49 male and seven female, median age 66 years) who received ESD at a single institute for EGC with fibrosis in the resected lesion were selected. Various clinicopathological factors, including the histological findings of fibrotic changes within the cancer area in the resected specimen, were evaluated statistically for correlation with ESD procedure time. Results: Univariate linear regression analysis with logarithmic ESD procedure time revealed the upper-third portion of lesion in the stomach (P = 0.02), histological classification of dense fibrosis (ulcer/ulcer scar-III/IV) within EGC (P

Pancreatic ductal adenocarcinoma (PDAC) is still one of the most fatal cancers, although its prognosis has improved recently with the introduction of multimodal therapy. To further develop effective treatment for PDAC, establishment of prognostic indicators for patients receiving multimodal therapy is essential. Sixty-eight patients receiving curative extended resection combined with preoperative chemoradiation and postoperative chemotherapy for primary PDAC were selected. Immunohistochemistry using anti-CD74 antibody on paraffin-embedded tissue samples was performed, and cases were divided into two groups according to the ratio of CD74-positive cells: expression level I, CD74-positive cells

Forkhead box O1 (FOXO1; forkhead in rhabdomyosarcoma, FKHR) is a key transcription factor that regulates the cell cycle and apoptosis, and therefore is considered to be involved in cell transformation and tumorigenesis. Expression of FOXO1 in soft tissue sarcoma (STS) and its correlation with clinicopathological factors and prognostic significance were evaluated. Expression of phosphorylated FOXO1 (p-FOXO1) in localized STS from 84 adult patients, 50 male and 34 female, aged 15–89 (median 54) years, was evaluated by immunohistochemistry. Staining intensity of p-FOXO1 in the tumors was judged separately for the nucleus and cytoplasm and categorized as follows: level 0, absent or faint staining; level 1, weaker than that of endothelial cells in the same specimen; and level 2, equal to or stronger than that of endothelial cells. Twenty-three (27.3%), 26 (31.0%), and 35 (41.7%), and 32 (38.1%), 30 (35.7%), and 22 (26.2%) of the tumors showed level 0, 1, and 2 expression of p-FOXO1 for the nucleus and cytoplasm, respectively. Nuclear p-FOXO1 expression correlated with mitotic count, and cytoplasmic p-FOXO1 expression with histological subtype, mitotic count, cellularity, myxoid change, Ki-67 labeling index, histological grade, American Joint Committee on Cancer stage, and patient age. Multivariate analysis revealed nuclear and cytoplasmic p-FOXO1 expression, mitotic count, and tumor size to be independent prognostic indicators for overall survival, and cytoplasmic p-FOXO1 expression for disease-free survival, respectively. The prognostic significance of p-FOXO1 expression level in STS was demonstrated.

In order to clarify the increased 2-deoxy-2-fluoro-(18)F-D: -glucopyranose ((18)F-FDG) accumulation in schwannoma by positron emission tomography (PET) analysis, immunohistochemical analysis for the factors involved in glucose transportation and vascular formation was performed.Twenty-six patients with schwannoma (13 men and 13 women) with ages ranging from 27 to 75 years, who received whole body (18)F-FDG PET scan, were enrolled for the present study. The retention index (RI) was calculated by dividing the increase in the standardized uptake value (SUVmax) at the delayed scan by the SUVmax in the early scan. SUVmax and RI were compared with the histologic variables, including the expression of glucose transporters 1 and 3, hexokinase II, vascular endothelial growth factor/vascular permeability factor (VEGF/VPF), and microvascular density shown by CD31 immunohistochemistry.Mean SUVmax values in the early and delayed scans were 2.64 +/- 1.47 and 2.71 +/- 1.57 (mean +/- SD), respectively. RI was -2.5 +/- 21 (percentage). SUVmax showed a positive correlation with the tumor size (tumor size5 cm, 2.06 +/- 0.72;5 cm, 3.95 +/- 1.89; p0.05) and the microvascular density (negative density, 2.16 +/- 1.12; positive density, 3.56 +/- 1.67; p0.05). RI correlated with VEGF/VPF expression in the tumors (negative expression, -11 +/- 6.1; positive expression, 13 +/- 8.1; p0.05). Other factors showed no correlation with SUVmax or RI.Microvascular density and vascular permeability of the tumor are suggested to affect the enhanced (18)F-FDG accumulation in schwannoma.

1.1. Background: Intraoral resection of early tongue cancer minimally affects the quality of life (QOL) of patients; however, local recurrence of the tumor requires radical resection and negatively affects QOL as well as patient prognosis. The present study was performed to clarify factors affecting recurrence of tongue cancers undergoing intraoral resection. 1.2. Methods: In total, 174 patients (T1: 105 patients and T2: 69 patients) with squamous cell carcinoma of the tongue receiving intraoral resection were enrolled in the study, including 106 male patients and 68 female patients (aged 27-88 years, mean 58 years). Tumor recurrence was observed in 10 of 105 patients with T1 stage cancer (9.5%) and in 6 of 69 patients with T2 stage cancer (8.7%). The clinicopathological factors, including immunohistochemistry for p53, Ki67, and vimentin, were analyzed. 1.3. Results: An infiltration pattern and vimentin expression were associated with tongue cancer recurrence. Specifically, tumors with positive vimentin expression exhibited a higher ratio of endophytic growth, and multivariate analysis revealed that the Ki67 labeling index and vimentin expression were independent factors affecting tumor recurrence. 1.4. Conclusion: The mode of tumor invasion and the epithelial-to-mesenchymal transition, as evidenced by vimentin immunohistochemistry, assisted the identification of high-risk patients with tongue cancer undergoing intraoral resection. Intense follow-up with the aid of multimodal therapies after surgery is necessary in this group of high-risk patients.

Wnt signaling plays a pivotal role in cell proliferation, tissue homeostasis, and tumorigenesis. Dishevelled (Dvl) is a central node of Wnt signaling. Insulin receptor substrates (IRSs), as a critical component of insulin signaling, are involved in cell proliferation, metabolism, and cancer development. In this study, we report that IRS1/2 promotes Wnt/β-catenin signaling by stabilizing Dvl2. We found that IRS1/2 interacts with Dvl2. Overexpression of IRS1/2 increased the protein level of Dvl2 and promoted canonical Wnt signaling, as evidenced by the increased T cell-specific factor 4 transcriptional activity and the up-regulation of expression of CYCLIN D1 and c-MYC, two Wnt target genes critical for cell growth, whereas depletion of IRS1/2 reduced the level of Dvl2 and attenuated Wnt/β-catenin signaling. Biochemical analyses revealed that IRS1/2 decreased Lys-63-linked ubiquitination of Dvl2 and stabilized Dvl2 protein via suppressing its autophagy-mediated degradation. We further revealed that IRS1/2 blocks autophagy-induced formation of the Dvl2-p62/SQSTM1 complex, resulting in disabled association of Dvl2 to autophagosomes. We demonstrated that IRS1/2 promoted the induction of epithelial-mesenchymal transition (EMT) and cell proliferation in response to Wnt stimulation, whereas depletion of Dvl2 impaired the IRS1/2-mediated EMT and cell growth. Our findings revealed that IRS1/2 promotes EMT and cell proliferation through stabilizing Dvl2.

We present the first reported case of intraductal polypoid growth (IPG) variant of pancreatic acinar cell carcinoma (ACC) metastasizing to the intrahepatic bile duct. A 58-year-old Japanese woman had previously presented with obstructive jaundice and a 7.0 cm mass in the pancreatic head. She underwent biliary drainage for 2 months followed by pancreatectomy. Histological examination revealed a carcinoma with acinar pattern, immunohistochemically positive for trypsin, and acinar cell carcinoma was diagnosed. IPGs were prominent in the main pancreatic duct and its tributaries, extending into the intrapancreatic bile duct with tumor casts in the lumen. Imaging examinations 6 years later revealed a growing lesion within the intrahepatic bile duct. Needle biopsy examination suggested metastasis of ACC, and she underwent chemoradiation therapy and partial hepatectomy. Histological examination demonstrated ACC confined to the intrahepatic bile duct. The localization of metastasis and slow growth may indicate indolent biologic behavior of the IPG variant.

A 70-year-old woman developed a malignant mixed tumor of the soft tissue 2 years after total knee arthroplasty. A 5×3×3-cm elastic hard tumor at the lateral side of the surgical scar was resected. The tumor showed focal infiltration into surrounding adipose and fibrous tissues, focal necrosis, and vascular infiltration. It was diagnosed as malignant. Mixed tumor, or myoepithelioma, of the soft tissue is a relatively rare tumor that was recently recognized as a disease entity; the vast spectrum of myoepithelial cell differentiation and the resultant morphologic diversity might increase the difficulty of the histological diagnosis. Postoperatively, the patient did not receive adjuvant therapy and no recurrence of the tumor was observed for 6 years. Range of motion of her left knee is −5° extension and 90° flexion; however, her activities of daily living are restricted because of general fatigue, partly due to hepatoma and chemotherapy. Despite the increase of artificial implant use worldwide, reports of peri-implant tumor formation are rare. Although we do not know the exact mechanism of tumor genesis, we consider the fibroblast formation in the routine healing process to be a possible mechanism. Further investigation is necessary to identify coexisting factors that increase the risk of tumor formation after implantation.

Factors correlating with the technical difficulty of endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) are still unclear. EGC coexisting with fibrosis inside lesions has been a common therapeutic indication for ESD. The aim of this study was to clarify the most important factor related to difficult ESD for EGC.Fifty-six patients (49 male and seven female, median age 66 years) who received ESD at a single institute for EGC with fibrosis in the resected lesion were selected. Various clinicopathological factors, including the histological findings of fibrotic changes within the cancer area in the resected specimen, were evaluated statistically for correlation with ESD procedure time. Univariate linear regression analysis with logarithmic ESD procedure time revealed the upper-third portion of lesion in the stomach (P = 0.02), histological classification of dense fibrosis (ulcer/ulcer scar-III/IV) within EGC (P0.001), and presence of peptic ulcer other than EGC (P = 0.04). Areas of the resected specimen (P0.001) and fibrosis (P0.001) were significant factors related to prolonged operation times. Multivariate analysis demonstrated that the upper-third portion of lesion (P = 0.007), ulcer/ulcer scar-III/IV findings (P = 0.006), and area of resected specimen (P = 0.006) were significant independent factors influencing ESD procedure time.Histological findings of fibrotic changes coexisting with EGC are closely related to technical difficulty in ESD as well as the location of tumors. Preoperative precise evaluation of fibrotic changes within EGC may be helpful to predict a technical difficulty in ESD.

We previously identified the novel gene, periodontal ligament-associated protein-1 (PLAP-1)/asporin and reported that PLAP-1/asporin inhibited bone morphogenetic protein-2 (BMP-2)-induced cytodifferentiation of periodontal ligament (PDL) cells probably by direct interaction with BMP-2. Here, we elucidated the detailed regulatory mechanism of this protein on BMP-2-induced cytodifferentiation of PDL cells. Recombinant PLAP-1/asporin inhibited BMP-2-induced cytodifferentiation of PDL cells and competitively prevented BMP-2 from binding to the BMP receptor-IB (BMPR-IB), resulting in inhibition of BMP-dependent activation of Smad proteins. The induction of mutation to the leucine-rich repeat (LRR) motif, especially LRR5, within PLAP-1/asporin rescued the inhibitory effect of PLAP-1/asporin on BMP-2. By contrast, a 26-amino acid peptide in the PLAP-1/asporin LRR5 sequence inhibited BMP-2 activity. Our findings indicate that PLAP-1/asporin inhibits BMP-2-induced differentiation of PDL cells resulting from inactivation of the BMP-2 signaling pathway and that LRR, especially LRR5 of PLAP-1/asporin, plays an important role in the PLAP-1/asporin–BMP-2 interaction.

Nicotine is a major component of tobacco smoke, and signals via nicotinic acetylcholine receptors (nAChR). However, little is known about the effects of nicotine on human dental pulp cells (HDPCs). In this study, we assessed the effects of nicotine on mineralization in HDPCs. We confirmed messenger RNA expression of nAChR subunits and examined the effects of nicotine on expression of extracellular matrices (ECMs), alkaline phosphatase (ALP) activity, and mineralized nodule formation by HDPCs. Gene expression of nAChR subunits alpha1, alpha2, alpha 4, alpha 5, alpha 6, alpha 7, beta1, beta2, and beta 4 was detected in HDPCs. Interestingly, the messenger RNA expression of dentin matrix acidic phosphoprotein-1, bone sialoprotein, and ALP activity were significantly reduced in nicotine-treated HDPC. In addition, mineralized nodule formation, which was examined by alizarin red staining, was also inhibited in HDPCs by the same treatment. These results indicate that nicotine suppresses the cytodifferentiation and mineralization of HDPCs, possibly via nAChR.

Periodontal ligament-associated protein-1 (PLAP-1)/asporin is a recently identified novel member of the small leucine-rich repeat proteoglycan family. PLAP-1/asporin is involved in chondrogenesis, and its involvement in the pathogenesis of osteoarthritis has been suggested. We report that PLAP-1/asporin is also expressed specifically and predominantly in the periodontal ligament (PDL) and that it negatively regulates the mineralization of PDL cells. In situ hybridization analysis revealed that PLAP-1/asporin was expressed specifically not only in the PDL of an erupted tooth but also in the dental follicle, which is the progenitor tissue of the PDL during tooth development. Overexpression of PLAP-1/asporin in mouse PDL-derived clone cells interfered with both naturally and bone morphogenetic protein 2 (BMP-2)-induced mineralization of the PDL cells. On the other hand, knockdown of PLAP-1/asporin transcript levels by RNA interference enhanced BMP-2-induced differentiation of PDL cells. Furthermore co-immunoprecipitation assays showed a direct interaction between PLAP-1/asporin and BMP-2 in vitro, and immunohistochemistry staining revealed the co-localization of PLAP-1/asporin and BMP-2 at the cellular level. These results suggest that PLAP-1/asporin plays a specific role(s) in the periodontal ligament as a negative regulator of cytodifferentiation and mineralization probably by regulating BMP-2 activity to prevent the periodontal ligament from developing non-physiological mineralization such as ankylosis.

Periodontal-ligament-associated protein-1 ( PLAP-1) is preferentially expressed in the periodontal ligament (PDL) and encodes a novel small leucine-rich repeat proteoglycan protein. PLAP-1 expression was induced during the course of cytodifferentiation of PDL cells into mineralized-tissue-forming cells in vitro, suggesting the possible involvement of PLAP-1 in the mineralization process of PDL cells. In this study, we hypothesized that PLAP-1 expression is regulated by mineralization-related cytokines in PDL cells. PLAP-1 expression was clearly down-regulated when the cytodifferentiation of PDL cells was reversibly inhibited by fibroblast growth factor-2 (FGF-2). In contrast, bone morphogenetic protein-2 (BMP-2) enhanced PLAP-1 expression. Up-regulation of PLAP-1 expression by BMP-2 was confirmed at the protein level when PDL cells were immunostained with anti-PLAP-1 polyclonal antibody. These results revealed the cytokine-mediated regulatory mechanisms of PLAP-1 expression and suggested that PLAP-1 expression may be associated with the process of cytodifferentiation of PDL cells.

A rare case is presented of a 61-year-old man with a malignant peripheral nerve sheath tumor associated with neurofibromatosis type 1, with metastasis to the heart. The primary tumor originated in the right thigh in 1982. Since then, the patient has had repeated local recurrences in spite of repeated surgical treatment and adjuvant chemotherapy. He has developed previous metastases of the lung and heart. The patient died of cardiac involvement.

A case of benign mixed tumor of the soft tissue in a 64-year-old Japanese male is presented. He noticed a painless, elastic hard mass sized 3 cm in the right knee, which gradually grew larger and harder in the last 5 years. Magnetic resonance imaging demonstrated a mass lesion embedded in the subcutaneous tissue with low and high signal intensity at T1- and T2-weighted images, respectively. Tl-201 scintigraphy showed an early uptake of Tl-201 within the lesion at 10 minutes after injection, which was slightly decreased but still continued at 2 hours later. The patient underwent a resection of tumor, and the pathological diagnosis was a benign mixed tumor of soft tissue without high vascularity, characterized by histological features similar to pleomorphic adenomas in the salivary glands. Immunohistochemical study proved expression of Na+/K+-ATPase of tumor cells. Overexpression of Na+/K+-ATPase of the tumor might be responsible for the early uptake of Tl-201, and poor vascular structure in this tumor might lead to continuous accumulation. The Tl-201 scintigraphic features of mixed tumor of soft tissue are assessed to resemble those of malignant soft tissue tumors.