GdX/UBL4A specifically stabilizes the TC45/STAT3 association and promotes dephosphorylation of STAT3 to repress tumorigenesis.

Impaired phosphatase activity contributes to the persistent activation of STAT3 in tumors. Given that STAT family members with various or even opposite functions are often phosphorylated or dephosphorylated by the same enzymes, the mechanism for STAT3-specific dephosphorylation in cells remains largely unknown. Here, we report that GdX (UBL4A) promotes STAT3 dephosphorylation via mediating the interaction between TC45 (the nuclear isoform of TC-PTP) and STAT3 specifically. GdX stabilizes the TC45-STAT3 complex to bestow upon STAT3 an efficient dephosphorylation by TC45. Inasmuch, GdX suppresses tumorigenesis and tumor development by reducing the level of phospho-STAT3 (p-STAT3), whereas deletion of GdX results in a high level of p-STAT3 and accelerated colorectal tumorigenesis induced by AOM/DSS. Thus, GdX converts TC45, a nonspecific phosphatase, into a STAT3-specific phosphatase by bridging an association between TC45 and STAT3.

Application of Immunohistochemistry in the Pathological Diagnosis of Liver Tumors.

Although radiological diagnostics have been progressing, pathological diagnosis remains the most reliable method for diagnosing liver tumors. In some cases, definite pathological diagnosis cannot be obtained by histological evaluation alone, especially when the sample is a small biopsy; in such cases, immunohistochemical staining is very useful. Immunohistochemistry is the most frequently used technique for molecular pathological diagnosis due to its broad application, ease of performance and evaluation, and reasonable cost. The results occasionally reflect specific genetic mutations. The immunohistochemical markers of hepatocellular carcinoma include those of hepatocellular differentiation-such as hepatocyte paraffin 1 and arginase-1-and those of malignant hepatocytes-such as glypican-3, heat shock protein 70, and glutamine synthetase (GS). To classify the subtypes of hepatocellular adenoma, examination of several immunohistochemical markers, such as liver fatty acid-binding protein, GS, and serum amyloid A, is indispensable. Immunohistochemical staining for GS is also important for the diagnosis of focal nodular hyperplasia. The representative immunohistochemical markers of intrahepatic cholangiocarcinoma include cytokeratin (CK) 7 and CK19. In this article, we provide an overview of the application of immunohistochemistry in the pathological diagnosis of liver tumors referring to the association with genetic alterations. Furthermore, we aimed to explain the practical points in the differential diagnosis of liver tumors by immunohistochemical staining.

Pathological assessment of the lymph node biopsies for lymphadenopathy in rheumatoid arthritis.

Objectives: To assess the incidence of reactive lymph node hyperplasia (RLH) and the diagnostic characteristics that can help differentiate it from lymphoproliferative disorders (LPD) in patients with rheumatoid arthritis (RA).Methods: Data on patient characteristic from 32 consecutive RA patients with lymphadenopathy at a single medical center over a 6-year period were collected and analyzed to determine whether any of these characteristics can differentiated RLH from LPD.Results: LPD including methotrexate (MTX) - associated LPD (MTX-LPD) and RLH were diagnosed in 19 and 10 patients, respectively. Conclusive diagnosis was not reached in the remaining three cases and they were regarded as grey-zone cases. Age, levels of lactate dehydrogenase (LDH) and soluble interleukin-2 receptor (sIL-2R), as well as maximum standardized uptake value (SUVmax), were significantly higher in LPD than in RLH patients. The diagnosis cut-off values for these parameters were 66 year, 169 U/L, 899 U/mL and 8.18, respectively, based on the receiver operating characteristics curve analysis for both RLH and LPD.Conclusions: About one-third of patients with RA who presented with lymphadenopathy had reactive lymph node enlargement. Older age and higher levels of LDH, sIL-2R, and SUVmax are more associated with LPD than should be considered when deciding to perform a biopsy.

Radiotherapy alone as a possible de-intensified treatment for human papillomavirus-related locally advanced oropharyngeal squamous cell carcinoma.

BACKGROUND: Human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) is defined by p16 positivity and/or HPV DNA positivity. Because survival of patients with HPV-related OPSCC after chemoradiotherapy is favorable, a de-intensified treatment is expected to lead to less morbidity while maintaining low mortality. The association of tumor p16 and HPV DNA status with survival after radiotherapy alone remains unknown. METHODS: We retrospectively examined survival of 107 patients with locally advanced OPSCC after radiotherapy alone (n = 43) or chemoradiotherapy (n = 64) with respect to tumor p16 and HPV DNA status, using Cox's proportional hazard model. RESULTS: Survival after radiotherapy alone was significantly worse in p16-positive/HPV DNA-negative locally advanced OPSCC than in p16-positive/HPV DNA-positive locally advanced OPSCC. In bivariable analyses that included T category, N category, TNM stage, and smoking history, the survival disadvantage of p16-positive/HPV DNA-negative locally advanced OPSCC remained significant. There was no significant difference in survival after chemoradiotherapy between p16-positive/HPV DNA-positive locally advanced OPSCC and p16-positive/HPV DNA-negative locally advanced OPSCC. Survival in p16-positive/HPV DNA-positive locally advanced OPSCC after radiotherapy alone was similar to that after chemoradiotherapy, which stayed unchanged in bivariable analyses after adjustment of every other covariable. Survival of p16-negative/HPV DNA-negative locally advanced OPSCC was poor irrespective of treatment modality. CONCLUSIONS: Survival in p16-positive locally advanced OPSCC differs depending on HPV DNA status. Radiotherapy alone can serve as a de-intensified treatment for p16-positive/HPV DNA-positive locally advanced OPSCC, but not for p16-positive/HPV DNA-negative locally advanced OPSCC.

Possible involvement of Enterococcus infection in the pathogenesis of chronic pancreatitis and cancer.

(Aim) Bacterial infection underlies the pathogenesis of many human diseases, including acute and chronic inflammation. Here, we investigated a possible role for bacterial infection in the progression of chronic pancreatitis. (Materials and Methods) Pancreatic juice was obtained from patients with pancreatic cancer (n = 20) or duodenal cancer/bile duct cancer (n = 16) and subjected to PCR using universal primers for the bacterial 16S ribosomal RNA gene. Bacterial species were identified by PCR using bile samples from four pancreatic cancer patients. PCR products were subcloned into T-vectors, and the sequences were then analyzed. Immunohistochemical and serologic analyses for Enterococcus faecalis infection were performed on a large cohort of healthy volunteers and patients with chronic pancreatitis or pancreatic cancer and on mice with caerulein-induced chronic pancreatitis. The effect of E. faecalis antigens on cytokine secretion by pancreatic cancer cells was also investigated. (Results) We found that 29 of 36 pancreatic juice samples were positive for bacterial DNA. Enterococcus and Enterobacter species were detected primarily in bile, which is thought to be a pathway for bacterial infection of the pancreas. Enterococcus faecalis was also detected in pancreatic tissue from chronic pancreatitis and pancreatic cancer patients; antibodies to E. faecalis capsular polysaccharide were elevated in serum from chronic pancreatitis patients. Enterococcus-specific antibodies and pancreatic tissue-associated E. faecalis were detected in mice with caerulein-induced chronic pancreatitis. Addition of Enterococcus lipoteichoic acid and heat-killed bacteria induced expression of pro-fibrotic cytokines by pancreatic cancer cells in vitro. (Conclusion) Infection with E. faecalis may be involved in chronic pancreatitis progression, ultimately leading to development of pancreatic cancer.

Kawasaki disease: Epidemiological differences between past and recent periods, and implications of distribution dynamism.

BACKGROUND: Epidemiological findings suggest that Kawasaki disease (KD) is mediated by infection, which triggers its onset. Although the mechanism of onset seems to involve preconditioning factors and triggering factors, the details remain unclarified. METHODS: Data for 330 662 patients reported in KD nationwide surveys in Japan implemented between 1961 and 2014 were chronologically compared in terms of patient age distribution, estimated mean onset age, and male-to-female ratio during four periods: pre-epidemic (P1), epidemic (P2), stable (P3), and recent (P4): 1961-1978, 1979-1986, 1987-1997, and 1998-2014, respectively. RESULTS: During P2, the number of patients aged 6 months-2 years increased, and the mean onset age was younger; during P4, however, the number of patients aged ≤1 year decreased, but the number of patients ≥2 years increased, with a flat onset age distribution chart, and the mean onset age was older. During P2, increases in the number of patients were accompanied by younger mean onset age, whereas during P4, increases in the number of patients were conversely accompanied by older mean onset ages. The male: female ratio tended to decrease during P2, but this tendency was not seen in P4. No outbreak occurred during a recent 28 year period (P3, P4). Specific preconditioning factors might have been present during the 8 years (P2) of the past three outbreaks. CONCLUSION: P2 and P4 were significantly different in epidemiological features. It is likely that they do not share the same mechanism of onset (preconditioning and/or trigger factors).

Dynamic Change of Polarity in Primary Cultured Spheroids of Human Colorectal Adenocarcinoma and Its Role in Metastasis.

Intestinal epithelial cells possess apical-basal polarity, which governs the exchange of nutrients and waste. Perturbation of cell polarity appears to be a general feature of cancers, although most colorectal cancers are differentiated adenocarcinomas, in which polarity is maintained to some extent. Little is known about the role of dysregulated polarity in cancer. The cancer tissue-originated spheroid method was applied to the preparation and culture of spheroids. Spheroids were cultured in suspension or in type I collagen gel. Polarity was assessed by IHC of apical markers and electron microscopy. Two types of polarity status in spheroids were observed: apical-in, with apical membrane located at cavities inside the spheroids in type I collagen gel; and apical-out, with apical membrane located at the outermost layer of spheroids in suspension. These polarities were highly interchangeable. Inhibitors of Src and dynamin attenuated the polarity switch. In patients, clusters of cancer cells that invaded vessels had both apical-in and apical-out morphologic features, whereas primary and metastatic tumors had apical-in features. In a mouse liver metastasis model, apical-out spheroids injected into the portal vein became apical-in spheroids in the liver within a few days. Inhibitors of Src and dynamin significantly decreased liver metastasis. Polarity switching was observed in spheroids and human cancer. The polarity switch was critical in an experimental liver metastasis model.

Incomplete resection rate of cold snare polypectomy: a prospective single-arm observational study.

Background and study aims Cold snare polypectomy (CSP) is considered to be safe for the removal of subcentimeter colorectal polyps. This study aimed to determine the rate of incomplete CSP resection for subcentimeter neoplastic polyps at our center. Patients and methods Patients with small or diminutive adenomas (diameter 1 - 9 mm) were recruited to undergo CSP until no polyp was visible. After CSP, a 1 - 3 mm margin around the resection site was removed using endoscopic mucosal resection. The polyps and resection site marginal specimens were microscopically evaluated. Incomplete resection was defined as the presence of neoplastic tissue in the marginal specimen. We also calculated the frequency at which the polyp lateral margins could be assessed for completeness of resection. Results A total of 307 subcentimeter neoplastic polyps were removed from 120 patients. The incomplete resection rate was 3.9 % (95 % confidence interval [CI] 1.7 % - 6.1 %); incomplete resection was not associated with polyp size, location, morphology, or operator experience. The polyp lateral margins could not be assessed adequately for 206 polyps (67.1 %). Interobserver agreement between incomplete resection and lateral polyp margins that were inadequate for assessment was poor (κ = 0.029, 95 %CI 0 - 0.04). Female sex was an independent risk factor for incomplete resection (odds ratio 4.41, 95 %CI 1.26 - 15.48; P  = 0.02). Conclusions At our center, CSP resection was associated with a moderate rate of incomplete resection, which was not associated with polyp characteristics. However, adequate evaluation of resection may not be routinely possible using the lateral margin from subcentimeter polyps that were removed using CSP.Trial registered at University Hospital Medical Information Network (UMIN 000010879).

Chondroblastoma of extra-craniofacial bones: Clinicopathological analyses of 103 cases.

We elucidated clinicopathological characteristics of chondroblastoma (CB) in Japan, and reliable clinicopathologic parameters predicting local recurrence and/or metastasis. Clinicopathological profiles of 103 CB (80 male, 23 female) in extra-craniofacial bones were retrieved. Numerical scoring of nine pathological and five radiological features was statistically analyzed to determine prognostic significance. Age ranged 8-61 years (average 19.6 years). Frequently involved sites were femur, tibia, calcaneus, patella and humerus. Radiologically, tumors were 2-80 mm (average 31.1 mm) in size. Marginal sclerosis and calcification were common. Histologically, pink cartilage, mitoses, and chicken-wire calcification were often seen. Within a follow-up period [2-260 months (average 53.5 months)], the local recurrence rate was 15.5%. No patient had metastasis. Recurrence was most frequently observed at the femur. By log-rank analysis, only cyst formation in images was significant for predicting recurrence free survival (RFS). By Cox hazard analysis with representative clinico-radiological and pathological features, only age (≥16 years) and cyst formation were significant predictors for RFS. Pathological features were not significant in both uni- and multivariate analyses.

p53 functional deficiency in human colon cancer cells promotes fibroblast-mediated angiogenesis and tumor growth.

Cancer-associated fibroblasts (CAFs) create a microenvironment that contributes to tumor growth; however, the mechanism by which fibroblasts are phenotypically altered to CAFs remains unclear. Loss or mutation of the tumor suppressor p53 plays a crucial role in cancer progression. Herein, we analyzed how the p53 status of cancer cells affects fibroblasts by investigating the in vivo and in vitro effects of loss of p53 function in cancer cells on phenotypic changes in fibroblasts and subsequent tumor progression in human colon cancer cell lines containing wild-type p53 and in cells with a p53 functional deficiency. The growth of p53-deficient tumors was significantly enhanced in the presence of fibroblasts compared with that of p53-wild-type tumors or p53-deficient tumors without fibroblasts. p53-deficient cancer cells produced reactive oxygen species, which activated fibroblasts to mediate angiogenesis by secreting vascular endothelial growth factor (VEGF) both in vivo and in vitro Activated fibroblasts significantly contributed to tumor progression. Deletion of fibroblast-derived VEGF or treatment with N-acetylcysteine suppressed the growth of p53-deficient xenograft tumors. The growth effect of blocking VEGF secreted from cancer cells was equivalent regardless of p53 functional status. Human colon cancer tissues also showed a significant positive correlation between p53 cancer cell staining activated fibroblasts and microvessel density. These results reveal that fibroblasts were altered by exposure to p53-deficient epithelial cancer cells and contributed to tumor progression by promoting neovascularization. Thus, p53 acts as a modulator of the tumor microenvironment.

Prostaglandin D2 Modulates Neuronal Excitation of the Trigeminal Ganglion to Augment Allergic Rhinitis in Guinea Pigs.

Prostaglandin D2(PGD2) is involved in the pathogenesis of allergic rhinitis. However, the sensory nervous system-mediated contributions of PGD2to the symptoms of allergic rhinitis remain unclear. We investigated the involvement of PGD2in these symptoms and in neuronal excitation by in vivo and ex vivo experiments. In an ovalbumin-induced model of allergic rhinitis in guinea pigs, the number of sneezing, nasal rubbing, and nasal secretion events were assessed after the nasal cavity instillation of PGD2, histamine, or a combination of PGD2and histamine. In situ hybridization for PGD2receptor 1 (DP1) mRNA transcripts and immunohistochemical analysis of histamine H1receptor protein expression in guinea pig trigeminal ganglion (TRG) were performed. The effects of DP1receptor activation on the excitability of TRG neurons to electrical and histamine stimuli were assessed using whole-cell patch-clamp recordings. Histamine induced more sneezing, nasal rubbing, and nasal secretion events than PGD2 PGD2augmented histamine-induced responses, whereas pretreatment with a DP1receptor-selective antagonist completely suppressed PGD2-induced augmentation. DP1receptor mRNA transcripts and H1receptor protein expression could be detected in TRG neurons. Moreover, a DP1receptor agonist caused significant increases in the number of histamine-induced action potentials and depolarization, and reduced the current threshold in small-diameter neurons. Our findings show that PGD2-DP1receptor signaling augments the symptoms of allergic rhinitis via the sensory nervous system by modulating nasal neuronal activation to various stimuli, such as histamine. These findings suggest that DP1receptor antagonist has therapeutic potential for the treatment of allergic rhinitis.

Role of Prostaglandin D2 and DP1 Receptor on Japanese Cedar Pollen-Induced Allergic Rhinitis in Mice.

Although we previously demonstrated the contribution of the DP1receptor in nasal obstruction using animals sensitized with ovalbumin in the presence of adjuvant, the contribution of the DP1receptor in sneezing is unclear. Here, we developed a mouse model of Japanese cedar (JC:Cryptomeria japonica) pollinosis to evaluate the symptoms of sneezing. To achieve this, we used JC pollen crude extract in the absence of adjuvant to sensitize mice to develop a model closer to the pathophysiology of human JC pollinosis. The immunologic and pharmacologic features of this model are highly similar to those observed in JC pollinosis in humans. Using this model, we found that DP1receptor antagonists suppressed JC pollen extract-induced sneezing and that a DP1receptor agonist induced sneezing. Moreover, JC pollen extract-induced sneezing was diminished in DP1receptor knockout mice. In conclusion, we developed a novel mouse model of allergic rhinitis that closely mimics human JC pollinosis. A strong contribution of DP1receptor signaling to sneezing was demonstrated using this model, suggesting that DP1receptor antagonists could suppress sneezing and nasal obstruction, and therefore these agents could be a new therapeutic option for allergic rhinitis.

Pancreatic juice cytology as sensitive test for detecting pancreatic malignancy in intraductal papillary mucinous neoplasm of the pancreas without mural nodule.

OBJECTIVE: Recent studies reported that mural nodule (MN) was the most associated with malignant intraductal papillary mucinous neoplasms (IPMNs). However, IPMNs without MN cannot be diagnosed as malignant if only MN is determined to be indicator of malignancy. This study aimed to investigate role of pancreatic juice cytology for IPMNs without MN. METHODS: Medical records of 50 patients with histologically proven malignant IPMNs were reviewed. Exclusively for non-invasive cancer, extent of high-grade dysplasia along the main pancreatic duct (MPD) was determined microscopically. RESULTS: Thirty-six percent IPMNs had no MN. Cyst and main MPD diameter were significantly smaller in IPMN without MN compared to those in IPMN with MN (23 ± 14.1 vs 35 ± 13.2 mm, p = 0.010; 6.6 ± 4.3 vs 10.9 ± 6.1 mm, p = 0.006). Sensitivity of pancreatic juice cytology was higher in IPMN without MN compared to that in IPMN with MN (94% vs 53%, p = 0.004) although it could be affected by selection bias of study patients. Absence of MN was determined to be an independent factor associated with true positive cytology (OR = 24.3, p = 0.005). Extent of high-grade dysplasia was significantly longer in IPMN with true positive cytology compared to that in IPMN with false negative cytology (46.8 ± 20.5 vs 26.4 ± 11.0 mm, p = 0.005), and tended to be longer in IPMN without MN compared to that in IPMN with MN (47.0 ± 19.0 vs 36.0 ± 20.1 mm, p = 0.16). CONCLUSIONS: Sensitivity of pancreatic juice cytology was excellent in IPMN without MN. Pancreatic juice cytology may be a sensitive test for detection of pancreatic malignancy in IPMN without MN compared to high-risk imaging features.

Mural nodule of 10 mm or larger as predictor of malignancy for intraductal papillary mucinous neoplasm of the pancreas: Pathological and radiological evaluations.

BACKGROUND: We had previously reported that mural nodule (MN) ≥10 mm was optimal predictor of malignancy for intraductal papillary mucinous neoplasm (IPMN). However, little is known about its microscopic findings and imaging detectability. METHODS: Medical records and resected specimens of consecutive patients with IPMNs harboring MN ≥ 10 mm were reviewed. Imaging detectability was determined on reports basis. Malignant IPMNs (noninvasive + invasive carcinomas) were microscopically classified according to localization of high-grade dysplasia (HGD) within MN. RESULTS: Thirty-six patients were included. Imaging detectability of MN ≥ 10 mm in CT, MRI, US and EUS were 64%, 68%, 89%, and 97%, respectively. Thirty-three (92%) IPMNs were histologically diagnosed as malignant. Thirty percent of malignant IPMNs were classified into "diffuse HGD within MN", 40% into "focal HGD within MN", and 30% into "HGD outside MN", in which HGD was not located within MN but in low papillary epithelia around MN. Overall sensitivity of pancreatic juice cytology was calculated as 58%, and for "diffuse HGD within MN", "focal HGD within MN", and "HGD outside MN" as 80%, 62%, and 30%, respectively (p = 0.0237). Univariate-analysis showed localization of HGD within MN was associated with true positive cytology (OR = 5.33, p = 0.043). CONCLUSIONS: Detectability of MN ≥ 10 mm is excellent in US and EUS. Although HGD is observed within MN in 70% of malignant IPMNs, HGD is located only in low papillary epithelia around MN in the remaining 30%, in which sensitivity of pancreatic juice cytology is shown to be inadequate.

Insulin receptor substrate 1/2 (IRS1/2) regulates Wnt/ß-catenin signaling through blocking autophagic degradation of dishevelled2.

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/ß-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/ß-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.

Imaging morphological changes of intraductal papillary mucinous neoplasm of the pancreas was associated with its malignant transformation but not with development of pancreatic ductal adenocarcinoma.

BACKGROUND/OBJECTIVE: A considerable number of branch duct intraductal papillary mucinous neoplasm (BD-IPMN) developed not infrequently pancreatic malignancy, either as part of IPMN (malignant IPMN) or as concomitant pancreatic ductal adenocarcinoma (PDAC). To date, imaging morphological changes predicting occurrence of malignancy in BD-IPMN are not well-investigated. This study aimed to evaluate the relationships between occurrence of malignancy in BD-IPMN and imaging morphological changes of the tumors observed during follow-up. METHODS: 515 BD-IPMN patients with mural nodule <10 mm and negative cytology were included. 19 patients developed malignant IPMN and 8 patients developed concomitant PDAC during mean follow-up of 4.7 years. The following imaging morphological features were assessed: cyst/main pancreatic duct (MPD) diameter, occurrence of additional cyst/mural nodule. RESULTS: Growth rate of cyst/MPD diameter were significantly larger in patients who developed malignant IPMN compared to those in patients whose IPMN remained benign (p = 0.013, p = 0.01). Occurrence of additional cyst/mural nodule were more frequently observed in patients who developed malignant IPMN (p = 0.009, p = 0.04). In contrast, none of the factors associated with imaging morphological changes of IPMN were shown to be significantly different between patients who developed concomitant PDAC and patients whose IPMN remained benign. Growth rate of MPD diameter and occurrence of additional cyst were independent factors associated with development of malignant IPMN (odds ratio 21.5, and 5.62, respectively). CONCLUSIONS: Imaging morphological changes of IPMN, such as growth rate of MPD diameter and occurrence of additional cyst, could be indicators for development of malignant IPMN, but not for development of concomitant PDAC.

Optimal number of needle passes in endoscopic ultrasound-guided fine needle aspiration for pancreatic lesions.

OBJECTIVES: Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is accurate in cytological diagnosis of pancreatic lesions. Our aim was to determine optimal number of needle passes in EUS-FNA for pancreatic lesions without onsite cytopathologist, who is not routinely available to participate in the procedure. METHODS: Results of all needle passes in EUS-FNAs for 117 pancreatic neoplasms in 115 patients were reviewed retrospectively. Factors that required 2 or more needle passes for correct diagnosis were identified by multivariate logistic regression analysis. In each lesion group defined by the factors that required 2 or more passes and were known at the time of EUS-FNA, number of needle passes was regarded as optimal when an increase in diagnostic sensitivity by an additional needle pass did not reach 10%. RESULTS: Size of 15 mm or less (OR 4.58, 95% CI 1.70-12.3, P < 0.01), location of head (OR 5.02, 95% CI 1.82-13.9, P < 0.01), and neuroendocrine tumor (NET) (OR 5.04, 95% CI 1.38-18.4, P = 0.01) independently required 2 or more needle passes. Optimal numbers of needle passes for lesions of 15 mm or less in the head, those of more than 15 mm in the head, those of 15 mm or less in the body or tail, and those of more than 15 mm in the body or tail were 3, 2, 2, and 1, respectively. When these numbers of needle passes were performed, 93% of pancreatic lesions were correctly diagnosed. CONCLUSIONS: Optimal numbers of needle passes in EUS-FNA for pancreatic lesions without onsite cytopathologist were between 1 and 3.

Endoscopic submucosal dissection as minimally invasive treatment for superficial pharyngeal cancer: a phase II study (with video).

BACKGROUND AND AIMS: Although endoscopic submucosal dissection (ESD) has been applied for superficial pharyngeal cancer, no prospective trials have been reported. To investigate the efficacy and safety of ESD for superficial pharyngeal cancer, we conducted a prospective phase II trial. METHODS: Fifty-four patients with 73 lesions were enrolled from September 2010 to August 2014, and ESD was performed. The primary endpoint was the complete resection rate. Secondary endpoints were safety, recurrence-free survival, overall survival, and incidence of metachronous pharyngeal cancer. RESULTS: Fifty-four patients had stage 0-III cancer: stage 0, n = 22; stage I, n = 14; stage II, n = 17; and stage III, n = 1. The en bloc resection rate was 100%, and the complete resection rate was 79.5% (58/73 lesions; 95% confidence interval, 68%-88%). No serious adverse events related to ESD were encountered. Four patients required nasogastric intubation and feeding. No patients required percutaneous endoscopic gastrostomy and tracheotomy. Swallowing, speech, and airway functions were preserved in all patients. One of the 54 patients died of an unrelated illness. Median follow-up was 27 months (range 6-55 months). Local cervical lymph node metastasis was observed in 1 patient, and the case was salvaged successfully with lymph node dissection. The 3-year overall and recurrence-free survival rates were 97.7% and 98.1%, respectively. Cumulative development of multiple cancers of the pharynx at 3 years was 18.4%. CONCLUSIONS: ESD appears to be a safe and effective minimally invasive treatment in patients with superficial pharyngeal cancer. ( CLINICAL TRIAL REGISTRATION NUMBER: UMIN000003623.).

Diagnostic features of sessile serrated adenoma/polyps on magnifying narrow band imaging: a prospective study of diagnostic accuracy.

BACKGROUND AND AIMS: The narrow band imaging classification system (NBI International Colorectal Endoscopic [NICE] classification) classifies colorectal polyps very accurately. However, sessile serrated adenoma/polyps (SSA/Ps) pathologically resembles hyperplastic polyp and has a possibility to be left in situ on NICE classification. The aim of this study was to establish and evaluate new simple diagnostic features for SSA/Ps using magnifying narrow band imaging (M-NBI). METHODS: We performed a single-arm observational study of diagnostic accuracy in two stages, as follows: seeking stage, development of simple diagnostic features for SSA/P and definition of diagnostic criteria based on retrospective assessments of M-NBI; and validation stage, prospective validation and evaluation of the new diagnostic criteria. RESULTS: In the seeking stage, we identified brownish, oval, expanded crypt openings and thick-branched vessels on the surfaces of SSA/Ps. We named these "expanded crypt openings" (ECOs) and "thick and branched vessels" (TBVs), respectively. In the validation stage, we enrolled 796 polyps in 261 patients, and classified 126 polyps as NICE type 1; all these lesions were endoscopically removed and assessed histopathologically. The sensitivity, specificity, and accuracy of ECOs for SSA/Ps were 84.3%, 81.1%, and 82.4%, whereas those of TBVs were 45.1%, 68.9%, and 59.2%, respectively. M-NBI provided a sensitivity of 98% and specificity of 59.5% for discrimination of SSA/Ps from other lesions classified as NICE type 1. CONCLUSIONS: Identification of ECOs, supplemented with TBVs, has high sensitivity for the diagnosis of SSA/P. These findings may facilitate the use of endoscopic optical diagnosis in clinical practice.

Primary central chondrosarcoma of long bone, limb girdle and trunk: Analysis of 174 cases by numerical scoring on histology.

The aims of this study were: (i) to elucidate clinicopathological characteristics of pcCHS of long bones (L), limb girdles (LG) and trunk (T) in Japan; (ii) to investigate predictive pathological findings for outcome of pcCHS of L, LG and T, objectively; and (iii) to elucidate a discrepancy of grade between biopsy and resected specimens. Clinicopathological profiles of 174 pcCHS (79 male, 95 female), of L, LG, and T were retrieved. For each case, a numerical score was given to 18 pathological findings. The average age was 50.5 years (15-80 years). Frequently involved sites were femur, humerus, pelvis and rib. The 5-year and 10-year disease-specific survival (DSS) rates [follow-up: 1-258 months (average 65.5)] were 87.0% and 80.4%, respectively. By Cox hazards analysis on pathological findings, age, sex and location, histologically higher grade and older age were unfavorable predictors, and calcification was a favorable predictor in DSS. The histological grade of resected specimen was higher than that of biopsy in 37.7% (26/69 cases). In conclusion, higher histological grade and older age were predictors for poor, but calcification was for good prognosis. Because there was a discrepancy in grade between biopsy and resected specimens, comprehensive evaluation is necessary before definitive operation for pcCHS.