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Paterson E.L.,Center for Cancer Biology | Paterson E.L.,University of Adelaide | Kazenwadel J.,Center for Cancer Biology | Bert A.G.,Center for Cancer Biology | And 5 more authors.
Neoplasia (United States) | Year: 2013

Cancer progression is a complex series of events thought to incorporate the reversible developmental process of epithelial-to-mesenchymal transition (EMT). In vitro, the microRNA-200 family maintains the epithelial phenotype by posttranscriptionally inhibiting the E-cadherin repressors, ZEB1 and ZEB2. Here, we used in situ hybridization and immunohistochemistry to assess expression of miR-200 and EMT biomarkers in formalin-fixed paraffin-embedded human colorectal adenocarcinomas. In addition, laser capture microdissection and quantitative real-time polymerase chain reaction were employed to quantify levels of miR-200 in the normal epithelium, tumor core, invasive front, and stroma. We find that miR-200 is downregulated at the invasive front of colorectal adenocarcinomas that have destroyed and invaded beyond the basement membrane. However, regional lymph node metastases and vascular carcinoma deposits show strong expression of miR-200, suggesting this family of miRNAs is involved in the recapitulation of the primary tumor phenotype at metastatic sites. In contrast, adenomas and adenocarcinomas with intact basement membranes showed uniform miR-200 expression from the tumor core to the tumor-host interface. Taken together, these data support the involvement of EMT and mesenchymal-to-epithelial transition (MET) in the metastasis cascade and show that miR-200 is downregulated in the initial stages of stromal invasion but is restored at metastatic sites. © 2013 Neoplasia Press, Inc. All rights reserved.


Nguyen N.Q.,Royal Adelaide Hospital | Nguyen N.Q.,University of Adelaide | Schoeman M.N.,Royal Adelaide Hospital | Ruszkiewicz A.,Surgical Pathology
Gastrointestinal Endoscopy | Year: 2013

Background Biliary tract malignancies can be assessed with either EUS or SpyGlass cholangioscopy (SGC). Objective To evaluate the impact of EUS and guided biopsy before considering SGC in patients who had biliary strictures with negative ductal brushing. Design Prospective, observational study. Setting Tertiary level referral hospital. Patients Forty consecutive patients with biliary strictures. Intervention EUS evaluation and biopsy, where possible, were performed in all patients. If EUS examination failed to provide a definitive diagnosis, SGC and ductal biopsy was performed. Results were compared with surgical specimens or positive histocytology. Main Outcome Measurements Tissue diagnosis, technical success, adverse events, and clinical outcomes. Results On EUS, abnormalities responsible for the biliary strictures were identified in 39 patients (98%), with FNA achievable in 30 patients (75%). EUS-FNA provided positive histocytology in 23 patients (58%). SGC-guided biopsy was performed to evaluate nondiagnostic EUS-FNA (17 patients) and to clarify autoimmune pancreatitis on FNA (2 patients). The procedure was successful in 18 patients (95%) and provided tissue diagnosis in 16 patients (88%), with 2 false-negative results from extrinsic pathologies. When EUS was used before the SGC approach, the need for SGC was avoided in 24 patients (60%), cholangitis was minimized in 2.5%, and a cost saving of U.S.$110,000 was realized. Tissue diagnosis was achieved in 38 patients (94%) with this approach. Limitations Relatively small sample size. Conclusions EUS evaluation in patients with difficult biliary stricture prevents the need, cost, and adverse events of SGC in 60% of patients. Together, EUS followed by the SGC approach provides correct clinical diagnosis in 94% of patients with minimal adverse events. Copyright © 2013 by the American Society for Gastrointestinal Endoscopy.


Hassoun P.,Surgical Pathology | Mannion C.,Surgical Pathology | Goy A.H.,Hackensack University Medical Center | Feldman T.,Hackensack University Medical Center | And 2 more authors.
Journal of Clinical Microbiology | Year: 2013

A 51-year-old man with a history of stage IV angioimmunoblastic T-cell lymphoma was diagnosed with osteomyelitis of the patella. Legionella anisa was identified by 16S rRNA gene sequencing and culture. The patient had pneumonia 2 months prior to this osteomyelitis episode. L. anisa was retrospectively detected in his lung tissue by 16S rRNA gene sequencing and was considered the source of the L. anisa that caused his patella osteomyelitis. Copyright © 2013, American Society for Microbiology.


Gustafsson J.O.R.,University of Adelaide | Oehler M.K.,University of Adelaide | Ruszkiewicz A.,Surgical Pathology | McColl S.R.,University of Adelaide | Hoffmann P.,University of Adelaide
International Journal of Molecular Sciences | Year: 2011

MALDI imaging mass spectrometry (MALDI-IMS) allows acquisition of mass data for metabolites, lipids, peptides and proteins directly from tissue sections. IMS is typically performed either as a multiple spot profiling experiment to generate tissue specific mass profiles, or a high resolution imaging experiment where relative spatial abundance for potentially hundreds of analytes across virtually any tissue section can be measured. Crucially, imaging can be achieved without prior knowledge of tissue composition and without the use of antibodies. In effect MALDI-IMS allows generation of molecular data which complement and expand upon the information provided by histology including immuno-histochemistry, making its application valuable to both cancer biomarker research and diagnostics. The current state of MALDI-IMS, key biological applications to ovarian cancer research and practical considerations for analysis of peptides and proteins on ovarian tissue are presented in this review. © 2010 by the authors; licensee MDPI, Basel, Switzerland.


Abu-Sneineh A.,Royal Adelaide Hospital | Tam W.,Royal Adelaide Hospital | Schoeman M.,Royal Adelaide Hospital | Schoeman M.,University of Adelaide | And 9 more authors.
Alimentary Pharmacology and Therapeutics | Year: 2010

Background Acid reflux is often difficult to control medically. Aim To assess the effect of 40 mg twice daily esomeprazole (high-dose) on gastric and oesophageal pH and symptoms, and biomarkers relevant to adenocarcinoma, in patients with Barrett's oesophagus (BO). Methods Eighteen patients, treated with proton pump inhibitors as prescribed by their treating doctor, had their therapy increased to high-dose esomeprazole for 6 months. Results At entry into the study, 9/18 patients had excessive 24-h oesophageal acid exposure, and gastric pH remained <4 for >16 h in 8/18. With high-dose esomeprazole, excessive acid exposure occurred in 2/18 patients, and gastric pH <4 was decreased from 38% of overall recording time and 53% of the nocturnal period to 15% and 17%, respectively (P < 0.001). There was a reduction in self-assessed symptoms of heartburn (P = 0.0005) and regurgitation (P < 0.0001), and inflammation and proliferation in the Barrett's mucosa. There was no significant change in p53, MGMT or COX-2 expression, or in aberrant DNA methylation. Conclusions High-dose esomeprazole achieved higher levels of gastric acid suppression and control of oesophageal acid reflux and symptoms, with significant decreases in inflammation and epithelial proliferation. There was no reversal of aberrant DNA methylation. © 2010 Blackwell Publishing Ltd.


Smith E.,University of Adelaide | Kelly J.J.,University of Adelaide | Ruskiewicz A.R.,Surgical Pathology | Sullivan T.,University of Adelaide | And 2 more authors.
Annals of Surgery | Year: 2010

Objective: We investigated the relationship between reflux and aberrant deoxyribonucleic acid (DNA) methylation, comparing methylation in the columnar epithelium following successful fundoplication to that in subjects with a failed fundoplication. Summary Background Data: Gastroesophageal reflux is the main risk factor for Barrett esophagus and adenocarcinoma. In these diseases, there is a high level of DNA methylation. Methods: We enrolled 41 patients with Barrett esophagus and a fundoplication at least 5 years earlier for a 24-hour pH study, endoscopy, and collection of biopsies. Biopsies were obtained from 17 Barrett esophagus subjects who had not undergone esophageal surgery. Results: At the time of the study, 31 subjects were pH normal, 10 abnormal. Columnar biopsies were collected from 21 of the pH normal and 9 pH abnormal subjects, and all no surgery subjects. Complete regression of columnar mucosa was seen in 7 subjects with pH normal and 1 with pH abnormal. The length of Barrett esophagus did not differ between groups preoperatively, but was significantly less at the time of the study in the pH normal compared with pH abnormal or no surgery groups. Significantly, fewer genes were methylated in the pH normal than the pH abnormal or no surgery groups, which did not differ from each other. The number of methylated genes correlated with increased reflux, intestinal metaplasia, and increased columnar-lined esophagus length, but not acid-suppression medication. Conclusions: Fundoplication that reduces reflux to normal levels can lead to regression of the columnar mucosa. Reflux is associated with aberrant DNA methylation, and control of reflux reduces deleterious genomic changes associated with cancer. Copyright © 2010 by Lippincott Williams & Wilkins.


Greggi S.,Instituto Nazionale Dei Tumori G Pascale | Mangili G.,Gynecology and Obstetrics | Scaffa C.,Instituto Nazionale Dei Tumori G Pascale | Scala F.,Instituto Nazionale Dei Tumori G Pascale | And 7 more authors.
International Journal of Gynecological Cancer | Year: 2011

Introduction: Uterine papillary serous and clear cell carcinomas (UPSCs/CCs) show a different spreading from that of poorly differentiated endometrioid carcinomas (PDECs) and are usually thought to be prognostically more aggressive than PDECs. On the contrary, it has been recently claimed that UPSC/CC and PDEC have a similar prognosis. In this retrospective study on 2 institutional databases, the surgical-pathological data and survival have been compared in patients with UPSC/CC and PDEC. Methods: A total of 139 surgically staged consecutive patients, 63 with UPSC/CC (37 UPSC; 26 CC) and 76 with PDEC clinically limited to the uterine corpus, have been compared for nuclear ploidy, myometrial invasion, (occult) cervical extension, peritoneal, and lymph node metastasis. Prognostic factors have been correlated through multivariate analysis with survival (disease-specific [DSS] and disease-free [DFS]). Results: Peritoneal metastases and aneuploidy were found to be the only parameters significantly different in the 2 groups: peritoneal metastases 28.6% in UPSC/CC (extrapelvic 19%) and 7.9% in PDEC (extrapelvic 2.6%) (P = 0.001), aneuploidy 48.6% in UPSC/CC and 30.6% in PDEC (P = 0.05). Five-year DSS was 57.9% versus 75.2% (P = 0.02), and DFS was 52.3% versus 71.4% (P = 0.04) for UPSC/CC and PDEC, respectively. All but cervical and lymph node involvement were significant predictors of survival. After multivariate analysis, histotype (DSS: hazard ratio [HR], 1.98; 95% confidence interval [CI], 1.02Y3.86; P = 0.04; DFS: HR, 1.94; 95% CI, 1.04Y3.63; P = 0.04), stage (DSS: HR, 2.26; 95% CI, 1.10Y4.65; P = 0.03; DFS: HR, 2.21; 95% CI, 1.12Y4.38; P = 0.02), and myometrial invasion (DSS: HR, 2.86; 95% CI, 1.22Y6.69; P = 0.01; DFS: HR, 3.96; 95% CI, 1.63Y9.62; P = 0.002) were independent risk factors for survival. Conclusions: Uterine papillary serous and clear cell carcinomas spread to abdominal peritoneum more frequently than PDEC; multivariate analysis confirms UPSC/CC as an independent, unfavorable predictor of outcome. Copyright © 2011 by IGCS and ESGO.


PubMed | University of Pisa, Surgical Pathology and Pisa
Type: | Journal: Thyroid : official journal of the American Thyroid Association | Year: 2016

Thyroid ultrasound elastography (US elastography) provides an estimation of tissue stiffness and is helpful to differentiate malignant from benign lesions. Tissue proprieties and molecules causing stiffness are not established. The aim of the study was to correlate US elastography findings with tissue properties in thyroid nodules.115 thyroid nodules from 112 patients who underwent surgery for the presence of of Thy 3 (indeterminate) cytology (n=67), Thy 4-5 (suspicious-indicative of carcinoma) cytology (n= 47) or large goiter in the presence of Thy 2 cytology (n= 1) and suspicious US features were examined by US elastography. Tissues obtained after surgery were characterized for cell number, microvessel density, fibrosis, expression of galectin-3 (Gal-3) and fibronectin-1(FN-1).Low elasticity at qualitative US elastography (LoEl) was found in 66 nodules, 1 benign and 65 carcinomas, high elasticity (HiEl) in 49 nodules, 46 benign and 3 carcinomas (p<0.0001). Quantitative analysis, performed in 24 nodules and expressed as elastic ratio between the strain of the nodule and that of the surrounding thyroid parenchyma, was 1.90 (1.18-2.77) (median and IQR) in 14 nodules with LoEl and 1.01-(0.91-1.10) in 10 nodules with HiEl (p=0.002). Stiffness did not correlate with cell number and was inversely correlated with microvessel density. Fibrosis was higher in nodules with LoEl than in those with HiEl (p=0.009) and in carcinomas than in benign nodules (p=0.02). Fibrosis was higher in nodules with high expression of Gal-3 (p<0.001) and FN-1 (p=0.004). Fibrosis and expression of Gal-3 and FN-1 were higher in the classic vs the follicular variant of papillary thyroid carcinoma and lower in follicular adenoma.i) Low elasticity at US elastography is highly correlated with malignancy; ii) nodule stiffness is correlated with fibrosis and expression of Gal-3 and FN-1; iii) these features are more evident in the classic than the follicular variant of papillary thyroid carcinoma.


Palmerini E.,Instituto Ortopedico Rizzoli | Benassi M.S.,Laboratory of Experimental Research | Quattrini I.,Laboratory of Experimental Research | Pazzaglia L.,Laboratory of Experimental Research | And 7 more authors.
Orphanet Journal of Rare Diseases | Year: 2015

Background: Synovial sarcoma (SS) is a rare tumor, with dismal survival when metastatic. The role of adjuvant chemotherapy is debated. New prognostic and predictive factors are needed. Methods: We reviewed patients with localized SS; SS18-SSX fusion transcript presence was confirmed by FISH and RT-PCR. Expression of CXCR4, IGF-1R and Ezrin were evaluated by immunohistochemistry. Results: Tumor samples from 88 SS patients (45 female; 43 male) with median age 37 years (range 11-63) were selected. The size of the lesion was > 5 cm in 68% of patients and 34% of cases presented biphasic histotype. All patients underwent surgery, 56% adjuvant radiotherapy (RT), 65% adjuvant chemotherapy. A positive stain for IGF-1R was detected in 55 patients, with nucleus expression in 21 patients. CXCR4 was expressed in 74 patients, nuclear pattern in 31 patients. 80 SS were positive to Ezrin, 48 had cytoplasmatic location, 32 membrane location. With a median follow-up of 6 years (1-30 years), the 5-year overall survival (OS) was 70% (95% CI 60-81). 5-year OS was 63% (95% CI 41-85%) for patients with positive IGF-1R/nuclear expression, and 73% (95% CI 61-85%; P = 0.05) in negative patients. 5-year OS was 47% (95% CI 27-66%) in patients with positive CXCR4/nuclear staining, and 86% (95% CI 76-96% P = 0.0003) in negative cases. No survival difference was found according to Ezrin expression. By multivariate analysis, nuclear expression of CXCR4 and IGF-1R was confirmed independent adverse prognostic factor for SS patient survival linked to the use of chemotherapy. Conclusions: Our findings have important potential implications demonstrating that together with clinical prognostic factors such as radiotherapy and age, CXCR4 and IGF-1R negatively influences survival in patients with localized SS. We believe that further studies addressed to the effects of CXCR4 and IGF-1R inhibitors on cell viability and function are needed to plan new and more appropriate SS treatments. © 2015 Palmerini et al.; licensee BioMed Central.


Pasquinelli G.,University of Bologna | Papadopulos F.,University of Bologna | Nigro M.,Surgical Pathology
Ultrastructural Pathology | Year: 2010

Nanobacteria are controversial infectious agents with nanometric size, the capacity to nucleate hydroxyapatite and grow in culture, and present in human diseases associated with calcification and psammoma bodies. The authors report a case of pathological placental calcifications associated with nanobacteria. Electron microscopy and electron energy loss spectroscopy imaging were used to recognize 160-nm-sized calcium-free bodies mainly presenting as extracellular fibrillary tangles and 500-nm-sized calcified bodies; they encrusted the syncito-trophoblast basal membrane and aggregated into miniaturized psammoma bodies. Nanobacteria may be composed of a prionoid protein with self-assembling and self-propagating abilities whose growth is associated with the formation of psammoma bodies. © 2010 Informa Healthcare USA, Inc.

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