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Several studies support an important role of angiogenesis in breast cancer growth and metastasis. The main objectives of the study were to investigate the immunohistochemical expression of vascular endothelial growth factor (VEGF) family ligands (VEGF-A and VEGF-C) and receptors (VEGFR1, VEGFR2 and VEGFR3) in breast cancer and their associations with clinicopathological parameters, cancer subtypes/subgroups and patient outcome. Formalin-fixed paraffin-embedded tumor tissue samples were collected from early-stage breast cancer patients treated with anthracycline-based chemotherapy within a randomized trial. Immunohistochemistry was performed on serial 2.5 μm thick tissue sections from tissue microarray blocks. High VEGF-A, VEGF-C, VEGFR1, VEGFR2 and VEGFR3 protein expression was observed in 11.8% (N = 87), 80.8% (N = 585), 28.1% (N = 202), 64.6% (N = 359) and 71.8% (N = 517) of the cases, respectively. Significant associations were observed among all proteins (all p-values

Background/objectives: Left ventricular restraint attenuates post-infarction remodeling, but may be associated with unfavorable long-term histological response. We hypothesized that beneficial effects can be obtained with short-term restraint during the early post-infarction period; for this purpose, we evaluated a biodegradable scaffold in the in vivo rat model and compared it with epicardial hydrogel application. Methods: A total of 230 Wistar rats (358 ± 7 g) were studied. Implantation was performed with and without prior myocardial infarction, induced by permanent coronary artery ligation. Diastolic filling was evaluated by left ventricular pressure recordings after scaffold implantation. Degradation rates and inflammatory/foreign body response were studied at 3, 7 and 15 days post-ligation. Remodeling indices were evaluated by echocardiography 15 days post-ligation. Results: No differences were found in diastolic pressure. Biodegradability was ~ 50% by 7 days and 100% by 15 days for both materials. Likewise, inflammatory/foreign body response peaked at 3 days post-implant, with subsequent remission, but fibroblastic reaction was more pronounced after scaffold than after hydrogel implantation. Post-ligation, ejection fraction was higher in the scaffold (40.0 ± 1.5%) or hydrogel groups (37.0 ± 1.3%), compared to controls (30.6 ± 1.9%). Wall tension index was lower with either biomaterial, but left ventricular end-diastolic diameter was shorter (p = 0.044) and sphericity was attenuated (p = 0.029) after scaffold, compared to hydrogel implantation. Conclusions: Both biomaterials showed a favorable histological response and attenuated remodeling, but epicardial restraint produced better results compared to hydrogel alone. The latter approach merits further investigation due to the ease of implantation. © 2012 Elsevier Ireland Ltd.

Oral cancer accounts for 2-3% of all malignancies and according to the World Health Organization (WHO) is the fifth most common cancer worldwide. On the other hand, "oxidative stress" implies a cellular state whereby reactive oxygen species (ROS) production exceeds its metabolism resulting in excessive ROS accumulation and overwhelmed cellular defenses. Such a state has been shown to be involved in the multistage process of human carcinogenesis (including oral cancer) via many different mechanisms. Amongst them are ROS-induced oxidative modifications on major cellular macromolecules like DNA, proteins and lipids with the resulting byproducts being involved in the pathophysiology of human oral malignant and pre-malignant lesions. Throughout this manuscript, we review the current state of knowledge on the role of these oxidative-modified cellular byproducts in serving as reliable biomarkers for oral cancer detection, prognosis and diagnosis. Curr Mol Med

Modern Pathology

Background: The aim of the present study was to investigate the efficacy of adjuvant dose-dense sequential chemotherapy with epirubicin, paclitaxel, and CMF in subgroups of patients with high-risk operable breast cancer, according to tumor subtypes defined by immunohistochemistry (IHC). Materials and Methods: Formalin-fixed paraffin-embedded (FFPE) tumor tissue samples from 1,039 patients participating in two adjuvant dose-dense sequential chemotherapy phase III trials were centrally assessed in tissue micro-arrays by IHC for 6 biological markers, that is, estrogen receptor (ER), progesterone receptor (PgR), HER2, Ki67, cytokeratin 5 (CK5), and EGFR. The majority of the cases were further evaluated for HER2 amplification by FISH. Patients were classified as: luminal A (ER/PgR-positive, HER2-negative, Ki67low); luminal B (ER/PgR-positive, HER2-negative, Ki67high); luminal-HER2 (ER/PgR-positive, HER2-positive); HER2-enriched (ER-negative, PgR-negative, HER2-positive); triple-negative (TNBC) (ER-negative, PgR-negative, HER2-negative); and basal core phenotype (BCP) (TNBC, CK5-positive and/or EGFR-positive). Results: After a median follow-up time of 105.4 months the 5-year disease-free survival (DFS) and overall survival (OS) rates were 73.1% and 86.1%, respectively. Among patients with HER2-enriched tumors there was a significant benefit in both DFS and OS (log-rank test; p = 0.021 and p = 0.006, respectively) for those treated with paclitaxel. The subtype classification was found to be of both predictive and prognostic value. Setting luminal A as the referent category, the adjusted for prognostic factors HR for relapse for patients with TNBC was 1.91 (95% CI: 1.31-2.80, Wald's p = 0.001) and for death 2.53 (95% CI: 1.62-3.60, p

Purpose: To study the phenomenon of positive urine cytology in patients with lung cancer in the absence of obvious urothelial metastases. Patients and methods: 150 patients with small (SCLC) and non-small cell lung cancer (NSCLC) of all stages and 3 control groups were prospectively studied. Immunocytochemical study (cytokeratins 7-20, TTF1) in all positive urine specimens and chemokine profile (CXCR4, CCL21) study of the primary tumor in selected positive patients was performed. In experimental study, C57Bl/6 BALB/C mice injected with LLC lung and 4T1 mammary cancer cells were used for the detection of positive urine cytology. Results: 11% of patients with NSCLC, 7% of patients with SCLC and none of the control group had positive urine cytology. In NSCLC, metastatic disease and high tumor burden positively correlated (p = 0.01 and 0.03 respectively) with the phenomenon. In SCLC, correlation with extensive disease and multiple metastatic sites (p = 0.02 and 0.04 respectively) was found. No correlation was found in either group with: age, gender, histology, performance status, line of chemotherapy, previous platinum-based chemotherapy, adrenal metastases, renal function, abnormal urinary sediment, response to chemotherapy and overall survival (p = 0.9). Distinctive chemokine expression was identified in positive patients studied and was not observed in negative patients (x2 p = 0.008). In the experimental study, only the LLC lung cancer cells were detected in the urine cytology of mice. Conclusion: This phenomenon, carrying undefined pathophysiological mechanisms, seems to characterize only patients with metastatic/extensive disease and high tumor burden. Further studies are needed to validate our preliminary chemokine expression results. (C) 2010 Elsevier Ireland Ltd. All rights reserved.

European Journal of Cancer

Virchows Archiv

Modern Pathology

PURPOSE: Multidrug resistance (MDR) remains a major obstacle to successful chemotherapeutic treatment of cancer. Several chemotherapeutic and radiopharmaceutical agents are substrates of the pumps encoded by the MDR genes, and therefore, their accumulation is prevented. We evaluated in vivo whether [(99m)Tc]tetrofosmin ((99m)Tc-TF) uptake is influenced by the MDR profile of gliomas. PROCEDURES: Eighteen patients with histologically confirmed glioma were included in the study. Brain single-photon emission computed tomography by (99m)Tc-TF was performed within a week prior to surgical excision, and the expression of MRP5 was assessed by immunohistochemistry. Radiotracer accumulation was assessed by a semiquantitative method, calculating the lesion-to-normal uptake ratio. RESULTS: Using Spearman's rho analysis, we found no correlation between tracer uptake expressed as lesion-to-normal and MRP5 expression. There was a significant correlation between glioma aggressiveness as assessed by Ki-67/MIB-1 and MRP5 expression. CONCLUSION: The present data suggest that (99m)Tc-TF uptake is not influenced by glioma's MDR phenotype. Thus, (99m)Tc-TF constitutes a suitable radiotracer for imaging gliomas. Mol Imaging Biol

The complex biological trait 'susceptibility to apoptosis' is a nosological feature distinguishing squamous cell carcinomas (SCC) from keratoacanthomas (KA). The purpose of this study was to compare the expression of apoptosis-inducing factor (AIF), a major effector of the caspase-independent apoptosis pathway, in formalin-fixed SCC (N = 23) and KA (N = 29) resection specimens. SCC express statistically significant more AIF than KA both as proportion of AIF+ cells by immunohistochemistry (median: 54% vs 33%; P < 0.01) and as total AIF protein content by western blot quantification (six-fold increased; P < 0.01). However, the contribution of AIF to apoptosis, measured as fraction of apoptotic nuclei with overt DNA fragmentation by the TUNEL method that co-express AIF translocated to nucleus, is significantly less prevalent among SCC (median: 19% vs 48% in KA; P < 0.01). These findings indicate to a distinctive involvement of AIF in the progression of certain epithelial skin tumors that might be exploited as a promising treatment target. Exp Dermatol

Virchows Archiv

Objective. The detection of high-grade cervical intraepithelial neoplasia (CIN) amongst patients with low-grade cytology (LSIL) is challenging. This study evaluated the role of high-risk HPV (HR-HPV) DNA test and p16INK4a immunostaining in identifying women with LSIL cytology at risk of harboring CIN2 or worse (CIN2+) and the role of p16INK4a in the triage of a population of HR-HPV positive LSIL. Methods. We conducted a prospective study including women with LSIL cytology. Detection of HR-HPV was carried out by means of a polymerase chain reaction based assay. p16INK4a immunostaining was performed using the Dako CINtec cytology kit. All patients had colposcopically directed punch biopsies or large loop excision of the transformation zone of the cervix. The endpoint was detection of a biopsy-confirmed CIN2+. Results. A series of 126 women with LSIL cytology were included. HR-HPV test had sensitivity 75% and specificity 64% for an endpoint of CIN2+. p16INK4a had significantly higher specificity of 89% (p = 0.0000) but low sensitivity of 42%. The role of p16INK4a immunostaining in the triage of LSIL positive for HR-HPV was also evaluated. p16INK4a triage had 70% positive predictive value (PPV); however, this was not significantly higher than the PPV (56%) of HR-HPV test alone (p = 0.4). Conclusions. The results indicate that HR-HPV or p16INK4a cannot be used as solitary markers for the assessment of LSIL. The addition of p16INK4a immunostaining led to an increase in HR-HPV specificity; however, the biomarker needs to be assessed further to establish its role as an adjunct test in the triage of LSIL. © 2010 Elsevier Inc.

Over the last few years there has been an increasing effort in identifying environmental and occupational carcinogenic agents and linking them to the incidence of a variety of human cancers. The carcinogenic process itself is multistage and rather complex involving several different mechanisms by which various carcinogenic agents exert their effect. Amongst them are epigenetic mechanisms often involving silencing of tumor suppressor genes and/or activation of proto-oncogenes, respectively. These alterations in gene expression are considered critical during carcinogenesis and have been observed in many environmental- and occupational-induced human cancers. Some of the underlying mechanisms proposed to account for such differential gene expression include alterations in DNA methylation and/or histone modifications. Throughout this article, we aim to provide a current account of our understanding on how the epigenetic pathway is involved in contributing to an altered gene expression profile during human carcinogenesis that ultimately will allow us for better cancer diagnostics and therapeutic strategies. Chem Biol Interact

Acta Cytol

Although we have greatly benefited from the use of traditional epidemiological approaches in linking environmental exposure to human disease, we are still lacking knowledge in to how such exposure participates in disease development. However, molecular epidemiological studies have provided us with evidence linking oxidative stress with the pathogenesis of human disease and in particular carcinogenesis. To this end, oxidative stress-based biomarkers have proved to be essential in revealing how oxidative stress may be mediating toxicity induced by many known carcinogenic environmental agents. Therefore, throughout this review article, we aim to address the current state of oxidative stress-based biomarker development with major emphasis pertaining to biomarkers of DNA, lipid and protein oxidation. Chem Biol Interact

Virchows Archiv

Virchows Archiv

Background: To assess the prognostic and predictive significance of HER-1/EGFR protein levels in high-risk patients with breast cancer treated with dose-dense sequential adjuvant chemotherapy. Methods: 595 high-risk breast cancer patients were treated with adjuvant anthracycline-based dose-dense sequential chemotherapy (E-CMF vs. E-T-CMF). Disease-free survival (DFS) was the primary end point. HER-1/EGFR was assessed by immunohistochemistry (IHC) in 312 patients. Results: HER-1/EGFR expression was detected in 54 of 312 patients (17%). Positive expression of HER-1/EGFR was significantly associated with negative receptor status (52 vs. 17%, p < 0.001), worse histological grade (70 vs. 45%, p = 0.001), HER-2 overexpression (46 vs. 27%, p = 0.01) and positive p53 expression (48 vs. 19%, p < 0.001). With a median follow-up of 7 years, the total number of relapses was 105 (34%), and the total number of deaths 69 (22%). The analysis for DFS provides significant evidence that the HER-1/EGFR effect on the risk of disease progression was different according to treatment (interaction p = 0.02). Regarding overall survival, a trend towards a significant difference for an interaction of HER-1/EGFR and treatment was found (p = 0.07). Conclusion: The present study demonstrated a differential effect of positive HER-1/EGFR expression in the two treatment groups, with HER-1/EGFR being a negative prognostic marker in the absence of paclitaxel. Copyright © 2008 S. Karger AG.

Urine cytology has been a useful tool for the diagnosis of urinary tract malignancies. However, the presence of tumor cells in the urine sediment without an obvious urothelial metastatic deposit is a rare phenomenon and in patients with lung cancer has never been reported. We present five cases with metastatic lung cancer and positive urine cytology. The possible mechanisms underlining this phenomenon and its implications are discussed. Lung Cancer

Virchows Archiv

INTRODUCTION: Pulmonary hypertension portends an adverse outcome. Animal models have improved current understanding of the complex pathophysiology of the disease, but may be technically demanding. Moreover, plexiform vascular lesions are rarely observed, limiting the extrapolation to human pathophysiology. The aim of the present study was first, to assess the feasibility of closed-chest pressure recordings, and mainly, to further characterise a new model of endothelin receptor-B deficient rats. METHODS: Jugular venous catheterisation was assessed in 15 Wistar rats. Pressure recordings via a left lateral thoracotomy and histological findings were compared in three rat groups (age 20 +/- 1 weeks, weight 200-250 g): (a) wild type (n = 10, group A); (b) wild type after monocrotaline injection (n=10, group B); and (c) endothelin receptor-B deficient rats (n = 10, group C) after monocrotaline injection. RESULTS: Pressure recordings via the jugular approach were feasible in only 3 (20%) rats. Compared to group A, there was a trend (H = 4.6, p = 0.0962) towards increased mortality in groups B and C, due to respiratory arrest during intubation attempts. Pulmonary artery systolic pressure in group C was 24.7 +/- 1.3 mmHg, higher than in group B (21.5 +/- 1.2, p = 0.036) or group A (11.8 +/- 0.5, p < 0.0001). Adverse pulmonary vascular remodelling was more prominent in group C than in group B. CONCLUSIONS: Endothelin receptor-B deficient rats constitute a useful model of pulmonary artery hypertension after monocrotaline injection. The ease of pressure recordings via a left lateral thoracotomy may aid in the more widespread use of this model. Hellenic J Cardiol

Apoptosis has been suggested to have an important role in the pathogenesis of restenosis in addition to cell migration and proliferation. The aim of the present study was to investigate in an experimental in vivo model the occurrence of apoptosis postangioplasty and its relation to bcl-2 and peroxynitrite detection. Eighteen hypercholesterolemic rabbits underwent transluminal angioplasty of the right iliac artery. The rabbits were sacrificed on the 1st, 2nd, 3rd, 7th, 15th, and 28th day postangioplasty (3 animals per time point) and both the angioplasted and non-injured arteries were studied. Apoptosis was assessed by the terminal uridine nick-end labeling method (TUNEL). Bcl-2 and peroxynitrite were detected by immunochemistry using anti-bcl-2 and anti-nitrotyrosine antibodies. In the angioplasted arteries the number of apoptotic cells was

Virchows Archiv

BACKGROUND: The aim of this study was to investigate pancreatic injury after 45 min of thoracoabdominal aortic occlusion in a porcine model. METHODS: Twenty-four pigs were used. Six pigs underwent sham operation and 18 intravascular balloon thoracoabdominal aortic occlusions for 45 min. The animals were randomly killed at 12, 48 and 120 h after reperfusion. After killing, all pancreata were examined macroscopically for any signs of acute pancreatitis, whereas gland specimens were harvested for histological study to evaluate pancreatic injury (haematoxylin and eosin staining) and acinar cell apoptosis (Terminal deoxynucleotidyl transferase mediated dUTP Nick-End Labelling staining). RESULTS: Pancreatic injury severity score was mildly increased in terms of oedematous features at 12 h after reperfusion, but normalized to sham levels by the second day and thereafter. Necrotic injury was not statistically significant at any time point. Acinar cell apoptotic index was mildly increased at 12 and 48 h, but showed a tendency to decrease towards sham levels by the fifth day. One animal developed acute pancreatitis. CONCLUSION: Acute pancreatitis is unlikely to occur after 45 min of thoracoabdominal aortic occlusion. However, an early, mild oedematous and apoptotic injury that occurs subclinically seems to be a constant event. This injury might have clinical significance when combined with pre-existent pancreatic pathologies. ANZ J Surg

Background: Thrombospondin-1 (TSP-1) is an extracellular matrix component glycoprotein, which is known to be a potent inhibitor of angiogenesis and may be important in cancer invasiveness. We examined the TSP-1 expression in correlation with conventional clinicopathological parameters to clarify its prognostic significance in bladder cancer. In addition, the possible correlation of TSP-1 expression with microvessel count, VEGF expression, p53 expression as well as with the expression of the extracellular matrix components was studied to explore its implication in vascularization and tumour stroma remodeling. Methods: The immunohistochemical expression of TSP-1 in tumour cells and in the tumour stroma was studied in 148 formalin-fixed paraffin-embedded urothelial cell carcinoma tissue samples. Results: TSP-1 was detected in perivascular tissue, at the epithelial-stromal junction, in the stroma and in tumour cells in the majority of the cases. In tumour cells, low TSP-1 expression was observed in 43% of the cases, moderate and high in 7%, while 50% showed absence of TSP expression. A higher TSP-1 immunoreactivity in well and moderately differentiated tumours compared to poorly differentiated was noted. PT1 tumours showed decreased TSP-1 expression in comparison to pTa and pT2-4 tumours. Increased tumour cell TSP-1 expression was related to increased microvessel density. In the tumour stroma, 37% of the cases showed small amount of TSP-1 expression, 7.5% moderate and high, while 55% of the cases showed absence of TSP-1 stromal immunoreactivity. Stromal TSP-1 expression was inversely correlated with tumour stage and tumour size. This expression was also positively correlated with microvessel density, VEGF expression and extracellular matrix components tenascin and fibronectin. Using univariate and multivariate analysis we didn't find any significant correlation of TSP-1 expression in superficial tumours in both tumour cells and tumour stroma in terns of the risk of recurrence and disease progression. Conclusion: Our data suggest that both tumour and stromal TSP-1 expression may play a role in tumour aggressiveness and angiogenesis. In addition, the correlation of stromal TSP-1 expression with extracellular matrix components fibronectin and tenascin indicate its possible implication in tumour stroma remodeling. © 2006 Ioachim et al; licensee BioMed Central Ltd.

Purpose. To assess the prognostic and predictive significance of HER-2 overexpression and high expression of VEGF in high-risk patients with breast cancer treated with dose-dense sequential chemotherapy. Patients and methods. From June 1997 until November 2000, 595 patients were randomized to three cycles of epirubicin (E) 110 mg/m2 followed by three cycles of paclitaxel (T) 250 mg/m2 followed by three cycles of "intensified" CMF (cyclophosphamide 840 mg/m2, methotrexate 47 mg/m2 and fluorouracil 840 mg/m2) or to four cycles of E, followed by four cycles of CMF. HER-2 was assessed by immunohistochemistry (IHC) in 394 patients, and by fluorescence in situ hybridization (FISH) in cases scored as 2+ by IHC. VEGF was evaluated in 323 patients by IHC. Results. HER-2 overexpression was detected in 123 patients (31%) and high expression of VEGF in 233 (72%). The rate of HER-2 overexpression was significantly higher in patients with positive VEGF staining (35% vs. 21%, p = 0.02). Overexpression of HER-2 was significantly associated with negative hormonal status, high histologic grade and larger tumors. HER-2 overexpression was a significant negative predictor of DFS (p = 0.002), but not of OS. Adjusting for HER-2 overexpression, DFS and OS did not significantly differ between treatment groups. Positive VEGF staining was not associated with receptor status, number of positive nodes, grade, tumor size, incidence of relapse or death. Conclusions. For both treatments, HER-2 overexpression was a significant negative prognostic factor for DFS but not for OS, while high expression of VEGF was not significantly associated to either DFS or OS. No predictive ability of HER-2 status or VEGF overexpression for T treatment was evident. © Springer 2006.

Hypoxia-inducible factors (HIF-1 alpha- and HIF-2 alpha) are closely related protein complexes that activate transcription of target genes in response to hypoxia. The immunohistochemical expression of these two proteins was investigated in 144 bladder cancer tissue samples and correlated with standard clinicopathological features, in order to elucidate their prognostic significance. We also evaluated their possible associations with other angiogenesis related markers such as microvessel density (MVD), vascular endothelial growth factor, thymidine phosphorylase, tenascin, fibronectin, p53 and bcl-2 to further clarify their implication in tumor stroma vascularization. Nuclear HIF-1 alpha expression in tumor cells was detected in 57.1% of the cases. A trend of correlation of this expression with poorly differentiated tumors was observed. In addition, HIF-1 alpha expression was positively correlated with stromal cells thymidine phosphorylase expression. Tumors that were progressed in muscle-infiltrating disease showed a higher HIF-1 alpha expression. A higher HIF-1 alpha expression was also observed in tumors with an in situ component. In tumor cells, low HIF-2 alpha. expression was observed in 6.3%, moderate in 31.9% and high in 61.8% of the cases. A trend of correlation of this expression with MVD was observed. In addition, HIF-2 alpha expression was positively correlated with thymidine phosphorylase and fibronectin expression. A lower HIF-2 alpha expression was detected in tumors that recurred earlier in univariate methods of analysis. HIF-2 alpha was expressed in tumor stroma associated cells in 53.5% of specimens and was correlated with advance tumor stage, thymidine phosphorylase and tenascin expression. There was no statistically significant difference in the expression of both HIF-1 alpha and HIF-2 alpha between primary and recurrent tumors. In multivariate analysis including T stage, T grade, multifocality and T size, both HIF-1 alpha and HIF-2 alpha expression were not considered dependent in the prediction of recurrence or progression. In conclusion, the results of the present study indicate that HIF-1 alpha and HIF-2 alpha expression may help to predict recurrence or progression to muscle invasive disease but not as independent prognostic factors. In addition, the expression of HIF-1 alpha and HIF-2 alpha, appear to play a role in bladder cancer, vascularization possibly and in cooperation with other angiogenic factors. Copyright (c) 2006 S. Karger AG, Basel

Purpose: To assess the prognostic and predictive significance of p53 and Bcl-2 protein expression in high risk patients with breast cancer treated with dose-dense sequential chemotherapy. Patients and methods: From June 1997 until November 2000, 595 patients were randomized to three cycles of epirubicin (E) 110 mg/m 2 followed by three cycles of paclitaxel (P) 250 mg/m 2 followed by three cycles of 'intensified' CMF (cyclophosphamide 840 mg/m 2, methotrexate 47 mg/m 2 and fluorouracil 840 mg/m 2) or to four cycles of E, followed by four cycles of CMF. p53 and Bcl-2 expression was investigated by immunohistochemistry in 392 and 397 patients respectively. Results: Positive expression of p53 was detected in 104 (26.5%) patients and was significantly associated with negative hormonal status, worse histologic grade, higher incidence of disease relapse and higher rate of death. p53 positive expression was a significant negative predictor of overall survival (OS) (P = 0.002) and disease-free survival (DFS) (P = 0.001). Negative expression of Bcl-2 was detected in 203 (51%) patients and was significantly associated with negative hormonal status. Multivariate analysis revealed that, positive p53 expression, higher number of positive nodes and worse tumor grade were related to significantly poorer OS and DFS. Conclusions: For both treatments, p53 positive expression was a significant negative prognostic factor for OS and DFS while Bcl-2 was not. No predictive ability of p53 status or Bcl-2 status for paclitaxel treatment was evident. © 2006 Oxford University Press.

OBJECTIVE: Ventricular remodeling is a common corollary of myocardial infarction. We hypothesized that this process may be attenuated by growth hormone, administered as a single high-dose, selectively in the infarct zone, early postmyocardial infarction. DESIGN: In 35 pigs (29+/-4 kg), myocardial infarction was generated by inflation of an over-the-wire angioplasty balloon in the circumflex artery for 60 min and 5 further pigs were sham-operated. Ten minutes after reperfusion, the pigs were randomized (2:1) to either growth hormone (1 IU/kg) (n=23) or normal saline (n=12), delivered via the balloon catheter. All survivors were treated with captopril and were sacrificed 4 weeks after myocardial infarction. RESULTS: Compared to controls, growth hormone-treated animals displayed lower heart weight (4.1+/-0.5 g/kg body weight, versus 3.4+/-0.4 g/kg, respectively, p=0.003) and dimensions (left ventricular short axis diameter 46+/-7 mm versus 37+/-6 mm, p=0.01; right ventricular short axis diameter 38+/-7 mm versus 30+/-5 mm p=0.001). Growth hormone increased wall thickness in the infarct (6.0+/-1.8 in controls versus 9.9+/-3.7 in treated animals, p=0.004) and non-infarct zones (10.6+/-1.8 in controls versus 15.5+/-3.8 in treated animals, p=0.0006) and produced higher (p

Hypoxia-inducible factors (HIF-1alpha and HIF-2alpha) are closely related protein complexes that activate transcription of target genes in response to hypoxia. The immunohistochemical expression of these two proteins was investigated in 144 bladder cancer tissue samples and correlated with standard clinicopathological features, in order to elucidate their prognostic significance. We also evaluated their possible associations with other angiogenesis related markers such as microvessel density (MVD), vascular endothelial growth factor, thymidine phosphorylase, tenascin, fibronectin, p53 and bcl-2 to further clarify their implication in tumor stroma vascularization. Nuclear HIF-1alpha expression in tumor cells was detected in 57.1% of the cases. A trend of correlation of this expression with poorly differentiated tumors was observed. In addition, HIF-1alpha expression was positively correlated with stromal cells thymidine phosphorylase expression. Tumors that were progressed in muscle-infiltrating disease showed a higher HIF-1alpha expression. A higher HIF-1alpha expression was also observed in tumors with an in situ component. In tumor cells, low HIF-2alpha expression was observed in 6.3%, moderate in 31.9% and high in 61.8% of the cases. A trend of correlation of this expression with MVD was observed. In addition, HIF-2alpha expression was positively correlated with thymidine phosphorylase and fibronectin expression. A lower HIF-2alpha expression was detected in tumors that recurred earlier in univariate methods of analysis. HIF-2alpha was expressed in tumor stroma associated cells in 53.5% of specimens and was correlated with advance tumor stage, thymidine phosphorylase and tenascin expression. There was no statistically significant difference in the expression of both HIF-1alpha and HIF-2alpha between primary and recurrent tumors. In multivariate analysis including T stage, T grade, multifocality and T size, both HIF-1alpha and HIF-2alpha expression were not considered dependent in the prediction of recurrence or progression. In conclusion, the results of the present study indicate that HIF-1alpha and HIF-2alpha expression may help to predict recurrence or progression to muscle invasive disease but not as independent prognostic factors. In addition, the expression of HIF-1alpha and HIF-2alpha, appear to play a role in bladder cancer, vascularization possibly and in cooperation with other angiogenic factors. Urol Int

OBJECTIVE To measure the immunohistochemical expression of the extracellular matrix (ECM) components tenascin, fibronectin, collagen type IV and laminin in urothelial carcinomas, and to correlate their expression with clinicopathological features to clarify the prognostic value of these molecules and their role in tumour progression. MATERIALS AND METHODS Tumour specimens obtained during transurethral resection of bladder tumour (TURBT) from 103 patients (82 men and 2 1 women, mean age 66.7 years, range 27-89) were studied retrospectively. The expression of tenascin, fibronectin, collagen type IV and laminin was correlated with clinicopathological features (tumour grade and stage, multiplicity, simultaneous in situ component, the proliferative activity as estimated by the two proliferation associated indices, Ki-67 and proliferating cell nuclear antigen, the recurrence rate, and the progression of invading tumour). Specimens investigated for tenascin expression from patients with superficial bladder cancers were categorized into 28 treated by TURBT only and 53 who had TURBT followed by intravesical instillations of interferon. RESULTS Cytoplasmic tenascin expression was detected in tumour cells in 20% of specimens. Tenascin was expressed in the tumour stroma in 76% of specimens, and was positively correlated with tumour grade and stage. Stromal tenascin expression was positively correlated with proliferative activity, and with the expression of filbronectin and collagen type IV. Fibronectin was expressed in the tumour stroma in 89% of specimens and was positively correlated with tumour stage, proliferative activity, and expression of collagen type IV and laminin. Collagen type IV was expressed in 93% of specimens, and was positively correlated with tumour grade and stage. Laminin was expressed in 78% of specimens and had no significant correlation with the clinicopathological features. Patients treated with TURBT alone and who had low levels of tenascin had a longer tumour-free interval than those with high levels of tenascin. CONCLUSION Levels of tenascin might be valuable for predicting the risk of early recurrence. The expression of tenascin, filbronectin and collagen type IV seems to be correlated with more aggressive tumour behaviour. Furthermore, their interrelationships could indicate that they are involved in the remodelling of bladder cancer tissue, probably influencing tumour progression.

Fine-needle aspiration biopsy (FNAB) of the thyroid gland is the most cost-effective examination in the evaluation of thyroid nodules. The aim of this study was to present our experience from all patients who underwent thyroid FNA in the University Hospital of Ioannina, Greece, in the period 1993-2003, and its value in the diagnostic management of patients with thyroid nodules. FNA was performed in 900 patients of whom 753 were females and 147 males. The cases were classified according to diagnosis into five groups: benign/negative 628, primary carcinoma 28, metastatic carcinoma 5, suspicious/indeterminate 60 and non-diagnostic 179. Cytological findings were compared with histopathological findings and the statistical analysis in our data yielded the following results: sensitivity 92.1%, specificity 93.2%. These results are in accordance with the already published data in the international literature. In cases of differential diagnosis between adenomatoid hyperplasia and follicular neoplasia, four cases were diagnosed as hot nodules. In the benign group, three cases were diagnosed as nodular hyperplasia with cystic degeneration on FNA, but, after surgical treatment, histologically were diagnosed as papillary carcinomas. In the group of suspicious/indeterminate, two cases were diagnosed as suspicious for follicular neoplasia on FNA and, after surgical treatment, were diagnosed histopathologically as medullary carcinomas. In conclusion, we suggest that routine measurement of serum calcitonin is useful and mandatory in the detection of medullary carcinoma among patients with nodular thyroid diseases. Taking into consideration the clinical data can minimize false-positive and false-negative rates. We conclude that FNA is an effective screening test in the evaluation of the necessity for surgical treatment in patients with thyroid nodules. In Vivo

Preoperative diagnosis of fallopian tube carcinoma is difficult due to the rarity and silent course of this neoplasm. We present herein the case of a 58-year-old woman with primary fallopian tube carcinoma that was diagnosed preoperatively on the basis of a positive for adenocarcinoma Papanicolaou vaginal smear, repeated episodes of vaginal bleeding, negative endocervical and endometrial curettage, characteristic features on ultrasonography and elevated CA-125 levels. The patient was treated by total abdominal hysterectomy, bilateral salpigno-oophorectomy and omentectomy. Pathologic confirmation of primary serous papillary adenocarcinoma of the left fallopian tube was made. Peritoneal washings were positive for malignancy. FIGO stage was considered as IIIb and the patient received six courses of combined carboplatin-taxol chemotherapy. At two years from onset of therapy the patient underwent a modified radical mastectomy and lymphadenectomy because of primary carcinoma of the right breast. The patient was started on tamoxifen therapy, which she is still taking. At 60 months after initial surgery, the patient is alive and well. In conclusion, our study suggests an association between fallopian tube carcinoma and breast cancer and a good response of the patient to platinum-based chemotherapy. Eur J Gynaecol Oncol

Annals of Oncology

We describe 6 bilateral cases of progressive Mooren's ulcer treated by performing conjunctival excision (regional or 360 degrees peritomy). The histopathological study of the conjunctiva adjacent to the lesion showed an hyperaemic and edematous stroma infiltrated mainly by plasma cells and lymphocytes without signs of vasculitis. The peripheral portion of the ulcer was characterized by necrobiotic and hemorrhagic elements along with an absence of the overlying epithelium and Bowman's membrane. Inflammation of the corneal stroma was present in the peripheral but absent in the central edge of the ulcer, a characteristic sign of a rodent ulcer. Therefore, the histopathological study was very useful for the final diagnosis and the differential diagnosis of Mooren's ulcer from other cases of peripheral ulcerative keratitis. In all 6 cases conjunctival excision appeared to be an effective procedure in halting the progression of the disease: absence of recurrences during a follow-up period of 1-2 years provided an essential healing of the cornea. Int Ophthalmol

OBJECTIVE: Ischemic preconditioning has been found to protect various organs from a subsequent longer ischemic insult. We investigated whether the late phase of ischemic preconditioning reduces spinal cord injury from occlusion of the descending thoracic aorta. METHODS: Twenty-four pigs (27 to 30 kg) were randomly divided in four groups: group I (n = 4) underwent a sham operation, group II (n = 4) underwent aortic occlusion for 20 minutes, group III (n = 8) underwent aortic occlusion for 35 minutes, and group IV (n = 8) underwent aortic occlusion for 20 minutes and, 48 hours later, aortic occlusion for 35 minutes. Aortic occlusion was accomplished with two balloon occlusion catheters placed fluoroscopically at T(6) to T(8) above the diaphragm and at the aortic bifurcation. Neurologic evaluation was performed by an independent observer according to Tarlov's scale (0 to 4, with 4 as normal). The lower thoracic and lumbar spinal cords were harvested at 120 hours and examined histologically with hematoxylin and eosin stain. Histologic results (number of neurons and grade of inflammation) were scored 0 to 4 (4, intact spinal cord; 0, no neurons and high inflammation) and were similarly analyzed. Results were expressed as the mean +/- the standard error of the mean, and statistical analysis used the Kruskal-Wallis test. RESULTS: Group IV had a better neurologic outcome at 24, 48, and 120 hours in comparison with group III (P

OBJECTIVE: Postoperative neurologic deficits after thoracic aortic reconstruction vary widely. Our previous study showed that delayed ischemic preconditioning could prevent spinal cord injury caused by occlusion of the descending thoracic aorta in pigs. We investigated early ischemic preconditioning in the same model. METHODS: Twenty-eight pigs were divided into 4 groups: group 1 (n = 6) underwent a sham operation, group 2 (n = 6) underwent aortic occlusion for 20 minutes, group 3 (n = 8) underwent aortic occlusion for 35 minutes, and group 4 (n = 8) underwent aortic occlusion for 20 minutes and underwent aortic occlusion 80 minutes later without hypotension for 35 minutes. Aortic occlusion was accomplished by using 2 balloon occlusion catheters placed fluoroscopically at T6 to T8 above the diaphragm and at the aortic bifurcation. Neurologic evaluation was performed by an independent observer according to the Tarlov scale (0-4). The lower thoracic and lumbar spinal cords were harvested at 120 hours and examined histologically with hematoxylin-and-eosin stain. Histologic results (number of neurons and grade of inflammation) were scored (0-4) and were similarly analyzed. Statistical analysis was by means of the Kruskal-Wallis test. RESULTS: Group 4 had a better neurologic outcome at 24, 48, and 120 hours in comparison with group 3 (P