The clinical significance of cathepsin S expression in human astrocytomas

Early local invasion by astrocytoma. cells results in tumor recurrence even after apparent total surgical resection, leading to the poor prognosis associated with malignant astrocytomas. Proteolytic enzymes have been implicated in facilitating tumor cell invasion and the current study was designed to characterize the expression of the cysteine proteinase cathepsin S (CatS) in astrocytomas and examine its potential role in invasion. Immunohistochemical analysis of biopsies demonstrated that CatS was expressed in astrocytoma cells but absent from normal astrocytes, oligodendrocytes, neurones and endothelial cells. Microglial cells and macrophages were also positive. Assays of specific activity in 59 astrocytoma biopsies confirmed CatS expression and in addition demonstrated that the highest levels of activity were expressed in grade IV tumors. CatS activity was also present in astrocytoma cells in vitro and the extracellular levels of activity were highest in cultures derived from grade IV tumors. In vitro invasion assays were carried out using the U251MG cell line and the invasion rate was reduced by up to 61% in the presence of the selective CatS inhibitor 4-Morpholineurea-LeuHomoPhe-vinylsulphone. We conclude that CatS expression is up-regulated in astrocytoma. cells and provide evidence for a potential role for CatS in invasion.

The use of morphological characteristics and texture analysis in the identification of tissue composition in prostatic neoplasia

Quantitative examination of prostate histology offers clues in the diagnostic classification of lesions and in the prediction of response to treatment and prognosis. To facilitate the collection of quantitative data, the development of machine vision systems is necessary. This study explored the use of imaging for identifying tissue abnormalities in prostate histology. Medium-power histological scenes were recorded from whole-mount radical prostatectomy sections at × 40 objective magnification and assessed by a pathologist as exhibiting stroma, normal tissue (nonneoplastic epithelial component), or prostatic carcinoma (PCa). A machine vision system was developed that divided the scenes into subregions of 100 × 100 pixels and subjected each to image-processing techniques. Analysis of morphological characteristics allowed the identification of normal tissue. Analysis of image texture demonstrated that Haralick feature 4 was the most suitable for discriminating stroma from PCa. Using these morphological and texture measurements, it was possible to define a classification scheme for each subregion. The machine vision system is designed to integrate these classification rules and generate digital maps of tissue composition from the classification of subregions; 79.3% of subregions were correctly classified. Established classification rates have demonstrated the validity of the methodology on small scenes; a logical extension was to apply the methodology to whole slide images via scanning technology. The machine vision system is capable of classifying these images. The machine vision system developed in this project facilitates the exploration of morphological and texture characteristics in quantifying tissue composition. It also illustrates the potential of quantitative methods to provide highly discriminatory information in the automated identification of prostatic lesions using computer vision.

Correlation of TACC3, FGFR3, MMSET and p21 expression with the t(4;14)(p16.3;q32) in multiple myeloma

The t(4;14)(p16;q32) translocation seen in c. 18% of newly diagnosed multiple myeloma (MM) cases, results in FGFR3 activation and creation of an IGH/MMSET fusion transcript. We have recently shown that FGFR3 is activated in only 75% of t(4;14)(+) cases, suggesting that alternative genes near the breakpoint may be involved in the transforming event. The gene, TACC3, located just 50 kb telomeric of FGFR3, with transforming capacity, therefore represented a candidate gene. Using a real-time quantitative polymerase chain reaction-based approach on a cohort of 54 patients, we found a statistically significant, twofold increase in TACC3 expression in t(4;14)(+) cases. TACC3, MMSET and p21 values were positively correlated in all cases and, of particular interest, six patient samples [three t(4;14)(-), three t(4;14)(+)] samples showed a joint up-regulation of TACC3, MMSET and p21. Although a poor prognosis is linked with elevated MMSET expression, an extended follow-up period will be required to evaluate the significance of elevated TACC3 and p21 expression in this subgroup of MM.

Cyclooxygenase-2 expression correlates with phaeochromocytoma malignancy.

Abstract Aims: Phaeochromocytomas are rare but potentially life-threatening neuroendocrine tumours of the adrenal medulla or sympathetic nervous system ganglia. There are no histological features which reliably differentiate benign from malignant phaeochromocytomas. The current study evaluated cyclooxygenase-2 (Cox-2) and Bcl-2 as tissue-based biomarkers of phaeochromocytoma prognosis. Methods and Results: Cox-2 and Bcl-2 expression were examined immunohistochemically in tissue from forty-one sporadic phaeochromocytoma patients followed up for a minimum of five years after diagnosis. There was a statistically significant association between Cox-2 histoscore (intensity x porportion) and the development of tumour recurrence or metastases (p=0.006). A significant relationship between the co-expression of Cox-2 and Bcl-2 in the primary tumour and the presence of recurrent disease was observed (p=0.034). A highly significant association was observed between, (i) the tumour-associated expression of these two oncoproteins (p=0.001) and, (ii) Cox-2 histoscore and the presence of Bcl-2 expression (p=0.002). Cox regression analysis demonstrated no significant relationship between, (i) the presence or absence of either Cox-2 or Bcl-2 and patient survival or, (ii) between Cox-2 histoscore and patient survival. Conclusions: These results suggest that Cox-2 and Bcl-2 may promote phaeochromocytoma malignancy and that these oncoproteins may be valuable surrogate markers of an aggressive tumour phenotype.

BRCA1, a potential biomarker in the treatment of breast cancer

To date, estrogen receptor, progestogen receptor, and HER2/neu represent molecular biomarkers currently used in routine clinical practice to aid treatment decisions. Over the last few years, a large body of preclinical and retrospective clinical data has accumulated that suggests that BRCA1 mutation functions as a novel predictive marker of response to chemotherapy. This article reviews the role of BRCA1 as a predictive marker of chemotherapy response in breast cancer and examines the link between BRCA1 deficiency and the basal-like phenotype. Search strategy. Data for this article were identified through MEDLINE and PubMed searches for published reports using the terms BRCA1, breast cancer, basal-like, chemotherapy, prognosis, and predictive markers. In some cases, due to the restriction of space, readers are referred to review articles to allow further reading. Only articles published in English were included.

Survival patterns among lymphoma patients with a family history of lymphoma

Purpose: Genetic factors are important in the etiology and pathogenesis of chronic lymphocytic leukemia (CLL), Hodgkin's lymphoma (HL), and non-Hodgkin's lymphoma (NHL). Only a few small studies have assessed clinical characteristics and prognosis for familial patients, with inconsistent findings. Methods: Using population-based registries from Sweden and Denmark, 7,749 patients with CLL, 7,476 patients with HL, and 25,801 patients with NHL with linkable first-degree relatives were identified. Kaplan-Meier curves were constructed to compare survival in patients with lymphoma with and without a family history of lymphoma. The risk of dying was assessed using adjusted Cox proportional hazard models. Results: We found 85 patients with CLL (1.10%), 95 patients with HL (1.28%), and 206 patients with NHL (0.80%) with a family history of any lymphoma. Five-year mortality was similar for patients with CLL (hazard ratio [HR], 1.28; 95% CI, 0.95 to 1.72), HL (HR, 0.78; 95% CI, 0.49 to 1.25), and NHL (HR, 0.91; 95% CI, 0.74 to 1.12) versus without a family history of any lymphoma. Mortality was also similar for patients with versus without a family history of the same lymphoma. T-cell/anaplastic lymphoma patients with a family history of NHL had poorer outcome 5-years after diagnosis (HR, 5.38; 95% CI, 1.65 to 17.52). Results were similar for 10 years of follow-up. Conclusion: With the exception of T-cell/anaplastic lymphoma, survival patterns for patients with CLL, HL, and NHL with a family history of lymphoma were similar to those for sporadic patients, suggesting that most familial lymphomas do not have an altered clinical course. Our findings provide no evidence to modify therapeutic strategies for patients with CLL, HL, or NHL based solely on family history. © 2008 by American Society of Clinical Oncology.


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High bax expression is a good prognostic indicator in acute myeloid leukaemia

Most cytotoxic drugs kill cells by instigating the process of apoptosis and it has been suggested that apoptotic markers may provide an indication of tumour chemosensitivity. The aim of this study was to determine if such a relationship exists in acute myeloid leukaemia (AML). The levels of spontaneous apoptosis, bcl-2 and bax were evaluated in 56 newly diagnosed AML patients to determine if they correlated with a response to cytotoxic therapy. Spontaneous apoptosis was lower, but bcl-2, bax and the bcl-2/bax ratio were higher in AML compared with normal individuals. AML patients with high bax expression at diagnosis had significantly better prognosis for disease-free survival, event-free survival and overall survival (P = 0.016). In the standard risk group, high bax expression was in keeping with significantly improved survival. Multivariate analysis revealed bax to be an independent predictor of survival. There was a significant reduction in bcl-2 and bax expression when AML patients entered complete remission and also in relapsed AML patients who entered a second remission. This study suggests that bax is a useful prognostic indicator in AML and may assist with therapeutic decision-making for patients in the standard risk category.

The impact of dose escalation and resistance modulation in older patients with acute myeloid leukaemia and high risk myelodysplastic syndrome: the results of the LRF AML14 trial.:the results of the LRF AML14 trial

The acute myeloid leukaemia (AML)14 trial addressed four therapeutic questions in patients predominantly aged over 60 years with AML and High Risk Myelodysplastic Syndrome: (i) Daunorubicin 50 mg/m(2) vs. 35 mg/m(2); (ii) Cytarabine 200 mg/m(2) vs. 400 mg/m(2) in two courses of DA induction; (iii) for part of the trial, patients allocated Daunorubicin 35 mg/m(2) were also randomized to receive, or not, the multidrug resistance modulator PSC-833 in a 1:1:1 randomization; and (iv) a total of three versus four courses of treatment. A total of 1273 patients were recruited. The response rate was 62% (complete remission 54%, complete remission without platelet/neutrophil recovery 8%); 5-year survival was 12%. No benefits were observed in either dose escalation randomization, or from a fourth course of treatment. There was a trend for inferior response in the PSC-833 arm due to deaths in induction. Multivariable analysis identified cytogenetics, presenting white blood count, age and secondary disease as the main predictors of outcome. Although patients with high Pgp expression and function had worse response and survival, this was not an independent prognostic factor, and was not modified by PSC-833. In conclusion, these four interventions have not improved outcomes in older patients. New agents need to be explored and novel trial designs are required to maximise prospects of achieving timely progress.

Heart Rhythm UK position statement on clinical indications for implantable cardioverter defibrillators in adult patients with familial sudden cardiac death syndromes

Whilst the decision regarding defibrillator implantation in a patient with a familial sudden cardiac death syndrome is likely to be most significant for any particular individual, the clinical decision-making process itself is complex and requires interpretation and extrapolation of information from a number of different sources. This document provides recommendations for adult patients with the congenital Long QT syndromes, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, hypertrophic cardiomyopathy, and arrhythmogenic right ventricular cardiomyopathy. Although these specific conditions differ in terms of clinical features and prognosis, it is possible and logical to take an approach to determining a threshold for implantable cardioveter-defibrillator implantation that is common to all of the familial sudden cardiac death syndromes based on estimates of absolute risk of sudden death. Published on behalf of the European Society of Cardiology. © The Author 2010.

Identification of gene networks associated with acute myeloid leukemia by comparative molecular methylation and expression profiling

Around 80% of acute myeloid leukemia (AML) patients achieve a complete remission, however many will relapse and ultimately die of their disease. The association between karyotype and prognosis has been studied extensively and identified patient cohorts as having favourable [e.g. t(8; 21), inv (16)/t(16; 16), t(15; 17)], intermediate [e.g. cytogenetically normal (NK-AML)] or adverse risk [e.g. complex karyotypes]. Previous studies have shown that gene expression profiling signatures can classify the sub-types of AML, although few reports have shown a similar feature by using methylation markers. The global methylation patterns in 19 diagnostic AML samples were investigated using the Methylated CpG Island Amplification Microarray (MCAM) method and CpG island microarrays containing 12,000 CpG sites. The first analysis, comparing favourable and intermediate cytogenetic risk groups, revealed significantly differentially methylated CpG sites (594 CpG islands) between the two subgroups. Mutations in the NPM1 gene occur at a high frequency (40%) within the NK-AML subgroup and are associated with a more favourable prognosis in these patients. A second analysis comparing the NPM1 mutant and wild-type research study subjects again identified distinct methylation profiles between these two subgroups. Network and pathway analysis revealed possible molecular mechanisms associated with the different risk and/or mutation sub-groups. This may result in a better classification of the risk groups, improved monitoring targets, or the identification of novel molecular therapies.

Pre-Operative Visits to Reduce Patient Anxiety: A Study

The aim of this study was to evaluate the effect of pre-operative visits by theatre nurses on pre- and post-operative levels of anxiety in two groups of general surgical patients, and to see if the outcome was reflected in the level of post-operative pain, nausea, mobility or length of hospitalisation. One group received pre-operative visits while the other group did not. Results of the study showed a significant decrease in anxiety 24 to 72 hours post-operatively for the visited group. A positive relationship between pre-operative anxiety levels and the level of pain, nausea and lack of independence experienced by both groups was also found. Length of hospitalisation was unaffected by the level of anxiety experienced in both groups. The author recommends that all surgical patients should receive a visit from theatre nurses before their operation.

Breast cancer genetics: Unsolved questions and open perspectives in an expanding clinical practice

Breast cancer is the most common cause of cancer death in the United Kingdom, with a lifetime risk of one in nine in women. Only 5-10% of all cancers is thought to be due to strongly penetrant inherited predisposing genes, such as BRCA1 and BRCA2. However, other less penetrant genes, including some autosomal recessive genes, are likely to be of etiological importance in other families. This review addresses the current knowledge of breast cancer susceptibility genes and explores the possibilities for future developments. Features of tumor pathology, prognosis, and the scope for targeted treatments in mutation carriers are discussed, and the management of known carriers and those at increased risk for developing breast cancer are evaluated. Genetic testing for cancer susceptibility may become widely available in the future, and has important ethical and management implications. (C) 2004 Wiley-Liss, Inc.

Helix pomatia agglutinin lectin-binding oligosaccharides of aggressive breast cancer

Predicting long-term outcome after breast-cancer diagnosis remains problematic, particularly for patients with clinically small, axillary lymph node- negative tumours, Evidence suggests that the lectin Helix pomatia agglutinin (HPA) identifies oligosaccharides associated with poor-prognosis cancer. Our aim was to identify oligosaccharides that bind HPA in aggressive breast cancers. Breast-cancer cell lines (MCF-7, BT-549 and BT-20) and a cell line From human milk (HBL-100), which showed a range of HPA-binding intensities, were used to extract HPA-binding glycoproteins, Oligosaccharides were released using anhydrous hydrazine and separated on a range of HPLC matrices. We investigated whether HPA-binding oligosaccharides from cell lines were present in human breast-cancer tissues, using 69 breast-cancer specimens from patients with between 5 and 10 years' follow-up. A monosialylated oligosaccharide was over-expressed in the cell line that bound HPA strongly. Further analysis by normal-phase HPLC showed that the 2-aminobenzamide-conjugated oligosaccharide had a hydrodynamic volume of 4.58 glucose units (HPAgly 1), Increased expression of HPAgly 1 was associated with HPA staining of breast-cancer specimens (Student's t-test p = 0.025). Analysis of oligosaccharide levels and disease-free survival after treatment for breast cancer indicated a shorter disease-free interval for patients with elevated levels of HPAgly 1, This is the first time that histochemical lectin staining has been correlated with biochemical mapping of oligosaccharides, Using this approach, we have identified a monosialylated HPA lectin-binding oligosaccharide present in breast-cancer cells grown in vitro which is elevated in breast-cancer specimens that bind the lectin, (C) 2001 Wiley-Liss, Inc.

Expression of osteopontin coregulators in primary colorectal cancer and associated liver metastases

Background: A transcription regulatory complex (TRC) that includes Ets1, Ets2, PEA3 and ß-catenin/T-cell factors regulates osteopontin (OPN) that is implicated in colorectal cancer (CRC) dissemination. The consistency of OPN transcriptional control between primary CRC and metastases is unclear. This study investigates expression and prognostic significance of the OPN–TRC in primary human CRC and associated colorectal liver metastases (CRLM).

Methods: Osteopontin–TRC factors were assayed by digital microscopy in 38 primary CRCs and matched CRLM specimens and assessed against clinical prognosis.

Results: In primary CRC, OPN expression intensity correlated with that of its co-activators, PEA3 (r=0.600; P<0.01), Ets1 (r=0.552; P<0.01), Ets2 (r=0.521; P<0.01) and had prognostic significance. Osteopontin intensity in primary CRC inversely correlated with the interval between diagnosis and resection of CRLM. Overall OPN intensity was lower in CRLM than primary CRC and correlations with co-activators were weaker, for example, Ets1 (P=0.047), PEA3 (P=0.022) or nonsignificant (Ets2). The ratio of OPN expression in CRLM vs primary CRC had prognostic significance.

Conclusion: This study supports transcriptional control of OPN by known coregulators in both primary and secondary CRC. Weaker associations in CRLM suggest involvement of other unknown factors possibly from the liver microenvironment or resulting from additional genetic or epigenetic changes that drive tumour metastatic capability in OPN transcriptional control.