Tissue-based biomarkers predicting outcomes in metastatic colorectal cancer: a review

Although there have been recent advances in the treatment of metastatic colorectal cancer, particularly with systemic chemotherapy, new biological agents and surgical metastasectomy, the disease remains difficult to treat. To personalise the management of mCRC and optimise patient outcomes, it is vital to acquire a deeper understanding of its natural history and mechanisms behind disease progression. This may be achieved by extensive study of tumour biomarkers: proteins or genetic alterations within neoplastic cells or their surrounding stroma that may be used to predict patient outcomes, disease trajectory and response to various therapies. The discovery of mutant Kirsten-RAS in determining patients who may be refractory to anti-epidermal growth factor receptor treatments has reinvigorated and reiterated the importance of our attempts to individualise cancer care. While many biomarkers have been studied and shown promise in the setting of mCRC, they are, with the exception of K-ras testing not used currently in a clinical setting due to conflicting results, small patient samples and methodological variations. Larger, multi-centric studies with uniform methods of tumour marker study are required to effectively tailor systemic therapies and select appropriate candidates for surgical metastasectomy (AU)

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A systematic review of local excision combined with chemoradiotherapy for early rectal cancer.

AIM: Local excision of early rectal cancer is a less morbid alternative to major abdominal surgery. This review evaluates the role of local excision with neoadjuvant or adjuvant chemoradiotherapy to identify a select group of patients where local excision is appropriate without significantly compromising the oncological outcome. METHOD: MEDLINE, PubMed and the Cochrane Central Register of Controlled Trials databases were searched to identify relevant articles investigating the role of local excision with adjuvant or neoadjuvant chemoradiotherapy in patients with T1/T2N0M0 disease. Eleven studies comprising 455 patients were selected. Oncological end-points included overall survival, disease-free and disease-specific survival, recurrence rates as well as perioperative morbidity and mortality. RESULTS: At a range of 30.5-115.2 months, median overall survival, disease-specific and disease-free survival were 75% (66-80.6%), 89% (75-93.3%) and 74% (64-85.2%), respectively. Median local, distant and overall recurrence rates were 10% (4.8-25%), 4.7% (4-11.8%) and 13.1% (10.7-23.5%), respectively. Mortality was 0% in all studies except one (2.9%). Most reported complications were minor and were treated conservatively. CONCLUSION: This systematic review provides data suggesting that selected patients with T1/T2N0M0 rectal cancer may undergo local excision without compromising the oncological outcome otherwise conferred by total mesorectal excision. It may be a particularly useful option in patients in whom radical surgery is contraindicated. Randomized trials comparing both management strategies to consolidate this finding may lead to a paradigm change in the management of early rectal cancer.

Tissue-based biomarkers predicting outcomes in metastatic colorectal cancer: a review.

Although there have been recent advances in the treatment of metastatic colorectal cancer, particularly with systemic chemotherapy, new biological agents and surgical metastasectomy, the disease remains difficult to treat. To personalise the management of mCRC and optimise patient outcomes, it is vital to acquire a deeper understanding of its natural history and mechanisms behind disease progression. This may be achieved by extensive study of tumour biomarkers: proteins or genetic alterations within neoplastic cells or their surrounding stroma that may be used to predict patient outcomes, disease trajectory and response to various therapies. The discovery of mutant Kirsten-RAS in determining patients who may be refractory to anti-epidermal growth factor receptor treatments has reinvigorated and reiterated the importance of our attempts to individualise cancer care. While many biomarkers have been studied and shown promise in the setting of mCRC, they are, with the exception of K-ras testing not used currently in a clinical setting due to conflicting results, small patient samples and methodological variations. Larger, multi-centric studies with uniform methods of tumour marker study are required to effectively tailor systemic therapies and select appropriate candidates for surgical metastasectomy.

The psychosocial burden of human papillomavirus related disease and screening interventions.

OBJECTIVES: (i) To assess the psychosocial burden of testing for human papillomavirus (HPV) related genital disease or of a HPV-related diagnosis; (ii) to compare an instrument specifically designed to measure HPV-related psychosocial burden with other generic quality of life (QoL) instruments. METHODS: A cross-sectional design. Researchers recruited women from outpatient clinics at a major tertiary women's hospital and a sexual health centre who completed surveys within 3 months of receiving RESULTS: 331 women, 18-45 years, who had experienced a normal cervical Papanicolaou (Pap) result, an abnormal Pap result, biopsy confirmed cervical intraepithelial neoplasia (CIN) or external genital warts (EGW). MAIN OUTCOME MEASURES: The HPV impact profile (HIP) designed to assess the psychosocial impact of HPV; two general health-related QoL surveys-the EuroQoL VAS and the Sheehan disability scale; and a HPV knowledge survey. RESULTS: Response rate was 78%. Significant psychosocial impacts were found for women screened for, or having a diagnosis of, HPV-related genital disease. The largest impact was in women with CIN 2/3 and EGW. This HPV-related psychosocial impact was most sensitively detected with the HIP. Relative to generic measures of QoL, the HIP provided insight into the full range of psychosocial impacts of HPV testing and diagnoses. CONCLUSIONS: Clinicians need to be aware of the potential psychosocial impact of testing for or diagnosing HPV-related genital disease, in particular CIN 2/3 and EGW. The HIP survey is a more sensitive measure of the psychosocial impact of HPV-related genital disease than generic QoL surveys.

A loss-of-function polymorphic mutation in the cytolytic P2X7 receptor gene and chronic lymphocytic leukaemia: a molecular study.

BACKGROUND: Chronic lymphocytic leukaemia (CLL) has a familial incidence nearly three times higher than expected for the general population and one predisposing factor might be an inherited failure of mechanisms involved in apoptosis of lymphocytes. Our aim was to ascertain whether or not a defect in a proapoptotic pathway, caused by a single nucleotide polymorphism that results in loss-of-function of P2X7 in healthy individuals, was present in leukaemic B lymphocytes of patients with CLL. METHODS: We extracted genomic DNA from the peripheral blood leucocytes of 36 unrelated individuals with CLL, four individuals with familial CLL, and 46 age-matched controls. We sequenced a PCR product to detect mutations in exon 13 of P2X7. In most patients with CLL, we measured expression and function of the P2X7 receptor by flow cytometry in B lymphocytes and T lymphocytes. FINDINGS: The prevalence of the polymorphic mutation and the frequency of the mutant allele were three-fold greater in individuals with CLL than in white, elderly controls. Individuals homozygous for the polymorphic allele had no P2X7 receptor function and heterozygotes had half the mean function of that seen in individuals homozygous for the wildtype allele; amounts of ATP-induced apoptosis varied accordingly. In two families, in which we studied a father-son pair and a sister-sister pair with CLL, loss of P2X7 function arose because of inheritance of one or two 1513A-->C alleles for P2X7. INTERPRETATION: Activation of the P2X7 receptor leads to apoptosis of lymphocytes in individuals with CLL, and reduced function of this receptor has an anti-apoptotic effect, resulting in an increase in B-cell numbers. Thus, inheritance of a loss-of-function polymorphic mutation at position 1513 in the P2X7 gene could contribute to the pathogenesis of CLL.

Computerized breast thermography: study of image segmentation and temperature cyclic variations.

Breast cancer is a common and dreadful disease in women. The surface temperature and the vascularization pattern of the breast could indicate breast diseases. Establishing the surface isotherm pattern of the breast and the normal range of cyclic variations of temperature distribution can assist in identifying the abnormal infrared images of diseased breasts. This paper investigates the cyclic variation of temperature and vascularization of the normal breast thermograms under a controlled environment. More than 50 Asian women, were examined and some of them have been examined continuously for two month. All together, not less than 800 thermograms were obtained. Before these thermograms can be analysed objectively via a computer algorithm, they must be digitized and segmented. The authors present a method to segment thermograms and extract the useful region from the background. After the image processing, these thermograms can be analysed and then the best time to perform an examination can be chosen. All these results are important for establishing a data bank of normal breast thermography, to choose the best time for an examination and as a systematic methodology for evaluating and analysing the abnormal breast thermography in the future.

Clinical decisions using the National Triage Scale: how important is postgraduate education?

Triage is the formal nursing assessment of all patients who present to an Emergency Department (ED). The National Triage Scale (NTS) is used in most Australian EDs. Triage decision making involves the allocation of every patients presenting to an ED to one of the five NTS categories. The NTS directly relates a triage category to illness or injury severity and need for emergency care. Triage nurses' decisions not only have the potential to impact on the health outcomes of ED patients, they are also used, in part, to evaluate ED performance and allocate components of ED funding. This study was a correlational study that used survey methods. Triage decisions were classified as 'expected triage', 'overtriage' or 'undertriage' decisions. Participant's qualifications were allocated to five categories: 'nil'; 'emergency nursing'; 'critical care nursing'; 'midwifery'; and 'tertiary' qualifications. There was no correlation between triage decisions and length of experience in emergency nursing or triage. 'Expected triage' decisions were more common when the predicted triage category was Category 3 (P < 0.001) and 'overtriage' decisions were less common when the predicted triage category was Category 2 (P < 0.0010). The frequency of 'undertriage' decisions decreased significantly when the predicted triage category was Category 3 (P < 0.001) or Category 4 (P < 0.001). There was no correlation between triage decisions and qualifications in the 'nil', 'emergency nursing' or 'critical care nursing' categories. A midwifery qualification demonstrated a positive correlation with 'expected triage' decisions (P = 0.048) and a negative correlation with 'undertriage' decisions (P = 0.012). There was also a positive correlation between a tertiary qualification and 'expected triage' decisions (P = 0.012).

Statistical analysis of healthy and malignant breast thermography.

Analysis of thermograms has often been subjective and has resulted in inconsistency in the diagnosis of breast diseases by thermography. The aim of this paper is to study the problem of subjective interpretation of breast thermograms and hence using thermography as an adjunct tool for breast cancer diagnosis. It ws proposed that the thermograms should be taken within the recommended screening period, classified and analysed in conjunction with an artificial neural network (ANN). Qualitative interpretation of thermal images can be carried out using an active contours algorithm. The 256 x 200 pixel image can be segmented as one of the inputs to the ANN. To achieve quantitative analysis of the breast thermograms, firstly the inputs of the ANN should be determined, so that the thermograms could be successfuly classified and based on the suggested inputs.

Triage nurses' decisions using the National Triage Scale for Australian emergency departments.

The initiation of emergency care primarily depends on the decisions made by the triage nurse. Triage decisions can therefore have a profound effect on the health outcomes of patients who present for emergency care. If the National Triage Scale (NTS) was effective in providing a standardized approach to triage, a patient with a specific problem should be allocated to the same triage category, irrespective of the institution to which they present or the personnel performing the role of triage. This study examines triage nurses' level of agreement in their allocation of triage categories to patients with specific presenting problems using the NTS. Relationships between demographic characteristics of participants and triage decisions are examined and implications of any variation for triage practice and patient outcomes are explored.

Glucocorticoid-induced effects on pattern formation and epithelial cell differentiation in early embryonic rat lungs.

In this study, we examined the effects of dexamethasone (DEX) on airway branching and subsequent lung maturation. DEX treatment of fetal rat lung explants was initiated during the early pseudoglandular stage of development. Day 14 fetal lung explants were cultured with and without DEX for 4 d. Explants treated with 10 nM or higher concentrations of DEX showed features of both distorted and accelerated maturation. DEX-treated lungs had growth retardation, distorted branching, dilated proximal tubules, and suppressed proliferation of epithelial cells of the distal tubules. Several biochemical and morphologic features of accelerated maturation were also observed: 1) the epithelial cells lining the distal tubules (prospective respiratory airways) were generally cuboidal or flattened; 2) the cuboidal cells often contained lamellar bodies and abundant glycogen; 3) rudimentary septa and large airspace were present; 4) mesenchymal tissue was attenuated and compressed between adjacent epithelial tubules; 5) the distribution of SP-C mRNA in distal tubules was more mature, with individual and clusters of cells expressing SP-C transcripts; and 6) the transcript levels of several genes related to epithelial growth [keratinocyte growth factor (KGF), KGF receptor, and hepatocyte growth factor receptor] and differentiation [surfactant proteins, SP-A, SP-B and SP-C and the Clara cell secretory protein, CC10] were precociously increased. These results show that DEX treatment of the lung during the early pseudoglandular stage accelerates the acquisition of several features of advanced maturation that normally accompany late stages of fetal development. We postulate that KGF mediates at least some effects of DEX on lung maturation and gene expression.

Keratinocyte growth factor and embryonic rat lung morphogenesis.

We examined possible roles of keratinocyte growth factor (KGF) and hepatocyte growth factor (HGF) in lung morphogenesis. By polymerase chain reaction, transcripts for both KGF and its receptor were detected early (rat gestational days 16 and 14, respectively) and their abundance increased during lung morphogenesis. To evaluate possible role of KGF in lung morphogenesis, day 14 lung explants were cultured in Dulbecco's modified Eagle medium + 10% fetal calf serum for 1 to 4 days in the presence (5-50 ng/ml) or absence of KGF (control). KGF (at 25 and 50 ng/ml) induced a marked reduction in the number of terminal branches and destination of the distal epithelium into cyst-like structures. These effects of exogenous KGF were progressively diminished by increasing concentrations of anti-KGF (2-16 micrograms/ml). Electron microscopic examination revealed that the epithelial cells of the cystic structures contained lamellar bodies, and were therefore type II cells and/or their progenitors. Northern blot analysis showed higher expression of surfactant protein C (SP-C) mRNA (a marker for alveolar epithelial type II cells) in KGF-treated fetal lungs. In situ hybridization of the KGF-treated lungs revealed that the SP-C mRNA-expressing cells were arranged distally in the form of linear arrays, a pattern distinctly different from that in control lungs. Acidic fibroblast growth factor, which also binds KGF receptors, in the presence of heparin mimicked the effect of KGF on branching. Transforming growth factor-beta(1) (TGF-beta 1) inhibited branching of fetal lungs in culture, and this effect dominated over that induced by KGF. Blocking of endogenous HGF with antibodies or addition of HGF to cultures of fetal lung explants had no significant effect on branching or growth. In conclusion, KGF markedly influences branching, and epithelial growth, differentiation, and patterning during lung morphogenesis.