Emerging pathways in colorectal-cancer development

The past decade has seen the emergence of new pathways in the development of colorectal cancer. There is now clear evidence that subsets of these tumours do not show chromosomal instability and do not follow the suppressor pathway. Instead, about 15% of colorectal cancers are characterised by microsatellite instability (MSI). This feature arises through defective DNA mismatch repair, which is related either to a germline mutation (as in hereditary non-polyposis colorectal carcinoma) or to failure to express a mismatch-repair gene. CpG-island methylation has been linked to sporadic cancers with a high frequency of MSI. This type of methylation leads to loss of gene expression when it occurs in the promoter region of a gene. Tumours may have high or low type C (cancer-related) CpG-island methylation. When methylation affects hMLH1 (mismatch repair gene), the resultant cancer has high MSI.

Oral cancer in Australia: 1983-1996

Background: The aims of this study were to identify differences in oral cancer incidence and mortality between sexes, age groups, oral sites and Australian States and Territories and recent trends in oral cancer incidence, mortality and age-profile over time. Methods: Data were obtained from the Australian Institute for Health and Welfare and were age-standardized to the Australian 1991 Population Standard. Differences and trends were assessed with the Wilcoxon matched-pairs signed-ranks test and the Spearman correlation test, respectively. Results: In Australia in 1996, there were 2173 new oral cancers and 400 deaths due to oral cancer, the majority of oral cancers were in the 60+ age group, oral cancer affected men more than women (>2:1), lip cancer accounted for more than 50 per cent of oral cancers and the oral cancer mortality-to-incidence (M:I) ratio was greatest in ACT and NSW and least in QLD and SA. From 1983 to 1996, the annual incidence of lip cancer increased while the M:I ratio of lip cancer decreased. The annual incidence of cervical cancer decreased whereas the annual incidence of intra-oral cancer remained constant. The M:I ratio of cervical cancer was consistently lower than the MA ratio of intra-oral cancer. Conclusions; Reducing exposure to environmental carcinogens, increasing public awareness and population screening may reduce the incidence and mortality of oral cancer in Australia.

Morphological and molecular heterogeneity within nonmicrosatellite instability-high colorectal cancer

Colorectal cancer (CRC) has traditionally been classified into two groups: microsatellite stable/low-level instability (MSS/MSI-L) and high-level MSI (MSI-H) groups on the basis of multiple molecular and clinicopathologic criteria. Using methylated in tumor (MINT) markers 1, 2,12, and 31, we stratified 77 primary CRCs into three groups: MINT++ (>2), MINT+ (1-2), and MINT- (0 markers methylated). The MSS/MSI-L/ MINT++ group was indistinguishable from the MSI-H/MINT++ group with respect to methylation of p16(INK4a), p14(ARF), and RIZ1, and multiple morphological features. The only significant difference between MSI-H and non-MSI-H MINT++ cancers was the higher frequency of K-ras mutation (P < 0.004) and lower frequency of hMLH1 methylation (P < 0.001) in the latter. These data demonstrate that the separation of CRC into two nonoverlapping groups (MSI-H versus MSS/MSI-L) is a misleading oversimplification.

An inverse design of an open, head/neck RF coil for MRI

Radio-frequency (RF) coils are a necessary component of magnetic resonance imaging (MRI) systems. When used in transmit operation, they act to generate a homogeneous RF magnetic field within a volume of interest and when in receive operation, they act to receive the nuclear magnetic resonance signal from the RF-excited specimen. This paper outlines a procedure for the design of open RF coils using the time-harmonic inverse method. This method entails the calculation of an ideal current density on a multipaned planar surface that would generate a specified magnetic field within the volume of interest. Because of the averaging effect of the regularization technique in the matrix solution, the specified magnetic field is shaped within an iterative procedure until the generated magnetic field matches the desired magnetic field. The stream-function technique is used to ascertain conductor positions and a method of moments package is then used to finalize the design. An open head/neck coil was designed to operate in a clinical 2T MRI system and the presented results prove the efficacy of this design methodology.

Germline BRCA1 promoter deletions in UK and Australian familial breast cancer patients: Identification of a novel deletion consistent with BRCA1 :psi VBRCA1 recombination

Inherited susceptibility to breast cancer results from germline mutations in one of a number of genes including BRCA1. A significant number of BRCA1-linked familial breast cancer patients, however, have no detectable BRCA1 mutation. This could be due in part to the inability of commonly used mutation-detection techniques to identify mutations outside the BRCA1 coding region. This paper addresses the hypothesis that non coding region mutations, specifically in the BRCA1 promoter, account for some of these cases. We describe a new and detailed restriction map of the 5' region of the BRCA1 gene including the nearby NBR2, psiBRCA1, and NBR1 genes and the isolation of a number of new informative hybridization probes suitable for Southern analysis. Using this information we screened DNA from lymphoblastoid cell-lines made from 114 UK familial breast cancer patients and detected one large deletion in the 5' region of BRCA1. We show that the breakpoints for this deletion are in BRCA1 intron 2 and between NBR2 and exon 2 of psiBRCA1, raising the possibility that this deletion arose via a novel mechanism involving BRCA1:psiBRCA1 recombination. We have also screened 60 familial breast cancer patients from the Australian population, using an amplification refractory mutation system (ARMS) technique described previously by our group, and found one patient with a genotype consistent with a BRCA1 promoter deletion. These findings indicate that germline BRCA1 promoter deletions are a rare and yet significant mutation event and that they could arise via a novel genetic mechanism. Hum Mutat 19:435-442, 2002. (C) 2002 Wiley-Liss, Inc.

Barriers to effective cancer pain management: A survey of hospitalized cancer patients in Australia

The purpose of this study was to examine attitudinal barriers to effective pain management in a consecutively recruited cohort of 114 cancer patients from four Australian hospitals. When surveyed, 48% of this sample reported experiencing pain within the previous 24 hours. Of these, 56% reported this pain to be distressing, horrible or excruciating, with large proportions indicating that this pain had affected their movement, sleep and emotional well-being. Three factors were identified as potentially impacting on patients responses to pain-poor levels of patient knowledge about pain, low perceived control over pain, and a deficit in communication about pain. A trend for older patients to experience more severe pain was also identified. These older patients reported being more willing to tolerate pain and perceive less control over their pain. Suggestions are made for developing patient education programs and farther research using concepts drawn from broader social and behavioral models. J Pain Symptom Manage 2002:23:393-405. (C) U.S. Cancer Pain Relief Committee, 2002.

Evidence from mitochondrial DNA that head lice and body lice of humans (Phthiraptera : Pediculidae) are conspecific

The specific status of the head and body lice of humans has been debated for more than 200 yr. To clarify the specific status of head and body lice, we sequenced 524 base pairs (bp) of the cytochrome oxidase I (COI) gene of 28 head and 28 body lice from nine countries. Ten haplotypes that differed by 1-5 bp at II nucleotide positions were identified. A phylogeny of these sequences indicates that these head and body lice are not from reciprocally monophyletic lineages. Indeed, head and body lice share three of the 10 haplotypes we found. F-ST values and exact tests of haplotype frequencies showed significant differences between head and body lice. However, the same tests also showed significant differences among lice from different countries. Indeed, more of the variation in haplotype frequencies was explained by differences among lice from different countries than by differences between head and body lice. Our results indicate the following: (1) bead and body lice do not represent reciprocally monophyletic lineages and are conspecific; (2) gene flow among populations of lice from different countries is limited; and (3) frequencies of COI haplotypes can be used to study maternal gene flow among populations of head and body lice and thus transmission of lice among their human hosts.

Occult Axillary Lymph Node Metastases in Breast Cancer Do Matter: Results of 10-Year Survival Analysis

Axillary lymph node status is one of the most powerful prognostic factors for patients with breast cancer and is often critical in stratifying patients into adjuvant treatment regimens. In 203 apparently node-negative cases of breast cancer, a combination of immunohistochemical staining and step-sectioning identified occult metastases in 25% of cases. Ten-year follow-up information is available for these patients. Histologic features of the primary tumor and immunohistochemical staining for estrogen receptor, progesterone receptor, Her-2, and p53 were also evaluated. With multivariate analysis, both occult metastases and higher histologic grade of the primary tumor were independent predictors of disease-free survival. Histologic grade was the only significant independent predictor of overall survival. Estrogen receptor, progesterone receptor, Her-2, and p53 status did not predict the presence of metastases or survival when all tumor types were considered together. Metastases >0.5 mm significantly predicted a poorer disease-free survival when invasive ductal carcinomas were considered alone. Histologic grade was significantly associated with disease-free survival in the premenopausal and perimenopausal patients but not in the postmenopausal patients. The presence of occult metastases approached significance for overall survival in the premenopausal and perimenopausal patients but not in the postmenopausal patients.

Expression analysis of delta-catenin and prostate-specific membrane antigen: Their potential as diagnostic markers for prostate cancer

The current approach to prostate cancer diagnosis has major limitations including the inability of prostate-specific antigen (PSA) assays to accurately differentiate between prostate cancer and benign prostate hyperplasia (BPH) and the imprecision of transrectal ultrasound (TRUS) biopsy sampling. We have employed cDNA microarray screening to compare gene expression patterns in BPH and tumour samples to identify expression markers that may be useful in discriminating between these conditions. Screening of 3 individual cDNA arrays identified 8 genes with expression 3-fold greater in 6 tumour tissues than in 1 nontumour sample and I BPH sample. Real-time PCR was used to confirm the overexpression of these 8 genes and 12 genes selected from the literature against a panel of 17 tumours and I 1 BPH samples. Two genes, delta-catenin (delta-catenin; CTNND2) and prostate-specific membrane antigen (PSMA; FOLH1), were significantly overexpressed in prostate cancer compared to BPH. Prostate epithelial cells stained positively for S-catenin and PSMA in our prostate cancer tissues, whereas the majority of our BPH tissues were negative for both markers. Thus we have identified delta-catenin (not previously associated with prostatic adenocarcinoma) and confirmed the potential of PSMA as potential candidates for the diagnosis and management of prostate cancer. (C) 2002 Wiley-Liss. Inc.

Making decisions about treatment for localized prostate cancer

Objective To describe the decision-making processes used by men diagnosed with localized prostate cancer who were considering treatment. Patients and methods Men newly diagnosed with localized prostate cancer from outpatient urology clinics and urologist's private practices were approached before treatment. Their decision-making processes and information-seeking behaviour was assessed; demographic information was also obtained. Results Of 119 men approached, 108 (90%) were interviewed; 91% reported non-systematic decision processes, with deferral to the doctor, positive and negative recollections of others' cancer experiences, and the pre-existing belief that surgery is a better cancer treatment being most common. For systematic information processing the mean (SD, range) number of items considered was 4.19 (2.28, 0-11), with 57% of men considering four or fewer treatment/medical aspects of prostate cancer. Men most commonly considered cancer stage (59%), urinary incontinence (55%) and impotence (51%) after surgery, and low overall mortality (45%). Uncertainty about probabilities for cure was reported by 43% of men and fear of cancer spread by 37%. Men also described uncertainty about the probabilities of side-effects (27%), decisional uncertainty (25%) and anticipated decisional regret (18%). Overall, 73% of men sought information about prostate cancer from external sources, most commonly the Internet, followed by family and friends. Conclusions In general, men did not use information about medical treatments comprehensively or systematically when making treatment decisions, and their processing of medical information was biased by their previous beliefs about cancer and health. These findings have implications for the provision of informational and decisional support to men considering prostate cancer treatment.