Health-care workers' understanding of and barriers to palliative care services to Aboriginal children with cancer.

AIM: To identify barriers in the understanding and provision of optimal palliative care to Aboriginal children with cancer by health-care staff, with the aim to support education and training that highlights the importance of cultural, physical and spiritual needs at end-of-life. METHODS: Medical and nursing staff working in Departments of Palliative Care, Metabolic Medicine and Haematology/Oncology at the Women's and Children's Hospital in Adelaide, South Australia, were asked to complete a survey regarding their experience in treating Aboriginal children receiving palliative care. The survey addressed the understanding of cultural and spiritual needs, barriers encountered and opinions for improved services. RESULTS: The survey was completed by 34 participants. 91.2% (n = 31) had provided care to Aboriginal children who were receiving care during palliative and end-of-life phases for a diagnosis of cancer, 58.8% (n = 20) of which had supported children returning home. Only 23.5% of participants reported comfort in communicating about spiritual/cultural needs with patients and families. There was minimal previous exposure to education (17.6%), yet all participants were interested in future education opportunities. CONCLUSION: This study highlights a paucity in understanding and comfort among health-care workers in treating Aboriginal children at end-of-life. New models, including the training of staff, educational resources and involvement of Aboriginal health-care workers, may improve care.

BRCA1 and BRCA2 mutations and the risk for colorectal cancer.

Women who carry a BRCA1 or BRCA2 mutation are at high risk of breast and ovarian cancer, and may be at moderately increased risk of other cancer types. This review examines studies to date that have evaluated the risk of BRCA1 and BRCA2 mutations for colorectal cancer. Accurate knowledge of colorectal cancer risk in BRCA1/2 carriers is important, because colonoscopy screening can prevent colorectal cancer through the removal of adenomatous polyps. Most studies that have identified an increased risk for colorectal cancer in BRCA1/2 mutation carriers were in high-risk cancer families, while studies that found no association were conducted in specific populations and involved the analysis of founder mutations. A recent prospective study of 7015 women with a BRCA1 or BRCA2 mutation identified significant fivefold increased risk of colorectal cancer among BRCA1 mutation carriers younger than 50 years [standardized incidence ratio (SIR): 4.8; 95% CI: 2.2-9], but not in women with a BRCA2 mutation or in older women. Based on this evidence, women with BRCA1 mutations should be counseled about their increased risk for early-onset colorectal cancer, and offered colonoscopy at 3- to 5-year intervals between the ages of 40 and 50 years, and should follow population guidelines thereafter.

Incidence of colorectal cancer in BRCA1 and BRCA2 mutation carriers: results from a follow-up study.

BACKGROUND: The BRCA1 and BRCA2 genes confer increased susceptibility to breast and ovarian cancer and to a spectrum of other cancers. There is controversy regarding the risk of colorectal cancer conferred by germline mutations in these two genes. METHODS: We followed 7015 women with a BRCA mutation for new cases of colorectal cancer. Incidence rates in carriers were compared with population-specific incidence rates, and standardised incidence ratios (SIRs) were estimated. The expected numbers of cancers were computed by multiplying person-years at risk by the appropriate age-, sex- and country-specific incidence rates from the five countries. RESULTS: Twenty-one incident colorectal cancer cases were observed among all mutation carriers, compared with 23.6 cases expected. The SIR for BRCA1 carriers was 0.92 (95% confidence interval (CI), 0.54-1.40, P=0.7) and for BRCA2 carriers was 0.82 (95% CI, 0.30-1.81, P=0.7). The SIR for colon cancer was 3.81 (95% CI 1.77-7.23) for women below the age of 50 years (both genes combined) and was 0.60 (95% CI 0.33-1.00) for women aged 50 years and above. CONCLUSION: The risk of colorectal cancer is increased in female carriers of BRCA1 mutations below the age of 50 years but not in women with BRCA2 mutations or in older women.

Modes of delivery of genetic testing services and the uptake of cancer risk management strategies in BRCA1 and BRCA2 carriers.

BRCA testing services are now offered by various healthcare providers, thus it is important to evaluate whether the implementation of cancer risk management (CRM) strategies varies by service provider. Using a registry-based sample of 795 female BRCA mutation carriers, we explored the association between uptake of CRM strategies with duration of genetic counseling (GC) sessions, provider type, and other demographic and clinical variables. All participants completed a baseline questionnaire. Information about uptake of CRM strategies was collected for a subset of 438 participants who completed additional questions. Summary statistics and Pearson chi-squared analysis were used to examine the associations between demographic and clinical variables with service delivery factors and with the uptake of various CRM strategies. Overall uptake of CRM strategies was high across all provider types. However, GC sessions were longer when provided by a genetics professional than by another provider (p < 0.001). Furthermore, higher frequencies of uptake of most CRM strategies were associated with longer GC sessions and when testing was performed by a genetics professional. Identification of factors to optimize delivery of these specialized GC services is important to maximize implementation of CRM strategies in BRCA carriers.

Shaping the evanescent field of optical nanofibers for cold atom trapping.

We investigate trapping geometries for cold, neutral atoms that can be created in the evanescent field of a tapered optical fibre by combining the fundamental mode with one of the next lowest possible modes, namely the HE(21) mode. Counter propagating red-detuned HE(21) modes are combined with a blue-detuned HE(11) fundamental mode to form a potential in the shape of four intertwined spirals. By changing the polarization from circular to linear in each of the two counter-propagating HE(21) modes simultaneously the 4-helix configuration can be transformed into a lattice configuration. The modification to the 4-helix configuration due to unwanted excitation of the the TE(01) and TM(01) modes is also discussed.

Evidence for the complete inactivation of the NF2 gene in the majority of sporadic meningiomas.

Meningiomas are common central nervous system tumours which present usually in the 4th and 5th decades of life. Loss of constitutional heterozygosity on chromosome 22 in 60% of sporadic meningiomas has implied the involvement of a tumour suppressor gene. The neurofibromatosis type 2 gene (NF2), a prime candidate for involvement in meningioma, was screened for point mutations. After examining eight of the 16 known NF2 exons in 151 meningiomas, 24 inactivating mutations were characterized. Significantly, these aberrations were exclusively detected in tumours which lost the other chromosome 22 allele. These results provide strong evidence that the suppressor gene on chromosome 22, frequently inactivated in meningioma, is the NF2 gene, and suggest that another gene is involved in the development of 40% of meningiomas.

Mutation analysis of the BRCA2 gene in 49 site-specific breast cancer families.

The hereditary breast cancer gene BRCA2 was recently cloned and is believed to account for almost half of site-specific breast cancer families and the majority of male breast cancer families. We screened 49 site-specific breast cancer families for mutations in the BRCA2 gene using single strand conformation analysis (SSCA) followed by direct sequencing. We found mutations in eight families, including all four families with male breast cancer. The eight mutations were small deletions with the exception of a single nonsense mutation, an all were predicted to interrupt the BRCA2 coding sequence and to lead to a truncated protein product. Other factors which predicted the presence of a BRCA2 mutation included a case of breast cancer diagnosed at age 35 or below (P = 0.01) and a family history of pancreatic cancer (P = 0.03). Two mutations were seen twice, including a 8535delAG, which was detected in two French Canadian families. Our results suggest the possibility that the proportion of site-specific breast cancer families attributable to BRCA2 may be overestimated.

Ovarian cancer risk in BRCA1 carriers is modified by the HRAS1 variable number of tandem repeat (VNTR) locus.

Women who carry a mutation in the BRCA1 gene (on chromosome 17q21), have an 80% risk of breast cancer and a 40% risk of ovarian cancer by the age of 70 (ref. 1). The variable penetrance of BRCA1 suggests that other genetic and non-genetic factors play a role in tumourigenesis in these individuals. The HRAS1 variable number of tandem repeats (VNTR) polymorphism, located 1 kilobase (kb) downstream of the HRAS1 proto-oncogene (chromosome 11p15.5) is one possible genetic modifier of cancer penetrance. Individuals who have rare alleles of the VNTR have an increased risk of certain types of cancers, including breast cancer (2-4). To investigate whether the presence of rare HRAS1 alleles increases susceptibility to hereditary breast and ovarian cancer, we have typed a panel of 307 female BRCA1 carriers at this locus using a PCR-based technique. The risk for ovarian cancer was 2.11 times greater for BRCA1 carriers harbouring one or two rare HRAS1 alleles, compared to carriers with only common alleles (P = 0.015). The magnitude of the relative risk associated with a rare HRAS1 allele was not altered by adjusting for the other known risk factors for hereditary ovarian cancer (5). Susceptibility to breast cancer did not appear to be affected by the presence of rare HRAS1 alleles. This study is the first to show the effect of a modifying gene on the penetrance of an inherited cancer syndrome.

BRCA2 mutations in primary breast and ovarian cancers.

The second hereditary breast cancer gene, BRCA2, was recently isolated. Germline mutations of this gene predispose carriers to breast cancer, and, to a lesser extent, ovarian cancer. Loss of heterozygosity (LOH) at the BRCA2 locus has been observed in 30-40% of sporadic breast and ovarian tumours, implying that BRCA2 may act as a tumour suppressor gene in a proportion of sporadic cases. To define the role of BRCA2 in sporadic breast and ovarian cancer, we screened the entire gene for mutations using a combination of techniques in 70 primary breast carcinomas and in 55 primary epithelial ovarian carcinomas. Our analysis revealed alterations in 2/70 breast tumours and none of the ovarian carcinomas. One alteration found in the breast cancers was a 2-basepair (bp) deletion (4710delAG) which was subsequently shown to be a germline mutation, the other was a somatic missense mutation (Asp3095Glu) of unknown significance. Our results suggest that BRCA2 is a very infrequent target for somatic inactivation in breast and ovarian carcinomas, similar to the results obtained for BRCA1.

Optical trapping using cascade conical refraction of light.

Cascade conical refraction occurs when a beam of light travels through two or more biaxial crystals arranged in series. The output beam can be altered by varying the relative azimuthal orientation of the two biaxial crystals. For two identical crystals, in general the output beam comprises a ring beam with a spot at its centre. The relative intensities of the spot and ring can be controlled by varying the azimuthal angle between the refracted cones formed in each crystal. We have used this beam arrangement to trap one microsphere within the central spot and a second microsphere on the ring. Using linearly polarized light, we can rotate the microsphere on the ring with respect to the central sphere. Finally, using a half wave-plate between the two crystals, we can create a unique beam profile that has two intensity peaks on the ring, and thereby trap two microspheres on diametrically opposite points on the ring and rotate them around the central sphere. Such a versatile optical trap should find application in optical trapping setups.

Conical diffraction of a Gaussian beam with a two crystal cascade.

Internal conical diffraction by biaxial crystals with aligned optic axes, known as cascade conical diffraction is investigated. Formulae giving the intensity distributions for a cascade conically diffracted Gaussian beam are shown to compare well with experiment for the cases of two biaxial crystals with the same and different lengths and with the second crystal rotated with respect to the first. The effects of placing half wave-plates between crystals are also investigated.

Generation of a radially polarized light beam using internal conical diffraction.

Using a combination of internal conical diffraction and Mach-Zehnder interferometry we have theoretically and experimentally demonstrated an efficient new technique for the conversion of a linearly polarized Gaussian laser beam to one with radial polarization. These methods that can be adapted to yield either ring-shaped or first order Bessel beams which are radially polarized.

The creation and annihilation of optical vortices using cascade conical diffraction.

Internal conical diffraction produces a superposition of orthogonally polarised zero- and first-order Bessel like beams from an incident circularly polarised Gaussian beam. For right-circularly polarised light, the first-order beam has an optical vortex of charge -1. Upon propagation of the first-order beam through a second biaxial crystal, a process which is termed cascade conical refraction, the generated beam is a superposition of orthogonally polarised fields of charge 0 and -1 or 0 and -2. This spin to orbital angular momentum conversion provides a new method for the generation and annihilation of optical vortices in an all-optical arrangement that is solely dependent on the incident polarisation and vortex handedness.

Conical diffraction of linearly polarised light controls the angular position of a microscopic object.

Conical diffraction of linearly polarised light in a biaxial crystal produces a beam with a crescent-shaped intensity profile. Rotation of the plane of polarisation produces the unique effect of spatially moving the crescent-shaped beam around a ring. We use this effect to trap microspheres and white blood cells and to position them at any angular position on the ring. Continuous motion around the circle is also demonstrated. This crescent beam does not require an interferometeric arrangement to form it, nor does it carry optical angular momentum. The ability to spatially locate a beam and an associated trapped object simply by varying the polarisation of light suggests that this optical process should find application in the manipulation and actuation of micro- and nano-scale physical and biological objects.

Generation of continuously tunable fractional optical orbital angular momentum using internal conical diffraction.

When a left-circularly polarised Gaussian light beam, which has spin angular momentum (SAM) J(sp) = sigmah = 1h per photon, is incident along one of the optic axes of a slab of biaxial crystal it undergoes internal conical diffraction and propagates as a hollow cone of light in the crystal. The emergent beam is a superposition of equal amplitude zero and first order Bessel like beams. The zero order beam is left-circularly polarised with zero orbital angular momentum (OAM) J(orb) = [see text]h = 0, while the first order beam is right-circularly polarized but carries OAM of J(orb) = 1h per photon. Thus, taken together the two beams have zero SAM and J(orb) = (1/2)h per photon. In this paper we examine internal conical diffraction of an elliptically polarised beam, which has fractional SAM, and demonstrate an all-optical process for the generation light beams with fractional OAM up to +/- 1h.

Cell cycle genes and ovarian cancer susceptibility: a tagSNP analysis.

BACKGROUND: Dysregulation of the cell cycle is a hallmark of many cancers including ovarian cancer, a leading cause of gynaecologic cancer mortality worldwide. METHODS: We examined single nucleotide polymorphisms (SNPs) (n=288) from 39 cell cycle regulation genes, including cyclins, cyclin-dependent kinases (CDKs) and CDK inhibitors, in a two-stage study. White, non-Hispanic cases (n=829) and ovarian cancer-free controls (n=941) were genotyped using an Illumina assay. RESULTS: Eleven variants in nine genes (ABL1, CCNB2, CDKN1A, CCND3, E2F2, CDK2, E2F3, CDC2, and CDK7) were associated with risk of ovarian cancer in at least one genetic model. Seven SNPs were then assessed in four additional studies with 1689 cases and 3398 controls. Association between risk of ovarian cancer and ABL1 rs2855192 found in the original population [odds ratio, OR(BB vs AA) 2.81 (1.29-6.09), P=0.01] was also observed in a replication population, and the association remained suggestive in the combined analysis [OR(BB vs AA) 1.59 (1.08-2.34), P=0.02]. No other SNP associations remained suggestive in the replication populations. CONCLUSION: ABL1 has been implicated in multiple processes including cell division, cell adhesion and cellular stress response. These results suggest that characterization of the function of genetic variation in this gene in other ovarian cancer populations is warranted.

Conical diffraction and Bessel beam formation with a high optical quality biaxial crystal.

The manipulation of a Gaussian laser beam using conical diffraction in a high optical quality biaxial crystal of KGd(WO(4))(2) has been examined in detail with emphasis on the experimental techniques involved and intuitive explanations of the notable features. Two different optical arrangements were used to form the Pogendorff double-ring light pattern in the focal image plane. The formation of both diverging and non-diverging zeroth and first order Bessel beams was investigated. The various intensity distributions and polarization properties were measured and compared with the predictions of well-established theory.

Universal DNA array detection of small insertions and deletions in BRCA1 and BRCA2.

Array-based mutation detection methodology typically relies on direct hybridization of the fluorescently labeled query sequence to surface-bound oligonucleotide probes. These probes contain either small sequence variations or perfect-match sequence. The intensity of fluorescence bound to each oligonucleotide probe is intended to reveal which sequence is perfectly complementary to the query sequence. However, these approaches have not always been successful, especially for detection of small frameshift mutations. Here we describe a multiplex assay to detect small insertions and deletions by using a modified PCR to evenly amplify each amplicon (PCR/PCR), followed by ligase detection reaction (LDR). Mutations were identified by screening reaction products with a universal DNA microarray, which uncouples mutation detection from array hybridization and provides for high sensitivity. Using the three BRCA1 and BRCA2 founder mutations in the Ashkenazi Jewish population (BRCA1 185delAG; BRCA1 5382insC; BRCA2 6174delT) as a model system, the assay readily detected these mutations in multiplexed reactions. Our results demonstrate that universal microarray analysis of PCR/PCR/LDR products permits rapid identification of small insertion and deletion mutations in the context of both clinical diagnosis and population studies.

Classification of BRCA1 missense variants of unknown clinical significance.

BACKGROUND: BRCA1 is a tumour suppressor with pleiotropic actions. Germline mutations in BRCA1 are responsible for a large proportion of breast-ovarian cancer families. Several missense variants have been identified throughout the gene but because of lack of information about their impact on the function of BRCA1, predictive testing is not always informative. Classification of missense variants into deleterious/high risk or neutral/low clinical significance is essential to identify individuals at risk. OBJECTIVE: To investigate a panel of missense variants. METHODS AND RESULTS: The panel was investigated in a comprehensive framework that included (1) a functional assay based on transcription activation; (2) segregation analysis and a method of using incomplete pedigree data to calculate the odds of causality; (3) a method based on interspecific sequence variation. It was shown that the transcriptional activation assay could be used as a test to characterise mutations in the carboxy-terminus region of BRCA1 encompassing residues 1396-1863. Thirteen missense variants (H1402Y, L1407P, H1421Y, S1512I, M1628T, M1628V, T1685I, G1706A, T1720A, A1752P, G1788V, V1809F, and W1837R) were specifically investigated. CONCLUSIONS: While individual classification schemes for BRCA1 alleles still present limitations, a combination of several methods provides a more powerful way of identifying variants that are causally linked to a high risk of breast and ovarian cancer. The framework presented here brings these variants nearer to clinical applicability.

Consortium study on 1280 breast carcinomas: allelic loss on chromosome 17 targets subregions associated with family history and clinical parameters.

The pattern of loss of heterozygosity (LOH) on chromosome 17 in human breast cancer is complicated and shows many different regions of loss. In an attempt to narrow down the relevant regions of LOH on chromosome 17, we have studied the deletion pattern and its association with clinical parameters in 1280 breast carcinoma-venous blood lymphocyte pairs. In total, 42 different chromosome 17 loci were investigated, and between 25 and 625 cases were analyzed at each locus. The frequency of LOH observed on the p arm was much higher than that observed on the q arm. The opposite effect was observed in 52 ovarian cancer cases investigated, with less LOH on 17p than on 17q. Patterns of loss consistent with interstitial and terminal deletions, as well as loss of either the p or q arm or monosomy 17 were observed. To determine whether loss at particular loci may be associated with biological features of breast tumors, clinical data including age of onset, family history of breast cancer, tumor histopathology, tumor size, estrogen receptor (ER) status, and occurrence of lymph node or distant metastases were collected for each case. Overall, large-sized, ER-negative, lymph node-positive ductal tumors showed the highest frequencies of LOH, with ER-negative and ductal tumors showing LOH for markers along the majority of the chromosome. Eight regions of chromosome 17 appear to be associated with human breast cancer, two on 17p and six on 17q. These regions were not necessarily in the areas exhibiting the highest frequencies of LOH but were defined by interstitial and terminal deletions in multiple independent cases. Seven of these regions showed statistically significant differences in LOH associated with clinical parameters. These data strongly suggest that loci on chromosome 17 may determine aspects of tumor presentation and disease behavior in human breast cancer and pinpoint candidate tumor suppressor gene loci.