Injury trends and mortality in adult patients with major trauma in New South Wales.

OBJECTIVE: To examine trends in mechanism and outcome of major traumatic injury in adults since the implementation of the New South Wales trauma monitoring program, and to identify factors associated with mortality. DESIGN AND SETTING: Retrospective review of NSW Trauma Registry data from 1 January 2003 to 31 December 2007, including patient demographics, year of injury, and level of trauma centre where definitive treatment was provided. PARTICIPANTS: 9769 people aged ≥ 15 years hospitalised for trauma, with an injury severity score (ISS) > 15. MAIN OUTCOME MEASURES: The NSW Trauma Registry outcome measures included were overall hospital length of stay, length of stay in an intensive care unit and in ospital mortality. RESULTS: There was a decreasing trend in severe trauma presentations in the age group 16-34 years, and an increasing trend in presentations of older people, particularly those aged ≥ 75 years. Road trauma and falls were consistently the commonest injury mechanisms. There were 1328 inhospital deaths (13.6%). Year of injury, level of trauma centre, ISS, head/neck injury and age were all independent predictors of mortality. The odds of mortality was significantly higher among patients receiving definitive care at regional trauma centres compared with Level I centres (odds ratio, 1.34; 95% CI, 1.10-1.63). CONCLUSIONS: Deaths from major trauma in NSW trauma centres have declined since 2003, and definitive care at a Level 1 trauma centre was associated with a survival benefit. More comprehensive trauma data collection with timely analysis will improve injury surveillance and better inform health policy in NSW.

BRCA1 testing should be offered to individuals with triple-negative breast cancer diagnosed below 50 years.

BACKGROUND: Triple-negative (TN) tumours are the predominant breast cancer subtype in BRCA1 mutation carriers. Recently, it was proposed that all individuals below 50 years of age with TN breast cancer should be offered BRCA testing. We have evaluated the BRCA1 mutation frequency and the implications for clinical practice of undertaking genetic testing in women with TN breast cancer. METHODS: We undertook BRCA1 mutation analysis in 308 individuals with TN breast cancer, 159 individuals from unselected series of breast cancer and 149 individuals from series ascertained on the basis of young age and/or family history. RESULTS: BRCA1 mutations were present in 45 out of 308 individuals. Individuals with TN cancer <50 years had >10% likelihood of carrying a BRCA1 mutation in both the unselected (11 out of 58, 19%) and selected (26 out of 111, 23%) series. However, over a third would not have been offered testing using existing criteria. We estimate that testing all individuals with TN breast cancer <50 years would generate an extra 1200 tests annually in England. CONCLUSION: Women with TN breast cancer diagnosed below 50 years have >10% likelihood of carrying a BRCA1 mutation and are therefore eligible for testing in most centres. However, implementation may place short-term logistical and financial burdens on genetic services.

Geospatial analyses to prioritize public health interventions: a case study of pedestrian and pedal cycle injuries in New South Wales, Australia.

OBJECTIVES: Pedestrian and pedal cycle injuries are important causes of child morbidity and mortality. The combination of Bayesian methods and geographical distribution maps may assist public health practitioners to identify communities at high risk of injury. METHODS: Data were obtained on all hospitalizations of children from NSW (Australia), for pedestrian and pedal cycle injuries, from 2000-2001 to 2004-2005. Using Bayesian methods, posterior expected rate ratios (as an estimate of smoothed standardized hospitalization ratios for each injury mechanism) were mapped by local government area (LGA) across the state. RESULTS: There were over 7,000 hospitalizations for pedestrian and pedal cycle injuries. High risk LGAs accounted for more than one third of hospitalized pedestrian and pedal cycle injuries in NSW. CONCLUSIONS: LGAs at high risk for pedestrian injury tended to be urbanized metropolitan areas with a high population density, while high risk LGAs for pedal cycle injury tended to be either in urban regional areas, or on the margin of urbanized metropolitan areas. Geospatial analyses can assist policymakers and practitioners to identify high risk communities for which public health interventions can be prioritized.

Hereditary leiomyomatosis and renal cell cancer in families referred for fumarate hydratase germline mutation analysis.

Heterozygous fumarate hydratase (FH) germline mutations cause hereditary leiomyomatosis and renal cell cancer (HLRCC), an autosomal dominant syndrome characterized by multiple cutaneous piloleiomyomas, uterine leiomyomas and papillary type 2 renal cancer. The main objective of our study was to evaluate clinical and genetic data from families suspected of HLRCC on a nationwide level. All families referred for FH mutation analysis in the Netherlands were assessed. We performed FH sequence analysis and multiplex ligation-dependent probe amplification. Families with similar FH mutations were examined for haplotype sharing. In 14 out of 33 families, we identified 11 different pathogenic FH germline mutations, including 4 novel mutations and 1 whole-gene deletion. Clinical data were available for 35 FH mutation carriers. Cutaneous leiomyomas were present in all FH mutation carriers older than 40 years of age. Eleven out of 21 female FH mutation carriers underwent surgical treatment for symptomatic uterine leiomyomas at an average of 35 years. Two FH mutation carriers had papillary type 2 renal cancer and Wilms' tumour, respectively. We evaluated the relevance of our findings for clinical practice and have proposed clinical diagnostic criteria, indications for FH mutation analysis and recommendations for management.

The carrier clinic: an evaluation of a novel clinic dedicated to the follow-up of BRCA1 and BRCA2 carriers--implications for oncogenetics practice.

BACKGROUND: A novel oncogenetic clinic was established in 2002 at the Royal Marsden NHS Foundation Trust offering advice and specialist follow-up for families with a germline mutation in BRCA1 or BRCA2. The remit of this multidisciplinary clinic, staffed by individuals in both oncology and genetics, is to provide individualised screening recommendations, support in decision making, risk reducing strategies, cascade testing, and an extensive research portfolio. METHODS: A retrospective analysis was performed to evaluate uptake of genetic testing, risk reducing surgery and cancer prevalence in 346 BRCA1/BRCA2 families seen between January 1996 and December 2006. RESULTS: 661 individuals attended the clinic and 406 mutation carriers were identified; 85.8% mutation carriers have chosen to attend for annual follow-up. 70% of mutation carriers elected for risk reducing bilateral salpingo-oophorectomy (RRBSO). 32% of unaffected women chose risk reducing bilateral mastectomy. 32% of women with breast cancer chose contralateral risk reducing mastectomy at time of diagnosis. Some women took over 8 years to decide to have surgery. 91% of individuals approached agreed to participate in research programmes. INTERPRETATION: A novel specialist clinic for BRCA1/2 mutation carriers has been successfully established. The number of mutation positive families is increasing. This, and the high demand for RRBSO in women over 40, is inevitably going to place an increasing demand on existing health resources. Our clinic model has subsequently been adopted in other centres and this will greatly facilitate translational studies and provide a healthcare structure for management and follow-up of such people who are at a high cancer risk.

The G67E mutation in hMLH1 is associated with an unusual presentation of Lynch syndrome.

Germline mutations in the mismatch repair (MMR) genes are associated with Lynch syndrome, also known as hereditary non-polyposis colorectal cancer (HNPCC) syndrome. Here, we characterise a variant of hMLH1 that confers a loss-of-function MMR phenotype. The mutation changes the highly conserved Gly67 residue to a glutamate (G67E) and is reminiscent of the hMLH1-p.Gly67Arg mutation, which is present in several Lynch syndrome cohorts. hMLH1-Gly67Arg has previously been shown to confer loss-of-function (Shimodaira et al, 1998), and two functional assays suggest that the hMLH1-Gly67Glu protein fails to sustain normal MMR functions. In the first assay, hMLH1-Gly67Glu abolishes the protein's ability to interfere with MMR in yeast. In the second assay, mutation of the analogous residue in yMLH1 (yMLH1-Gly64Glu) causes a loss-of-function mutator phenotype similar to yMLH1-Gly64Arg. Despite these molecular similarities, an unusual spectrum of tumours is associated with hMLH1-Gly67Glu, which is not typical of those associated with Lynch syndrome and differs from those found in families carrying the hMLH1-Gly67Arg allele. This suggests that hMLH1 may have different functions in certain tissues and/or that additional factors may modify the influence of hMLH1 mutations in causing Lynch syndrome.

Breast cancer immunohistochemistry can be useful in triage of some HNPCC families.

Immunohistochemistry of tumour samples is increasingly used in the triage of families where hereditary non-polyposis colorectal cancer (HNPCC) due to mismatch repair defects is suspected. Usually, this is undertaken in tumours that are a recognised part of the spectrum of HNPCC-related cancers e.g. colon or endometrial cancers. Although breast cancers are not classed as part of this spectrum, this study examined the extent to which some breast tumours do arise by the mismatch repair pathway in these families. This may have clinical utility in families where an individual with a 'classic HNPPC-related' tumour is not available for evaluation. Immunohistochemistry of a breast tumour may identify an individual in whom germline mutation testing is worthwhile.

Geographic mapping as a tool for identifying communities at high risk of fire and burn injuries in children.

Burns are a significant cause of morbidity and mortality in children. Although industrialized countries have achieved significant declines in deaths and hospitalizations for these injuries in recent decades, the benefits have not been shared equally by children across all socioeconomic groups. We used Bayesian methods to map posterior expected relative risks, as an estimate of smoothed hospital separation ratios for fire and burns in children, across local government areas in New South Wales, Australia. The geographic pattern of relative risk varied by age group; higher than average risks were observed for children residing in rural and remote areas, as well as in scattered local government areas closer to the coast and in some metropolitan regions. Mapping the occurrence of injury gives injury practitioners the opportunity to identify high risk communities for further investigation of risk factors and implementation of targeted interventions within a defined area.

Predicting the likelihood of carrying a BRCA1 or BRCA2 mutation: validation of BOADICEA, BRCAPRO, IBIS, Myriad and the Manchester scoring system using data from UK genetics clinics.

OBJECTIVES: Genetic testing for the breast and ovarian cancer susceptibility genes BRCA1 and BRCA2 has important implications for the clinical management of people found to carry a mutation. However, genetic testing is expensive and may be associated with adverse psychosocial effects. To provide a cost-efficient and clinically appropriate genetic counselling service, genetic testing should be targeted at those individuals most likely to carry pathogenic mutations. Several algorithms that predict the likelihood of carrying a BRCA1 or a BRCA2 mutation are currently used in clinical practice to identify such individuals. DESIGN: We evaluated the performance of the carrier prediction algorithms BOADICEA, BRCAPRO, IBIS, the Manchester scoring system and Myriad tables, using 1934 families seen in cancer genetics clinics in the UK in whom an index patient had been screened for BRCA1 and/or BRCA2 mutations. The models were evaluated for calibration, discrimination and accuracy of the predictions. RESULTS: Of the five algorithms, only BOADICEA predicted the overall observed number of mutations detected accurately (ie, was well calibrated). BOADICEA also provided the best discrimination, being significantly better (p<0.05) than all models except BRCAPRO (area under the receiver operating characteristic curve statistics: BOADICEA = 0.77, BRCAPRO = 0.76, IBIS = 0.74, Manchester = 0.75, Myriad = 0.72). All models underpredicted the number of BRCA1 and BRCA2 mutations in the low estimated risk category. CONCLUSIONS: Carrier prediction algorithms provide a rational basis for counselling individuals likely to carry BRCA1 or BRCA2 mutations. Their widespread use would improve equity of access and the cost-effectiveness of genetic testing.

Surveillance and treatment of malignancy in Bloom syndrome.

We report a patient with Bloom syndrome, a rare autosomal recessive condition characterised by chromosomal instability leading to a high risk of cancer at an early age. The diagnosis should be considered in patients with any cancer of significantly early onset, short stature and a photosensitive lupus-like rash on the face. Diagnostic confirmation is obtained from chromosome studies that show significantly increased numbers of sister chromatid exchanges. There are important management implications, including minimising the use of ionising radiation in surveillance and treatment.

Delivery of cancer genetics services: The Royal Marsden telephone clinic model.

We have conducted a telelink telephone-led cancer genetic counselling model at The Royal Marsden NHS Foundation Trust. The study commenced in March 2004 and evaluation of the clinic was conducted over 17 months from March 2005 to the end of July 2006. A total of 612 patients had telephone consultations during this time, 228 of whom were referred from primary care with a median of 30 patients counselled per month (range of 19-63, depending on staff availability with average of two staff per clinic). Waiting times were measured for General Practitioner referrals and all 228 were counselled within the national target-stipulated 13 weeks (median 6 weeks, range 1-12). An additional 132 patients who were sent appointment letters after receipt of their family history questionnaires did not attend their appointments (18% of all potential referrals) and required recontacting by letter. After telephone counselling, 42% of patients were able to be discharged from the telephone clinic without a subsequent face-to-face appointment, thereby saving resources. The telephone clinic also had a short set-up time with flexibility on timing and day of administration, which would be an advantage in centres where outreach clinic facilities are scarce. The telelink telephone counselling model is highly efficient in triaging high risk individuals for face-to-face counselling as per the Kenilworth model, in effecting concentration of resources and in providing a flexible individual-centred approach to cancer genetic counselling delivery.

Increased level of chromosomal damage after irradiation of lymphocytes from BRCA1 mutation carriers.

Deleterious mutations in the BRCA1 gene predispose women to an increased risk of breast and ovarian cancer. Many functional studies have suggested that BRCA1 has a role in DNA damage repair and failure in the DNA damage response pathway often leads to the accumulation of chromosomal aberrations. Here, we have compared normal lymphocytes with those heterozygous for a BRCA1 mutation. Short-term cultures were irradiated (8Gy) using a high dose rate and subsequently metaphases were analysed by 24-colour chromosome painting (M-FISH). We scored the chromosomal rearrangements in the metaphases from five BRCA1 mutation carriers and from five noncarrier control samples 6 days after irradiation. A significantly higher level of chromosomal damage was detected in the lymphocytes heterozygous for BRCA1 mutations compared with normal controls; the average number of aberrations per mitosis was 3.48 compared with 1.62 in controls (P=0.0001). This provides new evidence that heterozygous mutation carriers have a different response to DNA damage compared with noncarriers and that BRCA1 has a role in DNA damage surveillance. Our finding has implications for treatment and screening of BRCA1 mutation carriers using modalities that involve irradiation.

The spectrum of patched mutations in a collection of Australian basal cell carcinomas.

Inactivating mutations in the human patched (PTCH) gene have been identified in both familial and sporadic basal cell carcinomas (BCCs). In some tumors mutations have been detected in both alleles thereby supporting the role of PTCH as a tumor suppressor gene. We have analyzed 22/23 coding exons of PTCH for mutations in 44 sporadic BCCs, and detected 10 novel mutations in nine tumors. In two of the mutant tumors the remaining allele was inactivated by loss of heterozygosity. Five novel PTCH polymorphisms were also identified. Most of the variations found were C>T substitutions at dipyrimidine sites, supporting previous studies which indicate a role for ultraviolet-B in the genesis of sporadic BCCs.

Most germ-line mutations in the nevoid basal cell carcinoma syndrome lead to a premature termination of the PATCHED protein, and no genotype-phenotype correlations are evident.

The human homologue of the Drosophila segment polarity gene patched is implicated in the development of nevoid basal cell carcinoma syndrome (NBCCS) and in the genesis of sporadic basal cell carcinomas. In order to examine the phenotypic variability in NBCCS and to highlight functionally important domains of the PTCH protein, we have now screened 71 unrelated NBCCS individuals for mutations in the PTCH exons. We identified 28 mutations that are distributed throughout the entire gene, and most (86%) cause protein truncation. As part of this analysis, we demonstrate that failure of one NBCCS family to show clear linkage to chromosome 9q22.3-31 is most likely due to germinal mosaicism. We have identified three families bearing identical mutations with variable phenotypes, suggesting phenotypic variability in NBCCS is a complex genetic event. No phenotype genotype correlation between the position of truncation mutations and major clinical features was evident. Two missense mutations have been identified, and their location within transmembrane domains supports the notion that PTCH may have a transport function. The preponderance of truncation mutants in the germ line of NBCCS patients suggests that the developmental defects associated with the disorder are most likely due to haploinsufficiency.

De novo mutations of the Patched gene in nevoid basal cell carcinoma syndrome help to define the clinical phenotype.

The demonstration that mutations in the Patched (PTCH) gene cause nevoid basal cell carcinoma syndrome (NBCCS) has led to the identification of the exact molecular lesion in a percentage of individuals with the syndrome. In addition, it has been possible to determine, through molecular analysis of parents and other relatives of these individuals, if the mutation is inherited or has arisen de novo. We have previously reported 28 mutations in individuals with NBCCS, and here we present an additional 4 novel mutations. We have also analyzed relatives of a number of the individuals in whom we have found mutations. In total we have identified 8 individuals who carry a de novo mutation in the PTCH gene. In 5 of these cases, clinical and radiological examination had not unequivocally ruled out a diagnosis in one of the parents. This helps to define the clinical phenotype and suggests that diagnostic criteria in this complex syndrome may require review.

Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome.

The nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder characterized by multiple basal cell carcinomas (BCCs), pits of the palms and soles, jaw keratocysts, a variety of other tumors, and developmental abnormalities. NBCCS maps to chromosome 9q22.3. Familial and sporadic BCCs display loss of heterozygosity in this region, consistent with the gene being a tumor suppressor. A human sequence (PTC) with strong homology to the Drosophila segment polarity gene, patched, was isolated from a YAC and cosmid contig of the NBCCS region. Mutation analysis revealed alterations of PTC in NBCCS patients and in related tumors. We propose that a reduction in expression of the patched gene can lead to the developmental abnormalities observed in the syndrome and that complete loss of patched function contributes to transformation of certain cell types.

Glutathione S-transferase GSTM1 null genotype is not overrepresented in Australian patients with nevoid basal cell carcinoma syndrome or sporadic melanoma.

The GSTM1 gene on chromosome 1p encodes the carcinogen-detoxification enzyme, glutathione S-transferase (mu subclass). The homozygous null genotype at this locus has been associated with increased susceptibility to malignancy, including some skin cancers. One hundred and twenty-four Australian patients with sporadic melanoma and 62 with familial basal cell carcinomas (a feature of nevoid basal cell carcinoma syndrome, NBCCS) were examined for germline homozygous deletions of GSTM1 using multiplex polymerase chain reactions. The homozygous null genotype was not overrepresented in either those with a single melanoma or in the NBCCS cases. Nor did it significantly accelerate tumorigenesis in either group. Analyses of much larger sample sizes will be required to investigate the representation of the null genotype in patients with multiple melanoma primaries and in those with melanoma co-existing with other non-cutaneous malignancies.

The prevalence of cervical and thoracic congenital skeletal abnormalities in basal cell naevus syndrome; a review of cervical and chest radiographs in 80 patients with BCNS.

The major clinical stigmata of basal cell naevus syndrome (BCNS) appear in adolescence and adult life but some occult skeletal abnormalities are congenital. BCNS is dominantly inherited and it would be useful to identify, as early in life as possible, which of the offspring of patients with BCNS are at risk of developing the syndrome. Radiographs of the neck and chest of 80 patients with BCNS diagnosed confidently on clinical criteria have been examined for abnormalities which were considered to be congenital skeletal anomalies. Congenital abnormalities of the cervical and thoracic spine, mainly spina bifida occulta, were found in 45%. Congenital abnormalities of ribs were found in 49% and of the shoulder(s) in 36%. Overall congenital abnormalities were shown on the neck or chest radiograph in 55 (69%) patients. The presence of one or more of these congenital abnormalities on the chest or neck radiograph of a child who is the offspring of a person with BCNS makes it extremely likely that the child also has BCNS. The absence of these features, and of any clinical features of BCNS, would suggest that the risk of the child developing BCNS has been reduced from the prior expectation of 50% to approximately half that (24%).

The diagnostic implication of falcine calcification on plain skull radiographs of patients with basal cell naevus syndrome and the incidence of falcine calcification in their relatives and two control groups.

The purpose of our study was to identify the incidence of falcine calcification shown on plain skull radiographs in people with basal cell naevus syndrome (BCNS) and in their relatives compared with a normal population. A population of people with BCNS and their relatives was identified on non-radiological grounds and the incidence of falcine calcification on skull radiographs in each of these two groups was compared with the incidence of falcine calcification in a control group of people and of a larger group who attended casualty departments. Falcine calcification was graded into dense, fine but definite, and faint. 85 people with BCNS had nearly 100% incidence of falcine calcification in adults. 83 first degree unaffected relatives showed no excess over "normal" incidence of falcine calcification. In the 970 casualty patients some falcine calcification was common (> 20%) in males over 30 and in females over 50 years of age. It occurred earlier and was more common in males than in females. Dense calcification occurred in 5-7% of females and males over 60 years of age. Dense calcification was rare (< 2%) under the age of 40 years. In conclusion, falcine calcification should be regarded as the fourth major feature and a very important diagnostic feature of BCNS. An adult labelled as a BCNS sufferer without falcine calcification probably has not got the syndrome. The genetic defect responsible for the metabolic defect resulting in dural calcification is probably the same as, or in close linkage disequilibrium to, that responsible for the major clinical features of the syndrome. The age and sex distribution of falcine calcification in a general hospital casualty population is described.

Fine deletion mapping on the long arm of chromosome 9 in sporadic and familial basal cell carcinomas.

Basal cell carcinomas (BCCs) are the most common sporadic cancers worldwide. They are also a cardinal manifestation of a familial cancer predisposition syndrome, naevoid BCC syndrome (NBCCS). The gene responsible for NBCCS is likely to be a tumour suppressor gene and has been genetically mapped to a 2cM region between microsatellite markers, D9S196 and D9S180 at 9q22.3-q31. 101 BCCs (63 sporadic and 38 familial) were examined for loss of heterozygosity (LOH) in the candidate region of the NBCCS gene. Deletions were found in 46% and all LOH is consistent with genetic mapping of the NBCC locus. These findings strongly support the hypothesis that inactivation of the putative tumour suppressor, the NBCCS gene, is important in the formation of sporadic BCCs. One sporadic tumour indicates that the smallest region of overlap of these deletions is within the interval between D9S287 and D9S180. If this is confirmed in additional tumours, it would further narrow down the NBCCS region and exclude one candidate gene, that for the C complementation group of Fanconi anaemia, which maps proximally to D9S287. However, it would not exclude another candidate, the gene for the A complementation group of xeroderma pigmentosum (XPAC). Evidence of imprinting was also sought but preliminary data indicate that it is unlikely to occur at the NBCCS locus.