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Background: Use of neoadjuvant (NA) chemotherapy is recommended when pancreatic ductal adenocarcinoma (PDAC) is borderline resectable METHOD: A retrospective analysis of consecutive patients with localized PDAC between January 2016 and March 2019 within the Australasian Pancreatic Cancer Registry (PURPLE, Pancreatic cancer: Understanding Routine Practice and Lifting End results) was performed. Clinicopathological characteristics, treatment, and outcome were analyzed. Overall survival (OS) comparison was performed using log-rank model and Kaplan-Meier analysis., Results: The PURPLE database included 754 cases with localised PDAC, including 148 (20%) cases with borderline resectable pancreatic cancer (BRPC). Of the 148 BRPC patients, 44 (30%) underwent immediate surgery, 80 (54%) received NA chemotherapy, and 24 (16%) were inoperable. The median age of NA therapy patients was 63 years and FOLFIRINOX (53%) was more often used as NA therapy than gemcitabine/nab-paclitaxel (31%). Patients who received FOLFIRINOX were younger than those who received gemcitabine/nab-paclitaxel (60 years vs. 67 years, p = .01). Surgery was performed in 54% (43 of 80) of BRPC patients receiving NA chemotherapy, with 53% (16 of 30) achieving R0 resections. BRPC patients undergoing surgery had a median OS of 30 months, and 38% (9 of 24) achieved R0 resection. NA chemotherapy patients had a median OS of 20 months, improving to 24 months versus 10 months for patients receiving FOLFIRINOX compared to gemcitabine/nab-paclitaxel (Hazard Ratio (HR) .3, p < .0001)., Conclusions: NA chemotherapy use in BRPC is increasing in Australia. One half of patients receiving NA chemotherapy proceed to curative resection, with 53% achieving R0 resections. Patients receiving Infusional 5-flurouracil, Irinotecan and Oxaliplatin (FOLIRINOX) had increased survival than gemcitabine/nab-paclitaxel. Treatment strategies are being explored in the MASTERPLAN and DYNAMIC-Pancreas trials., (© 2022 John Wiley & Sons Australia, Ltd.)

Background: As early detection of recurrent melanoma maximizes treatment options, patients usually undergo post-operative imaging surveillance, increasingly with FDG-PET/CT (PET). To assess this, we evaluated stage 3 melanoma patients who underwent prospectively applied and sub-stage-specific schedules of PET surveillance., Patients and Methods: From 2009, patients with stage 3 melanoma routinely underwent PET +/- MRI brain scans via defined schedules based on sub-stage-specific relapse probabilities. Data were collected regarding patient characteristics and outcomes. Contingency analyses were carried out of imaging outcomes., Results: One hundred and seventy patients (stage 3A: 34; 3B: 93; 3C: 43) underwent radiological surveillance. Relapses were identified in 65 (38%) patients, of which 45 (69%) were asymptomatic. False-positive imaging findings occurred in 7%, and 6% had treatable second (non-melanoma) malignancies. Positive predictive values (PPV) of individual scans were 56%-83%. Negative scans had predictive values of 89%-96% for true non-recurrence [negative predictive values (NPV)] until the next scan. A negative PET at 18 months had NPVs of 80%-84% for true non-recurrence at any time in the 47-month (median) follow-up period. Sensitivity and specificity of the overall approach of sub-stage-specific PET surveillance were 70% and 87%, respectively. Of relapsed patients, 33 (52%) underwent potentially curative resection and 10 (16%) remained disease-free after 24 months (median)., Conclusions: Application of sub-stage-specific PET in stage 3 melanoma enables asymptomatic detection of most recurrences, has high NPVs that may provide patient reassurance, and is associated with a high rate of detection of resectable and potentially curable disease at relapse.

We report on a 20-year-old man who presented in infancy with severe generalized lipodystrophy with a progeroid appearance and some Marfanoid features. He subsequently was diagnosed with bilateral lens subluxations at the age of 16 years which prompted analysis of the FBN1 gene. This analysis showed him to have a novel heterozygous, de novo, c.8156&#95;8175del, p.Lys2719ThrfsX12, frameshift mutation in exon 64 of his FBN1 gene. His phenotype is similar to a patient described by Graul-Neumann et al. [2010] who was found to have a de novo, heterozygous, c.8155&#95;8156del deletion in exon 64 of FBN1. Both mutations result in a truncated protein with an extremely charged C-terminus, containing two positive and four negative charges in the last eight amino acids. This most likely has a profound impact on protein–protein interactions, which are very important in the extracellular matrix. The similarities in the phenotypes, and overlapping molecular defects, provides further evidence that the phenotype with features of Marfan syndrome with neonatal progeroid syndrome-like lipodystrophy is a distinct clinical entity due to frameshift mutations in exon 64 of the FBN1 gene.

Cornelia de Lange syndrome (CdLS) is characterized by facial dysmorphism; hirsutism; internal organ anomalies, including diaphragmatic hernia, and limb defects. While causative mutations in three genes have been identified the etiology of a significant number of cases remains unknown. We report on a child with an 8p23.1 deletion with features of CdLS and congenital diaphragmatic hernia. We review cases with cytogenetic anomalies involving 8p23.1, discuss a potential relationship between 8p23.1 deletions and CdLS and suggest a novel candidate gene for CdLS-Tankyrase 1., (2008 Wiley-Liss, Inc.)

CHARGE syndrome is an autosomal dominant condition that is caused by mutations in the CHD7 gene. Few familial cases of this syndrome have been reported and these were characterized by a wide clinical variability. We here report on five CHD7 mutation positive families and comment on their clinical features. We observed somatic and germline mosaicism as well as parent-to-child transmission of non-mosaic CHD7 mutations as causes of familial CHARGE syndrome. In one family with two affected sibs a somatic mutation was identified in lymphocytes of a clinically unaffected parent (2520G > A in exon 8). This is the second report of somatic CHD7 mosaicism in an unaffected parent. In two further families with affected siblings, we could not detect the mutation in parental lymphocytes suggesting germline mosaicism. The previously reported clinical variability was strikingly present in all five families. We find that alterations in CHD7 can result in a very mild phenotype, characterized by only a few minor symptoms of the CHARGE syndrome clinical spectrum. Such a mild phenotype was present in two families that shared the same 6322G > A missense mutation. These two families showed parent-to-child transmission. Phenotypically milder forms of CHARGE syndrome have a higher risk of transmission to multiple family members., ((c) 2007 Wiley-Liss, Inc.)

Concerns about the safety of carbimazole in pregnancy were raised in 1985. Since this time many reports of children believed to have been affected by carbimazole in utero have appeared in the medical literature. Initial reports were of an increased incidence of scalp defects in the infants of treated mothers, but many other anomalies have now been described. Choanal atresia, gastrointestinal anomalies-particularly esophageal atresia, athelia/hypothelia, developmental delay, hearing loss, and dysmorphic facial features have all been reported. The phenotype associated with exposure to carbimazole appears to be rare but specific with distinctive facial features. We report on two new cases of carbimazole embryopathy with strikingly similar facial features.

We assessed cystic fibrosis (CF) knowledge and emotional consequences of CF population testing 18 months after screening was offered. Questionnaires were sent to 593 individuals and 353 responded (59.5%). All respondents had sound knowledge of CF disease, although carriers were more likely to correctly state the pattern of CF inheritance and CF carrier rate in Australia. Eleven of 47 carriers falsely believed they were only very likely to be carriers, while nearly a third of test-negative individuals falsely believed they were definitely not carriers. Imprecise recall of the meaning of results may be due to memory loss over time, simplification of result meaning and minimization of risk. The Health Orientation Scale (HOS) was used to assess emotional consequences of CF carrier testing 18 months after testing. Both carriers and test-negative individuals thought most carriers would experience more negative feelings than most non-carriers. Carriers experienced less positive feelings about their test result compared to non-carriers. Interestingly, the carriers' own feelings about their result were more positive compared to how they thought most carriers would feel. These results suggest that carriers experience minimal adverse psychological effects, although a negative social stigma may be attached to carrying the CF gene mutation., (Copyright 2003 Wiley-Liss, Inc.)

Nance-Horan syndrome (NHS) is an X-linked condition characterised by congenital cataracts, dental abnormalities, dysmorphic features, and mental retardation in some cases. Previous studies have mapped the disease gene to a 2 cM interval on Xp22.2 between DXS43 and DXS999. We report additional linkage data resulting from the analysis of eleven independent NHS families. A maximum lod score of 9.94 (theta=0.00) was obtained at the RS1 locus and a recombination with locus DXS1195 on the telomeric side was observed in two families, thus refining the location of the gene to an interval of around 1 Mb on Xp22.13. Direct sequencing or SSCP analysis of the coding exons of five genes (SCML1, SCML2, STK9, RS1 and PPEF1), considered as candidate genes on the basis of their location in the critical interval, failed to detect any mutation in 12 unrelated NHS patients, thus making it highly unlikely that these genes are implicated in NHS.

High-level microsatellite instability (MSI-H) is demonstrated in 10 to 15% of sporadic colorectal cancers and in most cancers presenting in the inherited condition hereditary nonpolyposis colorectal cancer (HNPCC). Distinction between these categories of MSI-H cancer is of clinical importance and the aim of this study was to assess clinical, pathological, and molecular features that might be discriminatory. One hundred and twelve MSI-H colorectal cancers from families fulfilling the Bethesda criteria were compared with 57 sporadic MSI-H colorectal cancers. HNPCC cancers presented at a lower age (P < 0.001) with no sporadic MSI-H cancer being diagnosed before the age of 57 years. MSI was less extensive in HNPCC cancers with 72% microsatellite markers showing band shifts compared with 87% in sporadic tumors (P < 0.001). Absent immunostaining for hMSH2 was only found in HNPCC tumors. Methylation of hMLH1 was observed in 87% of sporadic cancers but also in 55% of HNPCC tumors that showed loss of expression of hMLH1 (P = 0.02). HNPCC cancers were more frequently characterized by aberrant beta-catenin immunostaining as evidenced by nuclear positivity (P < 0.001). Aberrant p53 immunostaining was infrequent in both groups. There were no differences with respect to 5q loss of heterozygosity or codon 12 K-ras mutation, which were infrequent in both groups. Sporadic MSI-H cancers were more frequently heterogeneous (P < 0.001), poorly differentiated (P = 0.02), mucinous (P = 0.02), and proximally located (P = 0.04) than HNPCC tumors. In sporadic MSI-H cancers, contiguous adenomas were likely to be serrated whereas traditional adenomas were dominant in HNPCC. Lymphocytic infiltration was more pronounced in HNPCC but the results did not reach statistical significance. Overall, HNPCC cancers were more like common colorectal cancer in terms of morphology and expression of beta-catenin whereas sporadic MSI-H cancers displayed features consistent with a different morphogenesis. No individual feature was discriminatory for all HNPCC cancers. However, a model based on four features was able to classify 94.5% of tumors as sporadic or HNPCC. The finding of multiple differences between sporadic and familial MSI-H colorectal cancer with respect to both genotype and phenotype is consistent with tumorigenesis through parallel evolutionary pathways and emphasizes the importance of studying the two groups separately.

We measured acceptance of carrier testing for cystic fibrosis in the community when offered in a primary care setting, determined variables influencing acceptance, and assessed knowledge of cystic fibrosis 3-6 months later. A total of 5,102 individuals age 18-50 years attending general practices or a family planning clinic in Western Australia completed questionnaires about knowledge of cystic fibrosis and the State Anxiety Inventory. Testing for the delta F508 gene was offered. After 3-6 months, carriers, a sample of consenting participants who were not tested, and a sample of test-negative participants were sent a further questionnaire; 43.5% of participants chose to be tested for cystic fibrosis carrier status. Women, younger people, people with higher education, people without children, and people planning to have children were more likely to be tested. After 3-6 months, carriers gave correct responses to questions about cystic fibrosis more frequently than those who tested negative or were not tested; 82.2% of carriers knew that they were definitely a carrier and 31.1% of test-negative individuals believed they were definitely not carriers. Thus, population carrier screening for cystic fibrosis offered in a community setting in Western Australia was acceptable to almost half of those offered testing, particularly younger people and those planning to have children, for whom knowledge of carrier status could be useful in making reproductive decisions. There was evidence that tested individuals recalled information in a way that minimised their risk of being a carrier.

Genetic factors are important in the development of Alzheimer's disease (AD). Familial AD can result from rare mutations in some genes. Other genes, such as the apolipoprotein E gene (APOE), operate as risk factors for late-onset sporadic AD. On a background of advances in the genetics of AD we suggest a way in which genetic information may be used in the diagnosis of AD. If there is a positive family history of early-onset dementia and the clinical features suggest AD, patients may be tested for presenilin and amyloid precursor protein gene mutations with appropriate pretest and post-test counselling. Predictive testing should be performed under guidelines developed by the World Federation of Neurology and the Human Genetics Society of Australasia. The usefulness of APOE genotyping as an adjunct to conventional diagnostic tests is unknown; data suggest it has low sensitivity and specificity and may have little predictive value in an individual patient. APOE genotyping should not be performed in asymptomatic individuals, except as part of an ethically approved research project; this recommendation is supported by a number of international consensus statements. APOE testing should not be used as a diagnostic test without adequate pretest and post-test counselling, education and support. APOE testing should not be used as a sole diagnostic test in the work-up of patients with AD. Genetic risk factors other than APOE require validation and should not be used routinely, except as part of an ethically approved research protocol.

Objectives: The aim of this study was to evaluate ovarian cancer screening uptake and attitudes toward prophylactic oophorectomy in women at risk of developing hereditary breast/ovarian cancer., Study Methods: Ninety-five unaffected women, who approached 1 of 14 familial cancer clinics for advice about their breast/ovarian cancer risk and surveillance and prophylactic options, were assessed in a cross-sectional design when they attended the clinic., Results: Among high-risk women ages 30 and over who had not had a prophylactic oophorectomy, 48% reported ever having had an ovarian ultrasound, and among women ages 50 and over 23% had had a serum CA 125 test. Twenty-three percent of women would consider, and 27% would not consider, a prophylactic oophorectomy should the genetic test indicate a germline mutation associated with hereditary breast/ovarian cancer, while 38% were unsure. Twelve percent had already undergone a prophylactic oophorectomy. Interest in prophylactic oophorectomy was associated with increased breast/ovarian cancer anxiety (chi(2) = 5.14, P = 0.023), but not objective cancer risk (chi(2) = 0.40, P = 0.53)., Conclusion: Findings demonstrate that breast/ovarian cancer anxiety, rather than objective risk, is the major factor which determines women's attitude to prophylactic oophorectomy. Women are likely to benefit from interventions aimed at reducing breast/ovarian cancer anxiety. Research on the impact of prophylactic oophorectomy would be helpful in the development of educational strategies and decision aids to assist women who are trying to make a decision under conditions of uncertainty., (Copyright 1999 Academic Press.)

We present two sisters with microcephaly, developmental delay, marked microphthalmia, congenital cataracts, cerebral and cerebellar hypoplasia, and intracranial calcification. No evidence of intrauterine infection was found. There have been previous reports of microcephaly, intracranial calcification, and an intrauterine infection-like autosomal recessive condition, but the sibs in this report appear to represent a more severe form of such a condition or a previously undescribed entity.

Objective: To ascertain the frequency of 22q11 deletions in a representative population of conotruncal heart defects (CTD) and determine which children are at risk of having a deletion., Methodology: A clinical and laboratory evaluation of 90 children with CTD, including isolated and syndromic cases., Results: Fifteen children (17%) were shown to have 22q11 deletions by fluorescence in situ hybridization (FISH) studies with the Oncor probe N25. Varying degrees of developmental delay/learning disabilities and facial dysmorphism were common in these children. None of the isolated cases without dysmorphism had a deletion., Conclusion: 22q11 deletions are a significant cause of a specific form of congenital heart disease, CTD. It is important to have a high index of suspicion of the 22q11 deletion disorders in children with CTD and other extracardiac manifestations so that the diagnosis can be made early and appropriate interventions implemented.

Van Hippel-Lindau disease (VHL) is an autosomal dominantly inherited disorder, characterised by the development of clear cell renal carcinomas, CNS hemangioblastomas, retinal angiomas, pancreatic tumors, pheochromocytomas and hepatic cysts. Recently a number of families with dominant familial pheochromocytoma as the only clinical manifestation have been reported to carry mutations in the HVL gene. We describe a family in which a novel VHL S68W mutation was segregating and carrier individuals manifested with variable penetrance of isolated pheochromocytomas. Investigation of this kindred confirmed that a mutation in the VHL gene could produce isolated pheochromocytomas as the only clinical feature and was variably penetrant.

Crouzon syndrome is an autosomal dominant condition characterized by craniosynostosis with associated dentofacial anomalies. This paper describes the variable clinical features in affected individuals over two generations of a family with particular reference to the dentofacial deformities and discussion of management strategies.

Of 2002 randomly selected pregnant women recruited prospectively over a three-year period for an extensive questionnaire survey, a stratified subsample of 665 mothers was selected for mother-infant follow-up on the basis of pre-pregnancy alcohol intake. Infant outcome was assessed by detailed clinical examination and application of a modified Einstein Neonatal Behavioural Assessment Schedule (ENBAS) performed at 24 to 72 hours of age. Of the infant responses to 25 ENBAS items, only tonus showed a small but significant relationship to pre-pregnancy maternal alcohol intake. The authors conclude that low to moderate maternal alcohol intake has no significant effect on newborn neurological status.

Study Objective: to investigate the relationship between alcohol consumption and pregnancy outcome., Design: prospective randomised cohort survey with follow up sample stratified on level of alcohol intake., Setting: antenatal clinic of large maternity hospital in Western Australia., Participants: 2002 randomly selected pregnant women recruited over 3 year period for questionnaire survey (58% in 1st trimester, 33% in 2nd trimester, 8% in third trimester at recruitment). Only 19 refused participation. Stratified subsample of 665 women followed up, of whom 60 had miscarriage, stillbirth or neonatal death. Subsample was selected on basis of prepregnancy alcohol consumption. INVESTIGATIONS AND MAIN RESULTS: All 2002 women completed a comprehensive questionnaire on demographic, lifestyle, health (including diet) and obstetric factors. The stratified subsample was followed through pregnancy and data were collected on obstetric course and infant outcome. Results showed that beer, wine and spirits drinkers differed significantly in maternal characteristics, nutrition and other important variables such as smoking. Women with stillbirths or miscarriages drank more beer than those with live births, though total levels of alcohol intake did not differ. Beer drinkers were less likely to reduce their consumption in pregnancy than other drinkers if they also smoked more than 20 cigarettes per day., Conclusions: Studies of effects of maternal drinking must include extensive information on the variables examined in this study or conclusions relating to maternal drinking in pregnancy are likely to be invalid.

This paper describes the findings in three fatal cases of primary amoebic meningoencephalitis. Two children developed the infection in January, 1980, in widely separated wheat-belt towns. The third child's infection, diagnosed by retrospective examination of necropsy material, developed in February, 1963, in the town where the second child lived. Infection with Naegleria fowleri was demonstrated by histological examination supplemented by specific immunofluorescence in all three cases, and by culture in the second case. For early diagnosis it is important to search for amoebae both on wet preparations and on stained films of cerebrospinal fluid when primary amoebic meningoencephalitis is suspected on epidemiological grounds of from cerebrospinal fluid findings.