Publications by authors named "James Paul"

489 Publications

A prospective prostate cancer screening programme for men with pathogenic variants in mismatch repair genes (IMPACT): initial results from an international prospective study.

Lancet Oncol 2021 Oct 19. Epub 2021 Oct 19.

University Hospital Southampton, Southampton, UK; Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, UK.

Background: Lynch syndrome is a rare familial cancer syndrome caused by pathogenic variants in the mismatch repair genes MLH1, MSH2, MSH6, or PMS2, that cause predisposition to various cancers, predominantly colorectal and endometrial cancer. Data are emerging that pathogenic variants in mismatch repair genes increase the risk of early-onset aggressive prostate cancer. The IMPACT study is prospectively assessing prostate-specific antigen (PSA) screening in men with germline mismatch repair pathogenic variants. Here, we report the usefulness of PSA screening, prostate cancer incidence, and tumour characteristics after the first screening round in men with and without these germline pathogenic variants.

Methods: The IMPACT study is an international, prospective study. Men aged 40-69 years without a previous prostate cancer diagnosis and with a known germline pathogenic variant in the MLH1, MSH2, or MSH6 gene, and age-matched male controls who tested negative for a familial pathogenic variant in these genes were recruited from 34 genetic and urology clinics in eight countries, and underwent a baseline PSA screening. Men who had a PSA level higher than 3·0 ng/mL were offered a transrectal, ultrasound-guided, prostate biopsy and a histopathological analysis was done. All participants are undergoing a minimum of 5 years' annual screening. The primary endpoint was to determine the incidence, stage, and pathology of screening-detected prostate cancer in carriers of pathogenic variants compared with non-carrier controls. We used Fisher's exact test to compare the number of cases, cancer incidence, and positive predictive values of the PSA cutoff and biopsy between carriers and non-carriers and the differences between disease types (ie, cancer vs no cancer, clinically significant cancer vs no cancer). We assessed screening outcomes and tumour characteristics by pathogenic variant status. Here we present results from the first round of PSA screening in the IMPACT study. This study is registered with ClinicalTrials.gov, NCT00261456, and is now closed to accrual.

Findings: Between Sept 28, 2012, and March 1, 2020, 828 men were recruited (644 carriers of mismatch repair pathogenic variants [204 carriers of MLH1, 305 carriers of MSH2, and 135 carriers of MSH6] and 184 non-carrier controls [65 non-carriers of MLH1, 76 non-carriers of MSH2, and 43 non-carriers of MSH6]), and in order to boost the sample size for the non-carrier control groups, we randomly selected 134 non-carriers from the BRCA1 and BRCA2 cohort of the IMPACT study, who were included in all three non-carrier cohorts. Men were predominantly of European ancestry (899 [93%] of 953 with available data), with a mean age of 52·8 years (SD 8·3). Within the first screening round, 56 (6%) men had a PSA concentration of more than 3·0 ng/mL and 35 (4%) biopsies were done. The overall incidence of prostate cancer was 1·9% (18 of 962; 95% CI 1·1-2·9). The incidence among MSH2 carriers was 4·3% (13 of 305; 95% CI 2·3-7·2), MSH2 non-carrier controls was 0·5% (one of 210; 0·0-2·6), MSH6 carriers was 3·0% (four of 135; 0·8-7·4), and none were detected among the MLH1 carriers, MLH1 non-carrier controls, and MSH6 non-carrier controls. Prostate cancer incidence, using a PSA threshold of higher than 3·0 ng/mL, was higher in MSH2 carriers than in MSH2 non-carrier controls (4·3% vs 0·5%; p=0·011) and MSH6 carriers than MSH6 non-carrier controls (3·0% vs 0%; p=0·034). The overall positive predictive value of biopsy using a PSA threshold of 3·0 ng/mL was 51·4% (95% CI 34·0-68·6), and the overall positive predictive value of a PSA threshold of 3·0 ng/mL was 32·1% (20·3-46·0).

Interpretation: After the first screening round, carriers of MSH2 and MSH6 pathogenic variants had a higher incidence of prostate cancer compared with age-matched non-carrier controls. These findings support the use of targeted PSA screening in these men to identify those with clinically significant prostate cancer. Further annual screening rounds will need to confirm these findings.

Funding: Cancer Research UK, The Ronald and Rita McAulay Foundation, the National Institute for Health Research support to Biomedical Research Centres (The Institute of Cancer Research and Royal Marsden NHS Foundation Trust; Oxford; Manchester and the Cambridge Clinical Research Centre), Mr and Mrs Jack Baker, the Cancer Council of Tasmania, Cancer Australia, Prostate Cancer Foundation of Australia, Cancer Council of Victoria, Cancer Council of South Australia, the Victorian Cancer Agency, Cancer Australia, Prostate Cancer Foundation of Australia, Asociación Española Contra el Cáncer (AECC), the Instituto de Salud Carlos III, Fondo Europeo de Desarrollo Regional (FEDER), the Institut Català de la Salut, Autonomous Government of Catalonia, Fundação para a Ciência e a Tecnologia, National Institutes of Health National Cancer Institute, Swedish Cancer Society, General Hospital in Malmö Foundation for Combating Cancer.
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http://dx.doi.org/10.1016/S1470-2045(21)00522-2DOI Listing
October 2021

Universal genetic testing of patients with newly diagnosed breast cancer - ready for prime time?

Med J Aust 2021 Oct 22. Epub 2021 Oct 22.

Familial Cancer Centre, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, VIC.

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http://dx.doi.org/10.5694/mja2.51317DOI Listing
October 2021

The Bowel CLEANsing National Initiative: High-Volume Split-Dose Vs Low-Volume Split-Dose Polyethylene Glycol Preparations: A Randomized Controlled Trial.

Clin Gastroenterol Hepatol 2021 Sep 9. Epub 2021 Sep 9.

Université de Montréal, Montreal, Quebec, Canada.

Background & Aims: The aim of this study was to compare high-volume polyethylene glycol (PEG) with low-volume PEG with bisacodyl split-dosing regimens.

Methods: Adult outpatients in 10 Canadian tertiary hospitals were randomized, stratified by morning or afternoon colonoscopy, to high-volume split-dose PEG (2 + 2 L) (High-SD) or low volume (1 L + 1 L) + bisacodyl (15 mg) PEG (Low-SD), with a second randomization to liquid or low-residue diets. The primary end point, using noninferiority hypothesis testing, was adequate bowel cleansing (Boston Bowel Preparation Scale total score of ≥6, with each of 3 colonic segments subscores ≥2). Secondary objectives were willingness to repeat the preparation, withdrawal time, cecal intubation, and polyp detection rates.

Results: Over 29 months, 2314 subjects were randomized to High-SD (n = 1157) or Low-SD (n = 1157) (mean age, 56.2 ± 13.4 y; 52.1% women). Colonoscopy indications were 38.2% diagnostic, 36.8% screening, and 25.0% surveillance, with no between-group imbalances in patient characteristics. Low-SD met noninferiority criteria vs High-SD for adequate bowel cleanliness with only marginally inferior results (90.1% vs 88.1%; P = .02; difference, 2.0% [0.0%; 4.5%]). High-SD was associated with lower willingness to repeat (66.9% vs 91.9%; P < .01), was less well tolerated (7.3 ± 2.3 vs 8.1 ± 1.9; P < .01), causing more symptoms. No differences in procedural outcomes were noted except for more frequent cecal intubation rates after High-SD (97.4% vs 95.6%; P = .02). Among the High-SD group, adequate bowel preparation was greater after a clear liquid diet (93.6% vs 87.9%; P < .01), a finding not seen in the Low-SD group.

Conclusions: Low-SD is noninferior to High-SD in providing adequate bowel preparation. Low-SD results in less symptoms, with greater willingness to repeat and tolerability. The overall impact of diet was modest.The study was approved by the research ethic boards from all sites and was registered at ClinicalTrials.gov (NCT02547571).
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http://dx.doi.org/10.1016/j.cgh.2021.09.005DOI Listing
September 2021

Persistent Incisional Pain after Noncardiac Surgery: An International Prospective Cohort Study.

Anesthesiology 2021 10;135(4):711-723

the Departments of Health Research Methods, McMaster University, Hamilton, Ontario, Canada; Medicine, McMaster University, Hamilton, Ontario, Canada; the Population Health Research Institute, Hamilton, Ontario, Canada.

Background: The purpose of this study was to determine the incidence, characteristics, impact, and risk factors associated with persistent incisional pain. The hypothesis was that patient demographics and perioperative interventions are associated with persistent pain.

Methods: This was a secondary analysis of an international prospective cohort study from 2012 to 2014. This study included patients who were 45 yr of age or older who underwent major inpatient noncardiac surgery. Data were collected perioperatively and at 1 yr after surgery to assess for the development of persistent incisional pain (pain present around incision at 1 yr after surgery).

Results: Among 14,831 patients, 495 (3.3%; 95% CI, 3.1 to 3.6) reported persistent incisional pain at 1 yr, with an average pain intensity of 3.6 ± 2.5 (0 to 10 numeric rating scale), with 35% and 14% reporting moderate and severe pain intensities, respectively. More than half of patients with persistent pain reported needing analgesic medications, and 85% reported interference with daily activities (denominator = 495 in the above proportions). Risk factors for persistent pain included female sex (P = 0.007), Asian ethnicity (P < 0.001), surgery for fracture (P < 0.001), history of chronic pain (P < 0.001), coronary artery disease (P < 0.001), history of tobacco use (P = 0.048), postoperative patient-controlled analgesia (P < 0.001), postoperative continuous nerve block (P = 0.010), insulin initiation within 24 h of surgery (P < 0.001), and withholding nonsteroidal anti-inflammatory medication or cyclooxygenase-2 inhibitors on the day of surgery (P = 0.029 and P < 0.001, respectively). Older age (P < 0.001), endoscopic surgery (P = 0.005), and South Asian (P < 0.001), Native American/Australian (P = 0.004), and Latin/Hispanic ethnicities (P < 0.001) were associated with a lower risk of persistent pain.

Conclusions: Persistent incisional pain is a common complication of inpatient noncardiac surgery, occurring in approximately 1 in 30 adults. It results in significant morbidity, interferes with daily living, and is associated with persistent analgesic consumption. Certain demographics, ethnicities, and perioperative practices are associated with increased risk of persistent pain.

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http://dx.doi.org/10.1097/ALN.0000000000003951DOI Listing
October 2021

Investigating and addressing the immediate and long-term consequences of the COVID-19 pandemic on patients with substance use disorders: a scoping review and evidence map protocol.

BMJ Open 2021 09 7;11(9):e045946. Epub 2021 Sep 7.

Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada.

Introduction: The COVID-19 pandemic has driven unprecedented social and economic reform in efforts to curb the impact of disease. Governments worldwide have legislated non-essential service shutdowns and adapted essential service provision in order to minimise face-to-face contact. We anticipate major consequences resulting from such policies, with marginalised populations expected to bear the greatest burden of such measures, especially those with substance use disorders (SUDs).

Methods And Analysis: We aim to conduct (1) a scoping review to summarise the available evidence evaluating the impact of the COVID-19 pandemic on patients with SUDs, and (2) an evidence map to visually plot and categorise the current available evidence evaluating the impact of COVID-19 on patients with SUDs to identify gaps in addressing high-risk populations.

Ethics And Dissemination: Ethics approval is not required for this scoping review as we plan to review publicly available data. This is part of a multistep project, whereby we intend to use the findings generated from this review in combination with data from an ongoing prospective cohort study our team is leading, encompassing over 2000 patients with SUDs receiving medication-assisted therapy in Ontario prior to and during the COVID-19 pandemic.
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http://dx.doi.org/10.1136/bmjopen-2020-045946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8424417PMC
September 2021

Risk of adverse events associated with upper and lower endoscopic ultrasound: a population-based cohort study.

Endosc Int Open 2021 Sep 23;9(9):E1427-E1434. Epub 2021 Aug 23.

Department of Medicine, University of Calgary, Cumming School of Medicine, Calgary, Alberta, Canada.

 Endoscopic ultrasound (EUS) enables diagnostic evaluation and therapeutic interventions but is associated with adverse events. We conducted a population-based cohort study to determine the risk of adverse events for upper and lower EUS with and without fine-needle aspiration (FNA).  All adults who underwent EUS and resided in Calgary in 2007-2013 were included. Endoscopy and provincial databases were used to identify EUS procedures, unplanned emergency department visits, and hospital admissions within 30 days of the procedures, which were then characterized through formal chart review. Adverse events were defined a priori and classified as definitely, possibly, or not related to EUS. The primary outcome was 30-day risk of adverse events classified as definitely or possibly related to EUS. Univariable and multivariable analyses were conducted with risk factors known to be associated with EUS adverse events.  2895 patients underwent 3552 EUS procedures: 3034 (85 %) upper EUS, of which 710 (23 %) included FNA, and 518 (15 %) lower EUS, of which 23 (4 %) involved FNA. Overall, 69 procedures (2 %) involved an adverse event that was either definitely or possibly related to EUS, with 33 (1 %) requiring hospitalization. None of the adverse events required intensive care or resulted in death. On multivariable analysis, only FNA was associated with increased risk of adverse events (odds ratio 6.43, 95 % confidence interval 3.92-10.55;  < 0.001).  Upper and lower EUS were generally safe but FNA substantially increased the risk of adverse events. EUS-related complications requiring hospitalization were rare.
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http://dx.doi.org/10.1055/a-1512-9341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8382505PMC
September 2021

Cochlear reimplantation from mid-scala to lateral wall electrode array: Surgical and hearing outcome.

Clin Case Rep 2021 Jun 17;9(6):e04210. Epub 2021 Jun 17.

Department of Otorhinolaryngology Helios Hospital Berlin-Buch Berlin Germany.

A mid-scala cochlear implant electrode array, which was inserted with an atraumatic round window approach, could be replaced with longer lateral wall electrode array. Deeper electrode insertion seems to have beneficial influence on the hearing quality.
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http://dx.doi.org/10.1002/ccr3.4210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8374987PMC
June 2021

Polygenic score modifies risk for Alzheimer's disease in ε4 homozygotes at phenotypic extremes.

Alzheimers Dement (Amst) 2021 5;13(1):e12226. Epub 2021 Aug 5.

Department of Epidemiology and Preventive Medicine School of Public Health and Preventive Medicine Monash University Melbourne Australia.

Introduction: Diversity in cognition among apolipoprotein E () ε4 homozygotes can range from early-onset Alzheimer's disease (AD) to a lifetime with no symptoms.

Methods: We evaluated a phenotypic extreme polygenic risk score (PRS) for AD between cognitively healthy ε4 homozygotes aged ≥75 years (n = 213) and early-onset ε4 homozygote AD cases aged ≤65 years (n = 223) as an explanation for this diversity.

Results: The PRS for AD was significantly higher in ε4 homozygote AD cases compared to older cognitively healthy ε4/ε4 controls (odds ratio [OR] 8.39; confidence interval [CI] 2.0-35.2;  = .003). The difference in the same PRS between ε3/ε3 extremes was not as significant (OR 3.13; CI 0.98-9.92;  = .053) despite similar numbers and power. There was no statistical difference in an educational attainment PRS between these age extreme case-controls.

Discussion: A PRS for AD contributes to modified cognitive expression of the ε4/ε4 genotype at phenotypic extremes of risk.
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http://dx.doi.org/10.1002/dad2.12226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8339682PMC
August 2021

Breast cancer polygenic risk scores: a 12-month prospective study of patient reported outcomes and risk management behavior.

Genet Med 2021 Aug 2. Epub 2021 Aug 2.

Parkville Familial Cancer Centre, Peter MacCallum Cancer Centre and the Royal Melbourne Hospital, Melbourne, VIC, Australia.

Purpose: To prospectively assess patient reported outcomes and risk management behavior of women choosing to receive (receivers) or decline (decliners) their breast cancer polygenic risk score (PRS).

Methods: Women either unaffected or affected by breast cancer and from families with no identified pathogenic variant in a breast cancer risk gene were invited to receive their PRS. All participants completed a questionnaire at study enrollment. Receivers completed questionnaires at two weeks and 12 months after receiving their PRS, and decliners a second questionnaire at 12 months post study enrollment.

Results: Of the 208 participants, 165 (79%) received their PRS. Among receivers, there were no changes in anxiety or distress following testing. However, compared to women with a low PRS, those with a high PRS reported greater genetic testing-specific distress, perceived risk, decisional regret, and less genetic testing-positive response. At 12 months, breast screening and uptake of risk-reducing strategies were consistent with current Australian guidelines of breast cancer risk management. Reasons for declining PRS included being unable to attend the appointment in person and concerns over potential emotional response.

Conclusion: The outcomes of the study provide insight into women's responses to receiving PRS and highlight the issues that need to be addressed in the associated model of genetic counseling.
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http://dx.doi.org/10.1038/s41436-021-01288-6DOI Listing
August 2021

Breast and Prostate Cancer Risks for Male BRCA1 and BRCA2 Pathogenic Variant Carriers Using Polygenic Risk Scores.

J Natl Cancer Inst 2021 Jul 28. Epub 2021 Jul 28.

Department of Molecular Medicine, University La Sapienza, Rome, Italy.

Background: Recent population-based female breast cancer and prostate cancer polygenic risk scores (PRS) have been developed. We assessed the associations of these PRS with breast and prostate cancer risks for male BRCA1 and BRCA2 pathogenic variant carriers.

Methods: 483 BRCA1 and 1,318 BRCA2 European ancestry male carriers were available from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A 147-single nucleotide polymorphism (SNP) prostate cancer PRS (PRSPC) and a 313-SNP breast cancer PRS were evaluated. There were three versions of the breast cancer PRS, optimized to predict overall (PRSBC), estrogen-receptor (ER) negative (PRSER-) or ER-positive (PRSER+) breast cancer risk.

Results: PRSER+ yielded the strongest association with breast cancer risk. The odds ratios (ORs) per PRSER+ standard deviation estimates were 1.40 (95% confidence interval [CI] =1.07-1.83) for BRCA1 and 1.33 (95% CI = 1.16-1.52) for BRCA2 carriers. PRSPC was associated with prostate cancer risk for both BRCA1 (OR = 1.73, 95% CI = 1.28-2.33) and BRCA2 (OR = 1.60, 95% CI = 1.34-1.91) carriers. The estimated breast cancer ORs were larger after adjusting for female relative breast cancer family history. By age 85 years, for BRCA2 carriers, the breast cancer risk varied from 7.7% to 18.4% and prostate cancer risk from 34.1% to 87.6% between the 5th and 95th percentiles of the PRS distributions.

Conclusions: Population-based prostate and female breast cancer PRS are associated with a wide range of absolute breast and prostate cancer risks for male BRCA1 and BRCA2 carriers. These findings warrant further investigation aimed at providing personalized cancer risks for male carriers and to inform clinical management.
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http://dx.doi.org/10.1093/jnci/djab147DOI Listing
July 2021

Venous access devices for the delivery of long-term chemotherapy: the CAVA three-arm RCT.

Health Technol Assess 2021 07;25(47):1-126

Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.

Background: Venous access devices are used for patients receiving long-term chemotherapy. These include centrally inserted tunnelled catheters or Hickman-type devices (Hickman), peripherally inserted central catheters (PICCs) and centrally inserted totally implantable venous access devices (PORTs).

Objectives: To evaluate the clinical effectiveness, safety, cost-effectiveness and acceptability of these devices for the central delivery of chemotherapy.

Design: An open, multicentre, randomised controlled trial to inform three comparisons: (1) peripherally inserted central catheters versus Hickman, (2) PORTs versus Hickman and (3) PORTs versus peripherally inserted central catheters. Pre-trial and post-trial qualitative research and economic evaluation were also conducted.

Setting: This took place in 18 UK oncology centres.

Participants: Adult patients (aged ≥ 18 years) receiving chemotherapy (≥ 12 weeks) for either a solid or a haematological malignancy were randomised via minimisation.

Interventions: Hickman, peripherally inserted central catheters and PORTs.

Primary Outcome: A composite of infection (laboratory confirmed, suspected catheter related and exit site infection), mechanical failure, venous thrombosis, pulmonary embolism, inability to aspirate blood and other complications in the intention-to-treat population.

Results: Overall, 1061 participants were recruited to inform three comparisons. First, for the comparison of peripherally inserted central catheters ( = 212) with Hickman ( = 212), it could not be concluded that peripherally inserted central catheters were significantly non-inferior to Hickman in terms of complication rate (odds ratio 1.15, 95% confidence interval 0.78 to 1.71). The use of peripherally inserted central catheters compared with Hickman was associated with a substantially lower cost (-£1553) and a small decrement in quality-adjusted life-years gained (-0.009). Second, for the comparison of PORTs ( = 253) with Hickman ( = 303), PORTs were found to be statistically significantly superior to Hickman in terms of complication rate (odds ratio 0.54, 95% confidence interval 0.37 to 0.77). PORTs were found to dominate Hickman with lower costs (-£45) and greater quality-adjusted life-years gained (0.004). This was alongside a lower complications rate (difference of 14%); the incremental cost per complication averted was £1.36. Third, for the comparison of PORTs ( = 147) with peripherally inserted central catheters ( = 199), PORTs were found to be statistically significantly superior to peripherally inserted central catheters in terms of complication rate (odds ratio 0.52, 95% confidence interval 0.33 to 0.83). PORTs were associated with an incremental cost of £2706 when compared with peripherally inserted central catheters and a decrement in quality-adjusted life-years gained (-0.018) PORTs are dominated by peripherally inserted central catheters: alongside a lower complications rate (difference of 15%), the incremental cost per complication averted was £104. The qualitative work showed that attitudes towards all three devices were positive, with patients viewing their central venous access device as part of their treatment and recovery. PORTs were perceived to offer unique psychological benefits, including a greater sense of freedom and less intrusion in the context of personal relationships. The main limitation was the lack of adequate power (54%) in the non-inferiority comparison between peripherally inserted central catheters and Hickman.

Conclusions: In the delivery of long-term chemotherapy, peripherally inserted central catheters should be considered a cost-effective option when compared with Hickman. There were significant clinical benefits when comparing PORTs with Hickman and with peripherally inserted central catheters. The health economic benefits were less clear from the perspective of incremental cost per quality-adjusted life-years gained. However, dependent on the willingness to pay, PORTs may be considered to be cost-effective from the perspective of complications averted.

Future Work: The deliverability of a PORTs service merits further study to understand the barriers to and methods of improving the service.

Trial Registration: This trial is registered as ISRCTN44504648.

Funding: This project was funded by the National Institute for Health Research (NHIR) Health Technology Assessment programme and will be published in full in ; Vol. 25, No. 47. See the NIHR Journals Library website for further project information.
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http://dx.doi.org/10.3310/hta25470DOI Listing
July 2021

Genomic Risk Prediction for Breast Cancer in Older Women.

Cancers (Basel) 2021 Jul 14;13(14). Epub 2021 Jul 14.

Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC 3004, Australia.

Genomic risk prediction models for breast cancer (BC) have been predominantly developed with data from women aged 40-69 years. Prospective studies of older women aged ≥70 years have been limited. We assessed the effect of a 313-variant polygenic risk score (PRS) for BC in 6339 older women aged ≥70 years (mean age 75 years) enrolled into the ASPREE trial, a randomized double-blind placebo-controlled clinical trial investigating the effect of daily 100 mg aspirin on disability-free survival. We evaluated incident BC diagnoses over a median follow-up time of 4.7 years. A multivariable Cox regression model including conventional BC risk factors was applied to prospective data, and re-evaluated after adding the PRS. We also assessed the association of rare pathogenic variants (PVs) in BC susceptibility genes (). The PRS, as a continuous variable, was an independent predictor of incident BC (hazard ratio (HR) per standard deviation (SD) = 1.4, 95% confidence interval (CI) 1.3-1.6) and hormone receptor (ER/PR)-positive disease (HR = 1.5 (CI 1.2-1.9)). Women in the top quintile of the PRS distribution had over two-fold higher risk of BC than women in the lowest quintile (HR = 2.2 (CI 1.2-3.9)). The concordance index of the model without the PRS was 0.62 (95% CI 0.56-0.68), which improved after addition of the PRS to 0.65 (95% CI 0.59-0.71). Among 41 (0.6%) carriers of PVs in BC susceptibility genes, we observed no incident BC diagnoses. Our study demonstrates that a PRS predicts incident BC risk in women aged 70 years and older, suggesting potential clinical utility extends to this older age group.
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http://dx.doi.org/10.3390/cancers13143533DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8305131PMC
July 2021

An updated quantitative model to classify missense variants in the TP53 gene: A novel multifactorial strategy.

Hum Mutat 2021 Oct 4;42(10):1351-1361. Epub 2021 Aug 4.

Parkville Familial Cancer Centre, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Australia.

Multigene panel testing has led to an increase in the number of variants of uncertain significance identified in the TP53 gene, associated with Li-Fraumeni syndrome. We previously developed a quantitative model for predicting the pathogenicity of P53 missense variants based on the combination of calibrated bioinformatic information and somatic to germline ratio. Here, we extended this quantitative model for the classification of P53 predicted missense variants by adding new pieces of evidence (personal and family history parameters, loss-of-function results, population allele frequency, healthy individual status by age 60, and breast tumor pathology). We also annotated which missense variants might have an effect on splicing based on bioinformatic predictions. This updated model plus annotation led to the classification of 805 variants into a clinically relevant class, which correlated well with existing ClinVar classifications, and resolved a large number of conflicting and uncertain classifications. We propose this model as a reliable approach to TP53 germline variant classification and emphasize its use in contributing to optimize TP53-specific ACMG/AMP guidelines.
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http://dx.doi.org/10.1002/humu.24264DOI Listing
October 2021

Case-case analysis addressing ascertainment bias for multigene panel testing implicates BRCA1 and PALB2 in endometrial cancer.

Hum Mutat 2021 Oct 21;42(10):1265-1278. Epub 2021 Jul 21.

Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Australia.

Hereditary endometrial cancer (EC) is most commonly attributed to pathogenic variants in mismatch repair genes. Evidence supports the existence of additional genetic risk factors in the context of multiple cancer diagnoses and/or family history of EC. EC patients (n = 5292) referred for diagnostic multigene cancer panel testing were annotated for presence of a pathogenic gene variant; personal history of prior, concurrent, or subsequent cancer of another type; reported family history of Lynch syndrome or EC. The Pearson χ test was used to assess differences in gene variant prevalence between case sub-groups defined by personal and/or family history of cancer/s, using cases with no family history of Lynch/EC as reference. Another cancer diagnosis was reported for 55% of EC cases. EC cases with a prior and reported family history of Lynch cancer were enriched for variants in MLH1 (p = 3.5 × 10 ), MSH2 (p = 3.1 × 10 ), and PMS2 (p = .02). Consistent with expectations for a breast cancer gene also predisposing to EC, the variant frequency was increased in EC patients with prior BC and family history of EC for BRCA1 (p = 1.7 × 10 ) and PALB2 (p = .0002). Strategic case-case analyses to address cohort ascertainment bias have provided a rationale to direct future studies of candidate hereditary EC genes.
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http://dx.doi.org/10.1002/humu.24256DOI Listing
October 2021

Metaphors and why these are important in all aspects of genetic counseling.

J Genet Couns 2021 Jul 7. Epub 2021 Jul 7.

Genomic Medicine, The Royal Melbourne Hospital, Parkville, VIC, Australia.

Metaphors appear simple but are fundamental schemata allowing expression and processing of complex emotions and information. They are so embedded in language and thinking that we are often unaware of their impact, despite the crucial role of metaphors in communication, learning and creating meaning from experiences. A deeper understanding of how to recognize and work with client-generated and counselor-generated metaphors has great potential as an addition to the genetic counseling 'tool-box'. Here, we draw on studies from related health and psychotherapy fields to discuss how working purposefully with metaphors may offer a powerful way to enhance communication within a reciprocally engaged client-counselor relationship. Metaphors present ways to explain complex genetic concepts in a personally meaningful form, to gain a deeper understanding of client's experiences and emotions, to assist processing of experiences, emotions, and concepts, and to assist client and counselor to access and reflect on subconscious emotions, self-concept, and motivations. In addition, working with metaphors has been shown to facilitate coping and action. This paper sets the scene for why and how genetic counselors can utilize client-generated and counselor-generated metaphors purposefully in all areas of practice, including enhancing the therapeutic interaction with clients, as well as in supervision, training, cultural competence, and shaping of societal attitudes toward genetics.
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http://dx.doi.org/10.1002/jgc4.1463DOI Listing
July 2021

Polygenic risk in familial breast cancer: Changing the dynamics of communicating genetic risk.

J Genet Couns 2021 Jul 5. Epub 2021 Jul 5.

Psychosocial Research Group, Prince of Wales Clinical School, University of New South Wales, Sydney, NSW, Australia.

Hereditary breast cancer is associated with known genetic changes: either variants that affect function in a few rare genes or an ever-increasing number of common genomic risk variants, which combine to produce a cumulative effect, known as a polygenic risk (PR) score. While the clinical validity and utility of PR scores are still being determined, the communication of PR is a new challenge for genetic health professionals. This study investigated how PR scores are discussed in the familial cancer clinic compared with a previous study assessing the communication of monogenic risk (MR) for breast cancer. Sixty-five PR consultations between genetic health professionals and women at familial risk of breast cancer were audiotaped, transcribed, and coded using a methodology adapted from the MR study. Analysis of consultations shows that while there were similarities in communicating MR and PR, the complexity and novelty of the polygenic information influenced the style of counseling used by genetic health professionals toward a teaching model of genetic counseling, rather than a patient-centered approach. In particular, compared to MR consultations, in PR consultations significantly fewer counselees (a) were asked about their reasons for attending genetic counseling; or (b) had their information preferences, decision-making style, medical knowledge, understanding, or concerns checked. In conclusion, it is anticipated that PR scores will become part of standard clinical practice. Thus, it will be important for all genetic health professionals to be appropriately educated so that they can tailor their communication to meet patient needs.
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http://dx.doi.org/10.1002/jgc4.1458DOI Listing
July 2021

Evaluation of two population screening programmes for founder mutations in the Australian Jewish community: a protocol paper.

BMJ Open 2021 06 25;11(6):e041186. Epub 2021 Jun 25.

Hereditary Cancer Centre, Prince of Wales Hospital Cancer Services, Randwick, New South Wales, Australia.

Introduction: People of Ashkenazi Jewish (AJ) ancestry are more likely than unselected populations to have a pathogenic variant, which cause a significantly increased risk of breast, ovarian and prostate cancer. Three specific pathogenic variants, referred to as -Jewish founder mutations (B-JFM), account for >90% of pathogenic variants in people of AJ ancestry. Current practice of identifying eligible individuals for testing based on personal and/or family history has been shown to miss at least 50% of people who have one of these variants. Here we describe the protocol of the JeneScreen study-a study established to develop and evaluate two different population-based B-JFM screening programmes, offered to people of Jewish ancestry in Sydney and Melbourne, Australia.

Methods And Analysis: To rmeasure the acceptability of population-based B-JFM screening in Australia, two screening programmes using different methodologies have been developed. The Sydney JeneScreen programme provides information and obtains informed consent by way of an online tool. The Melbourne JeneScreen programme does this by way of community sessions attended in person. Participants complete questionnaires to measure clinical and psychosocial outcomes at baseline, and for those who have testing, 2 weeks postresult. Participants who decline testing are sent a questionnaire regarding reasons for declining. Participants with a B-JFM are sent questionnaires 12-month and 24-month post-testing. The questionnaires incorporate validated scales, which measure anxiety, decisional conflict and regret, and test-related distress and positive experiences, and other items specifically developed or adapted for the study. These measures will be assessed for each programme and the two population-based B-JFM screening methods will be compared.

Ethics And Dissemination: Institutional Human Research Ethics Committee approval was obtained from the South Eastern Area Health Service Human Research Ethics Committee: HREC Ref 16/125.Following the analysis of the study results, the findings will be disseminated widely through conferences and publications, and directly to participants in writing.
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http://dx.doi.org/10.1136/bmjopen-2020-041186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237737PMC
June 2021

Piezoelectric canalplasty for exostoses and osteoma.

Am J Otolaryngol 2021 Nov-Dec;42(6):103114. Epub 2021 Jun 18.

Department of Otorhinolaryngology, Helios Hospital Berlin-Buch, Berlin, Germany.

Objective: To evaluate the safety profile and surgical technique for removal of symptomatic exostoses and osteoma of the external auditory canal with a micro-oscillating piezoelectric device.

Method: A chart review was conducted on patients undergoing piezoelectric canalplasty between 2019 and 2021 at tertiary referral hospital. Surgery was performed by two surgeons with varying experience. Bone removal was achieved using both osteotomy and osteoplasty. Postoperative complications, operative time and hearing outcome were evaluated.

Results: The study comprised 16 patients (16 ears). No major complications occurred. The skin of the auditory canal was completely preserved in all patients without injury to the tympanic membrane. Except for one patient with known noise-induced hearing loss, there was no postoperative deterioration of the bone-conduction threshold more than 10 dB HL at any frequency. The difference of the bone-conduction threshold in pure-tone audiometry (average for 0.5, 1, 2 and 4 kHz) three weeks postoperatively had a median of 0.6 dB ± 5.7. One patient complained of temporary new tinnitus. One patient had prolonged wound healing. Mean operative time was comparable with literature data.

Conclusion: The atraumatic characteristics of the piezoelectric instrument enable low-risk removal of external auditory canal exostoses and osteoma. Through the combination of precise osteotomy and osteoplasty, this novel instrument has the potential to become established in routine canalplasty.
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http://dx.doi.org/10.1016/j.amjoto.2021.103114DOI Listing
June 2021

Genetic variants associated with inherited cardiovascular disorders among 13,131 asymptomatic older adults of European descent.

NPJ Genom Med 2021 Jun 16;6(1):51. Epub 2021 Jun 16.

Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia.

Genetic testing is used to optimise the management of inherited cardiovascular disorders that can cause sudden cardiac death. Yet more genotype-phenotype correlation studies from populations not ascertained on clinical symptoms or family history of disease are required to improve understanding of gene penetrance. We performed targeted sequencing of 25 genes used routinely in clinical genetic testing for inherited cardiovascular disorders in a population of 13,131 asymptomatic older individuals (mean age 75 years) enrolled in the ASPREE trial. Participants had no prior history of cardiovascular disease events, dementia or physical disability at enrolment. Variants were classified following ACMG/AMP standards. Sudden and rapid cardiac deaths were clinically adjudicated as ASPREE trial endpoints, and assessed during mean 4.7 years of follow-up. In total, 119 participants had pathogenic/deleterious variants in one of the 25 genes analysed (carrier rate of 1 in 110 or 0.9%). Participants carried variants associated with hypertrophic cardiomyopathy (N = 24), dilated cardiomyopathy (N = 29), arrhythmogenic right-ventricular cardiomyopathy (N = 22), catecholaminergic polymorphic ventricular tachycardia (N = 4), aortopathies (N = 1), and long-QT syndrome (N = 39). Among 119 carriers, two died from presumed sudden/rapid cardiac deaths during follow-up (1.7%); both with pathogenic variants in long-QT syndrome genes (KCNQ1, SCN5A). Among non-carriers, the rate of sudden/rapid cardiac deaths was significantly lower (0.08%, 11/12936, p < 0.001). Variants associated with inherited cardiovascular disorders are found in asymptomatic individuals aged 70 years and older without a history of cardiovascular disease.
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http://dx.doi.org/10.1038/s41525-021-00211-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209162PMC
June 2021

Investigation of monogenic causes of familial breast cancer: data from the BEACCON case-control study.

NPJ Breast Cancer 2021 Jun 11;7(1):76. Epub 2021 Jun 11.

Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.

Breast cancer (BC) has a significant heritable component but the genetic contribution remains unresolved in the majority of high-risk BC families. This study aims to investigate the monogenic causes underlying the familial aggregation of BC beyond BRCA1 and BRCA2, including the identification of new predisposing genes. A total of 11,511 non-BRCA familial BC cases and population-matched cancer-free female controls in the BEACCON study were investigated in two sequencing phases: 1303 candidate genes in up to 3892 cases and controls, followed by validation of 145 shortlisted genes in an additional 7619 subjects. The coding regions and exon-intron boundaries of all candidate genes and 14 previously proposed BC genes were sequenced using custom designed sequencing panels. Pedigree and pathology data were analysed to identify genotype-specific associations. The contribution of ATM, PALB2 and CHEK2 to BC predisposition was confirmed, but not RAD50 and NBN. An overall excess of loss-of-function (LoF) (OR 1.27, p = 9.05 × 10) and missense (OR 1.27, p = 3.96 × 10) variants was observed in the cases for the 145 candidate genes. Leading candidates harbored LoF variants with observed ORs of 2-4 and individually accounted for no more than 0.79% of the cases. New genes proposed by this study include NTHL1, WRN, PARP2, CTH and CDK9. The new candidate BC predisposition genes identified in BEACCON indicate that much of the remaining genetic causes of high-risk BC families are due to genes in which pathogenic variants are both very rare and convey only low to moderate risk.
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http://dx.doi.org/10.1038/s41523-021-00279-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196173PMC
June 2021

The predictive ability of the 313 variant-based polygenic risk score for contralateral breast cancer risk prediction in women of European ancestry with a heterozygous BRCA1 or BRCA2 pathogenic variant.

Genet Med 2021 09 10;23(9):1726-1737. Epub 2021 Jun 10.

Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic.

Purpose: To evaluate the association between a previously published 313 variant-based breast cancer (BC) polygenic risk score (PRS) and contralateral breast cancer (CBC) risk, in BRCA1 and BRCA2 pathogenic variant heterozygotes.

Methods: We included women of European ancestry with a prevalent first primary invasive BC (BRCA1 = 6,591 with 1,402 prevalent CBC cases; BRCA2 = 4,208 with 647 prevalent CBC cases) from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), a large international retrospective series. Cox regression analysis was performed to assess the association between overall and ER-specific PRS and CBC risk.

Results: For BRCA1 heterozygotes the estrogen receptor (ER)-negative PRS showed the largest association with CBC risk, hazard ratio (HR) per SD = 1.12, 95% confidence interval (CI) (1.06-1.18), C-index = 0.53; for BRCA2 heterozygotes, this was the ER-positive PRS, HR = 1.15, 95% CI (1.07-1.25), C-index = 0.57. Adjusting for family history, age at diagnosis, treatment, or pathological characteristics for the first BC did not change association effect sizes. For women developing first BC < age 40 years, the cumulative PRS 5th and 95th percentile 10-year CBC risks were 22% and 32% for BRCA1 and 13% and 23% for BRCA2 heterozygotes, respectively.

Conclusion: The PRS can be used to refine individual CBC risks for BRCA1/2 heterozygotes of European ancestry, however the PRS needs to be considered in the context of a multifactorial risk model to evaluate whether it might influence clinical decision-making.
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http://dx.doi.org/10.1038/s41436-021-01198-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8460445PMC
September 2021

Genetic Dominant Variants in Segregating in Families with SCA48, Display In Vitro Functional Impairments Indistinctive from Recessive Variants Associated with SCAR16.

Int J Mol Sci 2021 May 30;22(11). Epub 2021 May 30.

Department of Medical Genetics, Haukeland University Hospital, 5021 Bergen, Norway.

Variants in cause both autosomal recessive (SCAR16) and dominant (SCA48) spinocerebellar ataxia. Reports from 18 variants causing SCA48 show that the clinical picture includes later-onset ataxia with a cerebellar cognitive affective syndrome and varying clinical overlap with SCAR16. However, little is known about the molecular properties of dominant variants. Here, we describe three SCA48 families with novel, dominantly inherited variants (p.Arg51_Ile53delinsProAla, p.Lys143_Trp147del, and p.Gly249Val). All the patients developed symptoms from 30 years of age or later, all had cerebellar atrophy, and 4 had cognitive/psychiatric phenotypes. Investigation of the structural and functional consequences of the recombinant C-terminus of HSC70-interacting protein (CHIP) variants was performed in vitro using ubiquitin ligase activity assay, circular dichroism assay and native polyacrylamide gel electrophoresis. These studies revealed that dominantly and recessively inherited variants showed similar biochemical defects, including impaired ubiquitin ligase activity and altered oligomerization properties of the CHIP. Our findings expand the molecular understanding of SCA48 but also mean that assumptions concerning unaffected carriers of recessive variants in SCAR16 families must be re-evaluated. More investigations are needed to verify the disease status of SCAR16 heterozygotes and elucidate the molecular relationship between SCA48 and SCAR16 diseases.
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http://dx.doi.org/10.3390/ijms22115870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8199271PMC
May 2021

Evaluation of the association of heterozygous germline variants in NTHL1 with breast cancer predisposition: an international multi-center study of 47,180 subjects.

NPJ Breast Cancer 2021 May 12;7(1):52. Epub 2021 May 12.

School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW, Australia.

Bi-allelic loss-of-function (LoF) variants in the base excision repair (BER) gene NTHL1 cause a high-risk hereditary multi-tumor syndrome that includes breast cancer, but the contribution of heterozygous variants to hereditary breast cancer is unknown. An analysis of 4985 women with breast cancer, enriched for familial features, and 4786 cancer-free women revealed significant enrichment for NTHL1 LoF variants. Immunohistochemistry confirmed reduced NTHL1 expression in tumors from heterozygous carriers but the NTHL1 bi-allelic loss characteristic mutational signature (SBS 30) was not present. The analysis was extended to 27,421 breast cancer cases and 19,759 controls from 10 international studies revealing 138 cases and 93 controls with a heterozygous LoF variant (OR 1.06, 95% CI: 0.82-1.39) and 316 cases and 179 controls with a missense variant (OR 1.31, 95% CI: 1.09-1.57). Missense variants selected for deleterious features by a number of in silico bioinformatic prediction tools or located within the endonuclease III functional domain showed a stronger association with breast cancer. Somatic sequencing of breast cancers from carriers indicated that the risk associated with NTHL1 appears to operate through haploinsufficiency, consistent with other described low-penetrance breast cancer genes. Data from this very large international multicenter study suggests that heterozygous pathogenic germline coding variants in NTHL1 may be associated with low- to moderate- increased risk of breast cancer.
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http://dx.doi.org/10.1038/s41523-021-00255-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8115524PMC
May 2021

Management of individuals with germline variants in PALB2: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG).

Genet Med 2021 08 11;23(8):1416-1423. Epub 2021 May 11.

Department of Medicine, Vanderbilt University Medical Center/Vanderbilt-Ingram Cancer Center, Nashville, TN, USA.

Purpose: PALB2 germline pathogenic variants are associated with increased breast cancer risk and smaller increased risk of pancreatic and likely ovarian cancer. Resources for health-care professionals managing PALB2 heterozygotes are currently limited.

Methods: A workgroup of experts sought to outline management of PALB2 heterozygotes based on current evidence. Peer-reviewed publications from PubMed were identified to guide recommendations, which arose by consensus and the collective expertise of the authors.

Results: PALB2 heterozygotes should be offered BRCA1/2-equivalent breast surveillance. Risk-reducing mastectomy can be considered guided by personalized risk estimates. Pancreatic cancer surveillance should be considered, but ideally as part of a clinical trial. Typically, ovarian cancer surveillance is not recommended, and risk-reducing salpingo-oophorectomy should only rarely be considered before the age of 50. Given the mechanistic similarities, PALB2 heterozygotes should be considered for therapeutic regimens and trials as those for BRCA1/2.

Conclusion: This guidance is similar to those for BRCA1/2. While the range of the cancer risk estimates overlap with BRCA1/2, point estimates are lower in PALB2 so individualized estimates are important for management decisions. Systematic prospective data collection is needed to determine as yet unanswered questions such as the risk of contralateral breast cancer and survival after cancer diagnosis.
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http://dx.doi.org/10.1038/s41436-021-01151-8DOI Listing
August 2021

Oncologists' perspectives of telephone genetic counseling to facilitate germline BRCA1/2 testing for their patients with high-grade serous ovarian cancer.

J Community Genet 2021 Jul 6;12(3):449-457. Epub 2021 May 6.

Parkville Familial Cancer Centre, Peter MacCallum Cancer Centre, Melbourne, Victoria, 3000, Australia.

Poly ADP ribose polymerase (PARP) inhibitors offer a survival advantage to women with high-grade serous ovarian cancer who have a germline BRCA1/2 pathogenic variant (PV). Yet, rates of genetic testing among this population have remained persistently low. A national, centralized telephone genetic counseling service was established in January 2016 in Australia to improve access to genetic services and facilitate BRCA1/2 testing for this population to inform treatment. Medical oncologists can refer their patients with high-grade serous ovarian cancer to this service for genetic testing. This study aimed to explore oncologists' experiences of using this telephone genetic counseling service for their patients with high-grade serous ovarian cancer. A qualitative approach using semi-structured telephone interviews was undertaken with Australian oncologists who had referred patients to the telephone genetic counseling service. Sixteen oncologists participated and described referring patients to the telephone genetic counseling service due to the timeliness of obtaining a genetic counseling appointment and BRCA1/2 test results. They also reported this service offered convenience for patients living in regional or rural areas who then did not have to travel for an appointment with a clinical genetics service. Many oncologists noted the importance of in-person genetic counseling for patients who received positive BRCA1/2 results. Areas for improvement identified by the oncologists related to communication issues between the service and the patient. Overall, findings suggest that oncologists perceived telephone genetic counseling as an acceptable and useful healthcare service for patients with high-grade serous ovarian cancer. Moreover, they perceived telephone genetic counseling to be efficient, delivering convenient genetic counseling to patients.
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http://dx.doi.org/10.1007/s12687-021-00530-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8241936PMC
July 2021

Multisite Veno-Venous Cannulation for Neonates and Nonambulatory Children.

Pediatr Crit Care Med 2021 08;22(8):692-700

Department of Paediatric Intensive Care, Evelina London Children's Hospital, London, United Kingdom.

Objectives: Neonates with respiratory failure are ideally supported with veno-venous rather than veno-arterial extracorporeal membrane oxygenation due to the reduced rate of neurologic complications. However, the proportion of neonates supported with veno-venous extracorporeal membrane oxygenation is declining. We report multisite veno-venous extracorporeal membrane oxygenation, accessing the neck, returning to the inferior vena cava via the common femoral vein in neonates and children less than 10 kg.

Design: Retrospective case series with 1 year minimum follow-up.

Patients: Patients less than 10 kg supported with veno-venous extracorporeal membrane oxygenation accessing the jugular and returning to the femoral vein.

Setting: A 30-bed pediatric intensive care delivering extracorporeal membrane oxygenation to approximately 20 children annually.

Interventions: Veno-venous extracorporeal membrane oxygenation accessing the jugular and returning to the femoral vein was delivered using two single lumen cannulae.

Measurements And Main Results: January 2015 to August 2019, 11 patients underwent veno-venous extracorporeal membrane oxygenation accessing the jugular and returning to the femoral vein with median weight of 3.6 kg (interquartile range 2.8-6.1 kg), and median corrected gestational age of 13 days (interquartile range, 2-175 d). The smallest patient weighed 2.1 kg. Seven patients had comorbidities. Extracorporeal membrane oxygenation was technically successful in all patients with median flows of 126 mL/kg/min (interquartile range, 120-138 mL/kg/min) and median arterial oxygenation saturation of 94% (interquartile range, 91-98%) at 24 hours. Nine survived to home discharge, and two were palliated. Common femoral vein occlusion was observed in all patients on ultrasound post decannulation. There was no clinical or functional deficit in the cannulated limb at follow-up, a minimum of 1 year post extracorporeal membrane oxygenation.

Conclusions: Veno-venous extracorporeal membrane oxygenation accessing the jugular and returning to the femoral vein was performed safely in patients under 10 kg with the smallest patient weighing 2.1 kg. Although occlusion of the common femoral vein was observed in patients post decannulation, subsequent follow-up demonstrated no clinical implications. We challenge current practice that veno-venous extracorporeal membrane oxygenation accessing the jugular and returning to the femoral vein cannot be performed in nonambulatory patients and suggest that this strategy is preferred over veno-arterial extracorporeal membrane oxygenation in infants requiring extracorporeal membrane oxygenation for respiratory failure.
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http://dx.doi.org/10.1097/PCC.0000000000002753DOI Listing
August 2021

The economic impact of sudden cardiac arrest.

Resuscitation 2021 Apr 15;163:49-56. Epub 2021 Apr 15.

Baker Heart and Diabetes Institute, 75 Commercial Rd, Prahran, VIC, 3181, Australia; Alfred Hospital, 55 Commercial Rd, Prahran, VIC, 3181, Australia; St Vincent's Hospital Melbourne, 41 Victoria Pde, Fitzroy, VIC, 3065, Australia.

Background: There are 20,000 sudden cardiac arrests (SCAs) in Australia annually, with 90% case-fatality.

Objective: The present study calculated both the health and economic impact of SCAs in Victoria, Australia.

Methods: Data on all SCAs attended by Ambulance Victoria from July 2017 to June 2018 were collected regarding age, gender, and survival to hospital, discharge and 12 months. Pre-SCA employment status of all patients was modelled using age and gender-matched Australian economic data. A Markov state-transition model with a five-year horizon calculated health and economic impact in years of life lived (YLL), productivity-adjusted life years (PALYs) and gross domestic product (GDP) lost. A counterfactual Markov state-transition model assessed outcomes of an identical cohort of patients who did not experience SCA. All values were discounted by 5%.

Results: In 12 months, 4637 people suffered SCAs in Victoria, of whom 1516 (32.7%) were working at the time. 695 patients (15.0%) survived to hospital, 325 (7.0%) to discharge, and 303 (6.5%) to 12 months. In five years following their SCA, the cohort lost 15,922 years of life and 2327 PALYs. Reduced productivity led to GDP losses of AUD$448 million (92.8% relative reduction). Extrapolated to the 20,000 SCAs occurring across all of Australia, total GDP losses approached AUD$2 billion.

Conclusion: The health and economic burden of SCAs is high, predominantly underpinned by very high mortality. Annual national losses approach AUD$2 billion (USD$1.42 billion) and are comparable to productivity losses from all cancers combined. Prioritising research and state-of-the-art care for SCA patients appears economically sound.
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http://dx.doi.org/10.1016/j.resuscitation.2021.04.001DOI Listing
April 2021

Genetic testing in dementia-A medical genetics perspective.

Int J Geriatr Psychiatry 2021 08 28;36(8):1158-1170. Epub 2021 Mar 28.

Department of Genomic Medicine, The Royal Melbourne Hospital, Parkville, Victoria, Australia.

Objective: When a genetic cause is suspected in a person with dementia, it creates unique diagnostic and management challenges to the treating clinician. Many clinicians may be unaware of the practicalities surrounding genetic testing for their patients, such as when to test and what tests to use and how to counsel patients and their families. This review was conducted to provide guidance to clinicians caring for patients with dementia regarding clinically relevant genetics.

Methods: We searched PubMed for studies that involved genetics of dementia up to March 2020. Patient file reviews were also conducted to create composite cases.

Results: In addition to families where a strong Mendelian pattern of family history is seen, people with younger age of onset, especially before the age of 65 years were found to be at an increased risk of harbouring a genetic cause for their dementia. This review discusses some of the most common genetic syndromes, including Alzheimer disease, frontotemporal dementia, vascular dementia, Parkinson disease dementia/dementia with Lewy bodies and some rarer types of genetic dementias, along with illustrative clinical case studies. This is followed by a brief review of the current genetic technologies and a discussion on the unique genetic counselling issues in dementia.

Conclusions: Inclusion of genetic testing in the diagnostic pathway in some patients with dementia could potentially reduce the time taken to diagnose the cause of their dementia. Although a definite advantage as an addition to the diagnostic repository, genetic testing has many pros and cons which need to be carefully considered first.
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http://dx.doi.org/10.1002/gps.5535DOI Listing
August 2021

Mainstream genetic testing for breast cancer patients: early experiences from the Parkville Familial Cancer Centre.

Eur J Hum Genet 2021 05 15;29(5):872-880. Epub 2021 Mar 15.

Parkville Familial Cancer Centre, Peter MacCallum Cancer Centre and The Royal Melbourne Hospital, Parkville, VIC, Australia.

The demand for genetic testing of hereditary breast cancer genes such as BRCA1 and BRCA2 has continued to increase with the lowering costs of testing, raised awareness in the general public, and implications for breast cancer treatment when a patient is identified as having a germline pathogenic variant. Historically within Australia, patients affected by high genetic risk breast cancers have been referred to a familial cancer centre (FCC) for assessment and testing, resulting in wait times for an appointment for pre- and post-test genetic counselling and an increased demand on the public-funded FCC. To improve patient access and pace of genetic testing, as well as refocus FCC resources, a mainstream clinical genetic testing program was rolled out in September 2017 through the Parkville FCC (PFCC) in Australia at 10 hospital sites. This program enables specialist doctors of eligible patients affected by breast cancer to arrange genetic testing directly at an oncology/surgical appointment and follow up the results as part of the patients' routine clinical care. In this model, the specialist doctor is responsible for any treatment implications of the genetic test result, and the PFCC is responsible for result interpretation, future cancer risk, family cascade testing and segregation testing where warranted. To date the program has had successful uptake, a notable pathogenic variant detection rate, reduced the burden on the PFCC enabling a reallocation of resources and has streamlined the process of genetic testing for eligible patients. Investigation into the patient and clinician experiences of the mainstream program is required.
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http://dx.doi.org/10.1038/s41431-021-00848-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8111023PMC
May 2021
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