Publications by authors named "Mary Porteous"

109 Publications

SDHC phaeochromocytoma and paraganglioma: A UK-wide case series.

Clin Endocrinol (Oxf) 2021 Sep 24. Epub 2021 Sep 24.

Department of Clinical Genetics, Birmingham Women's Hospital, Birmingham, UK.

Objective: Phaeochromocytomas and paragangliomas (PPGL) are rare, but strongly heritable tumours. Variants in succinate dehydrogenase (SDH) subunits are identified in approximately 25% of cases. However, clinical and genetic information of patients with SDHC variants are underreported.

Design: This retrospective case series collated data from 18 UK Genetics and Endocrinology departments.

Patients: Both asymptomatic and disease-affected patients with confirmed SDHC germline variants are included.

Measurements: Clinical data including tumour type and location, surveillance outcomes and interventions, SDHC genetic variant assessment, interpretation, and tumour risk calculation.

Results: We report 91 SDHC cases, 46 probands and 45 non-probands. Fifty-one cases were disease-affected. Median age at genetic diagnosis was 43 years (range: 11-79). Twenty-four SDHC germline variants were identified including six novel variants. Head and neck paraganglioma (HNPGL, n = 30, 65.2%), extra-adrenal paraganglioma (EAPGL, n = 13, 28.2%) and phaeochromocytomas (PCC) (n = 3, 6.5%) were present. One case had multiple PPGLs. Malignant disease was reported in 19.6% (9/46). Eight cases had non-PPGL SDHC-associated tumours, six gastrointestinal stromal tumours (GIST) and two renal cell cancers (RCC). Cumulative tumour risk (95% CI) at age 60 years was 0.94 (CI: 0.79-0.99) in probands, and 0.16 (CI: 0-0.31) in non-probands, respectively.

Conclusions: This study describes the largest cohort of 91 SDHC patients worldwide. We confirm disease-affected SDHC variant cases develop isolated HNPGL disease in nearly 2/3 of patients, EAPGL and PCC in 1/3, with an increased risk of GIST and RCC. One fifth developed malignant disease, requiring comprehensive lifelong tumour screening and surveillance.
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http://dx.doi.org/10.1111/cen.14594DOI Listing
September 2021

ISHLT consensus document on lung transplantation in patients with connective tissue disease: Part III: Pharmacology, medical and surgical management of post-transplant extrapulmonary conditions statements.

J Heart Lung Transplant 2021 Jul 31. Epub 2021 Jul 31.

The Lung Transplant Unit, St. Vincent's Hospital, Sydney, New South Wales, Australia.

Patients with connective tissues disease (CTD) are often on immunomodulatory agents before lung transplantation (LTx). Till now, there's no consensus on the safety of using these agents perioperative and post-transplant. The International Society for Heart and Lung Transplantation-supported consensus document on LTx in patients with CTD addresses the risk and contraindications of perioperative and post-transplant management of the biologic disease-modifying antirheumatic drugs (bDMARD), kinase inhibitor DMARD, and biologic agents used for LTx candidates with underlying CTD, and the recommendations and management of non-gastrointestinal extrapulmonary manifestations, and esophageal disorders by medical and surgical approaches for CTD transplant recipients.
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http://dx.doi.org/10.1016/j.healun.2021.07.013DOI Listing
July 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

Creation and Worldwide Utilisation of New COVID-19 Online Information Hub for Genetics Health Professionals, Patients and Families.

Front Genet 2021 8;12:621683. Epub 2021 Jul 8.

Scottish Genetics Education Network, University of Dundee, Kirkcaldy, United Kingdom.

The current COVID-19 pandemic has unfortunately resulted in many significant concerns for individuals with genetic disorders and their relatives, regarding the viral infection and, particularly, its specific implications and additional advisable precautions for individuals affected by genetic disorders. To address this, the resulting requirement for guidance and information for the public and for genetics professionals was discussed among colleagues nationally, on the ScotGEN Steering Committee, and internationally on the Education Committee of the European Society of Human Genetics (ESHG). It was agreed that the creation of an online hub of genetics-related COVID-19 information resources would be particularly helpful. The proposed content, divided into a web page for professionals and a page for patients, was discussed with, and approved by, genetics professionals. The hub was created and provided online at www.scotgen.org.uk and linked from the ESHG's educational website for genetics and genomics, at www.eurogems.org. The new hub provides links, summary information and representative illustrations for a wide range of selected international resources. The resources for professionals include: COVID-19 research related hubs provided by Nature, Science, Frontiers, and PubMed; clinical guidelines; the European Centre for Disease Prevention and Control; the World Health Organisation; and molecular data sources including coronavirus 3D protein structures. The resources for patients and families include links to many accessible sources of support and relevant information. Since the launch of the pages, the website has received visits from over 50 countries worldwide. Several genetics consultants have commented on usefulness, clarity, readability, and ease of navigation. Visits have originated most frequently in the United Kingdom, Kuwait, Hong Kong, Moldova, United States, Philippines, France, and Qatar. More links have been added since the launch of the hub to include additional international public health and academic resources. In conclusion, an up-to-date online hub has been created and made freely available for healthcare professionals, patients, relatives and the public, providing categorised easily navigated links to a range of worldwide resources related to COVID-19. These pages are receiving a rapidly growing number of return visits and the authors continue to maintain and update the pages' content, incorporating new developments in this field of enormous worldwide importance.
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http://dx.doi.org/10.3389/fgene.2021.621683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8296805PMC
July 2021

Risk of primary graft dysfunction following lung transplantation in selected adults with connective tissue disease-associated interstitial lung disease.

J Heart Lung Transplant 2021 05 23;40(5):351-358. Epub 2021 Jan 23.

Division of Rheumatology, Department of Medicine, Columbia University Vagelos College of Physicians and Surgeons, New York, New York. Electronic address:

Background: Previous studies have reported similarities in long-term outcomes following lung transplantation for connective tissue disease-associated interstitial lung disease (CTD-ILD) and idiopathic pulmonary fibrosis (IPF). However, it is unknown whether CTD-ILD patients are at increased risk of primary graft dysfunction (PGD), delays in extubation, or longer index hospitalizations following transplant compared to IPF patients.

Methods: We performed a multicenter retrospective cohort study of CTD-ILD and IPF patients enrolled in the Lung Transplant Outcomes Group registry who underwent lung transplantation between 2012 and 2018. We utilized mixed effects logistic regression and stratified Cox proportional hazards regression to determine whether CTD-ILD was independently associated with increased risk for grade 3 PGD or delays in post-transplant extubation and hospital discharge compared to IPF.

Results: A total of 32.7% (33/101) of patients with CTD-ILD and 28.9% (145/501) of patients with IPF developed grade 3 PGD 48-72 hours after transplant. There were no significant differences in odds of grade 3 PGD among patients with CTD-ILD compared to those with IPF (adjusted OR 1.12, 95% CI 0.64-1.97, p = 0.69), nor was CTD-ILD independently associated with a longer post-transplant time to extubation (adjusted HR for first extubation 0.87, 95% CI 0.66-1.13, p = 0.30). However, CTD-ILD was independently associated with a longer post-transplant hospital length of stay (median 23 days [IQR 14-35 days] vs17 days [IQR 12-28 days], adjusted HR for hospital discharge 0.68, 95% CI 0.51-0.90, p = 0.008).

Conclusion: Patients with CTD-ILD experienced significantly longer postoperative hospitalizations compared to IPF patients without an increased risk of grade 3 PGD.
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http://dx.doi.org/10.1016/j.healun.2021.01.1391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102314PMC
May 2021

Second International Guidelines for the Diagnosis and Management of Hereditary Hemorrhagic Telangiectasia.

Ann Intern Med 2020 12 8;173(12):989-1001. Epub 2020 Sep 8.

Mayo Clinic, Rochester, Minnesota (V.N.I.).

Description: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease with an estimated prevalence of 1 in 5000 that is characterized by the presence of vascular malformations (VMs). These result in chronic bleeding, acute hemorrhage, and complications from shunting through VMs. The goal of the Second International HHT Guidelines process was to develop evidence-based consensus guidelines for the management and prevention of HHT-related symptoms and complications.

Methods: The guidelines were developed using the AGREE II (Appraisal of Guidelines for Research and Evaluation II) framework and GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology. The guidelines expert panel included expert physicians (clinical and genetic) in HHT from 15 countries, guidelines methodologists, health care workers, health care administrators, patient advocacy representatives, and persons with HHT. During the preconference process, the expert panel generated clinically relevant questions in 6 priority topic areas. A systematic literature search was done in June 2019, and articles meeting a priori criteria were included to generate evidence tables, which were used as the basis for recommendation development. The expert panel subsequently convened during a guidelines conference to conduct a structured consensus process, during which recommendations reaching at least 80% consensus were discussed and approved.

Recommendations: The expert panel generated and approved 6 new recommendations for each of the following 6 priority topic areas: epistaxis, gastrointestinal bleeding, anemia and iron deficiency, liver VMs, pediatric care, and pregnancy and delivery (36 total). The recommendations highlight new evidence in existing topics from the first International HHT Guidelines and provide guidance in 3 new areas: anemia, pediatrics, and pregnancy and delivery. These recommendations should facilitate implementation of key components of HHT care into clinical practice.
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http://dx.doi.org/10.7326/M20-1443DOI Listing
December 2020

Local complement activation is associated with primary graft dysfunction after lung transplantation.

JCI Insight 2020 09 3;5(17). Epub 2020 Sep 3.

Department of Medicine, Perlman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

BACKGROUNDThe complement system plays a key role in host defense but is activated by ischemia/reperfusion injury (IRI). Primary graft dysfunction (PGD) is a form of acute lung injury occurring predominantly due to IRI, which worsens survival after lung transplantation (LTx). Local complement activation is associated with acute lung injury, but whether it is more reflective of allograft injury compared with systemic activation remains unclear. We proposed that local complement activation would help identify those who develop PGD after LTx. We also aimed to identify which complement activation pathways are associated with PGD.METHODSWe performed a multicenter cohort study at the University of Pennsylvania and Washington University School of Medicine. Bronchoalveolar lavage (BAL) and plasma specimens were obtained from recipients within 24 hours after LTx. PGD was scored based on the consensus definition. Complement activation products and components of each arm of the complement cascade were measured using ELISA.RESULTSIn both cohorts, sC4d and sC5b-9 levels were increased in BAL of subjects with PGD compared with those without PGD. Subjects with PGD also had higher C1q, C2, C4, and C4b, compared with subjects without PGD, suggesting classical and lectin pathway involvement. Ba levels were higher in subjects with PGD, suggesting alternative pathway activation. Among lectin pathway-specific components, MBL and FCN-3 had a moderate-to-strong correlation with the terminal complement complex in the BAL but not in the plasma.CONCLUSIONComplement activation fragments are detected in the BAL within 24 hours after LTx. Components of all 3 pathways are locally increased in subjects with PGD. Our findings create a precedent for investigating complement-targeted therapeutics to mitigate PGD.FUNDINGThis research was supported by the NIH, American Lung Association, Children's Discovery Institute, Robert Wood Johnson Foundation, Cystic Fibrosis Foundation, Barnes-Jewish Hospital Foundation, Danish Heart Foundation, Danish Research Foundation of Independent Research, Svend Andersen Research Foundation, and Novo Nordisk Research Foundation.
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http://dx.doi.org/10.1172/jci.insight.138358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526453PMC
September 2020

Prostate Cancer Risk by BRCA2 Genomic Regions.

Eur Urol 2020 10 10;78(4):494-497. Epub 2020 Jun 10.

Department of Medical Genetics, National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, UK.

A BRCA2 prostate cancer cluster region (PCCR) was recently proposed (c.7914 to 3') wherein pathogenic variants (PVs) are associated with higher prostate cancer (PCa) risk than PVs elsewhere in the BRCA2 gene. Using a prospective cohort study of 447 male BRCA2 PV carriers recruited in the UK and Ireland from 1998 to 2016, we estimated standardised incidence ratios (SIRs) compared with population incidences and assessed variation in risk by PV location. Carriers of PVs in the PCCR had a PCa SIR of 8.33 (95% confidence interval [CI] 4.46-15.6) and were at a higher risk of PCa than carriers of other BRCA2 PVs (SIR = 3.31, 95% CI 1.97-5.57; hazard ratio = 2.34, 95% CI 1.09-5.03). PCCR PV carriers had an estimated cumulative PCa risk of 44% (95% CI 23-72%) by the age of 75 yr and 78% (95% CI 54-94%) by the age of 85 yr. Our results corroborate the existence of a PCCR in BRCA2 in a prospective cohort. PATIENT SUMMARY: In this report, we investigated whether the risk of prostate cancer for men with a harmful mutation in the BRCA2 gene differs based on where in the gene the mutation is located. We found that men with mutations in one region of BRCA2 had a higher risk of prostate cancer than men with mutations elsewhere in the gene.
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http://dx.doi.org/10.1016/j.eururo.2020.05.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7532700PMC
October 2020

Thoracic Visceral Adipose Tissue Area and Pulmonary Hypertension in Lung Transplant Candidates. The Lung Transplant Body Composition Study.

Ann Am Thorac Soc 2020 11;17(11):1393-1400

Department of Medicine and.

Obesity is associated with an increased risk of pulmonary hypertension (PH); however, regional adipose tissue deposition is heterogeneous with distinct cardiovascular phenotypes. To determine the association of body mass index (BMI) and thoracic visceral and subcutaneous adipose tissue areas (VAT and SAT, respectively) with PH in patients with advanced lung disease referred for lung transplantation. We studied patients undergoing evaluation for lung transplantation at three centers from the Lung Transplant Body Composition Study. PH was defined as mean pulmonary artery pressure >20 mm Hg and pulmonary vascular resistance ≥3 Wood units. VAT and SAT were measured on chest computed tomography and normalized to height squared. One hundred thirty-seven (34%) of 399 patients included in our study had PH. Doubling of thoracic VAT was associated with significantly lower pulmonary vascular resistance (β, -0.24; 95% confidence interval [95% CI], -0.46 to -0.02;  = 0.04), higher pulmonary arterial wedge pressure (β, 0.79; 95% CI, 0.32 to 1.26;  = 0.001), and decreased risk of PH (relative risk, 0.86; 95% CI, 0.74 to 0.99;  = 0.04) after multivariate adjustment. Vaspin levels were higher in patients without PH (median, 101.8 vs. 92.0 pg/ml;  < 0.001) but did not mediate the association between VAT and the risk of PH. SAT and BMI were not independently associated with risk of PH. Lower thoracic VAT was associated with a higher risk of PH in patients with advanced lung disease undergoing evaluation for lung transplantation. The role of adipokines in the pulmonary vascular disease remains to be evaluated.
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http://dx.doi.org/10.1513/AnnalsATS.202003-247OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7640728PMC
November 2020

Skeletal muscle adiposity and outcomes in candidates for lung transplantation: a lung transplant body composition cohort study.

Thorax 2020 09 1;75(9):801-804. Epub 2020 Jun 1.

Medicine, University of California, San Francisco, California, USA.

CT measurement of body composition may improve lung transplant candidate selection. We assessed whether skeletal muscle adipose deposition on abdominal and thigh CT scans was associated with 6 min walk distance (6MWD) and wait-list survival in lung transplant candidates. Each ½-SD decrease in abdominal muscle attenuation (indicating greater lipid content) was associated with 14 m decrease in 6MWD (95% CI -20 to -8) and 20% increased risk of death or delisting (95% CI 10% to 40%). Each ½-standard deviation decrease in thigh muscle attenuation was associated with 15 m decrease in 6MWD (95% CI -21 to -10). CT imaging may improve candidate risk stratification.
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http://dx.doi.org/10.1136/thoraxjnl-2019-214461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7888552PMC
September 2020

Characteristics of Early Paget's Disease in SQSTM1 Mutation Carriers: Baseline Analysis of the ZiPP Study Cohort.

J Bone Miner Res 2020 07 20;35(7):1246-1252. Epub 2020 Apr 20.

Department of Rheumatology, Hospital Clinic, CIBERehd, Barcelona, Spain.

Mutations in SQSTM1 are strongly associated with Paget's disease of bone (PDB), but little is known about the clinical characteristics of those with early disease. Radionuclide bone scans, biochemical markers of bone turnover, and clinical characteristics were analyzed in SQSTM1 mutation carriers who took part in the Zoledronic acid in the Prevention of Paget's disease (ZiPP) study. We studied 222 individuals, of whom 54.9% were female, with mean ± SE age of 50.1 ± 0.6 years. Twelve SQSTM1 mutations were observed, including p.Pro392Leu, which was present in 141 of 222 (63.5%) subjects. Bone scan examination revealed evidence of PDB in 20 subjects (9.0%), ten of whom (50%) had a single affected site. Participants with lesions were older than those without lesions but the difference was not significant (53.6 ± 9.1 versus 49.8 ± 8.9; p = .07). The mean age of participants with lesions was not significantly different from the age at which their parents were diagnosed with PDB (55 years versus 59 years, p = .17). All individuals with lesions were asymptomatic. Serum concentrations of total alkaline phosphatase (ALP) normalized to the upper limit of normal in each center were higher in those with lesions (0.75 ± 0.69 versus 0.42 ± 0.29 arbitary units; p < .0001). Similar findings were observed for other biochemical markers of bone turnover, but the sensitivity of ALP and other markers in detecting lesions was poor. Asymptomatic PDB is present in about 9% of SQSTM1 mutation carriers by the fifth decade. Further follow-up of this cohort will provide important information on the natural history of early PDB and its response to treatment. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbmr.4007DOI Listing
July 2020

Relationship between neuropsychiatric disorders and cognitive and behavioural change in MND.

J Neurol Neurosurg Psychiatry 2020 03 23;91(3):245-253. Epub 2019 Dec 23.

Human Cognitive Neurosciences, Department of Psychology, The University of Edinburgh, Edinburgh, UK.

Objective: In this population-based study, we aimed to determine whether neuropsychiatric history, medication or family history of neuropsychiatric disorders predicted cognitive and/or behavioural impairment in motor neuron disease (MND).

Methods: People with MND (pwMND) on the Scottish Clinical, Audit, Research and Evaluation of MND (CARE-MND) register, diagnosed from January 2015 to January 2018, with cognitive and/or behavioural data measured using the Edinburgh Cognitive and Behavioural ALS Screen were included. Data were extracted on patient neuropsychiatric, medication and family history of neuropsychiatric disorders. We identified patients with cognitive impairment (motor neuron disease with cognitive impairment (MNDci)), behavioural impairment (motor neuron disease with behavioural impairment (MNDbi), both (motor neuron disease with cognitive and behavioural impairment (MNDcbi)) or motor neuron disease-frontotemporal dementia (MND-FTD).

Results: Data were available for 305 pwMND (mean age at diagnosis=62.26 years, SD=11.40), of which 60 (19.7%) had a neuropsychiatric disorder. A family history of neuropsychiatric disorders was present in 36/231 (15.58%) of patients. Patient premorbid mood disorders were associated with increased apathy (OR=2.78, 95% CI 1.083 to 7.169). A family history of any neuropsychiatric disorder was associated with poorer visuospatial scores, MNDbi (OR=3.14, 95% CI 1.09 to 8.99) and MND-FTD (OR=5.08, 95% CI 1.26 to 20.40). A family history of mood disorders was associated with poorer overall cognition (exp(b)=0.725, p=0.026), language, verbal fluency and visuospatial scores, and MND-FTD (OR=7.57, 95% CI 1.55 to 46.87). A family history of neurotic disorders was associated with poorer language (exp(b)=0.362, p<0.001), visuospatial scores (exp(b)=0.625, p<0.009) and MND-FTD (OR=13.75, 95% CI 1.71 to 110.86).

Conclusion: Neuropsychiatric disorders in patients and their families are associated with cognitive and behavioural changes post-MND diagnosis, with many occurring independently of MND-FTD and C9orf72 status. These findings support an overlap between MND, frontotemporal dementia and neuropsychiatric disorders, particularly mood disorders.
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http://dx.doi.org/10.1136/jnnp-2019-321737DOI Listing
March 2020

Alcohol Consumption, Cigarette Smoking, and Risk of Breast Cancer for and Mutation Carriers: Results from The BRCA1 and BRCA2 Cohort Consortium.

Cancer Epidemiol Biomarkers Prev 2020 02 2;29(2):368-378. Epub 2019 Dec 2.

Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.

Background: Tobacco smoking and alcohol consumption have been intensively studied in the general population to assess their effects on the risk of breast cancer, but very few studies have examined these effects in and mutation carriers. Given the high breast cancer risk for mutation carriers and the importance of and in DNA repair, better evidence on the associations of these lifestyle factors with breast cancer risk is essential.

Methods: Using a large international pooled cohort of and mutation carriers, we conducted retrospective (5,707 mutation carriers and 3,525 mutation carriers) and prospective (2,276 mutation carriers and 1,610 mutation carriers) analyses of alcohol and tobacco consumption using Cox proportional hazards models.

Results: For both and mutation carriers, none of the smoking-related variables was associated with breast cancer risk, except smoking for more than 5 years before a first full-term pregnancy (FFTP) when compared with parous women who never smoked. For mutation carriers, the HR from retrospective analysis (HR) was 1.19 [95% confidence interval (CI), 1.02-1.39] and the HR from prospective analysis (HR) was 1.36 (95% CI, 0.99-1.87). For mutation carriers, smoking for more than 5 years before an FFTP showed an association of a similar magnitude, but the confidence limits were wider (HR = 1.25; 95% CI, 1.01-1.55 and HR = 1.30; 95% CI, 0.83-2.01). For both carrier groups, alcohol consumption was not associated with breast cancer risk.

Conclusions: The finding that smoking during the prereproductive years increases breast cancer risk for mutation carriers warrants further investigation.

Impact: This is the largest prospective study of mutation carriers to assess these important risk factors.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-0546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611162PMC
February 2020

Association of Genomic Domains in and with Prostate Cancer Risk and Aggressiveness.

Cancer Res 2020 02 13;80(3):624-638. Epub 2019 Nov 13.

Unité de Prévention et d'Epidémiologie Génétique, Centre Léon Bérard, Lyon, France.

Pathogenic sequence variants (PSV) in or () are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 and 171 male PSV carriers with prostate cancer, and 3,388 and 2,880 male PSV carriers without prostate cancer. PSVs in the 3' region of (c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001-c.7913 [HR = 1.78; 95% confidence interval (CI), 1.25-2.52; = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63-5.95; = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71-4.68; = 0.00004) and elevated risk of Gleason 8+ prostate cancer (HR = 4.95; 95% CI, 2.12-11.54; = 0.0002). No genotype-phenotype associations were detected for PSVs in . These results demonstrate that specific PSVs may be associated with elevated risk of developing aggressive prostate cancer. SIGNIFICANCE: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-1840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7553241PMC
February 2020

Prostate Cancer Risks for Male BRCA1 and BRCA2 Mutation Carriers: A Prospective Cohort Study.

Eur Urol 2020 01 6;77(1):24-35. Epub 2019 Sep 6.

Oncogenetics Team, Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK; Cancer Genetics Unit, Royal Marsden NHS Foundation Trust, London, UK.

Background: BRCA1 and BRCA2 mutations have been associated with prostate cancer (PCa) risk but a wide range of risk estimates have been reported that are based on retrospective studies.

Objective: To estimate relative and absolute PCa risks associated with BRCA1/2 mutations and to assess risk modification by age, family history, and mutation location.

Design, Setting, And Participants: This was a prospective cohort study of male BRCA1 (n = 376) and BRCA2 carriers (n = 447) identified in clinical genetics centres in the UK and Ireland (median follow-up 5.9 and 5.3 yr, respectively).

Outcome Measurements And Statistical Analysis: Standardised incidence/mortality ratios (SIRs/SMRs) relative to population incidences or mortality rates, absolute risks, and hazard ratios (HRs) were estimated using cohort and survival analysis methods.

Results And Limitations: Sixteen BRCA1 and 26 BRCA2 carriers were diagnosed with PCa during follow-up. BRCA2 carriers had an SIR of 4.45 (95% confidence interval [CI] 2.99-6.61) and absolute PCa risk of 27% (95% CI 17-41%) and 60% (95% CI 43-78%) by ages 75 and 85 yr, respectively. For BRCA1 carriers, the overall SIR was 2.35 (95% CI 1.43-3.88); the corresponding SIR at age <65 yr was 3.57 (95% CI 1.68-7.58). However, the BRCA1 SIR varied between 0.74 and 2.83 in sensitivity analyses to assess potential screening effects. PCa risk for BRCA2 carriers increased with family history (HR per affected relative 1.68, 95% CI 0.99-2.85). BRCA2 mutations in the region bounded by positions c.2831 and c.6401 were associated with an SIR of 2.46 (95% CI 1.07-5.64) compared to population incidences, corresponding to lower PCa risk (HR 0.37, 95% CI 0.14-0.96) than for mutations outside the region. BRCA2 carriers had a stronger association with Gleason score ≥7 (SIR 5.07, 95% CI 3.20-8.02) than Gleason score ≤6 PCa (SIR 3.03, 95% CI 1.24-7.44), and a higher risk of death from PCa (SMR 3.85, 95% CI 1.44-10.3). Limitations include potential screening effects for these known mutation carriers; however, the BRCA2 results were robust to multiple sensitivity analyses.

Conclusions: The results substantiate PCa risk patterns indicated by retrospective analyses for BRCA2 carriers, including further evidence of association with aggressive PCa, and give some support for a weaker association in BRCA1 carriers.

Patient Summary: In this study we followed unaffected men known to carry mutations in the BRCA1 and BRCA2 genes to investigate whether they are at higher risk of developing prostate cancer compared to the general population. We found that carriers of BRCA2 mutations have a high risk of developing prostate cancer, particularly more aggressive prostate cancer, and that this risk varies by family history of prostate cancer and the location of the mutation within the gene.
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http://dx.doi.org/10.1016/j.eururo.2019.08.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6926480PMC
January 2020

Zoledronate in the prevention of Paget's (ZiPP): protocol for a randomised trial of genetic testing and targeted zoledronic acid therapy to prevent -mediated Paget's disease of bone.

BMJ Open 2019 09 4;9(9):e030689. Epub 2019 Sep 4.

Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.

Introduction: Paget's disease of bone (PDB) is characterised by increased and disorganised bone remodelling affecting one or more skeletal sites. Complications include bone pain, deformity, deafness and pathological fractures. Mutations in sequestosome-1 () are strongly associated with the development of PDB. Bisphosphonate therapy can improve bone pain in PDB, but there is no evidence that treatment alters the natural history of PDB or prevents complications. The Zoledronate in the Prevention of Paget's disease trial (ZiPP) will determine if prophylactic therapy with the bisphosphonate zoledronic acid (ZA) can delay or prevent the development of PDB in people who carry mutations.

Methods And Analysis: People with a family history of PDB aged >30 years who test positive for mutations are eligible to take part. At the baseline visit, participants will be screened for the presence of bone lesions by radionuclide bone scan. Biochemical markers of bone turnover will be measured and questionnaires completed to assess pain, health-related quality of life (HRQoL), anxiety and depression. Participants will be randomised to receive a single intravenous infusion of 5 mg ZA or placebo and followed up annually for between 4 and 8 years at which point baseline assessments will be repeated. The primary endpoint will be new bone lesions assessed by radionuclide bone scan. Secondary endpoints will include changes in biochemical markers of bone turnover, pain, HRQoL, anxiety, depression and PDB-related skeletal events.

Ethics And Dissemination: The study was approved by the Fife and Forth Valley Research Ethics Committee on 22 December 2008 (08/S0501/84). Following completion of the trial, a manuscript will be submitted to a peer-reviewed journal. The results of this trial will inform clinical practice by determining if early intervention with ZA in presymptomatic individuals with mutations can prevent or slow the development of bone lesions with an adverse event profile that is acceptable.

Trial Registration Number: ISRCTN11616770.
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http://dx.doi.org/10.1136/bmjopen-2019-030689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6731944PMC
September 2019

RNA sequencing of transplant-stage idiopathic pulmonary fibrosis lung reveals unique pathway regulation.

ERJ Open Res 2019 Jul 12;5(3). Epub 2019 Aug 12.

Pulmonary and Critical Care Medicine, University of Pennsylvania, Philadelphia PA, USA.

Idiopathic pulmonary fibrosis (IPF), the scarring of lung parenchyma resulting in the loss of lung function, remains a fatal disease with a significant unmet medical need. Patients with severe IPF often develop acute exacerbations resulting in the rapid deterioration of lung function, requiring transplantation. Understanding the pathophysiological mechanisms contributing to IPF is key to develop novel therapeutic approaches for end-stage disease. We report here RNA-sequencing analyses of lung tissues from a cohort of patients with transplant-stage IPF (n=36), compared with acute lung injury (ALI) (n=11) and nondisease controls (n=19), that reveal a robust gene expression signature unique to end-stage IPF. In addition to extracellular matrix remodelling pathways, we identified pathways associated with T-cell infiltration/activation, tumour development, and cholesterol homeostasis, as well as novel alternatively spliced transcripts that are differentially regulated in the advanced IPF lung ALI or nondisease controls. Additionally, we show a subset of genes that are correlated with percent predicted forced vital capacity and could reflect disease severity. Our results establish a robust transcriptomic fingerprint of an advanced IPF lung that is distinct from previously reported microarray signatures of moderate, stable or progressive IPF and identifies hitherto unknown candidate targets and pathways for therapeutic intervention in late-stage IPF as well as biomarkers to characterise disease progression and enable patient stratification.
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http://dx.doi.org/10.1183/23120541.00117-2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6689672PMC
July 2019

Lung Innate Lymphoid Cell Composition Is Altered in Primary Graft Dysfunction.

Am J Respir Crit Care Med 2020 01;201(1):63-72

Division of Pulmonary, Allergy, and Critical Care Medicine, and.

Primary graft dysfunction (PGD) is the leading cause of early morbidity and mortality after lung transplantation, but the immunologic mechanisms are poorly understood. Innate lymphoid cells (ILC) are a heterogeneous family of immune cells regulating pathologic inflammation and beneficial tissue repair. However, whether changes in donor-derived lung ILC populations are associated with PGD development has never been examined. To determine whether PGD in chronic obstructive pulmonary disease or interstitial lung disease transplant recipients is associated with alterations in ILC subset composition within the allograft. We performed a single-center cohort study of lung transplantation patients with surgical biopsies of donor tissue taken before, and immediately after, allograft reperfusion. Donor immune cells from 18 patients were characterized phenotypically by flow cytometry for single-cell resolution of distinct ILC subsets. Changes in the percentage of ILC subsets with reperfusion or PGD (grade 3 within 72 h) were assessed. Allograft reperfusion resulted in significantly decreased frequencies of natural killer cells and a trend toward reduced ILC populations, regardless of diagnosis (interstitial lung disease or chronic obstructive pulmonary disease). Seven patients developed PGD (38.9%), and PGD development was associated with selective reduction of the ILC2 subset after reperfusion. Conversely, patients without PGD exhibited significantly higher ILC1 frequencies before reperfusion, accompanied by elevated ILC2 frequencies after allograft reperfusion. The composition of donor ILC subsets is altered after allograft reperfusion and is associated with PGD development, suggesting that ILCs may be involved in regulating lung injury in lung transplant recipients.
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http://dx.doi.org/10.1164/rccm.201906-1113OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6938146PMC
January 2020

Oral Contraceptive Use and Breast Cancer Risk: Retrospective and Prospective Analyses From a BRCA1 and BRCA2 Mutation Carrier Cohort Study.

JNCI Cancer Spectr 2018 Apr 28;2(2):pky023. Epub 2018 Jun 28.

Department of Pathology and Molecular Medicine, Juravinski Hospital and Cancer Centre, McMaster University, Hamilton, Ontario, Canada.

Background: For BRCA1 and BRCA2 mutation carriers, the association between oral contraceptive preparation (OCP) use and breast cancer (BC) risk is still unclear.

Methods: Breast camcer risk associations were estimated from OCP data on 6030 BRCA1 and 3809 BRCA2 mutation carriers using age-dependent Cox regression, stratified by study and birth cohort. Prospective, left-truncated retrospective and full-cohort retrospective analyses were performed.

Results: For BRCA1 mutation carriers, OCP use was not associated with BC risk in prospective analyses (hazard ratio [HR] = 1.08, 95% confidence interval [CI] = 0.75 to 1.56), but in the left-truncated and full-cohort retrospective analyses, risks were increased by 26% (95% CI = 6% to 51%) and 39% (95% CI = 23% to 58%), respectively. For BRCA2 mutation carriers, OCP use was associated with BC risk in prospective analyses (HR = 1.75, 95% CI = 1.03 to 2.97), but retrospective analyses were inconsistent (left-truncated: HR = 1.06, 95% CI = 0.85 to 1.33; full cohort: HR = 1.52, 95% CI = 1.28 to 1.81). There was evidence of increasing risk with duration of use, especially before the first full-term pregnancy (BRCA1: both retrospective analyses, < .001 and = .001, respectively; BRCA2: full retrospective analysis, = .002).

Conclusions: Prospective analyses did not show that past use of OCP is associated with an increased BC risk for BRCA1 mutation carriers in young middle-aged women (40-50 years). For BRCA2 mutation carriers, a causal association is also not likely at those ages. Findings between retrospective and prospective analyses were inconsistent and could be due to survival bias or a true association for younger women who were underrepresented in the prospective cohort. Given the uncertain safety of long-term OCP use for BRCA1/2 mutation carriers, indications other than contraception should be avoided and nonhormonal contraceptive methods should be discussed.
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http://dx.doi.org/10.1093/jncics/pky023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6649757PMC
April 2018

The association of post-lung transplant acute kidney injury with mortality is independent of primary graft dysfunction: A cohort study.

Clin Transplant 2019 10 28;33(10):e13678. Epub 2019 Aug 28.

Pulmonary, Allergy, and Critical Care Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Background: Prior studies of post-lung transplant acute kidney injury (AKI) have not accounted for confounding effects of primary graft dysfunction (PGD). We sought to test the impact of PGD on AKI risk factors and on the association of AKI with mortality.

Methods: We included patients transplanted at the University of Pennsylvania from 2005-12, defined AKI using consensus criteria during transplant hospitalization, and defined PGD as grade 3 at 48-72 hours. We used multivariable logistic regression to test the impact of PGD on AKI risk factors and Cox models to test association of AKI with one-year mortality adjusting for PGD and other confounders.

Results: Of 299 patients, 188 (62.9%) developed AKI with 142 (75%) cases occurring by postoperative day 4. In multivariable models, PGD was strongly associated with AKI (OR 3.76, 95% CI 1.72-8.19, P = .001) but minimally changed associations of other risk factors with AKI. Both AKI (HR 3.64, 95% CI 1.68-7.88, P = .001) and PGD (HR 2.55, 95% CI 1.40-4.64, P = .002) were independently associated with one-year mortality.

Conclusions: Post-lung transplant AKI risk factors and association of AKI with mortality were independent of PGD. AKI may therefore be a target for improving lung transplant mortality rather than simply an epiphenomenon of PGD.
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http://dx.doi.org/10.1111/ctr.13678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823116PMC
October 2019

Resequencing Study Confirms That Host Defense and Cell Senescence Gene Variants Contribute to the Risk of Idiopathic Pulmonary Fibrosis.

Am J Respir Crit Care Med 2019 07;200(2):199-208

7 Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Several common and rare genetic variants have been associated with idiopathic pulmonary fibrosis, a progressive fibrotic condition that is localized to the lung. To develop an integrated understanding of the rare and common variants located in multiple loci that have been reported to contribute to the risk of disease. We performed deep targeted resequencing (3.69 Mb of DNA) in cases ( = 3,624) and control subjects ( = 4,442) across genes and regions previously associated with disease. We tested for associations between disease and ) individual common variants via logistic regression and ) groups of rare variants via sequence kernel association tests. Statistically significant common variant association signals occurred in all 10 of the regions chosen based on genome-wide association studies. The strongest risk variant is the promoter variant rs35705950, with an odds ratio of 5.45 (95% confidence interval, 4.91-6.06) for one copy of the risk allele and 18.68 (95% confidence interval, 13.34-26.17) for two copies of the risk allele ( = 9.60 × 10). In addition to identifying for the first time that rare variation in is associated with disease, we confirmed the role of rare variation in the and gene regions in the risk of IPF, and found that the and regions have independent common and rare variant signals. A limited number of common and rare variants contribute to the risk of idiopathic pulmonary fibrosis in each of the resequencing regions, and these genetic variants focus on biological mechanisms of host defense and cell senescence.
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http://dx.doi.org/10.1164/rccm.201810-1891OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6635791PMC
July 2019

Postreperfusion plasma endothelial activation markers are associated with acute kidney injury after lung transplantation.

Am J Transplant 2019 08 23;19(8):2366-2373. Epub 2019 May 23.

Pulmonary, Allergy, and Critical Care Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

Acute kidney injury (AKI) is common after lung transplantation, but molecular markers remain poorly studied. The endothelial activation markers soluble thrombomodulin (sTM), protein C, and plasminogen activator inhibitor-1 (PAI-1) are implicated in kidney microcirculatory injury in animal models of AKI. We tested the association of 6-hour postreperfusion plasma levels of these markers with posttransplant AKI severity in patients enrolled in the Lung Transplant Outcomes Group prospective cohort study at the University of Pennsylvania during two eras: 2004-06 (n = 61) and 2013-15 (n = 67). We defined AKI stage through postoperative day 5 using Kidney Disease Improving Global Outcomes creatinine criteria. We used multivariable ordinal logistic regression to determine the association of each biomarker with AKI, adjusted for primary graft dysfunction and extracorporeal life support. AKI occurred in 57 (45%) patients across both eras: 28 (22%) stage 1, 29 (23%) stage 2-3. Higher sTM and lower protein C plasma levels were associated with AKI stage in each era and remained so in multivariable models utilizing both eras (sTM: OR 1.76 [95% CI 1.19-2.60] per standard deviation, P = .005; protein C: OR 0.54 [1.19-2.60], P = .003). We conclude that 6-hour postreperfusion plasma sTM and protein C levels are associated with early postlung transplant AKI severity.
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http://dx.doi.org/10.1111/ajt.15402DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6658345PMC
August 2019

Negotiating jurisdictional boundaries in response to new genetic possibilities in breast cancer care: The creation of an 'oncogenetic taskscape'.

Soc Sci Med 2019 03 13;225:26-33. Epub 2019 Feb 13.

Ethox Centre and Wellcome Centre for Ethics and Humanities, Nuffield Department of Population Health, Big Data Institute University of Oxford, UK.

Changes in the nature and structure of healthcare pathways have implications for healthcare professionals' jurisdictional boundaries. The introduction of treatment focused BRCA1 and 2 genetic testing (TFGT) for newly diagnosed patients with breast cancer offers a contemporary example of pathway change brought about by technological advancements in gene testing and clinical evidence, and reflects the cultural shift towards genomics. Forming part of an ethnographically informed study of patient and practitioner experiences of TFGT at a UK teaching hospital, this paper focuses on the impact of a proposal to pilot a mainstreamed TFGT pathway on healthcare professionals' negotiations of professional jurisdiction. Based upon semi-structured interviews (n = 19) with breast surgeons, medical oncologists and members of the genetics team, alongside observations of breast multidisciplinary team meetings, during the time leading up to the implementation of the pilot, we describe how clinicians responded to the anticipated changes associated with mainstreaming. Interviews suggest that mainstreaming the breast cancer pathway, and the associated jurisdictional reconfigurations, had advocates as well as detractors. Medical oncologists championed the plans, viewing this adaptation in care provision and their professional role as a logical next step. Breast surgeons, however, regarded mainstreaming as an unfeasible expansion of their workload and questioned the relevance of TFGT to their clinical practice. The genetics team, who introduced the pilot, appeared cautiously optimistic about the potential changes. Drawing on sociological understandings of the negotiation of professional jurisdictions our work contributes a timely, micro-level examination of the responses among clinicians as they worked to renegotiate professional boundaries in response to the innovative application of treatment-focused BRCA testing in cancer care - a local and dynamic process which we refer to as an 'oncogenetic taskscape in the making'.
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http://dx.doi.org/10.1016/j.socscimed.2019.02.020DOI Listing
March 2019

Towards establishing consistency in triage in a tertiary specialty.

Eur J Hum Genet 2019 04 8;27(4):547-555. Epub 2019 Jan 8.

Department of Clinical Genetics, Our Lady's Children's Hospital Crumlin, Dublin, Ireland.

Clinical Genetics services provide a diagnostic, counselling and genetic testing service for children and adults affected by, or at risk of, a genetic condition, most of which are rare, and/or genetically heterogeneous. Appropriate triage of referrals is crucial to ensure that the most urgent referrals are seen as quickly as possible, without negatively impacting the waiting times of less urgent cases. We aimed to examine triage practice in six Clinical Genetic centres across the United Kingdom and Ireland. Thirteen simulated referrals were drafted based on common referrals to Clinical Genetics. Copies of each referral were forwarded to each centre, where 10 nominated clinicians were asked to triage each referral. Triaged referrals were returned to the coordinating author for analysis. An electronic questionnaire was contemporaneously completed by clinical leads in each unit to gather local demographic details and local operating procedures relevant to triage. Widespread inconsistencies were noted both within and between units, with respect to the acceptance of referrals to the services, prioritisation and designated clinic type. Referral rates, staffing levels and waiting lists varied widely between units. Inconsistencies observed between units are likely influenced by a number of factors, including staffing levels, referral rates and average family size. Inconsistency within units likely reflects the complex nature of many Clinical Genetic referrals, and triage guidelines should help improve decision-making in this setting.
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http://dx.doi.org/10.1038/s41431-018-0322-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6460635PMC
April 2019

Patients' Views of Treatment-Focused Genetic Testing (TFGT): Some Lessons for the Mainstreaming of BRCA1 and BRCA2 Testing.

J Genet Couns 2018 May 11. Epub 2018 May 11.

Big Data Institute, Ethox Centre, Wellcome Centre for Ethics and Humanities, Nuffield Department of Population Health, University of Oxford, Oxford, UK.

This paper explores patients' views and experiences of undergoing treatment-focused BRCA1 and BRCA2 genetic testing (TFGT), either offered following triaging to clinical genetics (breast cancer) or as part of a mainstreamed care pathway in oncology (ovarian cancer). Drawing on 26 in-depth interviews with patients with breast or ovarian cancer who had undergone TFGT, this retrospective study examines patients' views of genetic testing at this point in their care pathway, focusing on issues, such as initial response to the offer of testing, motivations for undergoing testing, and views on care pathways. Patients were amenable to the incorporation of TFGT at an early stage in their cancer care irrespective of (any) prior anticipation of having a genetic test or family history. While patients were glad to have been offered TFGT as part of their care, some questioned the logic of the test's timing in relation to their cancer treatment. Crucially, patients appeared unable to disentangle the treatment role of TFGT from its preventative function for self and other family members, suggesting that some may undergo TFGT to obtain information for others rather than for self.
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http://dx.doi.org/10.1007/s10897-018-0261-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6209051PMC
May 2018

Risks of breast or ovarian cancer in BRCA1 or BRCA2 predictive test negatives: findings from the EMBRACE study.

Genet Med 2018 12 22;20(12):1575-1582. Epub 2018 Mar 22.

Oncogenetics Team, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, London, UK.

Purpose: BRCA1/BRCA2 predictive test negatives are proven noncarriers of a BRCA1/BRCA2 mutation that is carried by their relatives. The risk of developing breast cancer (BC) or epithelial ovarian cancer (EOC) in these women is uncertain. The study aimed to estimate risks of invasive BC and EOC in a large cohort of BRCA1/BRCA2 predictive test negatives.

Methods: We used cohort analysis to estimate incidences, cumulative risks, and standardized incidence ratios (SIRs).

Results: A total of 1,895 unaffected women were eligible for inclusion in the BC risk analysis and 1,736 in the EOC risk analysis. There were 23 incident invasive BCs and 2 EOCs. The cumulative risk of invasive BC was 9.4% (95% confidence interval (CI) 5.9-15%) by age 85 years and the corresponding risk of EOC was 0.6% (95% CI 0.2-2.6%). The SIR for invasive BC was 0.93 (95% CI 0.62-1.40) in the overall cohort, 0.85 (95% CI 0.48-1.50) in noncarriers from BRCA1 families, and 1.03 (95% CI 0.57-1.87) in noncarriers from BRCA2 families. The SIR for EOC was 0.79 (95% CI 0.20-3.17) in the overall cohort.

Conclusion: Our results did not provide evidence for elevated risks of invasive BC or EOC in BRCA1/BRCA2 predictive test negatives.
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http://dx.doi.org/10.1038/gim.2018.44DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6033314PMC
December 2018

Incidence, risk factors, and clinical implications of post-operative delirium in lung transplant recipients.

J Heart Lung Transplant 2018 06 2;37(6):755-762. Epub 2018 Feb 2.

Division of Pulmonary, Allergy and Critical Care Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Background: Delirium significantly affects post-operative outcomes, but the incidence, risk factors, and long-term impact of delirium in lung transplant recipients have not been well studied.

Methods: We analyzed 155 lung transplant recipients enrolled in the Lung Transplant Outcomes Group (LTOG) cohort at a single center. We determined delirium incidence by structured chart review, identified risk factors for delirium, determined whether plasma concentrations of 2 cerebral injury markers (neuron-specific enolase [NSE] and glial fibrillary acidic protein [GFAP]) were associated with delirium, and determined the association of post-operative delirium with 1-year survival.

Results: Fifty-seven (36.8%) patients developed post-operative delirium. Independent risk factors for delirium included pre-transplant benzodiazepine prescription (relative risk [RR] 1.82; 95% confidence interval [CI] 1.08 to 3.07; p = 0.025), total ischemic time (RR 1.10 per 30-minute increase; 95% CI 1.01 to 1.21; p = 0.027), duration of time with intra-operative mean arterial pressure <60 mm Hg (RR 1.07 per 15-minute increase; 95% CI 1.00 to 1.14; p = 0.041), and Grade 3 primary graft dysfunction (RR 2.13; 95% CI 1.27 to 3.58; p = 0.004). Ninety-one (58.7%) patients had plasma available at 24 hours. Plasma GFAP was inconsistently detected, whereas NSE was universally detectable, with higher NSE concentrations associated with delirium (risk difference 15.1% comparing 75th and 25th percentiles; 95% CI 2.5 to 27.7; p = 0.026). One-year mortality appeared higher among delirious patients, 12.3% compared with 7.1%, but the difference was not significant (p = 0.28).

Conclusions: Post-operative delirium is common in lung transplant recipients, and several potentially modifiable risk factors deserve further study to determine their associated mechanisms and predictive values.
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http://dx.doi.org/10.1016/j.healun.2018.01.1295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5970008PMC
June 2018

Association of long pentraxin-3 with pulmonary hypertension and primary graft dysfunction in lung transplant recipients.

J Heart Lung Transplant 2018 06 20;37(6):792-794. Epub 2017 Dec 20.

Pulmonary, Allergy, and Critical Care Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA; Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA; Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

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http://dx.doi.org/10.1016/j.healun.2017.12.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6685262PMC
June 2018

Cell-free hemoglobin promotes primary graft dysfunction through oxidative lung endothelial injury.

JCI Insight 2018 01 25;3(2). Epub 2018 Jan 25.

Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

Primary graft dysfunction (PGD) is acute lung injury within 72 hours of lung transplantation. We hypothesized that cell-free hemoglobin (CFH) contributes to PGD by increasing lung microvascular permeability and tested this in patients, ex vivo human lungs, and cultured human lung microvascular endothelial cells. In a nested case control study of 40 patients with severe PGD at 72 hours and 80 matched controls without PGD, elevated preoperative CFH was independently associated with increased PGD risk (odds ratio [OR] 2.75, 95%CI, 1.23-6.16, P = 0.014). The effect of CFH on PGD was magnified by reperfusion fraction of inspired oxygen (FiO2) ≥ 0.40 (OR 3.41, P = 0.031). Isolated perfused human lungs exposed to intravascular CFH (100 mg/dl) developed increased vascular permeability as measured by lung weight (CFH 14.4% vs. control 0.65%, P = 0.047) and extravasation of Evans blue-labeled albumin dye (EBD) into the airspace (P = 0.027). CFH (1 mg/dl) also increased paracellular permeability of human pulmonary microvascular endothelial cell monolayers (hPMVECs). Hyperoxia (FiO2 = 0.95) increased human lung and hPMVEC permeability compared with normoxia (FiO2 = 0.21). Treatment with acetaminophen (15 μg/ml), a specific hemoprotein reductant, prevented CFH-dependent permeability in human lungs (P = 0.046) and hPMVECs (P = 0.037). In summary, CFH may mediate PGD through oxidative effects on microvascular permeability, which are augmented by hyperoxia and abrogated by acetaminophen.
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http://dx.doi.org/10.1172/jci.insight.98546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5821179PMC
January 2018

Causes, Preventability, and Cost of Unplanned Rehospitalizations Within 30 Days of Discharge After Lung Transplantation.

Transplantation 2018 05;102(5):838-844

Pulmonary and Critical Care Medicine, University of Pennsylvania, Philadelphia, PA.

Background: Unplanned rehospitalizations (UR) within 30 days of discharge are common after lung transplantation. It is unknown whether UR represents preventable gaps in care or necessary interventions for complex patients. The objective of this study was to assess the incidence, causes, risk factors, and preventability of UR after initial discharge after lung transplantation.

Methods: This was a single-center prospective cohort study. Subjects completed a modified short physical performance battery to assess frailty at listing and at initial hospital discharge after transplantation and the State-Trait Anxiety Inventory at discharge. For each UR, a study staff member and the patient's admitting or attending clinician used an ordinal scale (0, not; 1, possibly; 2, definitely preventable) to rate readmission preventability. A total sum score of 2 or higher defined a preventable UR.

Results: Of the 90 enrolled patients, 30 (33.3%) had an UR. The single most common reasons were infection (7 [23.3%]) and atrial tachyarrhythmia (5 [16.7%]). Among the 30 URs, 9 (30.0%) were deemed preventable. Unplanned rehospitalization that happened before day 30 were more likely to be considered preventable than those between days 30 and 90 (30.0% versus 6.2%, P = 0.04). Discharge frailty, defined as short physical performance battery less than 6, was the only variable associated with UR on multivariable analysis (odds ratio, 3.4; 95% confidence interval, 1.1-11.8; P = 0.04).

Conclusions: Although clinicians do not rate the majority of UR after lung transplant as preventable, discharge frailty is associated with UR. Further research should identify whether modification of discharge frailty can reduce UR.
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http://dx.doi.org/10.1097/TP.0000000000002101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5924417PMC
May 2018
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