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6. Correction: Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database (Genetics in Medicine, (2020), 22, 1, (15-25), 10.1038/s41436-019-0596-9)

Author

Dominguez-Valentin M., Sampson J. R., Seppala T. T., ten Broeke S. W., Plazzer J. -P., Nakken S., Engel C., Aretz S., Jenkins M. A., Sunde L., Bernstein I., Capella G., Balaguer F., Thomas H., Evans D. G., Burn J., Greenblatt M., Hovig E., de Vos tot Nederveen Cappel W. H., Sijmons R. H., Bertario L., Tibiletti M. G., Cavestro G. M., Lindblom A., Della Valle A., Lopez-Kostner F., Gluck N., Katz L. H., Heinimann K., Vaccaro C. A., Buttner R., Gorgens H., Holinski-Feder E., Morak M., Holzapfel S., Huneburg R., Knebel Doeberitz M., Loeffler M., Rahner N., Schackert H. K., Steinke-Lange V., Schmiegel W., Vangala D., Pylvanainen K., Renkonen-Sinisalo L., Hopper J. L., Win A. K., Haile R. W., Lindor N. M., Gallinger S., Le Marchand L., Newcomb P. A., Figueiredo J. C., Thibodeau S. N., Wadt K., Therkildsen C., Okkels H., Ketabi Z., Moreira L., Sanchez A., Serra-Burriel M., Pineda M., Navarro M., Blanco I., Green K., Lalloo F., Crosbie E. J., Hill J., Denton O. G., Frayling I. M., Rodland E. A., Vasen H., Mints M., Neffa F., Esperon P., Alvarez K., Kariv R., Rosner G., Pinero T. A., Gonzalez M. L., Kalfayan P., Tjandra D., Winship I. M., Macrae F., Moslein G., Mecklin J. -P., Nielsen M., Moller P., Dominguez-Valentin, M., Sampson, J. R., Seppala, T. T., ten Broeke, S. W., Plazzer, J. -P., Nakken, S., Engel, C., Aretz, S., Jenkins, M. A., Sunde, L., Bernstein, I., Capella, G., Balaguer, F., Thomas, H., Evans, D. G., Burn, J., Greenblatt, M., Hovig, E., de Vos tot Nederveen Cappel, W. H., Sijmons, R. H., Bertario, L., Tibiletti, M. G., Cavestro, G. M., Lindblom, A., Della Valle, A., Lopez-Kostner, F., Gluck, N., Katz, L. H., Heinimann, K., Vaccaro, C. A., Buttner, R., Gorgens, H., Holinski-Feder, E., Morak, M., Holzapfel, S., Huneburg, R., Knebel Doeberitz, M., Loeffler, M., Rahner, N., Schackert, H. K., Steinke-Lange, V., Schmiegel, W., Vangala, D., Pylvanainen, K., Renkonen-Sinisalo, L., Hopper, J. L., Win, A. K., Haile, R. W., Lindor, N. M., Gallinger, S., Le Marchand, L., Newcomb, P. A., Figueiredo, J. C., Thibodeau, S. N., Wadt, K., Therkildsen, C., Okkels, H., Ketabi, Z., Moreira, L., Sanchez, A., Serra-Burriel, M., Pineda, M., Navarro, M., Blanco, I., Green, K., Lalloo, F., Crosbie, E. J., Hill, J., Denton, O. G., Frayling, I. M., Rodland, E. A., Vasen, H., Mints, M., Neffa, F., Esperon, P., Alvarez, K., Kariv, R., Rosner, G., Pinero, T. A., Gonzalez, M. L., Kalfayan, P., Tjandra, D., Winship, I. M., Macrae, F., Moslein, G., Mecklin, J. -P., Nielsen, M., and Moller, P.

Abstract

The original version of this Article did not contain details of Dutch Cancer Society (DCS) funding (grant number UL 2017-8223) in the Acknowledgements section. This has now been corrected in both the PDF and HTML versions of the Article.

Published
2020

9. Analysis in the Prospective Lynch Syndrome Database identifies sarcoma as part of the Lynch syndrome tumor spectrum

Author

Dominguez-Valentin M., Sampson J. R., Moller P., Seppala T. T., Plazzer J. -P., Nakken S., Engel C., Aretz S., Jenkins M. A., Sunde L., Bernstein I., Capella G., Balaguer F., Thomas H., Evans D. G., Burn J., Greenblatt M., Hovig E., Nielsen M., de Vos tot Nederveen Cappel W. H., Sijmons R. H., Bertario L., Tibiletti M. G., Cavestro G. M., Lindblom A., Valle A. D., Lopez-Kostner F., Gluck N., Katz L. H., Heinimann K., Vaccaro C. A., Buttner R., Gorgens H., Holinski-Feder E., Morak M., Holzapfel S., Huneburg R., von Knebel Doeberitz M., Loeffler M., Rahner N., Weitz J., Steinke-Lange V., ten Broeke S. W., Schmiegel W., Vangala D., Pylvanainen K., Renkonen-Sinisalo L., Hopper J. L., Win A. K., Haile R. W., Lindor N. M., Gallinger S., Le Marchand L., Newcomb P. A., Figueiredo J. C., Thibodeau S. N., Jensen L. H., Madsen M. B., Kroldrup L., Nilbert M., Moreira L., Sanchez A., Serra-Burriel M., Pineda M., Navarro M., Vidal J. B., Blanco I., Green K., Lalloo F., Crosbie E. J., Hill J., Denton O. G., Rodland E. A., Vasen H., Mints M., Neffa F., Esperon P., Alvarez K., Kariv R., Rosner G., Pinero T. A., Gonzalez M. L., Kalfayan P., Tjandra D., Winship I. M., Macrae F., Moslein G., Mecklin J. -P., Dominguez-Valentin, M., Sampson, J. R., Moller, P., Seppala, T. T., Plazzer, J. -P., Nakken, S., Engel, C., Aretz, S., Jenkins, M. A., Sunde, L., Bernstein, I., Capella, G., Balaguer, F., Thomas, H., Evans, D. G., Burn, J., Greenblatt, M., Hovig, E., Nielsen, M., de Vos tot Nederveen Cappel, W. H., Sijmons, R. H., Bertario, L., Tibiletti, M. G., Cavestro, G. M., Lindblom, A., Valle, A. D., Lopez-Kostner, F., Gluck, N., Katz, L. H., Heinimann, K., Vaccaro, C. A., Buttner, R., Gorgens, H., Holinski-Feder, E., Morak, M., Holzapfel, S., Huneburg, R., von Knebel Doeberitz, M., Loeffler, M., Rahner, N., Weitz, J., Steinke-Lange, V., ten Broeke, S. W., Schmiegel, W., Vangala, D., Pylvanainen, K., Renkonen-Sinisalo, L., Hopper, J. L., Win, A. K., Haile, R. W., Lindor, N. M., Gallinger, S., Le Marchand, L., Newcomb, P. A., Figueiredo, J. C., Thibodeau, S. N., Jensen, L. H., Madsen, M. B., Kroldrup, L., Nilbert, M., Moreira, L., Sanchez, A., Serra-Burriel, M., Pineda, M., Navarro, M., Vidal, J. B., Blanco, I., Green, K., Lalloo, F., Crosbie, E. J., Hill, J., Denton, O. G., Rodland, E. A., Vasen, H., Mints, M., Neffa, F., Esperon, P., Alvarez, K., Kariv, R., Rosner, G., Pinero, T. A., Gonzalez, M. L., Kalfayan, P., Tjandra, D., Winship, I. M., Macrae, F., Moslein, G., and Mecklin, J. -P.

Subjects
Male, Adult, Oncology, Cancer Research, 2019-20 coronavirus outbreak, medicine.medical_specialty, sarcoma, Databases, Factual, Coronavirus disease 2019 (COVID-19), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Sarcoma/diagnosis, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Humans, Medicine, Aged, business.industry, Sarcoma, Syndrome, Middle Aged, medicine.disease, Colorectal Neoplasms, Hereditary Nonpolyposis, Lynch syndrome, MSH2, 030220 oncology & carcinogenesis, Colorectal Neoplasms, Hereditary Nonpolyposis/diagnosis, Female, 030211 gastroenterology & hepatology, business
Published
2020

10. Molecular classification of the PORTEC-3 trial for high-risk endometrial cancer: Impact on adjuvant therapy

Author

Creutzberg, C. L., Leon-Castillo, A., de Boer, S. M., Powell, M. E., Mileshkin, L. R., Mackay, H. J., Leary, A., Nijman, H. W., Singh, N., Pollock, P., Fyles, A., Haie-Meder, C., Smit, V. T. H. B. M., Edmondson, R. J., Putter, H., Kitchener, H. C., Crosbie, E. J., de Bruyn, M., Nout, R., Bosse, T., Targeted Gynaecologic Oncology (TARGON), and Translational Immunology Groningen (TRIGR)

Published
2019

11. The proportion of endometrial cancers associated with Lynch syndrome:a systematic review of the literature and meta-analysis

Author

Ryan, N A J, Glaire, M A, Blake, D, Cabrera-Dandy, M, Evans, D G, and Crosbie, E J

Subjects
Adult, Brain Neoplasms/genetics, Neoplastic Syndromes, Hereditary/genetics, Comorbidity, DNA Mismatch Repair/genetics, Middle Aged, Colorectal Neoplasms/genetics, Immunohistochemistry, Colorectal Neoplasms, Hereditary Nonpolyposis/genetics, Humans, Female, Microsatellite Instability, Genetic Testing, Endometrial Neoplasms/genetics, Early Detection of Cancer, Germ-Line Mutation
Abstract

PURPOSE: Endometrial cancer (EC) is often the sentinel cancer in women with Lynch syndrome (LS). However, efforts to implement universal LS screening in EC patients have been hampered by a lack of evidence detailing the proportion of EC patients that would be expected to screen positive for LS.METHODS: Studies were identified by electronic searches of Medline, Embase, Cochrane CENTRAL and Web of Science. Proportions of test positivity were calculated by random and fixed-effects meta-analysis models. I2 score was used to assess heterogeneity across studies.RESULTS: Fifty-three studies, including 12,633 EC patients, met the inclusion criteria. The overall proportion of endometrial tumors with microsatellite instability or mismatch repair (MMR) deficiency by immunohistochemistry (IHC) was 0.27 (95% confidence interval [CI] 0.25-0.28, I2: 71%) and 0.26 (95% CI 0.25-0.27, I2: 88%), respectively. Of those women with abnormal tumor testing, 0.29 (95% CI 0.25-0.33, I2: 83%) had LS-associated pathogenic variants on germline testing; therefore around 3% of ECs can be attributed to LS. Preselection of EC cases did increase the proportion of germline LS diagnoses.CONCLUSION: The current study suggests that prevalence of LS in EC patients is approximately 3%, similar to that of colorectal cancer patients; therefore our data support the implementation of universal EC screening for LS.

Published
2019

16. European guidelines from the EHTG and ESCP for Lynch syndrome: an updated third edition of the Mallorca guidelines based on gene and gender.

Author

Seppälä, T. T., Latchford, A., Negoi, I., Soares, A. Sampaio, Jimenez-Rodriguez, R., Sánchez-Guillén, L., Evans, D. G., Ryan, N., Crosbie, E. J., Dominguez-Valentin, M., Burn, J., Kloor, M., Doeberitz, M. von Knebel, van Duijnhoven, F. J. B., Quirke, P., Sampson, J. R., Møller, P., and Möslein, G.

Subjects
HEREDITARY nonpolyposis colorectal cancer, COLORECTAL cancer, GENDER, DISEASE risk factors, DNA mismatch repair, GASTROENTEROLOGISTS
Abstract

Background: Lynch syndrome is the most common genetic predisposition for hereditary cancer but remains underdiagnosed. Large prospective observational studies have recently increased understanding of the effectiveness of colonoscopic surveillance and the heterogeneity of cancer risk between genotypes. The need for gene- and gender-specific guidelines has been acknowledged. Methods: The European Hereditary Tumour Group (EHTG) and European Society of Coloproctology (ESCP) developed a multidisciplinary working group consisting of surgeons, clinical and molecular geneticists, pathologists, epidemiologists, gastroenterologists, and patient representation to conduct a graded evidence review. The previous Mallorca guideline format was used to revise the clinical guidance. Consensus for the guidance statements was acquired by three Delphi voting rounds. Results: Recommendations for clinical and molecular identification of Lynch syndrome, surgical and endoscopic management of Lynch syndrome-associated colorectal cancer, and preventive measures for cancer were produced. The emphasis was on surgical and gastroenterological aspects of the cancer spectrum. Manchester consensus guidelines for gynaecological management were endorsed. Executive and layperson summaries were provided. Conclusion: The recommendations from the EHTG and ESCP for identification of patients with Lynch syndrome, colorectal surveillance, surgical management of colorectal cancer, lifestyle and chemoprevention in Lynch syndrome that reached a consensus (at least 80 per cent) are presented. [ABSTRACT FROM AUTHOR]

Published
2021
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17. A mismatch in care: results of a United Kingdom-wide patient and clinician survey of gynaecological services for women with Lynch syndrome.

Author

Ryan, NAJ, Nobes, M, Sedgewick, D, Teoh, S‐N, Evans, DG, Crosbie, EJ, Teoh, S-N, Evans, D G, and Crosbie, E J

Subjects
HEREDITARY nonpolyposis colorectal cancer, WOMEN'S programs, ONCOLOGISTS, PATIENT surveys, SUPPORT groups, ENDOMETRIAL cancer
Abstract

Objective: To describe the current testing practice, referral pathways and gynaecological services available to women with Lynch syndrome (LS) in the UK.Design: Cross-sectional nationwide survey of gynaecological oncologists and women with LS.Setting: United Kingdom.Methods: Gynaecological oncologists were contacted directly. Women with LS were identified from national and regional clinical databases and the patient support group, Lynch syndrome UK.Main Outcome Measures: Gynaecological oncologists were asked to report rates of LS testing and current practice regarding risk-reducing strategies and gynaecological surveillance for women with LS. Women with LS were asked to describe their experiences of gynaecological care.Results: In total, 41 gynaecological oncologists and 298 women with LS responded to the survey. Of the gynaecological oncologists surveyed, 37% were unfamiliar with any clinical guidelines for the management of LS. Only 29% of gynaecological oncologists supported universal testing of endometrial cancer for LS; one centre routinely performed such testing. In all, 83% said they perform risk-reducing gynaecological surgery and 43% were aware of a local gynaecological surveillance service for women with LS. Of women with LS, most had undergone a hysterectomy (n = 191/64.1%), most frequently to reduce their gynaecological cancer risk (n = 86/45%). A total of 10% were initially referred for LS testing by their gynaecologist and 55% of those eligible regularly attended gynaecological surveillance; however, 62% wanted more regular surveillance. Regional variation was evident across all standards of care.Conclusions: There is widespread variation in the services offered to women with LS in the UK. As a community, gynaecological oncologists should move towards a nationally agreed provision of services.Tweetable Abstract: A mismatch in care for mismatch repair. Survey finds significant variation in gynaecological care for #Lynchsyndrome in the UK. [ABSTRACT FROM AUTHOR]

Published
2021
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18. Homozygous germ-line mutation of the PMS2 mismatch repair gene: a unique case report of constitutional mismatch repair deficiency (CMMRD)

Author

Ramchander, N. C., Ryan, N. A. J., Crosbie, E. J., and Evans, D. G.

Subjects
Adult, lcsh:Internal medicine, lcsh:QH426-470, DNA Mutational Analysis, Case Report, Mismatch repair, Neoplastic Syndromes, Hereditary, Genetics, Humans, Genetics(clinical), lcsh:RC31-1245, Germ-Line Mutation, Mismatch Repair Endonuclease PMS2, Base Sequence, Brain Neoplasms, Homozygote, Turcot syndrome, DNA, Exons, MMR, Colorectal Neoplasms, Hereditary Nonpolyposis, CMMRD, Pedigree, lcsh:Genetics, PMS2, Lynch syndrome, Female, Colorectal Neoplasms, Constitutional mismatch repair deficiency, Gene Deletion
Abstract

Background Constitutional mismatch repair deficiency syndrome results from bi-allelic inheritance of mutations affecting the key DNA mismatch repair genes: MLH1, MSH2, MSH6 or PMS2. Individuals with bi-allelic mutations have a dysfunctional mismatch repair system from birth; as a result, constitutional mismatch repair deficiency syndrome is characterised by early onset malignancies. Fewer than 150 cases have been reported in the literature over the past 20 years. This is the first report of the founder PMS2 mutation - NM_000535.5:c.1500del (p.Val501TrpfsTer94) in exon 11 and its associated cancers in this family. Case presentation The proband is 30 years old and is alive today. She is of Pakistani ethnic origin and a product of consanguinity. She initially presented aged 24 with painless bleeding per-rectum from colorectal polyps and was referred to clinical genetics. Clinical examination revealed two café-au-lait lesions, lichen planus, and a dermoid cyst. Her sister had been diagnosed in childhood with an aggressive brain tumour followed by colorectal cancer. During follow up, the proband developed 37 colorectal adenomatous polyps, synchronous ovarian and endometrial adenocarcinomas, and ultimately a metachronous gastric adenocarcinoma. DNA sequencing of peripheral lymphocytes revealed a bi-allelic inheritance of the PMS2 mutation NM_000535.5:c.1500del (p.Val501TrpfsTer94) in exon 11. Ovarian tumour tissue demonstrated low microsatellite instability. To date, she has had a total abdominal hysterectomy, bilateral salpingo-oophorectomy, and a total gastrectomy. Aspirin and oestrogen-only hormone replacement therapy provide some chemoprophylaxis and manage postmenopausal symptoms, respectively. An 18-monthly colonoscopy surveillance programme has led to the excision of three high-grade dysplastic colorectal tubular adenomatous polyps. The proband’s family pedigree displays multiple relatives with cancers including a likely case of ‘true’ Turcot syndrome. Conclusions Constitutional mismatch repair deficiency syndrome should be considered in patients who present with early onset cancer, a strong family history of cancer, and cutaneous features resembling neurofibromatosis type I. Immunohistochemistry analysis of tumour and normal tissue is sensitive and specific for identifying patients with mismatch repair deficiency and should direct DNA sequencing of lymphocytic tissue to establish a diagnosis. Microsatellite instability status appears to be of little value in identifying patients who may have constitutional mismatch repair deficiency syndrome.

Published
2017

19. Research priority setting in women's health: a systematic review.

Author

Graham, L, Illingworth, BJG, Showell, M, Vercoe, M, Crosbie, EJ, Gingel, LJ, Farquhar, CM, Horne, AW, Prior, M, Stephenson, JM, Magee, LA, Duffy, JMN, Crosbie, E J, Gingel, L J, Farquhar, C M, Horne, A W, Stephenson, J M, and Magee, L A

Subjects
WOMEN'S health, META-analysis, MEDICAL personnel, PILOT projects, SYSTEMATIC reviews, RESEARCH funding, MEDICAL research
Abstract

Background: Developing a shared agenda is an important step in ensuring future research has the necessary relevance.Objective: To characterise research priority setting partnerships (PSPs) relevant to women's health.Search Strategy: Included studies were identified by searching MEDLINE and the James Lind Alliance (JLA) database.Selection Criteria: Priority setting partnerships using formal consensus methods.Data Collection and Analysis: Descriptive narrative to describe the study characteristics, methods, and results.Main Results: Ten national and two international PSPs were identified. All PSPs used the JLA method to identify research priorities. Nine PSPs had published a protocol. Potential research uncertainties were gathered from guidelines (two studies), Cochrane reviews (five studies), and surveys (12 studies). The number of healthcare professionals (31-287), patients (44-932), and others (33-139) who responded to the survey, and the number of uncertainties submitted (52-4767) varied. All PSPs entered confirmed research uncertainties (39-104) into interim priority setting surveys and healthcare professionals (31-287), patients (44-932), and others (33-139) responded. All PSPs entered a short list of research uncertainties into a consensus development meeting, which enabled healthcare professionals (six to 21), patients (eight to 14), and others (two to 13) to identify research priorities (ten to 15). Four PSPs have published their results.Conclusion: Future research priority setting studies should publish a protocol, use formal consensus development methods, and ensure their methods and results are comprehensively reported.Tweetable Abstract: Research published in @BJOGtweets highlights future research priorities across women's health, including @FertilityTop10, @jamesmnduffy. [ABSTRACT FROM AUTHOR]

Published
2020
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21. A cluster randomized trial of strategies to increase uptake amongst young women invited for their first cervical screen: The STRATEGIC trial.

Author

Kitchener, H., Gittins, M., Cruickshank, M., Moseley, C., Fletcher, S., Albrow, R., Gray, A., Brabin, L., Torgerson, D., Crosbie, E. J., Sargent, A., and Roberts, C.

Subjects
CERVIX uteri tumors, CONFIDENCE intervals, HEALTH services accessibility, INTERNET, MEDICAL appointments, NURSES, HEALTH self-care, VAGINA, HUMAN papillomavirus vaccines, RANDOMIZED controlled trials, TREATMENT effectiveness, EARLY detection of cancer, ODDS ratio, DIAGNOSIS
Abstract

Objectives To measure the feasibility and effectiveness of interventions to increase cervical screening uptake amongst young women. Methods A two-phase cluster randomized trial conducted in general practices in the NHS Cervical Screening Programme. In Phase 1, women in practices randomized to intervention due for their first invitation to cervical screening received a pre-invitation leaflet and, separately, access to online booking. In Phase 2, non-attenders at six months were randomized to one of: vaginal self-sample kits sent unrequested or offered; timed appointments; nurse navigator; or the choice between nurse navigator or self-sample kits. Primary outcome was uplift in intervention vs. control practices, at 3 and 12 months post invitation. Results Phase 1 randomized 20,879 women. Neither pre-invitation leaflet nor online booking increased screening uptake by three months (18.8% pre-invitation leaflet vs. 19.2% control and 17.8% online booking vs. 17.2% control). Uptake was higher amongst human papillomavirus vaccinees at three months (OR 2.07, 95% CI 1.69–2.53, p < 0.001). Phase 2 randomized 10,126 non-attenders, with 32–34 clusters for each intervention and 100 clusters as controls. Sending self-sample kits increased uptake at 12 months (OR 1.51, 95% CI 1.20–1.91, p = 0.001), as did timed appointments (OR 1.41, 95% CI 1.14–1.74, p = 0.001). The offer of a nurse navigator, a self-sample kits on request, and choice between timed appointments and nurse navigator were ineffective. Conclusions Amongst non-attenders, self-sample kits sent and timed appointments achieved an uplift in screening over the short term; longer term impact is less certain. Prior human papillomavirus vaccination was associated with increased screening uptake. [ABSTRACT FROM AUTHOR]

Published
2018
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22. Prediction model for regional or distant recurrence in endometrial cancer based on classical pathological and immunological parameters

Author

Versluis, M A, primary, de Jong, R A, additional, Plat, A, additional, Bosse, T, additional, Smit, V T, additional, Mackay, H, additional, Powell, M, additional, Leary, A, additional, Mileshkin, L, additional, Kitchener, H C, additional, Crosbie, E J, additional, Edmondson, R J, additional, Creutzberg, C L, additional, Hollema, H, additional, Daemen, T, additional, de Bock, G H, additional, and Nijman, H W, additional

Published
2015
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27. Does the vaginal microbiome drive cervical carcinogenesis?

Author

Njoku, K, Crosbie, EJ, and Crosbie, E J

Subjects
PAPILLOMAVIRUSES, CARCINOGENESIS, MEDICAL research, CERVIX uteri diseases, CERVICAL intraepithelial neoplasia, LONGITUDINAL method, COMPARATIVE studies, RESEARCH methodology, MEDICAL cooperation, PAPILLOMAVIRUS diseases, RESEARCH, RESEARCH funding, VAGINA, CERVIX uteri tumors, EVALUATION research
Abstract

It is indeed plausible that women with certain vaginal microbiome CST groups are more prone to acquiring and failing to clear high-risk HPV and therefore identifying these CSTs is important to (1) predict cervical cancer risk, (2) develop targeted prevention strategies, and (3) test novel therapeutic strategies based on pre/probiotics. Well-designed longitudinal studies with adequate sample sizes, and using standardised sampling and analytical methods are now needed to provide robust evidence on what CST subtypes are linked with high-risk HPV and cervical cancer and importantly, to confirm causality. FundingKN is supported by a Cancer Research UK Manchester Cancer Research Centre Clinical Research Fellowship. [Extracted from the article]

Published
2020
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28. The vaginal microbiome and gynaecological cancer: exercise caution when considering causation.

Author

Ramchander, N. C. and Crosbie, E. J.

Subjects
*HUMAN microbiota, *CARCINOGENESIS, *PAPILLOMAVIRUSES, *CERVICAL cancer, *HYSTERECTOMY, *SALPINGECTOMY, *OVARIAN cancer, *ENDOMETRIAL cancer
Abstract

The article considers the role of vaginal microbiome in the aetiology of gynecological cancers. Topics discussed are factors that influence the acquisition of genital human papillomavirus (HPV) that are important in the pathogenesis of cervical cancer, efficacy of hysterectomy or salpingectomy with ovarian conservation and tubal ligation in reducing the risk of ovarian cancer, and role of vaginal microbiome in endometrial carcinogenesis.

Published
2018
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29. Population-based testing of non-mucinous epithelial ovarian cancer in Scotland.

Author

Evans, D. G., Edmondson, R., and Crosbie, E. J.

Subjects
BRCA genes, GERM cells, OVARIAN cancer & genetic, ADENOSINE diphosphate ribose, POLYMERASES, SOMATIC mutation
Abstract

The article focuses on extension of BRCA1/2 germline testing to all high-grade serous ovarian cancer (HGSOC) regardless of family history. It mentions benefits of poly ADP ribose polymerase inhibitor (PARPi) therapies and no endometrioid types were recorded and identify somatic mutations that would otherwise go undetected but may determine sensitivity to PARPi. It also mentions affected women would then only require germline testing if a pathogenic variant were identified in tumour material.

Published
2018
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32. Biomarkers needed to predict progestin response in endometrial cancer.

Author

Derbyshire, AE, Ryan, NAJ, Crosbie, EJ, Derbyshire, A E, and Crosbie, E J

Subjects
ENDOMETRIAL hyperplasia, HYPERPLASIA treatment, THERAPEUTIC use of progestational hormones, IMMUNOHISTOCHEMISTRY, DNA mismatch repair
Abstract

The article discusses the article by M. Zakhour and colleagues about women with atypical endometrial hyperplasia (AEH) or endometrial cancer (EC) who were treated with progestins. Topics include the use of immunohistochemistry to define lesions as mismatch repair (MMR)-competent or MMR-deficient, the senescence, differentiation, and apoptosis induced by progestin, and the response rate to intrauterine progestins.

Published
2017
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33. Urinary HPV testing may offer hope for cervical screening non-attenders.

Author

Blake, DA, Crosbie, EJ, Kitson, S, Blake, D A, and Crosbie, E J

Subjects
CERVICAL cancer diagnosis, PAPILLOMAVIRUSES, CERVICAL intraepithelial neoplasia, POLYMERASE chain reaction, COLPOSCOPY, MEDICAL screening, PAP test, PAPILLOMAVIRUS diseases, MEDICAL triage, CERVIX uteri tumors, CROSS-sectional method, EARLY detection of cancer
Abstract

Despite the success of cervical screening, cancer of the cervix is the fourth most common cancer affecting women worldwide (CRUK 2014). Rates are particularly high in developing nations, which lack the requisite infrastructure for cytology and colposcopy-based screening, and in certain demographic groups, where uptake of screening is poor. Recent research has focussed on developing less invasive and potentially more acceptable means of identifying women at high risk of cervical intraepithelial neoplasia (CIN). Urinary HPV testing has received particular attention because of the ease of obtaining samples and the opportunity this affords to overcoming barriers to cervical screening like embarrassment and discomfort. This article is protected by copyright. All rights reserved. [ABSTRACT FROM AUTHOR]

Published
2017
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35. No Difference in Penetrance between Truncating and Missense/Aberrant Splicing Pathogenic Variants in MLH1 and MSH2: A Prospective Lynch Syndrome Database Study

Author

Guy Rosner, Walter Hernán Pavicic, Claudia Perne, Carlos A. Vaccaro, Elke Holinski-Feder, Leticia Moreira, Wouter H. de Vos tot Nederveen Cappel, Stefan Aretz, Einar Andreas Rødland, Polly A. Newcomb, Karin Alvarez, Ariadna Sánchez, Lone Sunde, Wolff Schmiegel, Joan Brunet, Marc S. Greenblatt, Christina Therkildsen, Karl Heinimann, Lior H. Katz, Fiona Lalloo, Jürgen Weitz, Anna Lepistö, Rolf H. Sijmons, Maartje Nielsen, Hans F. A. Vasen, Deepak Vangala, Monika Morak, Jukka-Pekka Mecklin, Toni T. Seppälä, Sigve Nakken, Stefanie Holzapfel, Douglas Tjandra, Finlay A. Macrae, Päivi Peltomäki, Daniel D. Buchanan, Stephen N. Thibodeau, Adriana Della Valle, James Hill, Annika Lindblom, Bernardo Bonanni, Reinhard Büttner, Francisco López-Köstner, Giulia Martina Cavestro, John Burn, Emma J Crosbie, Lucio Bertario, Sanne W. ten Broeke, D. G. R. Evans, Kate Green, Verena Steinke-Lange, Eivind Hovig, Miquel Serra-Burriel, Francesc Balaguer, Kirsi Pylvänäinen, Gabriela Möslein, Revital Kariv, Thomas Hansen, Maria Grazia Tibiletti, Tamara Alejandra Piñero, Nils Rahner, Magnus von Knebel Doeberitz, Ingrid Winship, Nathan Gluck, Lars Joachim Lindberg, Christoph Engel, Mev Dominguez-Valentin, John-Paul Plazzer, Julian R. Sampson, Marta Pineda, John L. Hopper, Pablo Kalfayan, Heike Görgens, Aung Ko Win, Steven Gallinger, Loic Le Marchand, Mark A. Jenkins, Markus Loeffler, Noralane M. Lindor, Inge Bernstein, Pål Møller, Laura Renkonen-Sinisalo, Florencia Neffa, Huw Thomas, Gabriel Capellá, Jane C. Figueiredo, Miriam Mints, Patricia Esperon, Matilde Navarro, Robert Hüneburg, Guided Treatment in Optimal Selected Cancer Patients (GUTS), HUS Abdominal Center, Department of Surgery, Genome-Scale Biology (GSB) Research Program, II kirurgian klinikka, ATG - Applied Tumor Genomics, Research Programs Unit, Clinicum, Department of Medical and Clinical Genetics, Dominguez-Valentin, M., Plazzer, J. -P., Sampson, J. R., Engel, C., Aretz, S., Jenkins, M. A., Sunde, L., Bernstein, I., Capella, G., Balaguer, F., Macrae, F., Winship, I. M., Thomas, H., Evans, D. G., Burn, J., Greenblatt, M., de Vos tot Nederveen Cappel, W. H., Sijmons, R. H., Nielsen, M., Bertario, L., Bonanni, B., Tibiletti, M. G., Cavestro, G. M., Lindblom, A., Della Valle, A., Lopez-Kostner, F., Alvarez, K., Gluck, N., Katz, L., Heinimann, K., Vaccaro, C. A., Nakken, S., Hovig, E., Green, K., Lalloo, F., Hill, J., Vasen, H. F. A., Perne, C., Buttner, R., Gorgens, H., Holinski-Feder, E., Morak, M., Holzapfel, S., Huneburg, R., Doeberitz, M. V. K., Loeffler, M., Rahner, N., Weitz, J., Steinke-Lange, V., Schmiegel, W., Vangala, D., Crosbie, E. J., Pineda, M., Navarro, M., Brunet, J., Moreira, L., Sanchez, A., Serra-Burriel, M., Mints, M., Kariv, R., Rosner, G., Pinero, T. A., Pavicic, W. H., Kalfayan, P., Ten Broeke, S. W., Mecklin, J. -P., Pylvanainen, K., Renkonen-Sinisalo, L., Lepisto, A., Peltomaki, P., Hopper, J. L., Win, A. K., Buchanan, D. D., Lindor, N. M., Gallinger, S., Marchand, L. L., Newcomb, P. A., Figueiredo, J. C., Thibodeau, S. N., Therkildsen, C., Hansen, T. V. O., Lindberg, L., Rodland, E. A., Neffa, F., Esperon, P., Tjandra, D., Moslein, G., Seppala, T. T., and Moller, P.

Subjects
cancer incidence, 0302 clinical medicine, Malalties hereditàries, Missense mutation, 8Q23.3, Càncer, Cancer, Genetics, 0303 health sciences, medicine.diagnostic_test, Factors de risc en les malalties, MISMATCH REPAIR GENES, MLH1, General Medicine, Penetrance, Lynch syndrome, 3. Good health, syöpägeenit, 030220 oncology & carcinogenesis, Medicine, syöpätaudit, ilmaantuvuus, Genetic diseases, congenital, hereditary, and neonatal diseases and abnormalities, missense, 11Q23.1, Risk factors in diseases, CANCER-RISK, Article, aberrant splicing, 03 medical and health sciences, AGE, medicine, Genetic predisposition, ddc:610, MSH2, Lynchin oireyhtymä, penetrance, 030304 developmental biology, Genetic testing, truncating, perinnölliset taudit, business.industry, MUTATIONS, HMSH2, nutritional and metabolic diseases, medicine.disease, digestive system diseases, 3121 General medicine, internal medicine and other clinical medicine, business
Abstract

Background. Lynch syndrome is the most common genetic predisposition for hereditary cancer. Carriers of pathogenic changes in mismatch repair (MMR) genes have an increased risk of developing colorectal (CRC), endometrial, ovarian, urinary tract, prostate, and other cancers, depending on which gene is malfunctioning. In Lynch syndrome, differences in cancer incidence (penetrance) according to the gene involved have led to the stratification of cancer surveillance. By contrast, any differences in penetrance determined by the type of pathogenic variant remain unknown. Objective. To determine cumulative incidences of cancer in carriers of truncating and missense or aberrant splicing pathogenic variants of the MLH1 and MSH2 genes. Methods. Carriers of pathogenic variants of MLH1 (path_MLH1) and MSH2 (path_MSH2) genes filed in the Prospective Lynch Syndrome Database (PLSD) were categorized as truncating or missense/aberrant splicing according to the InSiGHT criteria for pathogenicity. Results. Among 5199 carriers, 1045 had missense or aberrant splicing variants, and 3930 had truncating variants. Prospective observation years for the two groups were 8205 and 34,141 years, respectively, after which there were no significant differences in incidences for cancer overall or for colorectal cancer or endometrial cancers separately. Conclusion. Truncating and missense or aberrant splicing pathogenic variants were associated with similar average cumulative incidences of cancer in carriers of path MLH1 and path_MSH2.

Published
2021

36. Uptake of hysterectomy and bilateral salpingo-oophorectomy in carriers of pathogenic mismatch repair variants:a Prospective Lynch Syndrome Database report

Author

Einar Andreas Rødland, Joan B. Vida, Heike Görgens, Eivind Hovig, Kirsi Pylvänäinen, Monika Morak, Wouter H. de Vos tot Nederveen Cappel, Lone Sunde, Mark A. Jenkins, Lucio Bertario, Patricia Esperon, Reinhard Büttner, Finlay A. Macrae, Inge Bernstein, Marc S. Greenblatt, Wolff Schmiegel, Giulia Martina Cavestro, Maria Grazia Tibiletti, Silke Redler, Zohreh Ketabi, Karl Heinimann, Fiona Lalloo, Huw Thomas, Christina Therkildsen, Deepak Vangala, Magnus von Knebel Doeberitz, Matilde Navarro, Erik Rokkones, Douglas Tjandra, D. G. Evans, Marta Pineda, Marian J.E. Mourits, Lior H. Katz, Bernardo Bonanni, Pablo Kalfayan, Stephen N. Thibodeau, Loic Le Marchand, Revital Kariv, Maartje Nielsen, Emma J Crosbie, Oliver G. Denton, Stefanie Holzapfel, Guy Rosner, Mev Dominguez-Valentin, John Burn, Verena Steinke-Lange, Carlos A. Vaccaro, Gabriela Möslein, Elke Holinski-Feder, Gabriel Capellá, Johanna Tecklenburg, Karin Wadt, Kate Green, Christoph Engel, Miriam Mints, Anna Lepistö, Tamara Alejandra Piñero, Jukka-Pekka Mecklin, John L. Hopper, Robert Hüneburg, Markus Loeffler, Florencia Neffa, Toni T. Seppälä, Claudia Perne, Polly A. Newcomb, Karin Alvarez, Adriana Della Valle, Julian R. Sampson, Sanne W. ten Broeke, Francisco Lopez-Koestner, John-Paul Plazzer, James Hill, Hans Georg Strauß, Ingrid Winship, Nathan Gluck, Aung Ko Win, Jane C. Figueiredo, Jürgen Weitz, Hans F. A. Vasen, Rolf H. Sijmons, Walter Hernán Pavicic, Stefan Aretz, Steven Gallinger, Noralane M. Lindor, Pål Møller, Laura Renkonen-Sinisalo, Guided Treatment in Optimal Selected Cancer Patients (GUTS), Damage and Repair in Cancer Development and Cancer Treatment (DARE), Targeted Gynaecologic Oncology (TARGON), Seppala, T. T., Dominguez-Valentin, M., Crosbie, E. J., Engel, C., Aretz, S., Macrae, F., Winship, I., Capella, G., Thomas, H., Hovig, E., Nielsen, M., Sijmons, R. H., Bertario, L., Bonanni, B., Tibiletti, M. G., Cavestro, G. M., Mints, M., Gluck, N., Katz, L., Heinimann, K., Vaccaro, C. A., Green, K., Lalloo, F., Hill, J., Schmiegel, W., Vangala, D., Perne, C., Strauss, H. -G., Tecklenburg, J., Holinski-Feder, E., Steinke-Lange, V., Mecklin, J. -P., Plazzer, J. -P., Pineda, M., Navarro, M., Vida, J. B., Kariv, R., Rosner, G., Pinero, T. A., Pavicic, W., Kalfayan, P., ten Broeke, S. W., Jenkins, M. A., Sunde, L., Bernstein, I., Burn, J., Greenblatt, M., de Vos tot Nederveen Cappel, W. H., Della Valle, A., Lopez-Koestner, F., Alvarez, K., Buttner, R., Gorgens, H., Morak, M., Holzapfel, S., Huneburg, R., von Knebel Doeberitz, M., Loeffler, M., Redler, S., Weitz, J., Pylvanainen, K., Renkonen-Sinisalo, L., Lepisto, A., Hopper, J. L., Win, A. K., Lindor, N. M., Gallinger, S., Le Marchand, L., Newcomb, P. A., Figueiredo, J. C., Thibodeau, S. N., Therkildsen, C., Wadt, K. A. W., Mourits, M. J. E., Ketabi, Z., Denton, O. G., Rodland, E. A., Vasen, H., Neffa, F., Esperon, P., Tjandra, D., Moslein, G., Rokkones, E., Sampson, J. R., Evans, D. G., Moller, P., Genome-Scale Biology (GSB) Research Program, HUS Abdominal Center, Clinicum, II kirurgian klinikka, Department of Surgery, and Doctoral Programme in Clinical Research

Subjects
0301 basic medicine, Cancer Research, Oophorectomy, Databases, Factual, Colorectal cancer, SURGERY, medicine.medical_treatment, Càncer d'ovari, computer.software_genre, DNA Mismatch Repair, 0302 clinical medicine, Endometrial cancer, munasarjasyöpä, Medicine, Prospective Studies, Colectomy, Salpingo-oophorectomy/methods, Database, Manchester Cancer Research Centre, COLON-CANCER, MLH1, WOMEN, Middle Aged, Prognosis, Lynch syndrome, 3. Good health, kohdunrungon syöpä, Oncology, COLECTOMY, 030220 oncology & carcinogenesis, Female, Biomarkers, Tumor/genetics, Adult, Heterozygote, Genital Neoplasms, Female, Salpingo-oophorectomy, Hysterectomy, 03 medical and health sciences, Genital Neoplasms, Female/prevention & control, Ovarian cancer, Colorectal Neoplasms, Hereditary Nonpolyposis/genetics, Biomarkers, Tumor, Mortalitat, Humans, Hysterectomy/methods, Mortality, Lynchin oireyhtymä, Risk-reducing surgery, Aged, business.industry, ResearchInstitutes_Networks_Beacons/mcrc, Cancer, MSH6, 3126 Surgery, anesthesiology, intensive care, radiology, medicine.disease, Colorectal Neoplasms, Hereditary Nonpolyposis, MSH2, 030104 developmental biology, Cross-Sectional Studies, PMS2, Càncer d'endometri, Mutation, kohdunpoisto, business, computer, Follow-Up Studies
Abstract

Purpose: This study aimed to report the uptake of hysterectomy and/or bilateral salpingo-oophorectomy (BSO) to prevent gynaecological cancers (risk-reducing surgery [RRS]) in carriers of pathogenic MMR (path_MMR) variants.Methods: The Prospective Lynch Syndrome Database (PLSD) was used to investigate RRS by a cross-sectional study in 2292 female path_MMR carriers aged 30-69 years.Results: Overall, 144, 79, and 517 carriers underwent risk-reducing hysterectomy, BSO, or both combined, respectively. Two-thirds of procedures before 50 years of age were combined hysterectomy and BSO, and 81% of all procedures included BSO. Risk-reducing hysterectomy was performed before age 50 years in 28%, 25%, 15%, and 9%, and BSO in 26%, 25%, 14% and 13% of path_MLH1, path_MSH2, path_MSH6, and path_PMS2 carriers, respectively. Before 50 years of age, 107 of 188 (57%) BSO and 126 of 204 (62%) hysterectomies were performed in women without any prior cancer, and only 5% (20/392) were performed simultaneously with colorectal cancer (CRC) surgery.Conclusion: Uptake of RRS before 50 years of age was low, and RRS was rarely undertaken in association with surgical treatment of CRC. Uptake of RRS aligned poorly with gene-and age-associated risk estimates for endometrial or ovarian cancer that were published recently from PLSD and did not correspond well with current clinical guidelines. The reasons should be clarified. Decision-making on opting for or against RRS and its timing should be better aligned with predicted risk and mortality for endometrial and ovarian cancer in Lynch syn-drome to improve outcomes. (C) 2021 The Author(s). Published by Elsevier Ltd.

Published
2021

37. Risk-reducing hysterectomy and bilateral salpingo-oophorectomy in female heterozygotes of pathogenic mismatch repair variants: a Prospective Lynch Syndrome Database report

Author

Eivind Hovig, Bernardo Bonanni, Monika Morak, Mark A. Jenkins, Patricia Esperon, Toni T. Seppälä, Lone Sunde, Pablo Kalfayan, Gabriel Capellá, Inge Bernstein, Matilde Navarro, Marc S. Greenblatt, John Burn, Zohreh Ketabi, Johanna Tecklenburg, Francisco Lopez-Koestner, Miriam Mints, Heike Görgens, Neil A J Ryan, Kate Green, Annika Auranen, Douglas Tjandra, Robert W. Haile, Marta Pineda, Tamara Alejandra Piñero, Stefan Aretz, Robert Hüneburg, Verena Steinke-Lange, Markus Loeffler, Christina Therkildsen, John L. Hopper, Deepak Vangala, Huw Thomas, Reinhard Büttner, James Hill, Einar Andreas Rødland, Revital Kariv, Maria Grazia Tibiletti, Sigve Nakken, Stefanie Holzapfel, D. Gareth Evans, Oliver G. Denton, Julian R. Sampson, Henrik Okkels, Joan Vidal, Loic Le Marchand, Hans Georg Strauß, Gabriela Möslein, Claudia Perne, Ingrid Winship, Nathan Gluck, Jane C. Figueiredo, Mev Dominguez-Valentin, Wolff Schmiegel, Karl Heinimann, Kirsi Pylvänäinen, Karin Alvarez, Maartje Nielsen, Wouter H. de Vos tot Nederveen Cappel, Fiona Lalloo, Aung Ko Win, Guy Rosner, Carlos A. Vaccaro, Polly A. Newcomb, Elke Holinski-Feder, John-Paul Plazzer, Lior H. Katz, Christoph Engel, Anna Lepistö, Jukka-Pekka Mecklin, Giulia Martina Cavestro, Adriana Della Valle, Finlay A. Macrae, Sanne W. ten Broeke, Florencia Neffa, Rolf H. Sijmons, María Laura Gonzalez, Nils Rahner, Jürgen Weitz, Hans F. A. Vasen, Stephen N. Thibodeau, Emma J Crosbie, Lucio Bertario, Steven Gallinger, Noralane M. Lindor, Pål Møller, Laura Renkonen-Sinisalo, Magnus von Knebel Doeberitz, Dominguez-Valentin, M., Crosbie, E. J., Engel, C., Aretz, S., Macrae, F., Winship, I., Capella, G., Thomas, H., Nakken, S., Hovig, E., Nielsen, M., Sijmons, R. H., Bertario, L., Bonanni, B., Tibiletti, M. G., Cavestro, G. M., Mints, M., Gluck, N., Katz, L., Heinimann, K., Vaccaro, C. A., Green, K., Lalloo, F., Hill, J., Schmiegel, W., Vangala, D., Perne, C., Strauss, H. -G., Tecklenburg, J., Holinski-Feder, E., Steinke-Lange, V., Mecklin, J. -P., Plazzer, J. -P., Pineda, M., Navarro, M., Vidal, J. B., Kariv, R., Rosner, G., Pinero, T. A., Gonzalez, M. L., Kalfayan, P., Ryan, N., ten Broeke, S. W., Jenkins, M. A., Sunde, L., Bernstein, I., Burn, J., Greenblatt, M., de Vos tot Nederveen Cappel, W. H., Della Valle, A., Lopez-Koestner, F., Alvarez, K., Buttner, R., Gorgens, H., Morak, M., Holzapfel, S., Huneburg, R., von Knebel Doeberitz, M., Loeffler, M., Rahner, N., Weitz, J., Pylvanainen, K., Renkonen-Sinisalo, L., Lepisto, A., Auranen, A., Hopper, J. L., Win, A. K., Haile, R. W., Lindor, N. M., Gallinger, S., Le Marchand, L., Newcomb, P. A., Figueiredo, J. C., Thibodeau, S. N., Therkildsen, C., Okkels, H., Ketabi, Z., Denton, O. G., Rodland, E. A., Vasen, H., Neffa, F., Esperon, P., Tjandra, D., Moslein, G., Sampson, J. R., Evans, D. G., Seppala, T. T., Moller, P., ATG - Applied Tumor Genomics, HUS Abdominal Center, II kirurgian klinikka, Department of Surgery, Clinicum, Helsinki University Hospital Area, and University of Helsinki

Subjects
0301 basic medicine, medicine.medical_treatment, DNA Mismatch Repair, Gynecologic surgery, 0302 clinical medicine, Malalties hereditàries, Prospective Studies, Prospective cohort study, Genetics (clinical), Mismatch Repair Endonuclease PMS2, Incidence (epidemiology), Middle Aged, 16. Peace & justice, Lynch syndrome, 3. Good health, 030220 oncology & carcinogenesis, Female, syöpätaudit, MutL Protein Homolog 1, Genetic diseases, Heterozygote, medicine.medical_specialty, Salpingo-oophorectomy, Cirurgia ginecològica, Hysterectomy, Article, 03 medical and health sciences, Càncer colorectal, CAPP2, medicine, Humans, Lynchin oireyhtymä, Gynecology, perinnölliset taudit, HEREDITARY COLORECTAL-CANCER, business.industry, Endometrial cancer, Cancer, medicine.disease, Colorectal Neoplasms, Hereditary Nonpolyposis, Colorectal cancer, ASPIRIN, 030104 developmental biology, Clinical research, 3121 General medicine, internal medicine and other clinical medicine, kohdunpoisto, 3111 Biomedicine, Ovarian cancer, business
Abstract

Purpose To determine impact of risk-reducing hysterectomy and bilateral salpingo-oophorectomy (BSO) on gynecological cancer incidence and death in heterozygotes of pathogenic MMR ( path_MMR ) variants. Methods The Prospective Lynch Syndrome Database was used to investigate the effects of gynecological risk-reducing surgery (RRS) at different ages. Results Risk-reducing hysterectomy at 25 years of age prevents endometrial cancer before 50 years in 15%, 18%, 13%, and 0% of path_MLH1 , path_MSH2 , path_MSH6 , and path_PMS2 heterozygotes and death in 2%, 2%, 1%, and 0%, respectively. Risk-reducing BSO at 25 years of age prevents ovarian cancer before 50 years in 6%, 11%, 2%, and 0% and death in 1%, 2%, 0%, and 0%, respectively. Risk-reducing hysterectomy at 40 years prevents endometrial cancer by 50 years in 13%, 16%, 11%, and 0% and death in 1%, 2%, 1%, and 0%, respectively. BSO at 40 years prevents ovarian cancer before 50 years in 4%, 8%, 0%, and 0%, and death in 1%, 1%, 0%, and 0%, respectively. Conclusion Little benefit is gained by performing RRS before 40 years of age and premenopausal BSO in path_MSH6 and path_PMS2 heterozygotes has no measurable benefit for mortality. These findings may aid decision making for women with LS who are considering RRS.

Published
2021

38. The Management of Peutz–Jeghers Syndrome: European Hereditary Tumour Group (EHTG) Guideline †

Author

Anja Wagner, Emma J Crosbie, Annika Auranen, Marta Puzzono, Marco J. Bruno, Andrew Latchford, Giulia Martina Cavestro, Monique E. van Leerdam, Ingrid Winship, Anne Goverde, Stefan Aretz, Gabriela Möslein, Anne Marie Jelsig, Anna Lepistö, Veronica Zuber, Wagner, A., Aretz, S., Auranen, A., Bruno, M. J., Cavestro, G. M., Crosbie, E. J., Goverde, A., Jelsig, A. M., Latchford, A., van Leerdam, M. E., Lepisto, A., Puzzono, M., Winship, I., Zuber, V., Moslein, G., Clinical Genetics, and Gastroenterology & Hepatology

Subjects
medicine.medical_specialty, MEDLINE, Delphi method, lcsh:Medicine, Peutz–Jeghers syndrome, Review, Guideline, Practical guideline, 03 medical and health sciences, 0302 clinical medicine, Medicine, Grading (education), business.industry, lcsh:R, STK11, Subject (documents), General Medicine, medicine.disease, 3. Good health, 030220 oncology & carcinogenesis, Family medicine, Keywords: Peutz–Jeghers syndrome, 030211 gastroenterology & hepatology, business, Variable number, guideline
Abstract

The scientific data to guide the management of Peutz–Jeghers syndrome (PJS) are sparse. The available evidence has been reviewed and discussed by diverse medical specialists in the field of PJS to update the previous guideline from 2010 and formulate a revised practical guideline for colleagues managing PJS patients. Methods: Literature searches were performed using MEDLINE, Embase, and Cochrane. Evidence levels and recommendation strengths were assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE). A Delphi process was followed, with consensus being reached when ≥80% of the voting guideline committee members agreed. Recommendations and statements: The only recent guidelines available were for gastrointestinal and pancreatic management. These were reviewed and endorsed after confirming that no more recent relevant papers had been published. Literature searches were performed for additional questions and yielded a variable number of relevant papers depending on the subject addressed. Additional recommendations and statements were formulated. Conclusions: A decade on, the evidence base for recommendations remains poor, and collaborative studies are required to provide better data about this rare condition. Within these restrictions, multisystem, clinical management recommendations for PJS have been formulated.

Published
2021

39. Correction:Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database

Author

Gabriel Capellá, Patricia Esperon, Christoph Engel, Rolf H. Sijmons, María Laura Gonzalez, Matilde Navarro, Francisco López-Köstner, Julian R. Sampson, Miquel Serra-Burriel, Karin Alvarez, Ingrid Winship, Nathan Gluck, Lone Sunde, Reinhard Büttner, Giulia Martina Cavestro, Wouter H. de Vos tot Nederveen Cappel, Jukka-Pekka Mecklin, Marc S. Greenblatt, Kate Green, Robert Hüneburg, Markus Loeffler, Maria Grazia Tibiletti, Tamara Alejandra Piñero, Florencia Neffa, Lucio Bertario, Ariadna Sánchez, Verena Steinke-Lange, Christina Therkildsen, Jane C. Figueiredo, Douglas Tjandra, Magnus von Knebel Doeberitz, Lior H. Katz, Steven Gallinger, Noralane M. Lindor, Gabriela Möslein, Adriana Della Valle, John L. Hopper, Einar Andreas Rødland, Miriam Mints, Annika Lindblom, Ian M. Frayling, Polly A. Newcomb, Pål Møller, Sanne W. ten Broeke, Laura Renkonen-Sinisalo, Sigve Nakken, Stefanie Holzapfel, Finlay A. Macrae, Stefan Aretz, Nils Rahner, Karin Wadt, Robert W. Haile, Francesc Balaguer, Revital Kariv, Stephen N. Thibodeau, Huw D. Thomas, Emma J Crosbie, Deepak Vangala, Monika Morak, Ignacio Blanco, Hans K. Schackert, Henrik Okkels, Mev Dominguez-Valentin, Oliver G. Denton, John-Paul Plazzer, Zohreh Ketabi, James Hill, Loic Le Marchand, Mark A. Jenkins, Inge Bernstein, D. Gareth Evans, Heike Görgens, Marta Pineda, John Burn, Kirsi Pylvänäinen, Eivind Hovig, Hans F. A. Vasen, Pablo Kalfayan, Toni T. Seppälä, Aung Ko Win, Maartje Nielsen, Wolff Schmiegel, Guy Rosner, Karl Heinimann, Fiona Lalloo, Carlos A. Vaccaro, Elke Holinski-Feder, Leticia Moreira, HUS Abdominal Center, Clinicum, II kirurgian klinikka, University of Helsinki, Department of Surgery, ATG - Applied Tumor Genomics, Research Programs Unit, Dominguez-Valentin, M., Sampson, J. R., Seppala, T. T., ten Broeke, S. W., Plazzer, J. -P., Nakken, S., Engel, C., Aretz, S., Jenkins, M. A., Sunde, L., Bernstein, I., Capella, G., Balaguer, F., Thomas, H., Evans, D. G., Burn, J., Greenblatt, M., Hovig, E., de Vos tot Nederveen Cappel, W. H., Sijmons, R. H., Bertario, L., Tibiletti, M. G., Cavestro, G. M., Lindblom, A., Della Valle, A., Lopez-Kostner, F., Gluck, N., Katz, L. H., Heinimann, K., Vaccaro, C. A., Buttner, R., Gorgens, H., Holinski-Feder, E., Morak, M., Holzapfel, S., Huneburg, R., Knebel Doeberitz, M., Loeffler, M., Rahner, N., Schackert, H. K., Steinke-Lange, V., Schmiegel, W., Vangala, D., Pylvanainen, K., Renkonen-Sinisalo, L., Hopper, J. L., Win, A. K., Haile, R. W., Lindor, N. M., Gallinger, S., Le Marchand, L., Newcomb, P. A., Figueiredo, J. C., Thibodeau, S. N., Wadt, K., Therkildsen, C., Okkels, H., Ketabi, Z., Moreira, L., Sanchez, A., Serra-Burriel, M., Pineda, M., Navarro, M., Blanco, I., Green, K., Lalloo, F., Crosbie, E. J., Hill, J., Denton, O. G., Frayling, I. M., Rodland, E. A., Vasen, H., Mints, M., Neffa, F., Esperon, P., Alvarez, K., Kariv, R., Rosner, G., Pinero, T. A., Gonzalez, M. L., Kalfayan, P., Tjandra, D., Winship, I. M., Macrae, F., Moslein, G., Mecklin, J. -P., Nielsen, M., Moller, P., and Guided Treatment in Optimal Selected Cancer Patients (GUTS)

Subjects
Oncology, Male, Colorectal cancer, Lynch syndrome, Penetrance, DNA Mismatch Repair, 0302 clinical medicine, Databases, Genetic, Malalties hereditàries, Prospective Studies, Càncer, PMS2, Genetics (clinical), Mismatch Repair Endonuclease PMS2, Cancer, 0303 health sciences, Sex Characteristics, Factors de risc en les malalties, 1184 Genetics, developmental biology, physiology, MLH1, Middle Aged, 16. Peace & justice, 3. Good health, DNA-Binding Proteins, MutS Homolog 2 Protein, syöpägeenit, MSH2, 030220 oncology & carcinogenesis, MSH6, 030211 gastroenterology & hepatology, DNA mismatch repair, Female, geneettiset tekijät, MutL Protein Homolog 1, Genetic diseases, Adult, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, Risk factors in diseases, suolistosyövät, MUTATION CARRIERS, Risk Assessment, Article, sukupuoli, Age and gender, 03 medical and health sciences, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, Lynchin oireyhtymä, Gene, 030304 developmental biology, Aged, business.industry, Endometrial cancer, Correction, nutritional and metabolic diseases, medicine.disease, Colorectal Neoplasms, Hereditary Nonpolyposis, Survival Analysis, digestive system diseases, Mutation, 3111 Biomedicine, ikä, business, Ovarian cancer
Abstract

Lynch syndrome (LS) results from pathogenic variants in the mismatch repair (MMR) genes and is the most common hereditary cancer syndrome, affecting an estimated 1 in 300 individuals. Pathogenic variants in each of the MMR genes path_MLH1, path_MSH2, path_MSH6, and path_PMS2 result in different risks for cancers in organs including the colorectum, endometrium, ovaries, stomach, small bowel, bile duct, pancreas, and upper urinary tract. Accurate estimates of these risks are essential for planning appropriate approaches to the prevention or early diagnosis of cancers but the robustness of previous studies has been limited by factors including retrospective design,1,2 lack of validation in independent cohorts,3-5 and inconsistent classification of genetic variants. Unexpected findings from previous studies have included path_MLH1 and path_MSH2 carriers appearing to have a lifetime risk of colorectal cancer (CRC) of approximately 50%, despite surveillance colonoscopy,6-8 and that shorter intervals between colonoscopies do not seem to reduce the incidence of CRC in LS.9,10 These findings challenge the assumptions that CRC in LS usually develops from a noninfiltrative adenoma precursor and that CRC can be prevented by colonoscopic detection and removal of adenomas in the colon and rectum. Additionally, previous studies in the Prospective Lynch Syndrome Database (PLSD) have shown no increase in cancer risk in path_PMS2 carriers before 40 years of age and, although observation years were limited in older path_PMS2 carriers, LS-associated cancers other than endometrial and prostate were not observed.6-8 In this study we collected prospective data from a new large cohort of path_MMR carriers to validate previous findings from PLSD. We also updated information on the original cohort to ensure consistent classification of pathogenicity of MMR gene variants. We then combined both data sets, providing larger numbers that allowed us to derive more precise risk estimates for cancers in LS categorized by gene and gender.

Published
2020

41. Eliminating Cervical Cancer: Progress and Challenges for High-income Countries.

Author

Davies-Oliveira JC, Smith MA, Grover S, Canfell K, and Crosbie EJ

Subjects
Adolescent, Adult, Developed Countries, Early Detection of Cancer, Female, Humans, Mass Screening, Papillomavirus Infections epidemiology, Papillomavirus Infections prevention & control, Uterine Cervical Neoplasms epidemiology, Uterine Cervical Neoplasms prevention & control
Abstract

In 2020, the World Health Organization launched a major initiative to eliminate cervical cancer globally. The initiative is built around the three key pillars of human papillomavirus (HPV) vaccination, cervical screening and treatment, with associated intervention targets for the year 2030. The '90-70-90' targets specify that 90% of adolescent girls receive prophylactic HPV vaccination, 70% of adult women receive a minimum twice-in-a-lifetime cervical HPV test and 90% receive appropriate treatment for preinvasive or invasive disease. Modelling has shown that if these targets are met, the elimination of cervical cancer, defined as fewer than four cases per 100 000 women per annum, will be achieved within a century. Many high-income countries are well positioned to eliminate cervical cancer within the coming decades, but few have achieved '90-70-90' and many challenges must still be addressed to deliver these critical interventions effectively. This review considers the current status of cervical cancer control in relation to each of the three elimination pillars in high-income countries and discusses some of the developments that will assist countries in reaching these ambitious targets by 2030., (Copyright © 2021 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Published
2021
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42. Impact of socio-economic deprivation on endometrial cancer survival in the North West of England: a prospective database analysis.

Author

Njoku K, Barr CE, Hotchkies L, Quille N, Wan YL, and Crosbie EJ

Subjects
Aged, Databases, Factual, Diabetes Mellitus epidemiology, Endometrial Neoplasms pathology, England epidemiology, Female, Humans, Middle Aged, Neoplasm Metastasis, Neoplasm Recurrence, Local mortality, Obesity epidemiology, Prospective Studies, Social Class, Endometrial Neoplasms mortality, Health Status Disparities, Socioeconomic Factors
Abstract

Objective: To assess the impact of socio-economic deprivation on endometrial cancer survival., Design: Single-centre prospective database study., Setting: North West England., Population: Women with endometrial cancer treated between 2010 and 2015., Methods: Areal-level socio-economic status, using the English indices of multiple deprivation from residential postcodes, was analysed in relation to survival using Kaplan-Meier estimation and multivariable Cox regression., Main Outcome Measures: Overall survival, cancer-specific survival and patterns and rates of recurrence., Results: A total of 539 women, with a median age of 66 years (interquartile range, IQR 56-73 years) and a body mass index (BMI) of 32 kg/m 2 (IQR 26-39 kg/m 2 ), were included in the analysis. Women in the most deprived social group were younger (median 64 years, IQR 55-72 years) and more obese (median 34 kg/m 2 , IQR 28-42 kg/m 2 ) than women in the least deprived group (median age 68 years, IQR 60-74 years; BMI 29 kg/m 2 , IQR 25-36 kg/m 2 ; P = 0.002 and <0.001, respectively). There were no differences in endometrial cancer type, stage or grade between social groups. There was no difference in recurrence rates, however, women in the middle and most deprived social groups were more likely to present with distant/metastatic recurrence (80.6 and 79.2%, respectively) than women in the least deprived group (43.5%, P < 0.001). Women in the middle and most deprived groups had a two-fold (adjusted hazard ratio, HR = 2.00, 95% CI 1.07-3.73, P = 0.030) and 53% (adjusted HR = 1.53, 95% CI 0.77-3.04, P = 0.221) increase in cancer-specific mortality compared with women in the least deprived group. There were no differences in overall survival., Conclusions: We found that socio-economically deprived women with endometrial cancer were more likely to develop fatal recurrence. Larger studies are needed to confirm these findings and to identify modifiable contributing factors., Tweetable Abstract: Socio-economic deprivation is linked to an increased risk of death from endometrial cancer in the North West of England., (© 2021 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

Published
2021
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43. A mismatch in care: results of a United Kingdom-wide patient and clinician survey of gynaecological services for women with Lynch syndrome.

Author

Ryan N, Nobes M, Sedgewick D, Teoh SN, Evans DG, and Crosbie EJ

Subjects
Adult, Aged, Cross-Sectional Studies, Female, Gynecology statistics & numerical data, Health Care Surveys, Health Services Accessibility statistics & numerical data, Healthcare Disparities statistics & numerical data, Humans, Middle Aged, Referral and Consultation statistics & numerical data, State Medicine organization & administration, State Medicine statistics & numerical data, United Kingdom, Women's Health Services statistics & numerical data, Colorectal Neoplasms, Hereditary Nonpolyposis diagnosis, Colorectal Neoplasms, Hereditary Nonpolyposis therapy, Gynecology organization & administration, Health Services Accessibility organization & administration, Practice Patterns, Physicians' statistics & numerical data, Referral and Consultation organization & administration, Women's Health Services organization & administration
Abstract

Objective: To describe the current testing practice, referral pathways and gynaecological services available to women with Lynch syndrome (LS) in the UK., Design: Cross-sectional nationwide survey of gynaecological oncologists and women with LS., Setting: United Kingdom., Methods: Gynaecological oncologists were contacted directly. Women with LS were identified from national and regional clinical databases and the patient support group, Lynch syndrome UK., Main Outcome Measures: Gynaecological oncologists were asked to report rates of LS testing and current practice regarding risk-reducing strategies and gynaecological surveillance for women with LS. Women with LS were asked to describe their experiences of gynaecological care., Results: In total, 41 gynaecological oncologists and 298 women with LS responded to the survey. Of the gynaecological oncologists surveyed, 37% were unfamiliar with any clinical guidelines for the management of LS. Only 29% of gynaecological oncologists supported universal testing of endometrial cancer for LS; one centre routinely performed such testing. In all, 83% said they perform risk-reducing gynaecological surgery and 43% were aware of a local gynaecological surveillance service for women with LS. Of women with LS, most had undergone a hysterectomy (n = 191/64.1%), most frequently to reduce their gynaecological cancer risk (n = 86/45%). A total of 10% were initially referred for LS testing by their gynaecologist and 55% of those eligible regularly attended gynaecological surveillance; however, 62% wanted more regular surveillance. Regional variation was evident across all standards of care., Conclusions: There is widespread variation in the services offered to women with LS in the UK. As a community, gynaecological oncologists should move towards a nationally agreed provision of services., Tweetable Abstract: A mismatch in care for mismatch repair. Survey finds significant variation in gynaecological care for #Lynchsyndrome in the UK., (© 2020 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd on behalf of Royal College of Obstetricians and Gynaecologists.)

Published
2021
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44. Research priority setting in women's health: a systematic review.

Author

Graham L, Illingworth B, Showell M, Vercoe M, Crosbie EJ, Gingel LJ, Farquhar CM, Horne AW, Prior M, Stephenson JM, Magee LA, and Duffy J

Subjects
Consensus, Female, Humans, Pilot Projects, Biomedical Research organization & administration, Research, Women's Health statistics & numerical data
Abstract

Background: Developing a shared agenda is an important step in ensuring future research has the necessary relevance., Objective: To characterise research priority setting partnerships (PSPs) relevant to women's health., Search Strategy: Included studies were identified by searching MEDLINE and the James Lind Alliance (JLA) database., Selection Criteria: Priority setting partnerships using formal consensus methods., Data Collection and Analysis: Descriptive narrative to describe the study characteristics, methods, and results., Main Results: Ten national and two international PSPs were identified. All PSPs used the JLA method to identify research priorities. Nine PSPs had published a protocol. Potential research uncertainties were gathered from guidelines (two studies), Cochrane reviews (five studies), and surveys (12 studies). The number of healthcare professionals (31-287), patients (44-932), and others (33-139) who responded to the survey, and the number of uncertainties submitted (52-4767) varied. All PSPs entered confirmed research uncertainties (39-104) into interim priority setting surveys and healthcare professionals (31-287), patients (44-932), and others (33-139) responded. All PSPs entered a short list of research uncertainties into a consensus development meeting, which enabled healthcare professionals (six to 21), patients (eight to 14), and others (two to 13) to identify research priorities (ten to 15). Four PSPs have published their results., Conclusion: Future research priority setting studies should publish a protocol, use formal consensus development methods, and ensure their methods and results are comprehensively reported., Tweetable Abstract: Research published in @BJOGtweets highlights future research priorities across women's health, including @FertilityTop10, @jamesmnduffy., (© 2020 Royal College of Obstetricians and Gynaecologists.)

Published
2020
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47. Targeted lung cancer screening selects individuals at high risk of cardiovascular disease.

Author

Balata H, Blandin Knight S, Barber P, Colligan D, Crosbie EJ, Duerden R, Elton P, Evison M, Greaves M, Howells J, Irion K, Karunaratne D, Kirwan M, Macnab A, Mellor S, Miller C, Newton T, Novasio J, Sawyer R, Sharman A, Slevin K, Smith E, Taylor B, Taylor S, Tonge J, Walsham A, Waplington S, Whittaker J, Booton R, and Crosbie PAJ

Subjects
Aged, Calcinosis, Cardiovascular Diseases epidemiology, England epidemiology, Female, Humans, Lung Neoplasms epidemiology, Male, Middle Aged, Risk, Risk Assessment, Cardiovascular Diseases diagnosis, Early Detection of Cancer methods, Lung Neoplasms diagnosis
Abstract

Background: Cardiovascular disease (CVD) is a major cause of morbidity and mortality in populations eligible for lung cancer screening. The aim of this study was to determine whether a brief CV risk assessment, delivered as part of a targeted community-based lung cancer screening programme, was effective in identifying individuals at high risk who might benefit from primary prevention., Methods: The Manchester Lung Screening Pilot consisted of annual low dose CT (LDCT) over 2 screening rounds, targeted at individuals in deprived areas at high risk of lung cancer (age 55-74 and 6-year risk ≥1.51%, using PLCO M2012 risk model). All participants of the second screening round were eligible to take part in the study. Ten-year CV risk was estimated using QRISK2 in participants without CVD and compared to age (±5 years) and sex matched Health Survey for England (HSE) controls; high risk was defined as QRISK2 score ≥10%. Coronary artery calcification (CAC) was assessed on LDCT scans and compared to QRISK2 score., Results: Seventy-seven percent (n=920/1,194) of screening attendees were included in the analysis; mean age 65.6 ± 5.4 and 50.4% female. QRISK2 and lung cancer risk (PLCO M2012 ) scores were correlated (r = 0.26, p < 0.001). Median QRISK2 score was 21.1% (IQR 14.9-29.6) in those without established CVD (77.6%, n = 714/920), double that of HSE controls (10.3%, IQR 6.6-16.2; n = 714) (p < 0.001). QRISK2 score was significantly higher in those with CAC (p < 0.001). Screening attendees were 10-fold more likely to be classified high risk (OR 10.2 [95% CI 7.3-14.0]). One third (33.7%, n = 310/920) of all study participants were high risk but not receiving statin therapy for primary CVD prevention., Discussion: Opportunistic CVD risk assessment within a targeted lung cancer screening programme is feasible and is likely to identify a very large number of individuals suitable for primary prevention., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Published
2018
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48. The association between diabetes, comorbidities, body mass index and all-cause and cause-specific mortality among women with endometrial cancer.

Author

Nagle CM, Crosbie EJ, Brand A, Obermair A, Oehler MK, Quinn M, Leung Y, Spurdle AB, and Webb PM

Subjects
Adolescent, Adult, Aged, Female, Humans, Middle Aged, Risk Factors, Survival Analysis, Young Adult, Body Mass Index, Comorbidity trends, Diabetes Mellitus mortality, Endometrial Neoplasms complications, Endometrial Neoplasms mortality
Abstract

Objective: Although endometrial cancer (EC) is associated with relatively good survival rates overall, women diagnosed with high-risk subtypes have poor outcomes. We examined the relationship between lifestyle factors and subsequent all-cause, cancer-specific and non-cancer related survival., Methods: In a cohort of 1359 Australian women diagnosed with incident EC between 2005 and 2007 pre-diagnostic information was collected by interview at recruitment. Clinical and survival information was abstracted from women's medical records, supplemented by linkage to the Australian National Death Index. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause and cause-specific survival (EC death vs. non-EC death) associated with each exposure, overall and by risk group (low-grade endometrioid vs. high-grade endometrioid and non-endometrioid)., Results: After a median follow-up of 7.1 years, 179 (13%) women had died, with 123 (69%) deaths from EC. As expected, elevated body mass index (BMI), diabetes and the presence of other co-morbidities were associated with a significantly increased risk of all-cause and non-cancer related death. Women with diabetes had higher cancer-specific mortality rates (HR 2.09, 95% CI 1.31-3.35), particularly those who had were not obese (HR 4.13, 95% CI 2.20-7.76). The presence of ≥2 other co-morbidities (excluding diabetes) was also associated with increased risk of cancer-specific mortality (HR 3.09, 95% CI 1.21-7.89). The patterns were generally similar for women with low-grade and high-grade endometrioid/non-endometrioid EC., Conclusion: Our findings demonstrate the importance of diabetes, other co-morbidities and obesity as negative predictors of mortality among women with EC but that the risks differ for cancer-specific and non-cancer related mortality., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Published
2018
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