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51.
Yoland C. Antill James G. Dowty Aung Ko Win Tina Thompson Michael D. Walsh Margaret C. Cummings Steven Gallinger Noralane M. Lindor Loïc Le Marchand John L. Hopper Polly A. Newcomb Robert W. Haile James Church Katherine M. Tucker Daniel D. Buchanan Joanne P. Young Ingrid M. Winship Mark A. Jenkins 《International journal of cancer. Journal international du cancer》2015,137(11):2757-2761
Carriers of germline mutations in DNA mismatch repair (MMR) genes are at increased risk of several cancers including colorectal and gynecologic cancers (Lynch syndrome). There is no substantial evidence that these mutations are associated with an increased risk of cervical cancer. A total of 369 families with at least one carrier of a mutation in a MMR gene (133 MLH1, 174 MSH2, 35 MSH6 and 27 PMS2) were ascertained via population cancer registries or via family cancer clinics in Australia, New Zealand, Canada, and USA. Personal and family histories of cancer were obtained from participant interviews. Modified segregation analysis was used to estimate the hazard ratio (incidence rates for carriers relative to those for the general population), and age‐specific cumulative risks of cervical cancer for carriers. A total of 65 cases of cervical cancer were reported (including 10 verified by pathology reports). The estimated incidence was 5.6 fold (95% CI: 2.3–13.8; p = 0.001) higher for carriers than for the general population with a corresponding cumulative risk to 80 years of 4.5% (95% CI: 1.9–10.7%) compared with 0.8% for the general population. The mean age at diagnosis was 43.1 years (95% CI: 40.0–46.2), 3.9 years younger than the reported USA population mean of 47.0 years (p = 0.02). Women with MMR gene mutations were found to have an increased risk of cervical cancer. Due to limited pathology verification we cannot be certain that a proportion of these cases were not lower uterine segment endometrial cancers involving the endocervix, a recognized cancer of Lynch syndrome. 相似文献
52.
Pierre‐Antoine Dugué PhD James G. Dowty PhD Jihoon E. Joo PhD Ee M. Wong PhD Enes Makalic PhD Daniel F. Schmidt PhD Dallas R. English PhD John L. Hopper PhD John Pedersen MBBS PhD Gianluca Severi PhD Robert J. MacInnis PhD Roger L. Milne PhD Graham G. Giles PhD Melissa C. Southey PhD 《The Prostate》2018,78(13):962-969
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Lindor NM Lindor RA Apicella C Dowty JG Ashley A Hunt K Mincey BA Wilson M Smith MC Hopper JL 《Familial cancer》2007,6(4):473-482
Context Models have been developed to predict the probability that a person carries a detectable germline mutation in the BRCA1 or BRCA2 genes. Their relative performance in a clinical setting is unclear.
Objective To compare the performance characteristics of four BRCA1/BRCA2 gene mutation prediction models: LAMBDA, based on a checklist and scores developed from data on Ashkenazi Jewish (AJ) women;
BRCAPRO, a Bayesian computer program; modified Couch tables based on regression analyses; and Myriad II tables collated by
Myriad Genetics Laboratories.
Design and setting Family cancer history data were analyzed from 200 probands from the Mayo Clinic Familial Cancer Program, in a multispecialty
tertiary care group practice. All probands had clinical testing for BRCA1 and BRCA2 mutations conducted in a single laboratory.
Main outcomes measures For each model, performance was assessed by the area under the receiver operator characteristic curve (ROC) and by tests of
accuracy and dispersion. Cases “missed” by one or more models (model predicted less than 10% probability of mutation when
a mutation was actually found) were compared across models.
Results All models gave similar areas under the ROC curve of 0.71 to 0.76. All models except LAMBDA substantially under-predicted
the numbers of carriers. All models were too dispersed.
Conclusions In terms of ranking, all prediction models performed reasonably well with similar performance characteristics. Model predictions
were widely discrepant for some families. Review of cancer family histories by an experienced clinician continues to be vital
to ensure that critical elements are not missed and that the most appropriate risk prediction figures are provided. 相似文献
55.
Jenkins MA Hayashi S O'Shea AM Burgart LJ Smyrk TC Shimizu D Waring PM Ruszkiewicz AR Pollett AF Redston M Barker MA Baron JA Casey GR Dowty JG Giles GG Limburg P Newcomb P Young JP Walsh MD Thibodeau SN Lindor NM Lemarchand L Gallinger S Haile RW Potter JD Hopper JL Jass JR;Colon Cancer Family Registry 《Gastroenterology》2007,133(1):48-56
BACKGROUND & AIMS: The revised Bethesda guidelines for Lynch syndrome recommend microsatellite instability (MSI) testing all colorectal cancers in patients diagnosed before age 50 years and colorectal cancers diagnosed in patients between ages 50 and 59 years with particular pathology features. Our aim was to identify pathology and other features that independently predict high MSI (MSI-H). METHODS: Archival tissue from 1098 population-based colorectal cancers diagnosed before age 60 years was tested for MSI. Pathology features, site, and age at diagnosis were obtained. Multiple logistic regression was performed to determine the predictive value of each feature, as measured by an odds ratio (OR), from which a scoring system (MsPath) was developed to estimate the probability a colorectal cancer is MSI-H. RESULTS: Fifteen percent of tumors (162) were MSI-H. Independent predictors were tumor-infiltrating lymphocytes (OR, 9.1; 95% confidence interval [CI], 5.9-14.1), proximal subsite (OR, 4.7; 95% CI, 3.1-7.3), mucinous histology (OR, 2.8; 95% CI, 1.7-4.8), poor differentiation (OR, 1.9; 95% CI, 1.2-3.1), Crohn's-like reaction (OR, 1.9; 95% CI, 1.2-2.9), and diagnosis before age 50 years (OR, 1.9; 95% CI, 1.3-2.9). MsPath score >or=1.0 had a sensitivity of 93% and a specificity of 55% for MSI-H. CONCLUSIONS: The probability an individual colorectal cancer is MSI-H is predicted well by the MsPath score. There is little value in testing for DNA mismatch repair loss in tumors, or for germline mismatch repair mutations, for colorectal cancers diagnosed in patients before age 60 years with an MSPath score <1 (approximately 50%). Pathology can identify almost all MSI-H colorectal cancers diagnosed before age 60 years. 相似文献
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A. Antonovsky B. Maoz N. Dowty H. Wijsenbeek 《Social psychiatry and psychiatric epidemiology》1971,6(4):186-193
Summary The central question raised is: To what extent does maladaptation and malfunctioning characterize survivors of the unimaginably extreme, prolonged trauma of the Nazi concentration camps, and to what extent do we find successful adaptation among such persons? The extensive literature on camp survivors is largely incapable of confronting this question. Even when not based only on a small number of patients in psychiatric treatment, most papers deal with select populations. Moreover, it is seldom that survivors are compared to appropriate controls. - A study which included Israeli women aged 45–54 of Central European birth and focused on problems of adaptation to climacterium provided data relevant to the central question. The respondents constituted a representative sample of all women in a middle-sized Israeli city meeting the criteria of age and nativity. Of the 287 women in the sample, 77 had been in a Nazi concentration camp during World War II. The remaining 210 women were used as a control group. - Adaptation was measured from several different points of view: menopausal symptomatology, the subjective sense of wellbeing, physical and emotional health status, and role satisfaction. The detailed data show camp survivors to be more poorly-adjusted than the controls. - Of greater import, however, is the fact that a not-inconsiderable number of concentration camp survivors were found to be well-adapted, despite the extreme trauma. It is suggested that this finding requires serious investigation. Three complementary explanations of the fact of successful adaptation are proposed: an initial underlying strength, a subsequent environment which provided opportunities to reestablish a satisfying and meaningful existence, and a hardening process which allow the survivor to view current stresses with some equanimity.
Zusammenfassung Die zentrale Fragestellung lautet: In welchem Ausmaß charakterisiert Fehlanpassung und schlechtes Funktionieren die Überlebenden des unvorstellbar extremen und langdauernden Traumas der nationalsozialistischen Konzentrationslager, und in welchem Ausmaß finden wir erfolgreiche Anpassung unter solchen Personen? Das ausgedehnte Schrifttum über die Überlebenden dieser Lager kann sich größ-tenteils mit dieser Frage nicht auseinandersetzen. Auch wenn die Arbeiten nicht nur auf einer kleinen Anzahl von Patienten in psychiatrischer Behandlung fußen, haben sie sich meistens mit ausgewählten Populationen befaßt. Außerdem werden selten Überlebende mit angemessenen Kontrollgruppen verglichen. Eine Untersuchung, die jüdische Frauen zwischen 45 und 54 Jahren, in Mitteleuropa geboren, erfaßte und auf Probleme der Anpassung an das Klimakterium abhob, lieferte für die zentrale Frage relevante Daten. Die Probanden bildeten eine repräsentative Gruppe aller Frauen in einer mittelgroßen israelischen Stadt, die ihrem Alter und ihrer Herkunft nach die Kriterien erfüllten. Von den 287 Frauen in der Gruppe waren 77 im zweiten Weltkrieg in einem nationalsozialistischen Konzentrationslager gewesen. Die übrigen 210 Frauen wurden als Kontrollgruppe verwandt. Anpassung wurde von verschiedenen Gesichtspunkten her beurteilt: Symptomatologie der Menopause, subjektives Gefühl des Wohlbefindens, körperlicher und seelischer Gesundheitszustand und Erfüllung in der eigenen Rolle. Die ausführlichen Daten zeigen, daß die den Lageraufenthalt Überlebenden schlechter angepaßt waren als die Kontrollfälle. Bedeutsamer ist jedoch die Tatsache, daß eine nicht unbeträchtliche Anzahl von den die Konzentrationslager Überlebenden als gut angepaßt gefunden wurde, trotz des extremen Traumas. Es wird vermutet, daß dieses Ergebnis eine gründliche Untersuchung fordert. Drei sich gegenseitig ergänzende Erklärungen für die Tatsache der erfolgreichen Anpassung werden vorgeschlagen: eine ursprünglich zugrundeliegende Vitalität, später eine Umgebung, die Möglichkeiten zum Wiederaufbau einer befriedigenden und bedeutungserfüllten Existenz lieferte, ein Härtungsprozeß, der dem Überlebenden einen gewissen Gleichmut gegenüber gegenwärtigem Stress gewährte.
Résumé La question principale soulevée dans ce travail est la suivante: jusqu'à quel point l'inadaptation est-elle une caractéristique des survivants aux traumatismes extrêmement graves et prolongés des camps de concentration nazis, et jusqu'à quel point trouvons-nous des adaptations réussies parmi ces personnes? L'abondante littérature existant sur les survivants des camps de concentration n'est pas capable de répondre à cette question. Même s'ils ne sont pas basés que sur un petit nombre de patients en traitement psychiatrique, la plupart des travaux ne concernent que des populations choisies. De plus, il est rare que les survivants soient comparés à des cas de contrôle appropriés. Une étude comprenant des femmes israëlites âgées de 45 à 54 ans, nées en Europe centrale, et centrée sur les problèmes de l'adaptation à la ménopause a fourni des données quant à la question principale ci-dessus. Les sujets constituaient un échantillon représentatif de toutes les femmes d'une ville israëlienne de moyenne importance en ce qui concerne les critères d'âge et de naissance. Des 287 femmes de l'échantillon, 77 avaient été dans un camp de concentration nazi pendant la seconde guerre mondiale. Les 210 autres femmes ont été utilisées comme groupe de contrôle. L'adaptation a été mesurée selon plusieurs points de vue différents: symptomatologie de la ménopause, sensation subjective de bien-être, état de santé physique et psychique, et satisfaction quant au rôle assumé. Les résultats détaillés montrent que les survivantes des camps sont moins bien adaptées que les cas contrôle. Il est cependant intéressant de noter qu'un nombre non négligeable de survivantes aux camps de concentration se sont avérées bien adaptées, malgré le grave traumatisme. On pense qu'il faudrait étudier ce résultat plus à fond. On propose trois explications complémentaires de cette adaptation réussie: une certaine force initiale sous-jacente, un environnement qui a permis aux intéressées de reprendre une existence satisfaisante et de lui donner un sens, et un processus de »durcissement« qui permet aux survivants d'envisager les stress de la vie quotidienne avec une certaine égalité d'âme.相似文献
58.
Hannele Erkko James G Dowty Jenni Nikkil? Kirsi Syrj?koski Arto Mannermaa Katri Pylk?s Melissa C Southey Kaija Holli Anne Kallioniemi Arja Jukkola-Vuorinen Vesa Kataja Veli-Matti Kosma Bing Xia David M Livingston Robert Winqvist John L Hopper 《Clinical cancer research》2008,14(14):4667-4671
PURPOSE: PALB2 is a recently identified breast cancer susceptibility gene. We have previously identified in the Finnish population a PALB2 c.1592delT founder truncation mutation that is associated with an increased risk of breast cancer. In the present study, we wanted to assess in more detail the increased risk (hazard ratio, HR) and the age-specific cumulative risk (penetrance) of c.1592delT with regard to susceptibility to breast and other forms of cancer. EXPERIMENTAL DESIGN: Modified segregation analyses fitted under maximum likelihood theory were used to estimate age-specific cumulative risks and HRs using the families of mutation carriers identified from a consecutive series of breast cancer cases unselected for age at onset or family history. RESULTS: We found a substantially increased risk of breast cancer [HR, 6.1; 95% confidence interval (95% CI), 2.2-17.2; P = 0.01] equivalent to a 40% (95% CI, 17-77) breast cancer risk by age 70 years, comparable to that for carriers of mutations in BRCA2. We found marginal evidence (P = 0.06) that the HR for breast cancer decreased with age by 4.2% per year (95% CI, 0.2-8.1), from 7.5-fold at age 30 years to 2.0-fold at age 60 years. CONCLUSIONS: Our results suggest that it may be appropriate to offer PALB2 c.1592delT mutation testing to Finnish women with breast cancer, especially those with an early age at onset or a family history of breast or related cancers, and to offer carriers the option of participation in extended disease surveillance programs. 相似文献
59.