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| 2. |
- Schlehofer, B, et al.
(author)
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Primary brain tumours and specific serum immunoglobulin E : a case-control study nested in the European prospective investigation into cancer and nutrition cohort
- 2011
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In: Allergy. European Journal of Allergy and Clinical Immunology. - : Wiley. - 0105-4538 .- 1398-9995. ; 66:11, s. 1434-1441
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Journal article (peer-reviewed)abstract
- ABSTRACT: Background: Case-control studies suggest that patients with allergic diseases have a lower risk of developing glioma but not meningioma or schwannoma. However, those data can be differentially biased. Prospective studies with objective measurements of immunologic biomarkers, like immunoglobulin E (IgE), in blood obtained before cancer diagnosis could help to clarify whether an aetiological association exists. Methods: The present case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) measured specific serum IgE as a biomarker for the most common inhalant allergens in 275 glioma, 175 meningioma and 49 schwannoma cases and 963 matched controls using the ImmunoCAP specific IgE test. Subjects with an IgE level ≥0.35 kUA/l (kilo antibody units per litre) were classified as sensitized by allergens. Odds ratios (OR) and 95% confidence intervals (CI) were estimated by adjusted conditional logistic regression models for each tumour subtype. The effect of dose-response relationship was assessed in five increasing IgE level categories to estimate P-values for trend. Results: The risk of glioma was inversely related to allergic sensitization (OR = 0.73; 95% CI 0.51-1.06), especially pronounced in women (OR = 0.53; 95% CI 0.30-0.95). In dose-response analyses, for high-grade glioma, the lowest OR was observed in sera with the highest IgE levels (P for trend = 0.04). No association was seen for meningioma and schwannoma. Conclusion: The results, based on serum samples prospectively collected in a cohort study, provide some support for the hypothesis that individuals with allergic sensitization are at reduced risk of glioma and confirm results from previous case-control studies.
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| 3. |
- Dankiewicz, Josef, et al.
(author)
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Hypothermia versus Normothermia after Out-of-Hospital Cardiac Arrest
- 2021
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In: New England Journal of Medicine. - : MASSACHUSETTS MEDICAL SOC. - 0028-4793 .- 1533-4406. ; 384:24, s. 2283-2294
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Journal article (peer-reviewed)abstract
- Hypothermia or Normothermia after Cardiac Arrest This trial randomly assigned patients with coma after out-of-hospital cardiac arrest to undergo targeted hypothermia at 33 degrees C or normothermia with treatment of fever. At 6 months, there were no significant between-group differences regarding death or functional outcomes. Background Targeted temperature management is recommended for patients after cardiac arrest, but the supporting evidence is of low certainty. Methods In an open-label trial with blinded assessment of outcomes, we randomly assigned 1900 adults with coma who had had an out-of-hospital cardiac arrest of presumed cardiac or unknown cause to undergo targeted hypothermia at 33 degrees C, followed by controlled rewarming, or targeted normothermia with early treatment of fever (body temperature, >= 37.8 degrees C). The primary outcome was death from any cause at 6 months. Secondary outcomes included functional outcome at 6 months as assessed with the modified Rankin scale. Prespecified subgroups were defined according to sex, age, initial cardiac rhythm, time to return of spontaneous circulation, and presence or absence of shock on admission. Prespecified adverse events were pneumonia, sepsis, bleeding, arrhythmia resulting in hemodynamic compromise, and skin complications related to the temperature management device. Results A total of 1850 patients were evaluated for the primary outcome. At 6 months, 465 of 925 patients (50%) in the hypothermia group had died, as compared with 446 of 925 (48%) in the normothermia group (relative risk with hypothermia, 1.04; 95% confidence interval [CI], 0.94 to 1.14; P=0.37). Of the 1747 patients in whom the functional outcome was assessed, 488 of 881 (55%) in the hypothermia group had moderately severe disability or worse (modified Rankin scale score >= 4), as compared with 479 of 866 (55%) in the normothermia group (relative risk with hypothermia, 1.00; 95% CI, 0.92 to 1.09). Outcomes were consistent in the prespecified subgroups. Arrhythmia resulting in hemodynamic compromise was more common in the hypothermia group than in the normothermia group (24% vs. 17%, P<0.001). The incidence of other adverse events did not differ significantly between the two groups. Conclusions In patients with coma after out-of-hospital cardiac arrest, targeted hypothermia did not lead to a lower incidence of death by 6 months than targeted normothermia. (Funded by the Swedish Research Council and others; TTM2 ClinicalTrials.gov number, .)
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| 4. |
- Tsilidis, K. K., et al.
(author)
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Oral contraceptives, reproductive history and risk of colorectal cancer in the European Prospective Investigation into Cancer and Nutrition
- 2010
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In: British Journal of Cancer. - : Springer Science and Business Media LLC. - 1532-1827 .- 0007-0920. ; 103:11, s. 1755-1759
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Journal article (peer-reviewed)abstract
- BACKGROUND: Oral contraceptive use and reproductive factors may initiate long-term changes to the hormonal milieu and thereby, possibly influence colorectal cancer risk. METHODS: We examined the association of hormonal and reproductive factors with risk of colorectal cancer among 337 802 women in the European Prospective Investigation into Cancer and Nutrition, of whom 1878 developed colorectal cancer. RESULTS: After stratification for center and age, and adjustment for body mass index, smoking, diabetes mellitus, physical activity and alcohol consumption, ever use of oral contraceptives was marginally inversely associated with colorectal cancer risk (hazard ratio (HR), 0.92; 95% confidence interval (CI), 0.83-1.02), although this association was stronger among post-menopausal women (HR, 0.84; 95% CI: 0.74-0.95). Duration of oral contraceptive use and reproductive factors, including age at menarche, age at menopause, type of menopause, ever having an abortion, parity, age at first full-term pregnancy and breastfeeding, were not associated with colorectal cancer risk. CONCLUSION: Our findings provide limited support for a potential inverse association between oral contraceptives and colorectal cancer risk. British Journal of Cancer (2010) 103, 1755-1759. doi:10.1038/sj.bjc.6605965 www.bjcancer.com Published online 2 November 2010 (C) 2010 Cancer Research UK
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| 5. |
- Borgquist, S., et al.
(author)
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Statins : a role in breast cancer therapy?
- 2018
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In: Journal of Internal Medicine. - : Wiley. - 0954-6820. ; 284:4, s. 346-357
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Research review (peer-reviewed)abstract
- Statin drugs have been used for more than two decades to treat hypercholesterolemia and as cardio-preventive drugs, resulting in a marked decrease in cardiovascular morbidity and mortality worldwide. Statins halt hepatic cholesterol biosynthesis by inhibiting the rate-limiting enzyme in the mevalonate pathway, hydroxymethylglutaryl-coenzyme A reductase (HMGCR). The mevalonate pathway regulates a host of biochemical processes in addition to cholesterol production. Attenuation of these pathways is likely responsible for the myriad benefits of statin therapy beyond cholesterol reduction – the so-called pleiotropic effects of statins. Chief amongst these purported effects is anti-cancer activity. A considerable body of preclinical, epidemiologic and clinical evidence shows that statins impair proliferation of breast cancer cells and reduce the risk of breast cancer recurrence. Potential mechanisms for this effect have been explored in laboratory models, but remain poorly understood and require further investigation. The number of clinical trials assessing the putative clinical benefit of statins in breast cancer is increasing. Currently, a total of 30 breast cancer/statin trials are listed at the global trial identifier website clinicaltrials.gov. Given the compelling evidence from performed trials in a variety of clinical settings, there have been calls for a clinical trial of statins in the adjuvant breast cancer setting. It would be imperative for such a trial to incorporate tumour biomarkers predictive of statin response in its design and analysis plan. Ongoing translational clinical trials aimed at biomarker discovery will help identify, which breast cancer patients are most likely to benefit from adjuvant statin therapy, and will add valuable clinical knowledge to the field.
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| 6. |
- He, W., et al.
(author)
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CYP2D6 genotype predicts tamoxifen discontinuation and drug response : a secondary analysis of the KARISMA trial
- 2021
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In: Annals of Oncology. - : Elsevier BV. - 0923-7534. ; 32:10, s. 1286-1293
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Journal article (peer-reviewed)abstract
- Background: Guidelines regarding whether tamoxifen should be prescribed based on women's cytochrome P450 2D6 (CYP2D6) genotypes are conflicting and have caused confusion. This study aims to investigate if CYP2D6 metabolizer status isa associated with tamoxifen-related endocrine symptoms, tamoxifen discontinuation, and mammographic density change. Patients and methods: We used data from 1440 healthy women who participated the KARISMA dose determination trial. Endocrine symptoms were measured using a modified Functional Assessment of Cancer Therapy – Endocrine Symptoms (FACT-ES) questionnaire. Change in mammographic density was measured and used as a proxy for tamoxifen response. Participants were genotyped and categorized as poor, intermediate, normal, or ultrarapid CYP2D6 metabolizers. Results: The median endoxifen level per mg oral tamoxifen among poor, intermediate, normal and ultrarapid CYP2D6 metabolizers were 0.18 ng/ml, 0.38 ng/ml, 0.56 ng/ml and 0.67 ng/ml, respectively. Ultrarapid CYP2D6 metabolizers were more likely than other groups to report a clinically relevant change in cold sweats, hot flash, mood swings, being irritable, as well as the overall modified FACT-ES score, after taking tamoxifen. The 6-month tamoxifen discontinuation rates among poor, intermediate, normal, and ultrarapid CYP2D6 metabolizers were 25.7%, 23.6%, 28.6%, and 44.4%, respectively. Among those who continued and finished the 6-month tamoxifen intervention, the mean change in dense area among poor, intermediate, normal, and ultrarapid CYP2D6 metabolizers were −0.8 cm2, −4.5 cm2, −4.1 cm2, and −8.0 cm2 respectively. Conclusions: Poor CYP2D6 metabolizers are likely to experience an impaired response to tamoxifen, measured through mammographic density reduction. In contrast, ultrarapid CYP2D6 metabolizers are at risk for exaggerated response with pronounced adverse effects that may lead to treatment discontinuation.
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| 7. |
- Michaud, Dominique S., et al.
(author)
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Anthropometric Measures, Physical Activity, and Risk of Glioma and Meningioma in a Large Prospective Cohort Study
- 2011
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In: Cancer Prevention Research. - Philadelphia, PA : American Association for Cancer Research, Inc.. - 1940-6207 .- 1940-6215. ; 4:9, s. 1385-1392
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Journal article (peer-reviewed)abstract
- Body fatness has been associated with increased risk of a number of hormone-dependent cancers. Recent studies suggest that body mass index (BMI) may be related to meningiomas, which are more common in women than men, and for which estrogens are believed to play a role. Using data from a large European propective cohort, 203 incident cases of meningioma and 340 cases of glioma were included in the analysis for measures of body fat, height, and physical activity among 380,775 participants. All analyses were conducted using Cox proportional hazards model and controlling for age, sex, country, and education. A 71% increase in risk of meningioma was observed among men and women in the top quartile of waist circumference (HR = 1.71, 95% CI = 1.08-2.73, P-trend = 0.01). A positive association was also observed for BMI and meningioma (HR = 1.48, 95% CI = 0.98-2.23, for BMI >= 30 compared with a BMI of 20-24.9, P-trend = 0.05). An association with height and meningioma was also suggestive (HR = 1.24, 95% 0.96-1.51, for each 10 cm increase). In contrast, no associations were observed for height and different measures of body fat and risk of glioma. Physical activity was not related to either type of brain tumors. Results from this study support an increase in risk of meningioma with higher body fatness among both men and women. No association was observed between anthropometric measures and risk of glioma. Cancer Prev Res; 4(9); 1385-92. (C) 2011 AACR.
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| 8. |
- Nielsen, Torsten O, et al.
(author)
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Abstract P2-03-01: Analytical validation of a standardized scoring protocol for Ki67 assessed on breast excision whole sections: An international multicenter collaboration
- 2018
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In: Cancer research. Supplement. - 1538-7445. ; 78:4
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Conference paper (peer-reviewed)abstract
- Aims: (i) Determine whether between-observer reproducibility for Ki67 when assessed on whole sections according to a standardized scoring protocol is adequate for clinical application. (ii) Compare between-observer reproducibility of Ki67 scores assessed on hot-spots to scores using a global method that averages across a tissue section.Background: The nuclear proliferation biomarker Ki67 has multiple potential roles in breast cancer, including aiding decisions based on prognosis, but unacceptable levels of between-laboratory variability have been observed. The International Ki67 in Breast Cancer Working Group has undertaken a systematic program to determine whether Ki67 measurement can be analytically validated and standardized across labs. In phase 1, variability in visual interpretation was identified as an important source of variability. Phases 2 and 3a showed that adherence to defined scoring methods substantially improved reproducibility in scoring tissue microarrays and core-cut biopsies. We now assess whether acceptable reproducibility can be achieved on whole sections.Methods: Adjacent sections from 30 primary ER+ breast cancers were centrally stained for Ki67 to assemble 4 sets of 30 stained tumor sections, circulated around 23 labs in 12 countries. Ki67 was scored by 2 methods by all labs: (a) global: 4 fields of 100 tumor cells each were selected to reflect observed heterogeneity in nuclear staining (b) hot-spot: the field with highest Ki67 percentage of tumor cells with nuclear staining was selected and up to 500 cells scored. Ki67 scores were log2-transformed for statistical analyses and back-transformed for presentation. The primary objective was to assess whether either method could achieve an intraclass correlation coefficient (ICC) significantly greater than 0.8, considered substantial to almost-perfect reproducibility. Secondary objectives were to assess which method had highest observed ICC and to assess whether observers identified the same “hot-spots”.Results: ICC for the global method was 0.87 (95%CI: 0.799-0.93), marginally meeting the prespecified success criterion. The ICC for the hot-spot method was 0.83 (95%CI: 0.74-0.90) and had a CI extending below the success criterion. Across the 23 labs, geometric mean value of the 30 scores ranged from 8.5 to 19.6 for the global method and from 12.8 to 30.3 for the hot-spot method. The overall mean (95% CI) of these values was 12.9 (11.9-14.0) and 20.9 (19.1-22.8), respectively. Visually, between-laboratory agreement in location of selected hot-spot varies between cases. The median times for scoring were 9 and 6 minutes for global and hot-spot methods respectively.Conclusions: The global method marginally met the prespecified criterion of success; it should now be evaluated for clinical validity in appropriate cohorts of cases. The hot-spot method was observed to have slightly less reproducibility between labs. The time taken for scoring by either method is practical using counting software we are making publicly available. Establishment of external quality assessment schemes is likely to improve the reproducibility between labs further
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| 9. |
- Polley, Mei-Yin C, et al.
(author)
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An international study to increase concordance in Ki67 scoring.
- 2015
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In: Modern Pathology. - : Elsevier BV. - 1530-0285 .- 0893-3952. ; 28:6, s. 778-786
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Journal article (peer-reviewed)abstract
- Although an important biomarker in breast cancer, Ki67 lacks scoring standardization, which has limited its clinical use. Our previous study found variability when laboratories used their own scoring methods on centrally stained tissue microarray slides. In this current study, 16 laboratories from eight countries calibrated to a specific Ki67 scoring method and then scored 50 centrally MIB-1 stained tissue microarray cases. Simple instructions prescribed scoring pattern and staining thresholds for determination of the percentage of stained tumor cells. To calibrate, laboratories scored 18 'training' and 'test' web-based images. Software tracked object selection and scoring. Success for the calibration was prespecified as Root Mean Square Error of scores compared with reference <0.6 and Maximum Absolute Deviation from reference <1.0 (log2-transformed data). Prespecified success criteria for tissue microarray scoring required intraclass correlation significantly >0.70 but aiming for observed intraclass correlation ≥0.90. Laboratory performance showed non-significant but promising trends of improvement through the calibration exercise (mean Root Mean Square Error decreased from 0.6 to 0.4, Maximum Absolute Deviation from 1.6 to 0.9; paired t-test: P=0.07 for Root Mean Square Error, 0.06 for Maximum Absolute Deviation). For tissue microarray scoring, the intraclass correlation estimate was 0.94 (95% credible interval: 0.90-0.97), markedly and significantly >0.70, the prespecified minimum target for success. Some discrepancies persisted, including around clinically relevant cutoffs. After calibrating to a common scoring method via a web-based tool, laboratories can achieve high inter-laboratory reproducibility in Ki67 scoring on centrally stained tissue microarray slides. Although these data are potentially encouraging, suggesting that it may be possible to standardize scoring of Ki67 among pathology laboratories, clinically important discrepancies persist. Before this biomarker could be recommended for clinical use, future research will need to extend this approach to biopsies and whole sections, account for staining variability, and link to outcomes.Modern Pathology advance online publication, 20 February 2015; doi:10.1038/modpathol.2015.38.
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