An investigation of the apparent breast cancer epidemic in France: screening and incidence trends in birth cohorts

<p>Abstract</p> <p>Background</p> <p>Official descriptive data from France showed a strong increase in breast-cancer incidence between 1980 to 2005 without a corresponding change in breast-cancer mortality. This study quantifies the part of incidence increase due to secular changes in risk factor exposure and in overdiagnosis due to organised or opportunistic screening. Overdiagnosis was defined as non progressive tumours diagnosed as cancer at histology or progressive cancer that would remain asymptomatic until time of death for another cause.</p> <p>Methods</p> <p>Comparison between age-matched cohorts from 1980 to 2005. All women residing in France and born 1911-1915, 1926-1930 and 1941-1945 are included. Sources are official data sets and published French reports on screening by mammography, age and time specific breast-cancer incidence and mortality, hormone replacement therapy, alcohol and obesity. Outcome measures include breast-cancer incidence differences adjusted for changes in risk factor distributions between pairs of age-matched cohorts who had experienced different levels of screening intensity.</p> <p>Results</p> <p>There was an 8-fold increase in the number of mammography machines operating in France between 1980 and 2000. Opportunistic and organised screening increased over time. In comparison to age-matched cohorts born 15 years earlier, recent cohorts had adjusted incidence proportion over 11 years that were 76% higher [95% confidence limits (CL) 67%, 85%] for women aged 50 to 64 years and 23% higher [95% CL 15%, 31%] for women aged 65 to 79 years. Given that mortality did not change correspondingly, this increase in adjusted 11 year incidence proportion was considered as an estimate of overdiagnosis.</p> <p>Conclusions</p> <p>Breast cancer may be overdiagnosed because screening increases diagnosis of slowly progressing non-life threatening cancer and increases misdiagnosis among women without progressive cancer. We suggest that these effects could largely explain the reported "epidemic" of breast cancer in France. Better predictive classification of tumours is needed in order to avoid unnecessary cancer diagnoses and subsequent procedures.</p

Themis2/ICB1 Is a Signaling Scaffold That Selectively Regulates Macrophage Toll-Like Receptor Signaling and Cytokine Production

BACKGROUND: Thymocyte expressed molecule involved in selection 1 (Themis1, SwissProt accession number Q8BGW0) is the recently characterised founder member of a novel family of proteins. A second member of this family, Themis2 (Q91YX0), also known as ICB1 (Induced on contact with basement membrane 1), remains unreported at the protein level despite microarray and EST databases reporting Themis2 mRNA expression in B cells and macrophages. METHODOLOGY/PRINCIPAL FINDINGS: Here we characterise Themis2 protein for the first time and show that it acts as a macrophage signalling scaffold, exerting a receptor-, mediator- and signalling pathway-specific effect on TLR responses in RAW 264.7 macrophages. Themis2 over-expression enhanced the LPS-induced production of TNF but not IL-6 or Cox-2, nor TNF production induced by ligands for TLR2 (PAM3) or TLR3 (poly IratioC). Moreover, LPS-induced activation of the MAP kinases ERK and p38 was enhanced in cells over-expressing Themis2 whereas the activation of JNK, IRF3 or NF-kappaB p65, was unaffected. Depletion of Themis2 protein by RNA inteference inhibited LPS-induced TNF production in primary human macrophages demonstrating a requirement for Themis2 in this event. Themis2 was inducibly tyrosine phosphorylated upon LPS challenge and interacted with Lyn kinase (P25911), the Rho guanine nucleotide exchange factor, Vav (P27870), and the adaptor protein Grb2 (Q60631). Mutation of either tyrosine 660 or a proline-rich sequence (PPPRPPK) simultaneously interrupted this complex and reduced by approximately 50% the capacity of Themis2 to promote LPS-induced TNF production. Finally, Themis2 protein expression was induced during macrophage development from murine bone marrow precursors and was regulated by inflammatory stimuli both in vitro and in vivo. CONCLUSIONS/SIGNIFICANCE: We hypothesise that Themis2 may constitute a novel, physiological control point in macrophage inflammatory responses

Ventriculoperitoneal Shunting After Aneurysmal Subarachnoid Hemorrhage: Analysis of the Indications Complications and Outcome With a Focus on Patients With Borderline Ventriculomegaly

OBJECTIVE: The goals of this study were to investigate the risk factors, indications, complications, and outcome for patients with ventriculoperitoneal shunts (VPSs) after subarachnoid hemorrhage and to define a subgroup eligible for future prospective studies designed to clarify indications for placement of a VPS. METHODS: Clinical characteristics of 236 prospectively evaluated patients with subarachnoid hemorrhage and 6 months of follow-up were analyzed. Hydrocephalus was estimated by the relative bicaudate index (RBCI) measured on computed tomographic scans at the time of shunting. Patients were divided into three groups by ventricle size: Group 1 included 121 patients with small ventricles (RBCI \u3c1.0), Group 2 included 88 patients with borderline ventricle size (RBCI 1.0-1.4), and Group 3 included 27 patients with markedly enlarged ventricles (RBCI \u3e1.4). RESULTS: Initially, 86 patients (36%) underwent ventriculoperitoneal shunting: 19 in Group 1 (16%), 43 in Group 2 (49%), and 24 in Group 3 (90%). Indications for placement of a VPS, risk factors, and outcome differed markedly by group. Four patients (3% of those not initially shunted) developed delayed hydrocephalus requiring a VPS, including one in Group 2 (2%). The 6-month shunt complication rate was 13%. Evaluation of patients in Group 2 indicated that functional status was an important factor in selecting candidates for shunting, and that patients receiving shunts and shunt-free patients demonstrated improvement in functional status during follow-up. CONCLUSION: Although we currently use a proactive shunting paradigm for posthemorrhagic hydrocephalus, this report demonstrates that a conservative approach to patients with borderline ventricle size (i.e., RBCI of 1.0-1.4) and normal intracranial pressure should be evaluated in a prospective randomized trial. Copyright © by the Congress of Neurological Surgeons

Low-Dose Versus Standard Warfarin After Mechanical Mitral Valve Replacement: A Randomized Controlled Trial.

Background: Current guidelines recommend a target international normalized ratio (INR) range of 2.5 to 3.5 in patients with a mechanical mitral prosthesis. The Prospective Randomized On-X Anticoagulation Clinical Trial (PROACT) Mitral randomized controlled trial assessed the safety and efficacy of warfarin at doses lower than currently recommended, in patients with an On-X mechanical mitral valve. Methods: After On-X mechanical mitral valve replacement followed by at least 3 months of standard anticoagulation, 401 patients at 44 North American centers were randomized to low-dose warfarin (target INR 2.0 to 2.5) or standard-dose warfarin (target INR 2.5 to 3.5). All patients were prescribed aspirin 81 mg daily and encouraged to use home INR testing. The primary endpoint was the sum of the linearized rates of thromboembolism, valve thrombosis, and bleeding events. Secondary endpoints included death, valve-related events, New York Heart Association classification, and valve hemodynamics. Results: Mean patient follow-up was 4.1 years. Mean INR was 2.47 and 2.92 (P \u3c.001) in the low-dose and standard-dose warfarin groups, respectively. Primary endpoint rates were 11.9%/patient-year in the low-dose group and 12.0%/patient-year in the standard-dose group (P = .97). The -0.07% difference (95% confidence interval: -0.07, -0.06) was noninferior (\u3c1.5% margin). Individual rates (expressed as %/patient-year) of thromboembolism (2.3% vs 2.5%), valve thrombosis (0.5% vs 0.5%), and major bleeding (4.9% vs 4.3%) were also similar and noninferior. Conclusions: Low-dose warfarin was noninferior to standard-dose warfarin in patients with an On-X mechanical mitral prosthesis, following \u3e3 postoperative months of standard anticoagulation therapy. (PROACT Clinicaltrials.gov number, NCT00291525)

Low-Dose vs Standard Warfarin After Mechanical Mitral Valve Replacement: A Randomized Trial.

BACKGROUND: Current guidelines recommend a target international normalized ratio (INR) range of 2.5 to 3.5 in patients with a mechanical mitral prosthesis. The Prospective Randomized On-X Anticoagulation Clinical Trial (PROACT) Mitral randomized controlled noninferiority trial assessed safety and efficacy of warfarin at doses lower than currently recommended in patients with an On-X (Artivion, Inc) mechanical mitral valve. METHODS: After On-X mechanical mitral valve replacement, followed by at least 3 months of standard anticoagulation, 401 patients at 44 North American centers were randomized to low-dose warfarin (target INR, 2.0-2.5) or standard-dose warfarin (target INR, 2.5-3.5). All patients were prescribed aspirin, 81 mg daily, and encouraged to use home INR testing. The primary end point was the sum of the linearized rates of thromboembolism, valve thrombosis, and bleeding events. The design was based on an expected 7.3% event rate and 1.5% noninferiority margin. RESULTS: Mean patient follow-up was 4.1 years. Mean INR was 2.47 and 2.92 (P1.5%, thus noninferiority was not achieved. Rates (percentage per patient-year) of the individual components of the primary end point were 2.3% vs 2.5% for thromboembolism, 0.5% vs 0.5% for valve thrombosis, and 9.13% vs 9.04% for bleeding. CONCLUSIONS: Compared with standard-dose warfarin, low-dose warfarin did not achieve noninferiority for the composite primary end point. (PROACT Clinicaltrials.gov number, NCT00291525)