The European Defense Community

In 1915 it was a common belief that World War II had just been fought to successful completion. The German and Japanese Empires were vanquished, with Germany destroyed more thoroughly than any of the co un tries she had occupied. The two large remaining powers, the United States and the Soviet Union, seemed to be working together for the common good of the whole world. They had even agreed to participate in the United Nations Organization, which, as a matter of fact, they had been prominently associated with since the earliest negotiations. Now universal peace, and maybe the Millennium, would be the order of the day. But Europe was utterly exhausted, her population decimated, and her industries destroyed. The states men of Western Europe set themselves up to rebuild their countries, both physically and morally. Generously, the United States furnished money and supplies to start the reconstruction. U.N.R.R.A., loan s, and Marshal aid were designed to accomplish this task. On the political front the collaborators, Nazis and Quislings drew long prison sentences, and faced the firing squad. The hangman\u27s noose was used extensively in the liberated Eastern Europe, which the Soviet Armies were occupying, or where Soviet troops were maintained to guard communication lines to Germany and Austria

Cluster Analysis Identifies Distinct Pathogenetic Patterns in C3 Glomerulopathies/Immune Complex-Mediated Membranoproliferative GN

Membranoproliferative GN (MPGN) was recently reclassified as alternative pathway complement-mediated C3 glomerulopathy (C3G) and immune complex-mediated membranoproliferative GN (IC-MPGN). However, genetic and acquired alternative pathway abnormalities are also observed in IC-MPGN. Here, we explored the presence of distinct disease entities characterized by specific pathophysiologic mechanisms. We performed unsupervised hierarchical clustering, a data-driven statistical approach, on histologic, genetic, and clinical data and data regarding serum/plasma complement parameters from 173 patients with C3G/IC-MPGN. This approach divided patients into four clusters, indicating the existence of four different pathogenetic patterns. Specifically, this analysis separated patients with fluid-phase complement activation (clusters 1-3) who had low serum C3 levels and a high prevalence of genetic and acquired alternative pathway abnormalities from patients with solid-phase complement activation (cluster 4) who had normal or mildly altered serum C3, late disease onset, and poor renal survival. In patients with fluid-phase complement activation, those in clusters 1 and 2 had massive activation of the alternative pathway, including activation of the terminal pathway, and the highest prevalence of subendothelial deposits, but those in cluster 2 had additional activation of the classic pathway and the highest prevalence of nephrotic syndrome at disease onset. Patients in cluster 3 had prevalent activation of C3 convertase and highly electron-dense intramembranous deposits. In addition, we provide a simple algorithm to assign patients with C3G/IC-MPGN to specific clusters. These distinct clusters may facilitate clarification of disease etiology, improve risk assessment for ESRD, and pave the way for personalized treatment

Breast cancer and hormonal contraceptives: Collaborative reanalysis of individual data on 53297 women with breast cancer and 100239 women without breast cancer from 54 epidemiological studies

Background The Collaborative Group on Hormonal Factors in Breast Cancer has brought together and reanalysed the worldwide epidemiological evidence on the relation between breast cancer risk and use of hormonal contraceptives. Methods Individual data on 53297 women with breast cancer and 100 239 women without breast cancer from 54 studies conducted in 25 countries were collected, checked, and analysed centrally. Estimates of the relative risk for breast cancer were obtained by a modification of the Mantel-Haenszel method. All analyses were stratified by study, age at diagnosis, parity, and, where appropriate, the age a woman was when her first child was born, and the age she was when her risk of conception ceased. Findings The results provide strong evidence for two main conclusions. First, while women are taking combined oral contraceptives and in the 10 years after stopping there is a small increase in the relative risk of having breast cancer diagnosed (relative risk [95% CI] in current users 1.24 [1.15-1.33], 2p<0.00001; 1-4 years after stopping 1.16 [1.08-1.23], 2p=0.00001; 5-9 years after stopping 1.07 [1.02-1.13], 2p=0.009). Second, there is no significant excess risk of having breast cancer diagnosed 10 or more years after stopping use (relative risk 1.01 [0.96-1.05], NS). The cancers diagnosed in women who had used combined oral contraceptives were less advanced clinically than those diagnosed in women who had never used these contraceptives: for ever-users compared with never-users, the relative risk for tumours that had spread beyond the breast compared with localised tumours was 0.88 (0.81-0.95; 2p=0.002). There was no pronounced variation in the results for recency of use between women with different background risks of breast cancer, including women from different countries and ethnic groups, women with different reproductive histories, and those with or without a family history of breast cancer. The studies included in this collaboration represent about 90% of the epidemiological information on the topic, and what is known about the other studies suggests that their omission has not materially affected the main conclusions. Other features of hormonal contraceptive use such as duration of use, age at first use, and the dose and type of hormone within the contraceptives had little additional effect on breast cancer risk, once recency of use had been taken into account. Women who began use before age 20 had higher relative risks of having breast cancer diagnosed while they were using combined oral contraceptives and in the 5 years after stopping than women who began use at older ages, but the higher relative risks apply at ages when breast cancer is rare and, for a given duration of use, earlier use does not result in more cancers being diagnosed than use beginning at older ages. Because breast cancer incidence rises steeply with age, the estimated excess number of cancers diagnosed in the period between starting use and 10 years after stopping increases with age at last use: for example, among 10 000 women from Europe or North America who used oral contraceptives from age 16 to 19, from age 20 to 24, and from age 25 to 29, respectively, the estimated excess number of cancers diagnosed up to 10 years after stopping use is 0.5 (95% CI 0.3-0.7), 1.5 (0.7-2.3), and 4.7 (2.7-6.7). Up to 20 years after cessation of use the difference between ever-users and never-users is not so much in the total number of cancers diagnosed, but in their clinical presentation, with the breast cancers diagnosed in ever-users being less advanced clinically than those diagnosed in never-users. The relation observed between breast cancer risk and hormone exposure is unusual, and it is not possible to infer from these data whether it is due to an earlier diagnosis of breast cancer in ever-users, the biological effects of hormonal contraceptives, or a combination of reasons. Interpretation Women who are currently using combined oral contraceptives or have used them in the past 10 years are at a slightly increased risk of having breast cancer diagnosed, although the additional cancers diagnosed tend to be localised to the breast. There is no evidence of an increase in the risk of having breast cancer diagnosed 10 or more years after cessation of use, and the cancers diagnosed then are less advanced clinically than the cancers diagnosed in never-users. RI Ranstam, Jonas/A-4386-2009; Colditz, Graham/A-3963-200

Breast cancer and hormonal contraceptives: Collaborative reanalysis of individual data on 53297 women with breast cancer and 100239 women without breast cancer from 54 epidemiological studies

Background: The Collaborative Group on Hormonal Factors in Breast Cancer has brought together and reanalysed the worldwide epidemiological evidence on the relation between breast cancer risk and use of hormonal contraceptives. Methods: Individual data on 53 297 women with breast cancer and 100 239 women without breast cancer from 54 studies conducted in 25 countries were collected, checked, and analysed centrally. Estimates of the relative risk for breast cancer were obtained by a modification of the Mantel-Haenszel method. All analyses were stratified by study, age at diagnosis, parity, and, where appropriate, the age a woman was when her first child was born, and the age she was when her risk of conception ceased. Findings: The results provide strong evidence for two main conclusions. First, while women are taking combined oral contraceptives and in the 10 years after stopping there is a small increase in the relative risk of having breast cancer diagnosed (relative risk [95% Cl] in current users 1·24 [1·15-1·33], 2p&lt;0·00001; 1-4 years after stopping 1·6 [1·08-1·23], 2p=0·00001; 5-9 years after stopping 1·07 [1·02-1·13], 2p=0·009). Second, there is no significant excess risk of having breast cancer diagnosed 10 or more years after stopping use (relative risk 1·01 [0·96-1·05], NS). The cancers diagnosed in women who had used combined oral contraceptives were less advanced clinically than those diagnosed in women who had never used these contraceptives: for ever-users compared with never-users, the relative risk for tumours that had spread beyond the breast compared with localised tumours was 0·88 (0·81-0·95; 2p=0·002). There was no pronounced variation in the results for recency of use between women with different background risks of breast cancer, including women from different countries and ethnic groups, women with different reproductive histories, and those with or without a family history of breast cancer. The studies included in this collaboration represent about 90% of the epidemiological information on the topic, and what is known about the other studies suggests that their omission has not materially affected the main conclusions. Other features of hormonal contraceptive use such as duration of use, age at first use, and the dose and type of hormone within the contraceptives had little additional effect on breast cancer risk, once recency of use had been taken into account. Women who began use before age 20 had higher relative risks of having breast cancer diagnosed while they were using combined oral contraceptives and in the 5 years after stopping than women who began use at older ages, but the higher relative risks apply at ages when breast cancer is rare and, for a given duration of use, earlier use does not result in more cancers being diagnosed than use beginning at older ages. Because breast cancer incidence rises steeply with age, the estimated excess number of cancers diagnosed in the period between starting use and 10 years after stopping increases with age at last use: for example, among 10 000 women from Europe or North America who used oral contraceptives from age 16 to 19, from age 20 to 24, and from age 25 to 29, respectively, the estimated excess number of cancers diagnosed up to 10 years after stopping use is 0·5 (95% Cl 0·3-0·7), 1·5 (0·7-2·3), and 4·7 (2·7-6·7). Up to 20 years after cessation of use the difference between ever-users and never-users is not so much in the total number of cancers diagnosed, but in their clinical presentation, with the breast cancers diagnosed in ever-users being less advanced clinically than those diagnosed in never-users. The relation observed between breast cancer risk and hormone exposure is unusual, and it is not possible to infer from these data whether it is due to an earlier diagnosis of breast cancer in ever-users, the biological effects of hormonal contraceptives, or a combination of reasons. Interpretation: Women who are currently using combined oral contraceptives or have used them in the past 10 years are at a slightly increased risk of having breast cancer diagnosed, although the additional cancers diagnosed tend to be localised to the breast. There is no evidence of an increase in the risk of having breast cancer diagnosed 10 or more years after cessation of use, and the cancers diagnosed then are less advanced clinically than the cancers diagnosed in never-users

Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53 297 women with breast cancer and 100 239 women without breast cancer from 54 epidemiological studies. Collaborative Group on Hormonal Factors in Breast Cancer

BACKGROUND The Collaborative Group on Hormonal Factors in Breast Cancer has brought together and reanalysed the worldwide epidemiological evidence on the relation between breast cancer risk and use of hormonal contraceptives. METHODS Individual data on 53 297 women with breast cancer and 100 239 women without breast cancer from 54 studies conducted in 25 countries were collected, checked, and analysed centrally. Estimates of the relative risk for breast cancer were obtained by a modification of the Mantel-Haenszel method. All analyses were stratified by study, age at diagnosis, parity, and, where appropriate, the age a woman was when her first child was born, and the age she was when her risk of conception ceased. FINDINGS The results provide strong evidence for two main conclusions. First, while women are taking combined oral contraceptives and in the 10 years after stopping there is a small increase in the relative risk of having breast cancer diagnosed (relative risk [95 percent CI] in current users 1.24 [1.15-1.33], 2p<0.00001; 1-4 years after stopping 1.16 [1.08-1.23], 2p=0.00001; 5-9 years after stopping 1.07 [1.02-1.13], 2p=0.009). Second, there is no significant excess risk of having breast cancer diagnosed 10 or more years after stopping use (relative risk 1.01 [0.96-1.05], NS). The cancers diagnosed in women who had used combined oral contraceptives were less advanced clinically than those diagnosed in women who had never used these contraceptives for ever-users compared with never-users, the relative risk for tumours that had spread beyond the breast compared with localised tumours was 0.88 (0.81-0.95; 2p=0.002). There was no pronounced variation in the results for recency of use between women with different background risks of breast cancer, including women from different countries and ethnic groups, women with different reproductive histories, and those with or without a family history of breast cancer. The studies included in this collaboration represent about 90 percent of the epidemiological information on the topic, and what is known about the other studies suggests that their omission has not materially affected the main conclusions. Other features of hormonal contraceptive use such as duration of use, age at first use, and the dose and type of hormone within the contraceptives had little additional effect on breast cancer risk, once recency of use had been taken into account. Women who began use before age 20 had higher relative risks of having breast cancer diagnosed while they were using combined oral contraceptives and in the 5 years after stopping than women who began use at older ages, but the higher relative risks apply at ages when breast cancer is rare and, for a given duration of use, earlier use does not result in more cancers being diagnosed than use beginning at older ages. Because breast cancer incidence rises steeply with age, the estimated excess number of cancers diagnosed in the period between starting use and 10 years after stopping increases with age at last use: for example, among 10 000 women from Europe or North America who used oral contraceptives from age 16 to 19, from age 20 to 24, and from age 25 to 29, respectively, the estimated excess number of cancers diagnosed up to 10 years after stopping use is 0.5 (95 percent CI 0.3-0.7), 1.5 (0.7-2.3), and 4.7 (2.7-6.7). Up to 20 years after cessation of use the difference between ever-users and never-users is not so much in the total number of cancers diagnosed, but in their clinical presentation, with the breast cancers diagnosed in ever-users being less advanced clinically than those diagnosed in never-users. The relation observed between breast cancer risk and hormone exposure is unusual, and it is not possible to infer from these data whether it is due to an earlier diagnosis of breast cancer in ever-users, the biological effects of hormonal contraceptives, or a combination of reasons..