Prescreening Period Research Articles

The incidence of fatal breast cancer measures the increased effectiveness of therapy in women participating in mammography screening.

BackgroundWomen and their health care providers need a reliable answer to this important question: If a woman chooses to participate in regular mammography screening, then how much will this choice improve her chances of avoiding a death from breast cancer compared with women who choose not to participate?MethodsTo answer this question, we used comprehensive registries for population, screening history, breast cancer incidence, and disease‐specific death data in a defined population in Dalarna County, Sweden. The annual incidence of breast cancer was calculated along with the annual incidence of breast cancers that were fatal within 10 and within 11 to 20 years of diagnosis among women aged 40 to 69 years who either did or did not participate in mammography screening during a 39‐year period (1977‐2015). For an additional comparison, corresponding data are presented from 19 years of the prescreening period (1958‐1976). All patients received stage‐specific therapy according to the latest national guidelines, irrespective of the mode of detection.ResultsThe benefit for women who chose to participate in an organized breast cancer screening program was a 60% lower risk of dying from breast cancer within 10 years after diagnosis (relative risk, 0.40; 95% confidence interval, 0.34‐0.48) and a 47% lower risk of dying from breast cancer within 20 years after diagnosis (relative risk, 0.53; 95% confidence interval, 0.44‐0.63) compared with the corresponding risks for nonparticipants.ConclusionsAlthough all patients with breast cancer stand to benefit from advances in breast cancer therapy, the current results demonstrate that women who have participated in mammography screening obtain a significantly greater benefit from the therapy available at the time of diagnosis than do those who have not participated.

Participation in Mammography Screening Accomplishes an Enduring and Significant Reduction in Breast Cancer Mortality in the Era of Modern Therapy: An Observational Study Spanning 52 Years

Background: A significant decrease in breast cancer mortality has been demonstrated in populations invited to mammography screening. There have been questions regarding the value of mammography in the era of modern therapies, and the relative contribution of mammography screening and modern therapy on mortality reduction. Aim: We have sought to clarify the extent to which early detection through mammography screening contributes to the reduction of breast cancer death in the era of modern adjuvant therapies. We address this question by studying five decades of continuous data from a stable population spanning the pre- and postscreening and adjuvant therapy periods. Methods: We analyzed changes in breast cancer mortality in a stable population in Dalarna County, Sweden, among women aged 40-69 years during the 52 years from 1964 through 2015. Mortality data were obtained from the National Cause of Death Register in Sweden, and incidence data from the Swedish National Cancer Registry. Crude and incidence-based mortality rates were compared among four successive 13-year periods: the prescreening period from 1964 through 1976, the Swedish Two-County randomized screening trial period from 1977 through 1989, and two service screening periods from 1990-2002 and from 2003-2015. Furthermore, we measured the effect of early detection upon breast cancer mortality in women exposed to mammography screening by comparison with breast cancer death in women not exposed to mammography screening, within these three screening periods. Data were analyzed by Poisson regression, with corrections for lead time and self-selection bias. Results: There were 5844 incident cases and 1425 breast cancer deaths during the 52 years of observation. The relative breast cancer mortality rates associated with exposure to screening, adjusted for self-selection bias, were 0.46 (95% CI 0.30-0.69) in the trial period (1977-1989), 0.44 (95% CI 0.30-0.65) in the 1990-2002 period, and 0.37 (95% CI 0.24-0.56) in the 2003-2015 period. The significant reductions in incidence-based breast cancer mortality associated with exposure to screening were independent of contemporaneous changes in therapy. Conclusion: The combination of early detection of breast cancer through mammography screening and the resultant earlier treatment has significantly reduced breast cancer mortality in Dalarna County in the women exposed to screening, compared with the women not participating in screening, by a factor of 2.2 in the screening trial period, increasing to a factor of 2.7 in the most recent service screening period. These mortality benefits can be attributed to the far greater effectiveness of modern therapeutic methods upon cancers detected at screening compared with the poorer effectiveness of the same therapeutic methods in women not participating in screening.

Impact of breast cancer screening in a population with high spontaneous coverage with mammography.

The impact of organized screening programs on breast cancer (BC) mortality is unclear in an era of high spontaneous referral of women to mammography. The aim of this study was to analyze if the introduction of mammographic screening programs reduced BC mortality in the Veneto region, Italy, despite already widespread spontaneous access to mammography. In Veneto, screening was introduced in different years between 1999 and 2009 across 21 local health units (LHUs), inviting asymptomatic women aged 50-69 years to undergo mammography biennially. We compared BC mortality for the 1995-2014 period of women aged 40-49 and 50-74 years who were resident in LHUs where screening programs started in 2003 (early LHUs) with women resident in LHUs where screening was introduced later (late LHUs). Poisson regression models were applied to incidence-based mortality (IBM), including only deaths from BC arising within the screening period. In the prescreening period and until 2010, BC mortality rates in early and late LHUs were similar in both age groups. In the last study period (2010-2014), we observed a 10% decrease in overall BC mortality in early compared to late LHU, limited to women aged 50-74 years. IBM was reduced by 8% (95% CI 1%-16%) in the overall study period and by 16% (6%-25%) in 2010-2014. In the Veneto region, screening programs were associated with a significant impact on BC-specific mortality; such effect appeared at least 8 years after screening implementation.

Effect of organized mammography screening on breast cancer mortality: a population-based cohort study in Norway

Background Reviews of the randomized controlled trials (RCTs) of mammography screening conducted during the 1970s and 1980s reported a 15–21% reduction in breast cancer mortality. Improved cancer treatment and enhanced awareness may however have reduced the potential net benefit from mammography screening. New RCTs are no longer feasible and observational studies yield widely varying estimates of the reduced breast cancer mortality (0% to 43%), depending on study design. In Norway, mammography screening was introduced gradually during the period 1996–2004. Using this as a natural experiment, we aimed to estimate the effect of organized mammography screening on incidence-based breast cancer mortality by comparing changes in mortality among women eligible for screening to concurrent changes in younger and older ineligible women. The use of un-screened age-groups as control groups allowed us to conduct a balanced incidence-based mortality study in which we aimed to distinguish the screening effect on breast cancer mortality from the effect of the concomitantly established diagnostic centers, which may also have improved treatment. Methods In a national county-wise balanced, open-cohort study in Norway, we used birth cohorts (1896–1982) to construct three age groups in both the historical and screening period: women eligible for screening and younger or older women ineligible for screening. We included women diagnosed with breast cancer who died within the same age-period group during 1987–2010 (n = 4903). We estimated relative incidence-based mortality rate ratios (relative MRR) comparing temporal changes in eligible women to concurrent changes in ineligible women. Additionally, we conducted analyses comparing the change in eligible women to younger, ineligible women with either continued accrual and follow-up period (eligible women only) or continued follow-up period. Finally, we checked for unadjusted confounding in two negative control analyses expected to produce a null result (relative MRR = 1). First, we compared the mortality change in younger women to the concurrent change in older women. Second, we extended the study period to include the period 1987–2010 for all counties and repeated our analysis as if screening had been introduced at the midpoint of the actual pre-screening period and the actual screening period in each county, respectively. Results All three age groups experienced a reduction in mortality when screening was introduced, but the decrease among eligible women was about the same among ineligible women (relative MRR = 1.05, 95% CI: [0.94–1.18]). Varying the definition of follow-up yields similar results. The negative control analyses all had relative MRRs close to 1 (estimates ranged from 0.91 to 1.04 and with all 95% CIs overlapping 1). Conclusion Mammography screening was not associated with a larger breast cancer mortality reduction than that of women ineligible for mammography screening. Based on the negative control analyses we found limited uncontrolled confounding in the applied observational design.

Early-onset group B Streptococcus (EOGBS) infection subsequent to cessation of screening-based intrapartum prophylaxis: findings of an observational study in West London, UK

ObjectivesTo describe the impact on early-onset group B Streptococcus (EOGBS) infection rates following reversion from screening-based to risk-based intrapartum antimicrobial prophylaxis (IAP) for prevention.SettingMaternity services provided by secondary healthcare organisation...

Carcinoma in situ of the breast in New South Wales, Australia: Current status and trends over the last 40 year

BackgroundThe incidence of non-invasive breast cancer has increased substantially over time. We aim to describe temporal trends in the incidence of carcinoma in situ of the breast in New South Wales (NSW), Australia. MethodsDescriptive study of trends in the incidence of ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (LCIS) in women who received a diagnosis from 1972 to 2012, recorded in the NSW Cancer Registry. ResultsCarcinoma in situ as a proportion of all breast cancer was 0.4% during the prescreening period 1972 to 1987 and is currently 14.1% (2006 to 2012). Among 10,810 women diagnosed with DCIS, incidence across all ages rose from 0.15 per 100,000 during 1972 to 1983 to 16.81 per 100,000 over 2006 to 2012, representing a 100-fold increase (IRR 113.10; 95% CI 81.94 to 156.08). Among women in the target age group for screening (50–69 years) incidence rose from 0.27 per 100,000 to 51.96 over the same period (IRR 195.50; 95% CI 117.26 to 325.89). DCIS incidence peaks in women aged 60–69 years. DCIS incidence has not stabilized despite screening being well established for over 20 years, and participation rates in the target age range remaining stable. ConclusionsOur findings raise questions about the value of the increasing detection of DCIS and aggressive treatment of these lesions, especially among older women, and support trials of de-escalated treatment.

Outcome of a screening programme for the prevention of neonatal invasive early-onset group B Streptococcus infection in a UK maternity unit: an observational study

BackgroundAgainst a background of failure to prevent neonatal invasive early-onset group B Streptococcus infections (GBS) in our maternity unit using risk-based approach for intrapartum antibiotic prophylaxis, we introduced an antenatal...

Breast Cancer Screening in Denmark: A Cohort Study of Tumor Size and Overdiagnosis.

Effective breast cancer screening should detect early-stage cancer and prevent advanced disease. To assess the association between screening and the size of detected tumors and to estimate overdiagnosis (detection of tumors that would not become clinically relevant). Cohort study. Denmark from 1980 to 2010. Women aged 35 to 84 years. Screening programs offering biennial mammography for women aged 50 to 69 years beginning in different regions at different times. Trends in the incidence of advanced (>20 mm) and nonadvanced (≤20 mm) breast cancer tumors in screened and nonscreened women were measured. Two approaches were used to estimate the amount of overdiagnosis: comparing the incidence of advanced and nonadvanced tumors among women aged 50 to 84 years in screening and nonscreening areas; and comparing the incidence for nonadvanced tumors among women aged 35 to 49, 50 to 69, and 70 to 84 years in screening and nonscreening areas. Screening was not associated with lower incidence of advanced tumors. The incidence of nonadvanced tumors increased in the screening versus prescreening periods (incidence rate ratio, 1.49 [95% CI, 1.43 to 1.54]). The first estimation approach found that 271 invasive breast cancer tumors and 179 ductal carcinoma in situ (DCIS) lesions were overdiagnosed in 2010 (overdiagnosis rate of 24.4% [including DCIS] and 14.7% [excluding DCIS]). The second approach, which accounted for regional differences in women younger than the screening age, found that 711 invasive tumors and 180 cases of DCIS were overdiagnosed in 2010 (overdiagnosis rate of 48.3% [including DCIS] and 38.6% [excluding DCIS]). Regional differences complicate interpretation. Breast cancer screening was not associated with a reduction in the incidence of advanced cancer. It is likely that 1 in every 3 invasive tumors and cases of DCIS diagnosed in women offered screening represent overdiagnosis (incidence increase of 48.3%). None.

Effects of Implementation of Lung Cancer Screening at One Veterans Affairs Medical Center

Lung cancer screening recommendations have been developed, but none are focused on veterans. We report the results of the lung cancer screening program at our Veterans Affairs medical center and compare them with historic results. All veterans between 55 and 74 years who were current smokers or quit within the past 15 years and had at least a 30-pack-year smoking history were invited to receive an annual low-dose chest CT scan beginning in December 2013. Demographics, CT scan results, and pathologic data of screened patients were recorded retrospectively. Overall results during the screening period were compared with results in veterans who received diagnoses from January 2011 to December 2013 (prescreening period). From December 2013 through December 2014 (screening period), 1,832 patients obtained a screening CT scan. Their mean age was 65 years. A lung nodule was present in 439of 1,832 patients (24%). Lung cancer was diagnosed in 55 of 1,832 screened patients (3.0%). During the prescreening period, 37%of every lung cancer detected at our center (30of 82) was stage I or stage II. After implementation of the screening program that percentage rose to 60%(52 of 87; P< .01). During the screening period, 55 of the 87 diagnosed lung cancers (63%) were detected through the screening program. The number of lung cancers detected per month rose from 2.4 to 6.7 after implementation of the screening program (P< .01). Implementation of lung cancer screening in the veteran population leads to detection of an increased number and proportion of early-stage lung cancers. Lung cancer screening in veterans may also increase the rate of lung cancer diagnoses in the immediate postimplementation period.

Trends in advanced breast cancer incidence rates after implementation of a mammography screening program in a German population

BackgroundMammography screening programs (MSPs) aim to detect early-stage breast cancers in order to decrease the incidence of advanced-stage breast cancers and to reduce breast cancer mortality. We analyzed the time trends of advanced-stage breast cancer incidence rates in the target population before and after implementation of the MSP in a region of northwestern Germany. MethodsThe MSP in the Münster district started in October 2005. A total of 13,874 women with an incident invasive breast cancer (BC) was identified by the population-based epidemiological cancer registry between 2000 and 2013 in the target group 50–69 years. Multiple imputation methods were used to replace missing data on tumor stages (10.4%). The incidence rates for early-stage (UICC I) and advanced-stage (UICC II+) BC were determined, and Poisson regression analyses were performed to assess trends over time. ResultsThe incidence rates for UICC I breast cancers increased during the step-up introduction of the MSP and remained elevated thereafter. By contrast, after increasing from 2006 to 2008, the incidence rates of UICC II+ breast cancers decreased to levels below the pre-screening period. Significantly decreasing UICC II+ incidence rates were limited to the age group 55–69 years and reached levels that were significantly lower than incidence rates in the pre-screening period. DiscussionThe incidence rates of advanced-stage breast cancers decreased in the age groups from 55 years to the upper age limit for screening eligibility, but not in the adjacent age groups. The findings are consistent with MSP lead time effects and seem to indicate that the MSP lowers advanced-stage breast cancer rates in the target population.

Estimation of overdiagnosis using short-term trends and lead time estimates uncontaminated by overdiagnosed cases: Results from the Norwegian Breast Screening Programme.

BackgroundEstimating overdiagnosis in cancer screening is complicated. Using observational data, estimation of the expected incidence in the screening period and taking account of lead time are two major problems.MethodsUsing data from the Cancer Registry of Norway and the Norwegian Breast Cancer Screening Programme, we estimated incidence trends, using age-specific trends by year in the pre-screening period (1985–95). We also estimated sojourn time and sensitivity using interval cancers only. Thus, lead time estimates were uncontaminated by overdiagnosed cases. Finally, we derived estimates of overdiagnosis separately for all cancers, and for invasive cancers only, correcting for lead time, using two different methods.ResultsOur results indicate that overdiagnosis of all cancers, invasive and in situ, constituted 15–17% of all screen-detected cancers in 1996–2009. For invasive cancers only, the corresponding figures were -2 to 7% in the same period, suggesting that a substantial proportion of the overdiagnosis in the Norwegian Programme was due to ductal carcinoma in situ.ConclusionUsing short-term trends, instead of long, prior to screening was more effective in predicting incidence in the screening epoch. In addition, sojourn time estimation using symptomatic cancers only avoids over-correction for lead time and consequently underestimation of overdiagnosis. Longer follow-up will provide more precise estimates of overdiagnosis.

Extrapolation of pre-screening trends: Impact of assumptions on overdiagnosis estimates by mammographic screening

BackgroundOverdiagnosis by mammographic screening is defined as the excess in breast cancer incidence in the presence of screening compared to the incidence in the absence of screening. The latter is often estimated by extrapolating the pre-screening incidence trend. The aim of this theoretical study is to investigate the impact of assumptions in extrapolating the pre-screening incidence trend of invasive breast cancer on the estimated percentage of overdiagnosis. MethodsWe extracted data on invasive breast cancer incidence and person-years by calendar year (1975⿿2009) and 5-year age groups (0⿿85 years) from Dutch databases. Different combinations of assumptions for extrapolating the pre-screening period were investigated, such as variations in the type of regression model, end of the pre-screening period, screened age range, post-screening age range and adjustment for a trend in women <45. This resulted in 69,120 estimates of the percentage of overdiagnosis, i.e. excess cancer incidence in the presence of screening as a proportion of the number of screen-detected and interval cancers. ResultsMost overdiagnosis percentages are overestimated because of inadequate adjustment for lead time. The overdiagnosis estimates range between ⿿7.1% and 65.1%, with a median of 33.6%. The choice of pre-screening period has the largest influence on the estimated percentage of overdiagnosis: the median estimate is 17.1% for extrapolations using 1975⿿1986 as the pre-screening period and 44.7% for extrapolations using 1975⿿1988 as the pre-screening period. ConclusionThe results of this theoretical study most likely cover the true overdiagnosis estimate, which is unknown, and may not necessarily represent the median overdiagnosis estimate. This study shows that overdiagnosis estimates heavily depend on the assumptions made in extrapolating the incidence in the pre-screening period, especially on the choice of the pre-screening period. These limitations should be acknowledged when adopting this approach to estimate overdiagnosis.

Mammographic screening has failed to improve pathohistological characteristics of breast cancers in Split region of Croatia

The national breast cancer screening program has been introduced in Croatia in the second half of 2006 with mammography as the screening method. We investigated the impact of screening mammography on the basic pathohistological characteristics of breast cancers retrieved from the database of large community hospital. The data were collected in the period following the initiation of national mamographic screening program (2007-2011), and compared with the data collected in the period before the program introduction (2002-2006) to explore the possible changing trends. In the screening period 1,320 breast cancers were diagnosed, while in the prescreening period 1,204 breast cancers were diagnosed (p=0.02). We found the reduction of mean tumor size (p=0.039), decrease of the diagnosed non-invasive cancers (p=0.001), and the higher percentage of the diagnosed ductal (p=0.0003) and grade 3 (p=0.038) invasive cancers in the screening period. We also noticed higher percentage of diagnosed advanced breast cancers with unknown tumor size in the screening period (p=0.027). We concluded that the implementation of national screening program did not improve the pathohistological features of breast cancers in our region probably due to low response rate to screening invitation.

Stage Distribution of Breast Cancer Diagnosed Before and After Implementation of Population-Based Mammographic Screening

The German mammographic screening program is very similar to the Norwegian Breast Cancer Screening Program (NBCSP), which started about 10 years earlier. This study analyzes the stage distribution of invasive breast cancers diagnosed in the pre-screening and screening period, and evaluates the overall mortality in women aged 55-74 in the pilot and non-pilot counties of the NBCSP. The NBCSP invites women aged 50-69 to participate in two-view mammography biennially. Chi-square statistics were used to compare percentages of the stage and treatment of invasive breast cancers diagnosed in women residing in the four pilot counties in the pre-screening (1984-1995) and screening (1996-2007) period. An ecological approach was used to analyze the age-specific mortality in the pilot and non-pilot counties for the period 1970-2007. 50% of the breast cancers diagnosed in the pre-screening period, 70% of the cases detected with screening, 43% of the interval cancers, and 52% of the cancers diagnosed outside the NBCSP were stage I. Stage III+was present in 11% of the cancers in the pre-screening period, and in 1% of the cancers detected with screening. In the screening period, the breast cancer mortality rate decreased substantially more in the pilot counties than in the non-pilot counties. The stage distribution of breast cancer diagnosed in the NBCSP is prognostically favorable compared to cancers diagnosed outside the screening program. The reduction in the breast cancer mortality rate was more pronounced in the four pilot counties compared to the non-pilot counties. It is necessary to evaluate the program based on individual data.

Does an organised screening programme reduce the inequalities in breast cancer survival?

The aim of the present study was to examine whether the implementation of an organised mammographic screening programme in Florence has been successful in reducing socioeconomic inequalities in breast cancer survival. All invasive breast cancer cases diagnosed in women resident in the city of Florence in a prescreening period and in the first 10 years of the screening programme were selected. Their socioeconomic status (SES) was determined by using the national census 2001 data. All breast cancers were followed up to 10 years after the diagnosis. In the prescreening period, the survival of deprived women was 12 percentage points lower than the reference class, both in the younger age class (<50 years old) and in the age class target of the screening programme (50-69 years old). This difference progressively decreases until disappearing completely during the first 10 years of the screening programme for the age class invited to screening, whereas it remains stable in the younger age class. Participation in breast cancer screening and diagnostic accuracy were similar by SES. The organised breast cancer screening implemented in the Florentine area achieved the goal of reducing inequalities in breast cancer survival.

Misplaced criticism of breast screening research

Dear Sir, The paper by Gotzsche and Jorgensen1 contains a number of inaccuracies and omissions in its criticism of my work and that of my colleagues.2 Firstly, Gotzsche and Jorgensen take exception to the quoted 50% improvement in breast cancer survival in screen-detected cancers. They omit to mention that the approximate 50% improvement is after correction for lead time and length bias – before correction, the figure was a 70% improvement.3,4 Secondly, they claim that the 28% reduction in breast cancer mortality in England in the screened ages compared to other ages did not occur. They are mistaken. Table 1 shows breast cancer mortality by epoch in ages 50–69 and in all other age groups. While mortality rose by 2% in the latest period compared to the earliest for all other age groups, it fell by 27% in the age group 50–69. The relative risk of breast cancer mortality is therefore: Table 1 Breast cancer mortality in England by age group and epoch That, is a 28% reduction compared to other age groups. In the published analysis, the estimate was age-adjusted, but I give the crude analysis here so that readers can see where the estimate comes from. Gotzsche and Jorgensen's criticisms are particularly error-prone on the subject of over-diagnosis. It might be illuminating to contrast our approach2 with that of Jorgensen and Gotzsche.5 Both teams attempted to estimate overdiagnosis by calculation of expected incidence of breast cancer in the screening epoch based on trends observed in the pre-screening epoch. However, the methods differed at each stage, as follows: Data Sources: Duffy et al. used data on numbers of cases and populations at risk in England from Cancer Registry data.2 Jorgensen and Gotzsche estimated rates for England and Wales from a published graph. Changes in Incidence Independent of Screening: Duffy et al. took full account of these changes by correcting for the 7% increase above expected values at ages below the target age group for screening.2 Jorgensen and Gotzsche failed to do so.5 Method of analysis: Duffy et al. used poisson regression, as is the correct procedure for rate data.2,6 Jorgensen and Gotzsche used linear regression, which is incorrect.5 Data selection: Duffy et al. used all pre-screening and screening epoch data available.2 Jorgensen and Gotzsche excluded the three years of highest incidence in the pre-screening period, and only included the year of highest incidence in their screening epoch data, 1999.5 This inflated their estimate of overdiagnosis. Adjustment for lead time: Duffy et al. subtracted the deficit in incidence above the screening age from the excess observed in screening ages.2 Jorgensen and Gotzsche failed to do so.5 To be fair, they claimed not to observe a deficit. This is partly because in 1999 too few women above the screening age range had been screened in the past, but also because of their failure to fully adjust for changes in incidence independent of screening, as noted in point 2 above. Ductal Carcinoma in situ (DCIS): In the absence of data, Duffy et al. restricted estimation to invasive disease, although in the same paper, they estimated overdiagnosis including DCIS in a randomized trial.2 Like Duffy et al, Jorgensen and Gotzsche had no data on DCIS in the UK, so they assumed a result which was not observed.5 From the above, it can be seen that our modest estimate of overdiagnosis has more reliability than the implausibly high estimate of Jorgensen and Gotzsche. Gotzsche and Jorgensen make a number of further errors in defence of their estimate, including: failure to acknowledge that in the 1990's in the age range for screening, a full paper (not an abstract as stated by Gotzsche and Jorgensen),7 has shown that around 40% of tumours were screen-detected; citation of figures from 2006 to justify their estimate for 1999; and misinterpretation of those figures from 2006, as pointed out previously.8 More importantly, one should not lose sight of the benefit of the NHS Breast Screening Programme and the fact that the only randomized trial with more than 25 years of follow-up, shows that the quoted benefit of one breast cancer death prevented for every 400 women screened is accurate and may even underestimate the benefit.9

Temsirolimus in Combination with Bendamustine and Rituximab for the Treatment of Relapsed Mantle Cell and Follicular Lymphoma: Report on An Ongoing Phase I/II Trial

Abstract 2697 Background:mTOR inhibition has been shown to be effective in various subtypes of malignant lymphomas. Based on a phase III trial in relapsed MCL which proved superiority of temsirolimus to standard options, the drug is approved for this indication in the EU. Additionally, promising response rates could be observed in patients with follicular and diffuse large B-cell lymphoma (Smith et al, JCO 2010). Whereas combination to single agent rituximab seems feasible and with improved efficacy (Ansell et al, Lancet Oncology 2011), there is limited information on the feasibility and efficacy in combination with chemotherapy. Bendamustine has been shown to be effective in indolent lymphoma and has a beneficial side effect profile (Rummel et al, JCO, 2005). To evaluate the potential of the combination of temsirolimus with bendamustine and rituximab an ongoing phase I/II trial was initiated. Methods:This is a multicenter, national, prospective trial, approved by the centralized EC. Patients were eligible if they had histologically proven follicular (FL) or mantle cell lymphoma (MCL), the latter with Cyclin D1 positivity or detectable t(11;14), 1–3 prior treatment lines, no curative option available, no refractoriness to bendamustine, measurable disease, ECOG < 3, sufficient bone marrow reserve, no severe concomitant diseases and given informed consent. Treatment consisted of bendamustine 90mg/m2 day 1–2, rituximab 375mg/m2 day 1 and temsirolimus day 2, 8, 15 of a 28d cycle. A total of 4 cycles was planned with interim staging after 2 cycles. In the ongoing phase I part (3+3 design) the following dose cohorts for temsirolimus were planed: A 25mg, B 50mg, C 75mg. Currently cohort C is ongoing. Toxicity was evaluated throughout the treatment and analysis for DLT was performed after 2 cycles. An independent data safety monitoring board decided on the escalation to the next dose level. Results:Overall 9 patients have been included until now (6 pts cohort A, 3 patients cohort B) and 4 patients are in the prescreening period (cohort C). Median age 64; Histology: 8MCL/1FL; sex 2F/7M, median number of pretreatments 2 (1–3). Adverse events: overall the treatment was well tolerated. Toxicity was predominant hematologic with mostly leukopenia and thrombocytopenia. In 29 evaluable cycles of chemotherapy the following grade 3/4 toxicities were noted: Thrombocytopenia in 3 (all grade 3); leukopenia in 11 (9 grade 3; 2 grade 4), and increase in triglycerides, hyperglycemia and hypertension in one patient each (all grade 3). Importantly, one case of pneumonitis occurred, which resolved after steroid treatment and study treatment could be resumed w/o further problems. In addition, one reaction to contrast agent, an allergic reaction to berries and a transient parasthesia during the study phase were noted, leading to hospitalization. All of these events occurred several days after the last application of study drug and were considered not to be associated to the study treatment. As the episode of hypertension led to hospital admission, it was considered to be potentially a DLT, and cohort A was escalated to 6 patients w/o further DLT. In cohort B no DLT were observed in 3 patients and cohort C has been opened for inclusion. 5 patients have completed the entire treatment, in one patient treatment was stopped after cycle 3 due to delayed recovery of platelets, and treatment is ongoing in 3 patients. At interim staging all 9 patients evaluable achieved a partial remission (ORR 100%). After completion of the entire treatment ORR was 100% with 1 CR and 5 PR in 6 evaluable patients. Summary:In this ongoing phase I/II trial the combination of temsirolimus with bendamustine and Rituximab was feasible applying 3 weekly doses of up to 50mg temsirolimus in a 4 week cycle. Until now promising response rates have been noticed. Cohort C is currently recruiting patients (Temsirolimus 75mg), updated results of the phase I part of the trial will be presented at the meeting. If no dose limiting toxicities are observed, the extended phase II part of the trial will be initiated with patients stratified according to lymphoma subtype (30 patients each with FL and MCL). Disclosures:Hess:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria. Keller:Pfizer: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Witzens-Harig:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy. Dreyling:Pfizer: Research Funding, Speakers Bureau, scientific advisory.

Mammography screening and surgical breast cancer treatment in Norway.

177 Background: We have investigated whether the introduction of organized mammography screening in Norway led to less aggressive breast cancer surgery in the invited age group. Methods: We obtained aggregate incidence and surgical treatment data for women treated for ductal carcinoma in situ or invasive breast cancer from the Norwegian Cancer Registry. Rates of breast operations (mastectomy plus breast conserving therapy) and rates of mastectomy only for three age groups; women aged 40-49, 50-69 and 70-79 years were calculated. Changes in rates from a pre-screening period (1993-95) to a screening introduction phase (1996-2004) and then to a screening period (2005-08) are presented as hazard ratios comparing invited and non-invited women. Results: From the pre-screening period (1993-95) to the screening period (2005-08) the annual breast operation rate increased by 70% (HR=1.70 95% CI 1.62 to 1.78), from 180 to 305 per 100 000 women in the invited age group (50-69 years). In contrast, the increase was only 8% (HR=1.08 95% CI 1.00 to 1.16), from 133 to 144 per 100 000 women per year in the younger, non-invited age group (40-49 years) while an 8% decline (HR=0.92 95% CI 0.86 to 1.00), from 227 to 214 per 100 000 women per year occurred in the older, non-invited age group (70-79 years). In the screening period (2005-08) mastectomy rates fell similarly in invited and non-invited women. However, during the screening introduction phase (1996-2004) the mastectomy rate was 31% (HR=1.31 95% CI 1.20 to 1.43) higher in screened compared to non-screened younger age group. Annual mastectomy rates increased in invited from the pre-screening period to the screening introduction period from 156 to 167 per 100,000 women compared to a decline from 109 to 91 per 100,000 women in younger non-invited. Conclusions: Mammography service screening is associated with a marked increase in breast operation rates in the invited age group and also an increase in mastectomy rates. While overdiagnosis likely caused the initial increase in mastectomy rates and the overall increase in use of surgery in the age group subjected to screening, the more recent decline in mastectomy rates has affected all age groups and is likely to have been caused by changes in surgical policy.

Effect of mammography screening on surgical treatment for breast cancer in Norway: comparative analysis of cancer registry data

Objective To determine the effect of mammography screening on surgical treatment for breast cancer.Design Comparative analysis of data from Norwegian cancer registry.Setting Mammography screening, Norway (screening of women aged 50-69...

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Concern about serious harm from the use of long-acting beta-agonists in asthmatic children is not new. While systematic reviews consistently show an increase in the rate of life-threatening exacerbations of asthma in patients on long-acting beta-agonists, it is uncertain whether or not concomitant use of inhaled corticosteroids is protective. This recent meta-analysis pooled all available data for both salmeterol and formoterol, and included previously unpublished data supplied to the US Food and Drug Administration from drug manufacturers. The authors compared ‘concomitant’ (consistent) to ‘variable’ (inconsistent) use of inhaled corticosteroids. The primary outcome measure was catastrophic asthma events (i.e. asthma-related intubations or deaths). Pooled data on over 36 500 adults and children found long-acting beta-agonists, irrespective of the use of inhaled corticosteroids, were associated with a significant increase in catastrophic asthma events; Odds Ratio (OR) = 2.10 (95% confidence interval (CI) 1.37–3.22). This is the first study showing that inhaled corticosteroids offer no protection, and the results were similar for both children and adults. An unexpected finding was the higher risk in trials with controlled concomitant inhaled corticosteroid use (OR = 8.2, 95% CI 1.1–61.2) than trials with no inhaled corticosteroid use (OR = 2.2, 95% CI 1.37–3.22). Despite the rarity of the outcome (59 events in 19 000 patients on long-acting beta-agonists, and 26 events in 17 500 patients on placebo), clinicians must carefully consider the risks and benefits of prescribing long-acting beta-agonists to children, particularly given that the data on their efficacy in children is weak. Submitted by: Craig Mellis (craig.mellis@sydney.edu.au) The role of cats and dogs in allergy is controversial. The authors examined 636 children of atopic parents annually from 1 year of age and performed skin prick testing (SPT). At 4 years of age, 90 children (14%) had eczema. Dog ownership before 1 year of age reduced the risk of eczema by 60% compared with no dog (Odds Ratio (OR) = 0.4, 95% confidence interval 0.2–0.7). Children with no dog in the home before 1 year who were or became SPT-positive to dog had a 3.9-fold increased risk of eczema, but this was only 30 of the 325 children with no dog, and does not imply causation. In contrast, cat ownership before 1 year was associated with an OR of 1.0 (0.6–1.7) of developing eczema. Of the 121 children with a cat in the home at 1 year, 13 became skin test-positive and seven (57%) developed eczema, so although the OR for skin positivity with a cat in the home was 13.3, this only refers to a very small number of children. This study suggests dog ownership may protect infants against developing eczema. Cat ownership does not affect the risk of eczema, although cat sensitisation is associated with eczema in a small number of children. However, this is only one of many studies, causation is unproven and killing cats is illegal. Reviewers: David Isaacs, davidi@chw.edu.au; Nick Wood, NicholW3@chw.edu.au This retrospective study analysed the live-birth prevalence of cystic fibrosis (CF) in Victoria, Australia before and after the introduction of routine newborn screening in 1989.1 Newborn screening for CF involves measuring neonatal immunoreactive trypsinogen (IRT) blood levels, a test with a sensitivity of around 95% for CF. Before 1991 an abnormal IRT was followed by a sweat test, but since 1991 an abnormal IRT result is followed by DNA testing and a sweat test is performed if the patient is heterozygous for the ΔF508 gene mutation. Prescreening (1979–1988), the live-birth prevalence of CF was 3.96 per 10 000 live births (95% confidence interval (CI) 3.48 to 4.49) compared with 3.28 per 10 000 live births (95% CI 2.97 to 3.63) from 1989 to 2006 postscreening. This 17% reduction in prevalence is attributed to the use of prenatal genetic testing on subsequent pregnancies by parents of infants with a positive newborn screening test. In the prescreening period, 10 prenatal tests were recorded (offered when there was a previous affected child or family history of CF), compared with 304 prenatal tests in the postscreening period. Most parents with an affected fetus on prenatal testing elected to terminate the pregnancy (70 of 76 affected pregnancies). The decline in the live-birth prevalence is more modest than the authors expected. Their explanation is the lack of uptake of wider family genetic testing for gene carrier status and the fact that 95% of parents with a baby identified as having CF on screening have no family history of CF. Link: http://adc.bmj.com/content/95/7/531.full Submitted by Jenny Gardner (jmg79@hermes.cam.ac.uk) and Aleisha Nielsen (AleishaN@chw.edu.au)