Causal analyses with target trial emulation for real-world evidence removed large self-inflicted biases: systematic bias assessment of ovarian cancer treatment effectiveness.

BACKGROUND AND OBJECTIVES: Drawing causal conclusions from real-world data (RWD) poses methodological challenges and risk of bias. We aimed to systematically assess the type and impact of potential biases that may occur when analyzing RWD using the case of progressive ovarian cancer. METHODS: We retrospectively compared overall survival with and without second-line chemotherapy (LOT2) using electronic medical records. Potential biases were determined using directed acyclic graphs. We followed a stepwise analytic approach ranging from crude analysis and multivariable-adjusted Cox model up to a full causal analysis using a marginal structural Cox model with replicates emulating a reference randomized controlled trial (RCT). To assess biases, we compared effect estimates (hazard ratios [HRs]) of each approach to the HR of the reference trial. RESULTS: The reference trial showed an HR for second line vs. delayed therapy of 1.01 (95% confidence interval [95% CI]: 0.82-1.25). The corresponding HRs from the RWD analysis ranged from 0.51 for simple baseline adjustments to 1.41 (95% CI: 1.22-1.64) accounting for immortal time bias with time-varying covariates. Causal trial emulation yielded an HR of 1.12 (95% CI: 0.96-1.28). CONCLUSION: Our study, using ovarian cancer as an example, shows the importance of a thorough causal design and analysis if one is expecting RWD to emulate clinical trial results.

Risk factors for diabetic foot complications in type 2 diabetes-A systematic review.

Aims: With increasing numbers of patients with type 2 diabetes mellitus (T2DM) worldwide, the number of associated diabetic foot complications might also increase. This systematic review was performed to summarize published data about risk factors for the diabetic foot (DF) syndrome in order to improve the identification of high-risk patients. Materials and methods: Six electronic databases were searched for publications up to August 2019 using predefined stringent inclusion and exclusion criteria. Results: Of 9,476 identified articles, 31 articles from 28 different study populations fulfilled the criteria for our evaluation. The overall quality of the studies was good, and the risk of bias was low. There was large heterogeneity among the studies concerning study protocols and patient populations analysed. A total of 79 risk factors were analysed within this review. The majority of studies described a consistently positive association with different outcomes of interest related to DF for gender, peripheral neuropathy, retinopathy, nephropathy, poor glycaemic control, insulin use, duration of diabetes, smoking and height. For age, hypertension, dyslipidaemia and body mass index, the results remain inconsistent. Conclusion: A most up-to-date literature review resulted in glycaemic control and smoking as the only amenable risk factors with a consistently positive association for DF. Due to the high personal and financial burden associated with DF and the large heterogeneity among included studies, additional longitudinal studies in large patient populations are necessary to identify more modifiable risk factors that can be used in the prediction and prevention of DF complications.

[Linkage of Clinical and Claims Data in the Evaluation of Post-Stroke Care - SeDaStro: Experiences from the Tyrolian StrokeCard Program]. / Linkage von klinischen Primärdaten und Krankenkassenabrechnungsdaten in der Evaluation der Schlaganfallversorgung ­ SeDaStro: Erfahrungen aus dem Tiroler StrokeCard-Programm.

AIMS AND OBJECTIVES: Data linkage is of paramount importance in the evaluation of treatment regimens for chronic diseases where different health care sectors are involved. A comprehensive picture of long-term treatment effects and, in particular, the cost-effectiveness ratio of treatment approaches can only be drawn when data from various sources are merged and analyzed together. METHODOLOGICAL PROBLEMS AND CHALLENGES: Regarding post-acute stroke care, the present study gives an example of an exact deterministic data linkage procedure including clinical patient records and claims data of TGKK, the main Tyrolean statutory health insurance fund. Typical problems known from other data linkage projects also emerged in the so-called StrokeCard program conducted at the Medical University of Innsbruck. Distinctive Austrian features (the majority of the Austrian population benefits from a mandatory social insurance system without freedom of choice) facilitated the feasibility of the data linkage procedures. RESULTS: Over the recruitment period 01/2014-12/2015, 540 patients could be assigned to the operative dataset. Of these, 367 patients were part of the StrokeCard group (i. e. the treatment group), and 173 belonged to the usual care group (i. e. the control group); 11 patients did not complete the one-year follow-up period (7 treatment group patients vs. 4 control group patients); 7 of them died during the study (5 treatment group patients vs. 2 control group patients). For all 540 patients, TGKK claims data were available for the time-frames of one year before recruitment and one year after discharge from the University hospital. All data could be used in the health-economic evaluation of the StrokeCard program. CONCLUSIONS: The linking of clinical patient records with data collected by SHI funds opens a window of opportunities for analyses of medical care. Counter-intuitively, Austrian health services research activities have limited experience in data linkage approaches, alhough studies based on the linkage of clinical patient records and claims data are indispensable for the evaluation of complex multi-sectoral treatment schemes. The current project proves the feasibility of data linkage mechanisms in the Austrian context. This should be regarded as an impetus for extending data linkage principles to evaluation studies in the future.

Effectiveness, benefit harm and cost effectiveness of colorectal cancer screening in Austria.

BACKGROUND: Clear evidence on the benefit-harm balance and cost effectiveness of population-based screening for colorectal cancer (CRC) is missing. We aim to systematically evaluate the long-term effectiveness, harms and cost effectiveness of different organized CRC screening strategies in Austria. METHODS: A decision-analytic cohort simulation model for colorectal adenoma and cancer with a lifelong time horizon was developed, calibrated to the Austrian epidemiological setting and validated against observed data. We compared four strategies: 1) No Screening, 2) FIT: annual immunochemical fecal occult blood test age 40-75 years, 3) gFOBT: annual guaiac-based fecal occult blood test age 40-75 years, and 4) COL: 10-yearly colonoscopy age 50-70 years. Predicted outcomes included: benefits expressed as life-years gained [LYG], CRC-related deaths avoided and CRC cases avoided; harms as additional complications due to colonoscopy (physical harm) and positive test results (psychological harm); and lifetime costs. Tradeoffs were expressed as incremental harm-benefit ratios (IHBR, incremental positive test results per LYG) and incremental cost-effectiveness ratios [ICER]. The perspective of the Austrian public health care system was adopted. Comprehensive sensitivity analyses were performed to assess uncertainty. RESULTS: The most effective strategies were FIT and COL. gFOBT was less effective and more costly than FIT. Moving from COL to FIT results in an incremental unintended psychological harm of 16 additional positive test results to gain one life-year. COL was cost saving compared to No Screening. Moving from COL to FIT has an ICER of 15,000 EUR per LYG. CONCLUSIONS: Organized CRC-screening with annual FIT or 10-yearly colonoscopy is most effective. The choice between these two options depends on the individual preferences and benefit-harm tradeoffs of screening candidates.

Combined screening with mammography and ultrasound in a population-based screening program.

OBJECTIVES: To compare the performance of screening with mammography combined with ultrasound versus mammography alone in women at average risk for breast cancer. METHODS: 66,680 women underwent physician-performed ultrasound as an adjunct to screening mammography. Histological results and follow-up at one year were used as reference standard for sensitivity. Main outcome measures were cancer detection rate, sensitivity, recall rate, biopsy rate, and positive predictive value of biopsy for combined screening with mammography plus ultrasound versus mammography alone. RESULTS: The overall sensitivity of mammography only was 61.5% in women with dense breasts and 86.6% in women with non-dense breasts. The sensitivity of mammography plus ultrasound combined was 81.3% in women with dense breasts and 95.0% in women with non-dense breasts. Adjunctive ultrasound increased the recall rate from 10.5 to 16.5 per 1000 women screened, and increased the biopsy rate from 6.3 to 9.3 per 1000 women screened. The positive predictive value of biopsy was 55.5% (95% CI 50.6%-60.3%) for mammography alone and 43.3 (95% CI 39.4%-47.3%) for combined mammography plus ultrasound. CONCLUSIONS: Supplemental ultrasound improves cancer detection in screening of women at average risk for breast cancer. Recall rates and biopsy rates can be kept within acceptable limits.

Performance of 4 years of population-based mammography screening for breast cancer combined with ultrasound in Tyrol / Austria.

BACKGROUND: Systems for the delivery of screening mammography vary among countries and these differences can influence screening effectiveness. We evaluated the performance of organized mammography screening for breast cancer combined with ultrasound in Tyrol / Austria, an approach that differs from many other population-based screening programs. METHODS: Data on women aged 40-69 years screened in the period from June 2008 to May 2012 were collected within the framework of an organized screening program. A total of 272,555 invitations were sent to the target population living in Tyrol and 176,957 screening examinations were performed. We analyzed the main performance indicators as defined by European Union (EU) guidelines and some important estimates of harms. RESULTS: The estimated 2­year participation rate was 56.9%. As ultrasound is implemented as second-line screening procedure, 76.2% of all women screened underwent supplementary ultrasound. In total 2322 women were recalled for further assessment (13.1 per 1000 screens) and 1351 biopsies were performed (7.6 per 1000 screens). The positive predictive value was 28.2% for assessment and 48.5% for biopsies. The cancer detection rate was 3.7 per 1000 screens and the proportion of all stage II+ screen-detected cancers was 35.5%. The interval cancer rate was 0.33 and 0.47 per 1000 screens in the first and second years, respectively. The estimated cumulative risk for a false positive screening result and an unnecessary biopsy for women following the invitation approach was 21.1% and 9.4%, respectively. CONCLUSION: The performance of our population-based screening approach combining mammography and ultrasound is very favorable and potential harm is kept very low compared to other European mammography screening programs for breast cancer.

The relative risk of second primary cancers in Austria's western states: a retrospective cohort study.

BACKGROUND: Cancer survivors are at risk of developing a second primary cancer (SPC) later in life because of persisting effects of genetic and behavioural risk factors, the long-term sequelae of chemotherapy, radiotherapy and the passage of time. This is the first study with Austrian data on an array of entities, estimating the risk of SPCs in a population-based study by calculating standardized incidence ratios (SIRs). METHODS: This retrospective cohort study included all invasive incident cancer cases diagnosed within the years 1988 to 2005 being registered in the Tyrol and Vorarlberg Cancer Registries. Person years at risk (PYAR) were calculated from time of first diagnosis plus 2 months until the exit date, defined as the date of diagnosis of the SPC, date of death, or end of 2010, whichever came first. SIR for specific SPCs was calculated based on the risk of these patients for this specific cancer. RESULTS: A total of 59,638 patients were diagnosed with cancer between 1988 and 2005 and 4949 SPCs were observed in 399,535 person-years of follow-up (median 5.7 years). Overall, neither males (SIR 0.90; 95% CI 0.86-0.93) nor females (SIR 1.00; 95% CI 0.96-1.05) had a significantly increased SIR of developing a SPC. The SIR for SPC decreased with age showing a SIR of 1.24 (95% CI 1.12-1.35) in the age group of 15-49 and a SIR of 0.85 (95% CI 0.82-0.89) in the age group of ≥ 65. If the site of the first primary cancer was head/neck/larynx cancer in males and females (SIR 1.88, 95% CI 1.67-2.11 and 1.74, 95% CI 1.30-2.28), cervix cancer in females (SIR 1.40, 95% CI 1.14-1.70), bladder cancer in males (SIR 1.20, 95% CI 1.07-1.34), kidney cancer in males and females (SIR 1.22, 95% 1.04-1.42 and 1.29, 95% CI 1.03-1.59), thyroid gland cancer in females (SIR 1.40, 95% CI 1.11-1.75), patients showed elevated SIR, developing a SPC. CONCLUSIONS: Survivors of head & neck, bladder/kidney, thyroid cancer and younger patients show elevated SIRs, developing a SPC. This has possible implications for surveillance strategies.

Potential years lost and life expectancy in adults with newly diagnosed epilepsy.

OBJECTIVE: Studies using relative measures, such as standardized mortality ratios, have shown that patients with epilepsy have an increased mortality. Reports on more direct and absolute measure such as life expectancy are sparse. We report potential years lost and how life expectancy has changed over 40 years in a cohort of patients with newly diagnosed epilepsy. METHODS: We analyzed life expectancy in a cohort of adult patients diagnosed with definite epilepsy between 1970 and 2010. Those with brain tumor as cause of epilepsy were excluded. By retrospective probabilistic record linkage, living or death status was derived from the national death registry. We estimated life expectancy by a Weibull regression model using gender, age at diagnosis, epilepsy etiology, and year of diagnosis as covariates at time of epilepsy diagnosis, and 5, 10, 15, and 20 years after diagnosis. Results were compared to the general population, and 95% confidence intervals are given. RESULTS: There were 249 deaths (105 women, age at death 19.0-104.0 years) in 1,112 patients (11,978.4 person-years, 474 women, 638 men). A substantial decrease in life expectancy was observed for only a few subgroups, strongly depending on epilepsy etiology and time of diagnosis: time of life lost was highest in patients with symptomatic epilepsy diagnosed between 1970 and 1980; the impact declined with increasing time from diagnosis. Over half of the analyzed subgroups did not differ significantly from the general population. This effect was reversed in the later decades, and life expectancy was prolonged in some subgroups, reaching a maximum in those with newly diagnosed idiopathic and cryptogenic epilepsy between 2001 and 2010. SIGNIFICANCE: Life expectancy is reduced in symptomatic epilepsies. However, in other subgroups, a prolonged life expectancy was found, which has not been reported previously. Reasons may be manifold and call for further study.

Benefits and harms of prostate cancer screening - predictions of the ONCOTYROL prostate cancer outcome and policy model.

BACKGROUND: A recent recalibration of the ONCOTYROL Prostate Cancer Outcome and Policy (PCOP) Model, assuming that latent prostate cancer (PCa) detectable at autopsy might be detectable by screening as well, resulted in considerable worsening of the benefit-harm balance of screening. In this study, we used the recalibrated model to assess the effects of familial risk, quality of life (QoL) preferences, age, and active surveillance. METHODS: Men with average and elevated familial PCa risk were simulated in separate models, differing in familial risk parameters. Familial risk was assumed to affect PCa onset and progression simultaneously in the base-case, and separately in scenario analyses. Evaluated screening strategies included one-time screening at different ages, and screening at different intervals and age ranges. Optimal screening strategies were identified depending on age and individual QoL preferences. Strategies were additionally evaluated with active surveillance by biennial re-biopsy delaying treatment of localized cancer until grade progression to Gleason score ≥ 7. RESULTS: Screening men with average PCa risk reduced quality-adjusted life expectancy (QALE) even under favorable assumptions. Men with elevated familial risk, depending on age and disutilities, gained QALE. While for men with familial risk aged 55 and 60 years annual screening to age 69 was the optimal strategy over most disutility ranges, no screening was the preferred option for 65 year-old men with average and above disutilities. Active surveillance greatly reduced overtreatment, but QALE gains by averted adverse events were opposed by losses due to delayed treatment and additional biopsies. The effect of active surveillance on the benefit-harm balance of screening differed between populations, as net losses and gains in QALE predicted for screening without active surveillance in men with average and familial PCa risk, respectively, were both reduced. CONCLUSIONS: Assumptions about PCa risk and screen-detectable prevalence significantly affect the benefit-harm balance of screening. Based on the assumptions of our model, PCa screening should focus on candidates with familial predisposition with consideration of individual QoL preferences and age. Active surveillance may require treatment initiation before Gleason score progression to 7. Alternative active surveillance strategies should be evaluated in further modeling studies.

High incidence of clinically significant concomitant prostate cancer in patients undergoing radical cystectomy for bladder cancer: A 10-year single-center experience.

AIM: To analyze prostate cancer (PCa) incidence, clinical significance, and recurrence in 213 patients who underwent radical cystectomy (RC) for advanced bladder cancer (BC). PATIENTS AND METHODS: We conducted a 10-year retrospective analysis of a single-center database comprising the effect of PCa in RC specimens. RESULTS: In total, 113/213 male patients (53.1%) had PCa in the RC specimen. Patients׳ age, prostate-specific antigen (PSA), and also free PSA% were significant predictors for PCa. In addition, adverse bladder histology (≥pT3) was found in 63.7% of patients with PCa. A total of 52.2% (59/113) of patients had at least a Gleason score (GS) 7 in final pathology and 10.6% of RC specimens showed an organ border growth (≥pT3a). It was noted that 28.3% of patients experienced a biochemical recurrence (PSA≥0.2ng/ml), among them 86.7% had GS≥7 in the RC specimen; however, 2 patients were diagnosed with a GS 5. Moreover, we found that 80% of patients with biochemical recurrence had an organ-extended (≥pT3) histology of the bladder and 40% of patients with biochemical recurrence died of PCa rather than from BC. CONCLUSION: Concomitant PCa is occurring in>50% of RC specimens with a significant proportion having characteristics (GS, pathological stage) of clinically relevant disease. Adverse bladder histology is a risk factor for both PCa and biochemical PSA recurrence. Follow-up analyses after RC should include PSA measurements also in low-risk PCa as a considerable number of patients develop biochemical recurrence and metastases from PCa partly ending up with death related to PCa in patients suffering from BC.

ENGOT-ov-6/TRINOVA-2: Randomised, double-blind, phase 3 study of pegylated liposomal doxorubicin plus trebananib or placebo in women with recurrent partially platinum-sensitive or resistant ovarian cancer.

AIMS: Trebananib, a peptide-Fc fusion protein, inhibits angiogenesis by inhibiting binding of angiopoietin-1/2 to the receptor tyrosine kinase Tie2. This randomised, double-blind, placebo-controlled phase 3 study evaluated whether trebananib plus pegylated liposomal doxorubicin (PLD) improved progression-free survival (PFS) in patients with recurrent epithelial ovarian cancer. METHODS: Women with recurrent ovarian cancer (platinum-free interval ≤12 months) were randomised to intravenous PLD 50 mg/m2 once every 4 weeks plus weekly intravenous trebananib 15 mg/kg or placebo. PFS was the primary end-point; key secondary end-points were objective response rate (ORR) and duration of response (DOR). Owing to PLD shortages, enrolment was paused for 13 months; the study was subsequently truncated. RESULTS: Two hundred twenty-three patients were enrolled. Median PFS was 7.6 months (95% CI, 7.2-9.0) in the trebananib arm and 7.2 months (95% CI, 4.8-8.2) in the placebo arm, with a hazard ratio of 0.92 (95% CI, 0.68-1.24). However, because the proportional hazards assumption was not fulfilled, the standard Cox model did not provide a reliable estimate of the hazard ratio. ORR in the trebananib arm was 46% versus 21% in the placebo arm (odds ratio, 3.43; 95% CI, 1.78-6.64). Median DOR was improved (trebananib, 7.4 months [95% CI, 5.7-7.6]; placebo, 3.9 months [95% CI, 2.3-6.5]). Adverse events with a greater incidence in the trebananib arm included localised oedema (61% versus 32%), ascites (29% versus 9%) and vomiting (45% versus 33%). CONCLUSIONS: Trebananib demonstrated anticancer activity in this phase 3 study, indicated by improved ORR and DOR. Median PFS was not improved. No new safety signals were identified. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01281254.

Cardiotoxicity with rituximab, cyclophosphamide, non-pegylated liposomal doxorubicin, vincristine and prednisolone compared to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone in frontline treatment of patients with diffuse large B-cell lymphoma: A randomised phase-III study from the Austrian Cancer Drug Therapy Working Group [Arbeitsgemeinschaft Medikamentöse Tumortherapie AGMT](NHL-14).

BACKGROUND: Chemoimmunotherapy containing rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) is the standard treatment for diffuse large B-cell lymphoma (DLBCL). Doxorubicin may induce early and late cardiotoxicity. Non-pegylated liposomal (NPL) doxorubicin may reduce cardiotoxicity. PATIENTS AND METHODS: Patients with untreated CD20+ DLBCL were randomised to conventional R-CHOP chemoimmunotherapy or rituximab, cyclophosphamide, non-pegylated liposomal doxorubicin, vincristine and prednisolone (R-COMP) with doxorubicin substituted by NPL-doxorubicin. Left ventricular ejection fraction (LVEF) and N-terminal pro B-type natriuretic peptide (NT-proBNP) levels were measured before each treatment cycle and after the end of treatment. RESULTS: The mean LVEF of 178 and 158 measurements in the R-COMP and R-CHOP arms was 63.31% and 62.25%, respectively (P = 0.167). During treatment the LVEF measurements were below 50% in 10/218 (4.6%) in the R-COMP arm and 31/196 (15.8%) in the R-CHOP arm (P<0.001). Thirty-six of 40 (90%) patients in the R-COMP arm, but only 24/36 (66.7%) in the R-CHOP arm had all NT-proBNP levels below 400 pg/ml during and at the end of treatment (P = 0.013). There were more serious adverse events in the R-CHOP arm (26 versus 40, P = 0.029). Infections were more common (15 versus 28) in the R-CHOP arm. INTERPRETATION: In patients with normal cardiac function, six cycles of R-CHOP resulted in a low rate of early cardiotoxicity. NPL-doxorubicin did not reduce cardiotoxicity, although cardiac safety signals were elevated in R-CHOP compared to R-COMP. FUNDING: Cephalon provided the Arbeitsgemeinschaft Medikamentöse Tumortherapie with NPL-doxorubicin and an unrestricted grant, but was not involved in the study protocol, data acquisition, data analysis or the writing of the paper.

The burden of malignant melanoma--lessons to be learned from Austria.

AIM OF STUDY: Incidence rates of melanoma, generated by cancer registries (CRs), are susceptible to reporting inconsistencies due to increasing decentralisation of diagnosis. We therefore independently assessed the burden of melanoma in Austria. METHODS: We collected histopathological reports on melanoma of all patients diagnosed in Austria in 2011. Demographic and clinical characteristics, histopathological tumour stages were assessed. Their regional distributions and incidence rates were analysed and compared with data of national and international CRs. RESULTS: A total of 5246 patients were diagnosed with 1951 in-situ and 3295 invasive melanomas in Austria in 2011 (population 8.4 million). Age, sex and anatomic distribution corresponded to findings in other European countries, however, the incidence of 25/100,000 (world age-standardised rate) for invasive melanomas was two-fold higher than published by the Austrian CR (12/100,000). Varying frequencies in diagnosing thin melanomas (≤1 mm; n = 4415) accounted exclusively for significant regional disparities, while advanced tumours (>1 mm; n = 761) were evenly distributed. Western Austria showed the highest rates (36/100,000). Patients from eastern Austria whose melanomas were diagnosed in laboratories in western Austria (n = 76) showed significantly higher proportions of in-situ lesions (n = 43; 57%) compared to those whose tumours were diagnosed in eastern Austria (n = 4014; in-situ = 1369; 34%) (p < 0.0001). CONCLUSIONS: In Austria, the melanoma burden and its potential socio-economic implications are significantly underestimated. Similarities of incidences indicate this could affect other European countries with well-established CRs and compromise international comparability of data. Austrian regional disparities suggest overdiagnosis of thin melanomas due to the variability of pathologists' thresholds for the diagnosis of early stage tumours.

High prevalence of BRCA1 stop mutation c.4183C>T in the Tyrolean population: implications for genetic testing.

Screening for founder mutations in BRCA1 and BRCA2 has been discussed as a cost-effective testing strategy in certain populations. In this study, comprehensive BRCA1 and BRCA2 testing was performed in a routine diagnostic setting. The prevalence of the BRCA1 stop mutation c.4183C>T, p.(Gln1395Ter), was determined in unselected breast and ovarian cancer patients from different regions in the Tyrol. Cancer registry data were used to evaluate the impact of this mutation on regional cancer incidence. The mutation c.4183C>T was detected in 30.4% of hereditary BRCA1-associated breast and ovarian cancer patients in our cohort. It was also identified in 4.1% of unselected (26% of unselected triple negative) Tyrolean breast cancer patients and 6.8% of unselected ovarian cancer patients from the Lower Inn Valley (LIV) region. Cancer incidences showed a region-specific increase in age-stratified breast and ovarian cancer risk with standardized incidence ratios of 1.23 and 2.13, respectively. We, thus, report a Tyrolean BRCA1 founder mutation that correlates to a local increase in the breast and ovarian cancer risks. On the basis of its high prevalence, we suggest that targeted genetic analysis should be offered to all women with breast or ovarian cancer and ancestry from the LIV region.

Evaluation of a mammography screening program within the population-based Vorarlberg Health Monitoring & Prevention Program (VHM&PP).

OBJECTIVES: To describe the mammography screening program from 1989 to 2005 within a population-based prevention program in Austria and to appraise it according to recommended quality indicators. MATERIAL AND METHOD: From 01.01.1989 all women aged 40 years or older participating in the Vorarlberg Health Monitoring & Prevention Program (VHM&PP) was offered to undergo additionally a "screening mammography". Passive follow-up has been performed by record linkages with the Vorarlberg cancer registry and mortality statistics for information on outcome variables. Interval cancer rates have been estimated and the survival after breast cancer has been calculated by life table technique by examination period and age groups (40-49 years, 50-69 years). RESULTS: Between 1989 and 2005 50,100 women aged 40 to 69 years participated in the program, of which 123,652 mammogram results have been collected. In the target population the participation rate was 65.1%. During median follow-up time 13.5 years and 633,342 person-years overall 665 invasive cancer and 87 ductal carcinoma in situ (11.6%) cases have been identified. Between 1996 and 2004 the detection rates were 239.9 per 100.000 among women aged 40-49 years and 543.2 per 100,000 among women aged 50-69 years. The rates for interval cancers were 160.4 and 277.4 per 100 000 negative screens, respectively. During median follow-up of 13.5 years 165 deaths occurred with no difference in survival between patients with interval and screen detected cancers. CONCLUSION: A mammography screening program has been performed between 1989 and 2005 in Vorarlberg. Till 2005 most quality indicators improved and met the EU-recommendations suggesting that alternative approaches to organized mammography screening based on routine data should be explored.

The ONCOTYROL Prostate Cancer Outcome and Policy Model: Effect of Prevalence Assumptions on the Benefit-Harm Balance of Screening.

BACKGROUND: The ONCOTYROL Prostate Cancer Outcome and Policy (PCOP) model is a state-transition microsimulation model evaluating the benefits and harms of prostate cancer (PCa) screening. The natural history and detection component of the original model was based on the 2003 version of the Erasmus MIcrosimulation SCreening ANalysis (MISCAN) model, which was not calibrated to prevalence data. Compared with data from autopsy studies, prevalence of latent PCa assumed by the original model is low, which may bias the model toward screening. Our objective was to recalibrate the original model to match prevalence data from autopsy studies as well and compare benefit-harm predictions of the 2 model versions differing in prevalence. METHODS: For recalibration, we reprogrammed the natural history and detection component of the PCOP model as a deterministic Markov state-transition cohort model in the statistical software package R. All parameters were implemented as variables or time-dependent functions and calibrated simultaneously in a single run. Observed data used as calibration targets included data from autopsy studies, cancer registries, and the European Randomized Study of Screening for Prostate Cancer. Compared models were identical except for calibrated parameters. RESULTS: We calibrated 46 parameters. Prevalence from autopsy studies could not be fitted using the original parameter set. Additional parameters, allowing for interruption of disease progression and age-dependent screening sensitivities, were needed. Recalibration to higher prevalence demonstrated a considerable increase of overdiagnosis and decline of screening sensitivity, which significantly worsened the benefit-harm balance of screening. CONCLUSIONS: Our calibration suggests that not all cancers are at risk of progression, and screening sensitivity may be lower at older ages. PCa screening models that use calibration to simulate disease progression in the unobservable latent phase are highly sensitive to prevalence assumptions.

Dual-energy contrast-enhanced spectral mammography (CESM).

Dual-energy contrast-enhanced mammography is one of the latest developments in breast care. Imaging with contrast agents in breast cancer was already known from previous magnetic resonance imaging and computed tomography studies. However, high costs, limited availability-or high radiation dose-led to the development of contrast-enhanced spectral mammography (CESM). We reviewed the current literature, present our experience, discuss the advantages and drawbacks of CESM and look at the future of this innovative technique.

Cause-specific mortality in adult epilepsy patients from Tyrol, Austria: hospital-based study.

Epilepsy is a devastating condition with a considerable increase in mortality compared to the general population. Few studies have focused on cause-specific mortality which we analyse in detail in over 4,000 well-characterized epilepsy patients. The cohort comprised of epilepsy patients ≥ 18, treated between 1970 and 2009 at the epilepsy clinic of Innsbruck Medical University, Austria, and living in the province of Tyrol, Austria. Epilepsy diagnosis was based on ILAE guidelines (1989); patients with brain tumor were excluded. Deceased patients and causes of death (ICD-codes) were obtained via record linkage to the national death registry. We computed age-, sex-, and period-adjusted standardized mortality rates (SMR) for 36 diagnoses subgroups in four major groups. Additional analyses were performed for an incidence cohort. Overall cohort: 4,295 patients, 60,649.1 person-years, 822 deaths, overall SMR 1.7 (95 % CI 1.6-1.9), highest elevated cause-specific SMR: congenital anomalies [7.1 (95 % CI 2.3-16.6)], suicide [4.2 (95 % CI 2.0-8.1)], alcohol dependence syndrome [3.9 (95 % CI 1.8-7.4)], malignant neoplasm of esophagus [3.1 (95 % CI 1.2-6.4)], pneumonia [2.7 (95 % CI 1.6-4.2)]. Incidence cohort: 1,299 patients, 14,215.4 person-years, 267 deaths, overall SMR 1.8 (95 % CI 1.6-2.1), highest elevated cause-specific SMR congenital anomalies [10.8 (95 % CI 1.3-39.3)], suicide [6.8 (95 % CI 1.4-19.8)], alcohol dependence syndrome (6.4 [95 % CI 1.8-16.5)], pneumonia [3.9 (95 % CI 1.8-7.4)], cerebrovascular disease at 3.5 (95 % CI 2.6-4.6). Mortality due to mental health problems, such as suicide or alcohol dependence syndrome, malignant neoplasms, and cerebrovascular diseases was highly increased in our study. In addition to aim for seizure freedom, we suggest improving general health promotion, including cessation of smoking, lowering of alcohol intake, and reduction of weight as well as early identification of psychiatric comorbidity in patients with epilepsy.

Increased cancer incidence risk in type 2 diabetes mellitus: results from a cohort study in Tyrol/Austria.

BACKGROUND: Recent meta-analyses revealed an association between type 2 diabetes mellitus (T2DM) and cancer. The strongest relationship was demonstrated for liver and pancreatic cancer, followed by endometrial cancer. We aimed at assessing the association between T2DM and cancer specifically for Tyrolean patients. METHODS: We investigated cancer incidence in Tyrolean subjects with T2DM by linking the data from the Diabetes and the Cancer Registries. 5709 T2DM patients were included and the sex- and age-adjusted standardized incidence ratio (SIR) was calculated, cancer incidence in the Tyrolean population serving as the standard. Endpoints were the time at which cancer was diagnosed, death or end of the observation period (31 December 2010). RESULTS: Site-specific analyses revealed statistically significantly elevated SIRs for cancer of the pancreas (1.78, 95% CI 1.02, 2.89) and corpus (1.79, 95% CI 1.15, 2.66) for women, and cancer of the liver (2.71, 95% CI 1.65, 4.18) and pancreas (1.87, 95% 1.11, 2.96) for men. Sub-analyses performed according to the time of diabetes diagnosis revealed that SIR was highest in the first year after diabetes diagnosis, but SIR was demonstrated to be elevated in women for cancer of the liver (SIR 3.37, 95% CI 1.24, 7.34) and corpus (SIR 1.94, 95% CI 1.09, 3.20) and in men for liver (SIR 2.71, 95% CI 1.40, 4.74) in the period more than five years after diabetes diagnosis. In addition, increased risk at borderline statistical significance was observed in females for liver cancer (SIR 2.40, 95% CI 0.96, 4.94) and cervical cancer (SIR 1.81, 95% CI 0.87, 3.32) and in males for kidney cancer (SIR 1.65, 95% CI 0.99, 2.57). CONCLUSION: This study revealed a higher risk for cancer at certain sites in Tyrolean patients with T2DM. However, it is important to interpret the results with great caution due to inherent methodological problems. Optimized care programs for patients with T2DM should be integrated into the recommended procedures for cancer screening.