Assessment of medication use during pregnancy by Web-based questionnaires, pharmacy records and serum screening.

OBJECTIVE: To compare assessment of early pregnancy medication exposure using three methods of data collection. METHODS: Serum samples were obtained from 752 women participating in the PRegnancy and Infant DEvelopment (PRIDE) Study before gestational week 17. For 52 women using medication at the date of blood sampling according to Web-based questionnaires or pharmacy records, we analysed serum samples using untargeted liquid chromatography time-of-flight spectrometry. RESULTS: Medication was detected in 18 serum samples (35%). Medications taken orally for chronic conditions reported in the questionnaire were detected in serum and vice versa. Pharmacy records did not identify additional exposed women, but missed exposure in 5 women mainly due to unavailability. We observed substantial discordance between the three methods for inhaled medication, dermatological preparations, and medications for short-term use, which went often undetected in serum. CONCLUSIONS: It remains challenging to assess medication use in large-scale studies as no 'gold standard' is currently available.

Genotype-Guided Thiopurine Dosing Does not Lead to Additional Costs in Patients With Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Decreased thiopurine S-methyltransferase [TPMT] enzyme activity increases the risk of haematological adverse drug reactions [ADRs] in patients treated with thiopurines. Clinical studies have shown that in patients with inflammatory bowel disease [IBD], pharmacogenetic TPMT-guided thiopurine treatment reduces this risk of ADRs. The aim of this study was to investigate whether this intervention impacts on healthcare costs and/or quality of life. METHODS: An a priori defined cost-effectiveness analysis was conducted in the Thiopurine response Optimization by Pharmacogenetic testing in Inflammatory bowel disease Clinics [TOPIC] trial, a randomized controlled trial performed in 30 Dutch hospitals. Patients diagnosed with IBD [age ≥18 years] were randomly assigned to the intervention [i.e. pre-treatment genotyping] or control group. Total costs in terms of volumes of care, and effects in quality-adjusted life years [QALYs], based on EuroQol-5D3L utility scores, were measured for 20 weeks. Mean incremental cost savings and QALYs with confidence intervals were calculated using non-parametric bootstrapping with 1000 replications. RESULTS: The intervention group consisted of 381 patients and the control group 347 patients. The mean incremental cost savings were €52 per patient [95% percentiles -682, 569]. Mean incremental QALYs were 0.001 [95% percentiles -0.009, 0.010]. Sensitivity analysis showed that the results were robust for potential change in costs of screening, costs of biologicals and costs associated with productivity loss. CONCLUSIONS: Genotype-guided thiopurine treatment in IBD patients reduced the risk of ADRs among patients carrying a TPMT variant, without increasing overall healthcare costs and resulting in comparable quality of life, as compared to standard treatment.

An assessment of the most reliable method to estimate the sagittal alignment of the cervical spine: analysis of a prospective cohort of 138 cases.

OBJECTIVE Although there is increasing recognition of the importance of cervical spinal sagittal balance, there is a lack of consensus as to the optimal method to accurately assess the cervical sagittal alignment. Cervical alignment is important for surgical decision making. Sagittal balance of the cervical spine is generally assessed using one of two methods; namely, measuring the angle between C-2 and C-7, and drawing a line between C-2 and C-7. Here, the best method to assess sagittal alignment of the cervical spine is investigated. METHODS Data from 138 patients enrolled in a randomized controlled trial (Procon) were analyzed. Two investigators independently measured the angle between C-2 and C-7 by using Harrison's posterior tangent method, and also estimated the shape of the sagittal curve by using a modified Toyama method. The mean angles of each quantitative assessment of the sagittal alignment were calculated and the results were compared. The interrater reliability for both methods was estimated using Cronbach's alpha. RESULTS For both methods the interrater reliability was high: for the posterior tangent method it was 0.907 and for the modified Toyama technique it was 0.984. For a lordotic cervical spine, defined by the modified Toyama method, the mean angle (defined by Harrison's posterior tangent method) was 23.4° ± 9.9° (range 0.4°-52.4°), for a kyphotic cervical spine it was -2.2° ± 9.2° (range -16.1° to 16.9°), and for a straight cervical spine it was 10.5° ± 8.2° (range -11° to 36°). CONCLUSIONS An absolute measurement of the angle between C-2 and C-7 does not unequivocally define the sagittal cervical alignment. As can be seen from the minimum and maximum values, even a positive angle between C-2 and C-7 could be present in a kyphotic spine. For this purpose, the modified Toyama method (drawing a line from the posterior inferior part of the vertebral body of C-2 to the posterior upper part of the vertebral body of C-7 without any measurements) is a better tool for a global assessment of cervical sagittal alignment. Clinical trial registration no.: ISRCTN41681847 ( https://www.isrctn.com ).

Early Assessment of Thiopurine Metabolites Identifies Patients at Risk of Thiopurine-induced Leukopenia in Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Only a quarter of thiopurine-induced myelotoxicity in inflammatory bowel disease [IBD] patients is related to thiopurine S-methyltransferase deficiency. We determined the predictive value of 6-thioguanine nucleotide [6-TGN] and 6-methylmercaptopurine ribonucleotide [6-MMPR] concentrations 1 week after initiation [T1] for development of leukopenia during the first 8 weeks of thiopurine treatment. METHODS: The study was performed in IBD patients starting thiopurine therapy as part of the Dutch randomized controlled TOPIC trial [ClinicalTrials.gov NCT00521950]. Blood samples for metabolite measurement were collected at T1. Leukopenia was defined by leukocyte counts of <3.0 × 109/L. For comparison, patients without leukopenia who completed the 8 weeks on the stable dose were selected from the first 272 patients of the TOPIC trial. RESULTS: Thirty-two patients with, and 162 patients without leukopenia were analysed. T1 threshold 6-TGN concentrations of 213 pmol/8 × 108 erythrocytes and 3525 pmol/8 × 108 erythrocytes for 6-MMPR were defined: patients exceeding these values were at increased leukopenia risk (odds ratio [OR] 6.2 [95% CI: 2.8-13.8] and 5.9 [95% CI: 2.7-13.3], respectively). Leukopenia rates were higher in patients treated with mercaptopurine, compared with azathioprine (OR 7.3 [95% CI: 3.1-17.0]), and concurrent anti-TNF therapy (OR 5.1 [95% CI: 1.6-16.4]). Logistic regression analysis of thiopurine type, threshold concentrations, and concurrent anti-tumour necrosis factor [TNF] therapy revealed that elevations of both T1 6-TGN and 6-MMPR resulted in the highest risk for leukopenia, followed by exceeding only the T1 6-MMPR or 6-TGN threshold concentration (area under the curve 0.84 [95% CI: 0.76-0.92]). CONCLUSIONS: In ~80% of patients, leukopenia could be explained by T1 6-TGN and/or 6-MMPR elevations. Validation of the predictive model is needed before implementing in clinical practice.

Breast cancer diagnosis and death in the Netherlands: a changing burden.

BACKGROUND: Lifetime risks are often used in communications on cancer to the general public. The most-cited estimate for breast cancer risk (1 in 8 women), however, appears to be outdated. Here we describe the breast cancer burden in the Netherlands over time by means of lifetime and age-conditional risks. The aim is to identify changes in absolute risk of primary breast cancer diagnosis and death. METHODS: Data on breast cancer incidence, mortality and size of the female population were retrieved from the Netherlands Cancer Registry and Statistics Netherlands. Lifetime and age-conditional risks were calculated for 1990, 2000 and 2010 using the life-table method (DevCan software). RESULTS: The lifetime risk of developing breast cancer (ductal carcinoma in situ and invasive) in 1990, 2000 and 2010 was estimated at 10.8 (1 in 9.3 women), 13.5 (1 in 7.4) and 15.2% (1 in 6.6), respectively. Most women were still diagnosed after the age of 50, with the highest risk between 60 and 70 years in 2010. The lifetime risk of breast cancer death was 3.8% (1 in 27) in 2010, which is lower than in 1990 (4.5%; 1 in 22) and 2000 (4.2%; 1 in 24). CONCLUSION: Breast cancer risk has increased to 1 in 6.6 women being diagnosed during their lifetime (invasive cancer only: 1 in 7.4), whereas risk of breast cancer death has decreased from 1 in 22 to 1 in 27 women. To keep cancer management and prevention up-to-date, it remains important to closely monitor the ever-changing breast cancer burden.

Timely assessment of cardiovascular risk after preeclampsia.

Evaluation of: Cusimano MC, Pudwell J, Roddy M, Chan-Kyung JC, Smith GN. The maternal health clinic: an initiative for cardiovascular identification in women with pregnancy-related complications. Am. J. Obstet. Gynecol. 438, e1 (2014). Cardiovascular risk management, for men and women alike, is a preventative means to detect individuals' running an elevated risk of myocardial disorders, stroke and metabolic syndrome. Because age is an important factor in the risk assessment, especially young women almost always are classified in the low-risk category and therefore do not qualify for preventive treatment. A history of preeclampsia identifies women who have underlying cardiovascular risk factors. Approximately 6-8% of all pregnancies are complicated by hypertensive disorders, about 2% ends in preeclampsia. For that very reason, the Maternal Health Clinic at Kingston General Hospital in Kingston, Canada, was established to provide postpartum cardiovascular risk counseling or follow-up for women with the pregnancy-related complications. The outcomes were significant: 17% of the young target population with an average age of 33 years met criteria of metabolic syndrome and 85% revealed elevated lifetime cardiovascular disease risk. These figures are to be compared with control results of women with uncomplicated pregnancies: 7% metabolic syndrome and 46% non-optimal risk. It is concluded that the clinic may serve as a prolific and effective primary prevention strategy.

Cost-effectiveness of non-invasive assessment in the Dutch breast cancer screening program versus usual care: a randomized controlled trial.

OBJECTIVE: Increased recall rates in the Dutch breast cancer screening program call for a new assessment strategy aiming to reduce unnecessary costs and anxiety. Diagnostic work-up (usual care) includes multidisciplinary hospital assessment and is similar for all recalled women, regardless of the radiologist's suspicion of breast cancer. This is similar in many Canadian settings. We developed a novel assessment strategy that offers women with a low suspicion of breast cancer a quick and non-invasive assessment by a screening radiologist (intervention). We compared these two strategies in a cost-effectiveness analysis based on a randomized controlled trial: multicentre randomized controlled trial (MASS trial, Netherlands National Trial Register: NTR1480). METHODS: Participants were enrolled between August 2010 and December 2012 and were randomly assigned to either the intervention or control group (allocation ratio 2:1). Fourteen assessment centres participated in the study. Questionnaires were used to record quality of life (EuroQol-5D), health care use and costs after recall. RESULTS: Our study comprised 366 women, of whom 288 were randomly assigned to the intervention group and 88 to the control group. The mean difference in cost was €153/CAD $226 (95% confidence interval €107-199/CAD $158-294, p<0.001). We found no significant differences in quality of life. The bootstrapped incremental cost-effectiveness ratios in the cost-effectiveness plane showed that the intervention was the efficient, cost-saving modality. CONCLUSION: Our data show the benefits of tailoring diagnostic assessment to the screening radiologist's suspicion of breast cancer. Scenarios of implementing such a strategy in the Dutch screening or health care system are currently being discussed with various stakeholders.

Quantifying short run cost-effectiveness during a gradual implementation process.

This paper examines the short run inefficiencies that arise during gradual implementation of a new cost-effective technology in healthcare. These inefficiencies arise when health gains associated with the new technology cannot be obtained immediately because the new technology does not yet supply all patients, and when there is overcapacity for the old technology in the short run because the supply of care is divided among two mutually exclusive technologies. Such efficiency losses are not taken into account in standard textbook cost-effectiveness analysis in which a steady state is presented where costs and effects are assumed to be unchanging over time. A model is constructed to quantify such short run inefficiencies as well as to inform the decision maker about the optimal implementation pattern for the new technology. The model operates by integrating the incremental net benefit equations for both the period of co-existence of mutually exclusive technologies and the period after complete substitution of the old technology. It takes into account the rate of implementation of the new technology, depreciation of capital of the old technology as well as the demand curves for both technologies. The model is applied to the real world case of converting from screen film to digital mammography in the Netherlands.

Impact of routine follow-up examinations on life expectancy in ovarian cancer patients: a simulation study.

OBJECTIVE: The clinical benefit of routine follow-up in patients treated for ovarian cancer is subject to debate. In this study, the magnitude of the potential survival benefit of routine examinations was evaluated by Markov modeling. METHODS: The clinical course of ovarian cancer was simulated using a 4-state nonstationary Markov model. Risk of recurrence and mortality probabilities were derived from individual patient data and Statistics Netherlands. The life expectancy was simulated for 3 follow-up scenarios: a current, withholding (all recurrences detected symptomatically), and perfect follow-up program (all recurrences detected asymptomatically). The impact of effective recurrence treatment in the future was modeled by varying the mortality ratio between patients with asymptomatically versus symptomatically detected recurrences. The model was validated using empirical data. RESULTS: The mean life expectancy of patients, aged 58 years and in complete clinical remission after primary treatment, was 10.8 years. Varying the transition probabilities with ±25% changed the life expectancy by up to 1.1 years. The modeled life expectancy for the withholding and perfect follow-up scenarios was also 10.8 years and insensitive to model assumptions. In patients with stages IIB to IV, the life expectancy was 7.0 years, irrespective of follow-up strategy. A mortality ratio of 0.8 for patients with asymptomatically versus symptomatically detected recurrences resulted in a gain in life expectancy of 5 months for withholding versus perfect follow-up. CONCLUSIONS: Routine follow-up in ovarian cancer patients is not expected to improve the life expectancy. The timing of detection of recurrent ovarian cancer is immaterial until markedly improved treatment options become available.

[Screening for and early detection of skin melanoma in the Netherlands]. / Screening en vroege detectie van huidmelanoom in Nederland.

During the past few decades, the incidence of skin melanoma has increased greatly in the Netherlands. At the same time, the mortality from skin melanoma has increased, especially amongst older men. Because of the strong association between disease stage and prognosis, screening and an increase in awareness would appear to be good strategies for early detection of skin melanoma, thus reducing the disease burden. At the moment there is no conclusive evidence that mass screening of the population will decrease morbidity and mortality due to skin melanoma. In addition, there is uncertainty about the cost-effectiveness and about the organization of mass screening. In theory, screening of high-risk populations based on risk factors should be more efficient, but it is unclear how this selection should be carried out. Results of a mass screening project currently underway in Germany will provide more clarity on this subject. Until then, educating the general population and general practitioners about recognition of skin melanoma is of major importance in achieving early detection.

Dutch digital breast cancer screening: implications for breast cancer care.

BACKGROUND: In comparison to other European population-based breast cancer screening programmes, the Dutch programme has a low referral rate, similar breast cancer detection and a high breast cancer mortality reduction. The referral rate in the Netherlands has increased over time and is expected to rise further, mainly following nationwide introduction of digital mammography, completed in 2010. This study explores the consequences of the introduction of digital mammography on the balance between referral rate, detection of breast cancer, diagnostic work-up and associated costs. METHODS: Detailed information on diagnostic work-up (chart review) was obtained from referred women (n = 988) in 2000-06 (100% analogue mammography) and 2007 (75% digital mammography) in Nijmegen, the Netherlands. RESULTS: The average referral rate increased from 15 (2000-06) to 34 (2007) per 1000 women screened. The number of breast cancers detected increased from 5.5 to 7.8 per 1000 screens, whereas the positive predictive value fell from 37% to 23%. A sharp rise in diagnostic work-up procedures and total diagnostic costs was seen. On the other hand, costs of a single work-up slightly decreased, as less surgical biopsies were performed. CONCLUSION: Our study shows that a low referral rate in combination with the introduction of digital mammography affects the balance between referral rate and detection rate and can substantially influence breast cancer care and associated costs. Referral rates in the Netherlands are now more comparable to other countries. This effect is therefore of value in countries where implementation of digital breast cancer screening has just started or is still under discussion.

[Responsible cancer screening]. / Verantwoord screenen op kanker.

In the Netherlands, national screening programs for breast and cervical cancer are operating, whilst that for colorectal cancer is in preparation. In the meantime, experimental studies have been conducted into the effectiveness of prostate and lung cancer screening. Death from these five types of cancer is reduced by these screening investigations. However, these screening programmes also have disadvantages, such as unnecessary referral for definitive diagnosis in the hospital. The average hospital would receive on a yearly basis via screening 156 referrals of women with breast cancer, 79 for cervical cancer and nearly 1100 persons for colorectal cancer. n average general practice encounters annually 3 positive screening results for breast cancer, almost 1 referral for cervical carcinoma or an early stage thereof, and every two years a patient with CIN III. For colorectal cancer around 22 referrals can be expected yearly, of which 8 will have adenoma or cancer.

Colorectal cancer screening comparing no screening, immunochemical and guaiac fecal occult blood tests: a cost-effectiveness analysis.

Comparability of cost-effectiveness of colorectal cancer (CRC) screening strategies is limited if heterogeneous study data are combined. We analyzed prospective empirical data from a randomized-controlled trial to compare cost-effectiveness of screening with either one round of immunochemical fecal occult blood testing (I-FOBT; OC-Sensor®), one round of guaiac FOBT (G-FOBT; Hemoccult-II®) or no screening in Dutch aged 50 to 75 years, completed with cancer registry and literature data, from a third-party payer perspective in a Markov model with first- and second-order Monte Carlo simulation. Costs were measured in Euros (€), effects in life-years gained, and both were discounted with 3%. Uncertainty surrounding important parameters was analyzed. I-FOBT dominated the alternatives: after one round of I-FOBT screening, a hypothetical person would on average gain 0.003 life-years and save the health care system €27 compared with G-FOBT and 0.003 life years and €72 compared with no screening. Overall, in 4,460,265 Dutch aged 50-75 years, after one round I-FOBT screening, 13,400 life-years and €320 million would have been saved compared with no screening. I-FOBT also dominated in sensitivity analyses, varying uncertainty surrounding important effect and cost parameters. CRC screening with I-FOBT dominated G-FOBT and no screening with or without accounting for uncertainty.

Validation of a translated version of the modified Japanese orthopaedic association score to assess outcomes in cervical spondylotic myelopathy: an approach to globalize outcomes assessment tools.

BACKGROUND: Although the Japanese Orthopaedic Association (JOA) originally developed in Japan, the modified English version (mJOA) has become widely used and is arguably now the accepted standard. OBJECTIVE: In order to apply the mJOA successfully at an international level, we have translated it with a validated approach into Dutch to pave the way for other translated versions. METHODS: After a thorough forward and backward translation procedure, a final Dutch version of the mJOA was developed. This translated version was used to assess the interobserver reliability among 2 independent examiners by using a cohort of patients with neurological impairment due to spinal pathology. RESULTS: The mJOA grading scale was used by 2 independent examiners in 25 patients with a variety of spinal diseases. Initially, the interobserver reliability expressed as kappa was 0.56 +/- 0.11. Then, instructions were given to the instructors to refrain from providing patients with an interpretation of the symptoms. Patients were asked to restrict themselves to the questionnaire and select the most appropriate score without bias from the examiner. Kappa increased to 0.78 +/- 0.05. This difference reached statistical significance (P < .001). CONCLUSION: We present a streamlined approach to translate the mJOA into a language other than English. The approach resulted in a Dutch version of the mJOA that had a high degree of interobserver reliability.

Effect of routine follow-up after treatment for laryngeal cancer on life expectancy and mortality: results of a Markov model analysis.

BACKGROUND: Routine follow-up is offered to all patients with laryngeal cancer who are treated with curative intent. Although time and resources are devoted to surveillance, the effect of asymptomatic recurrence detection is not well understood. For this study, the authors evaluated the effect that routine follow-up may have on life expectancy and disease-specific mortality rate for patients with laryngeal cancer. METHODS: Using a Markov model, a cohort simulation was performed on 4 hypothetical age groups of patients with laryngeal cancer. Three different follow-up strategies were compared-the current schedule, no follow-up, and the perfect follow-up-in which all recurrences were detected asymptomatically. Sensitivity analyses were performed to study the impact of variations in the transition rates on life expectancy. RESULTS: Compared with no follow-up, the current schedule showed a gain in life expectancy with a range from 0.3 years to 1.5 years that decreased with advancing age. Abolishing the current follow-up schedule raised the disease-specific mortality rate; the increase ranged from 2.8% to 5.9%. Variations of +/-25% in the transition rates produced only a modest effect on life expectancy. CONCLUSIONS: A small reduction in life expectancy was observed when follow-up was withheld from the majority of patients. Disease-specific mortality rates rose when no follow-up was provided. These rates probably were overestimated. A simplified version of the current follow-up protocol may be implemented.

Seventy-five years is an appropriate upper age limit for population-based mammography screening.

In this study, we assessed the results of the Dutch breast cancer screening programme for women aged 70-75, and discussed the current upper age limit of the women invited. We compared the main outcome parameters of the screening programme 1998-2000 for women aged 70-75, with those in women aged 50-69. Breast cancer detection rates were also compared with prediction from 2 variants of a simulation model of breast cancer screening, assuming the mean sojourn time, i.e., the duration of the preclinical detectable phase, to increase or not with age above the age of 65. The underlying idea is that an increase of the sojourn time with age will lead to a less favourable balance between screening benefits and harms from a certain age on. Of the 315,103 women (aged 70-75) invited, 65.6% participated. The attendance increased from 1998 to 2000. For women aged 74 and 75 years, this increase was almost 10%. As a result of the 187,207 screening examinations performed within this age group, 18.3 per 1,000 women were referred and 10.3 per 1,000 breast cancer were diagnosed. Detection rates in both initial and subsequent screens increased steadily with age and got close to those model-simulated rates, which assume a continuously increasing sojourn time with age. A major finding of this study is that the screening participation among elderly women is high. The outcomes of our study suggest a steadily increasing sojourn time of breast tumours beyond the age of 69, leading to a strong increase in detection of cancers, and therefore, disfavouring the balance with the benefits of screening. At present, 75 years of age can be regarded as an appropriate upper age limit for the Dutch programme.

The efficacy of different follow-up strategies in clinical stage I Non-seminomatous Germ Cell Cancer: a Markov simulation study.

OBJECTIVE: There is no universally accepted standard protocol for surveillance of patients with clinical stage I Non Seminomatous Germ Cell Tumors (CS I NSGCT). Prospective studies to compare different follow-up policies have not been performed, even though a great deal of time and resources is spent in surveillance. In this study, we constructed a Markov model to evaluate the impact of different follow-up strategies on disease-specific mortality (DSM) and life expectancy (LE) of patients with CS I NSGCT. METHODS: A discrete time non-homogeneous semi-Markov model was used to simulate different follow-up strategies for a hypothetical population of CS I NSGCT patients. Estimates of the model parameters were based on the literature. Output parameters were DSM and LE. Three different strategies were compared: (1) the intensive The Netherlands Cancer Institute/Antoni van Leeuwenhoek hospital (NCI/AvL) protocol; (2) the European Association of Urology (EAU) protocol; and (3) a hypothetical minimal protocol (i.e. follow-up limited to the first two years). Furthermore, we evaluated the impact of abdominal CT scans and chest X-rays on DSM. RESULTS: Comparing with the EAU protocol (DSM: 3.05%; LE: 53.3 years), the intensive NCI/AvL protocol leads to a 1.2% lower DSM and a 6 months higher LE (DSM: 1.81%; LE: 53.9 years). The hypothetical follow-up scenario during the first two years shows a DSM of 6.83% and an LE of 51.4 years. Abdominal CT scans of the retroperitoneal lymph nodes appear to be important, while chest X-rays have little impact on DSM. CONCLUSION: A follow-up policy limited to the first two years will result in an unacceptable high percentage of death from disease (6.83%). The relatively small benefit of an intensive follow-up protocol as proposed by the NCI/AvL, compared to that of the EAU, must be weighed against its economic and psychological costs. Our model suggests that CT-scanning is essential for a low DSM, whereas the large number of X-rays seem to have little additional effect.