Assessment of biological matrices for the detection of in utero cannabis exposure.

Cannabis consumption has been increasing worldwide among pregnant women. Due to the negative effects of prenatal cannabis exposure, it is necessary to develop an objective, sensitive, and specific method to determine cannabinoids use during pregnancy. In this study, we compared four different biological samples, maternal hair, meconium, umbilical cord, and placenta, for the detection of in utero cannabis exposure. The biological samples were collected from 627 mother-newborn dyads. All hair and meconium samples were analyzed, and umbilical cord and placenta if hair and/or meconium were positive for cannabinoids. Meconium and hair showed to complement each other, with an agreement between hair and meconium results of 96.7% but only 34.3% if just positive results were considered. Umbilical cord and placenta results showed a better agreement with meconium (91.3% and 92.6%, respectively) than with hair (39.1% and 34.6%, respectively). The predominant metabolites in meconium were 11-nor-carboxy-THC (THCCOOH) and 8,11-dihydroxy-THC (diOHTHC), and in umbilical cord and placenta was THCCOOH-glucuronide. Cannabidiol (CBD) and cannabinol (CBN) were detected in meconium but not in any umbilical cord or placenta. For the first time, prenatal marijuana exposure was analyzed and compared in paired hair, meconium, umbilical cord, and placental samples. Hair and meconium positivity rate was similar, but a more sensitive and specific analytical method for the hair may resolve discrepancies between the matrices. Umbilical cord and placenta may be considered suitable alternative matrices to meconium through the determination of THCCOOH-glucuronide as a biomarker of cannabis exposure.

Estimating extra length of stay due to healthcare-associated infections before and after implementation of a hospital-wide infection control program.

INTRODUCTION: Healthcare-associated infections (HAIs) are a major health concern and have substantial effects on morbidity and mortality and increase healthcare costs. We investigated the effect of a hospital-wide program for the prevention of HAIs on additional length of stay (LOS). METHODS: We analyzed data from a prospective, single-center, quasi-experimental study with two surveillance periods before and after implementation of an infection prevention intervention program. HAI diagnosis was made according to surveillance definition criteria established by the US Centers for Disease Control and Prevention. A multistate model was used to estimate additional LOS for patients with HAI in both surveillance periods. RESULTS: During the first and second periods, 1,568 and 2,336 HAIs were identified among 26,943 and 35,211 patients, respectively. For HAI patients exclusively treated in a general ward, additional LOS was 8.4 (95% confidence interval, CI: 6.8-10.0) days in the first period and 9.6 (95% CI: 8.3-11.0) days in the second period (p = 0.26). For HAI patients treated in both an intensive care unit (ICU) and a general ward, additional LOS was 8.1 (95% CI: 6.3-9.9) days in the first period to 7.3 (95% CI: 6.1-8.5) days in the second period (p = 0.47). CONCLUSIONS: Healthcare-associated infections prolong LOS. A hospital-wide infection control program did not alter the prolongation of LOS.

Sequential organ failure assessment score is an excellent operationalization of disease severity of adult patients with hospitalized community acquired pneumonia - results from the prospective observational PROGRESS study.

BACKGROUND: CAP (Community acquired pneumonia) is frequent, with a high mortality rate and a high burden on health care systems. Development of predictive biomarkers, new therapeutic concepts, and epidemiologic research require a valid, reproducible, and quantitative measure describing CAP severity. METHODS: Using time series data of 1532 patients enrolled in the PROGRESS study, we compared putative measures of CAP severity for their utility as an operationalization. Comparison was based on ability to correctly identify patients with an objectively severe state of disease (death or need for intensive care with at least one of the following: substantial respiratory support, treatment with catecholamines, or dialysis). We considered IDSA/ATS minor criteria, CRB-65, CURB-65, Halm criteria, qSOFA, PSI, SCAP, SIRS-Score, SMART-COP, and SOFA. RESULTS: SOFA significantly outperformed other scores in correctly identifying a severe state of disease at the day of enrollment (AUC = 0.948), mainly caused by higher discriminative power at higher score values. Runners-up were the sum of IDSA/ATS minor criteria (AUC = 0.916) and SCAP (AUC = 0.868). SOFA performed similarly well on subsequent study days (all AUC > 0.9) and across age groups. In univariate and multivariate analysis, age, sex, and pack-years significantly contributed to higher SOFA values whereas antibiosis before hospitalization predicted lower SOFA. CONCLUSIONS: SOFA score can serve as an excellent operationalization of CAP severity and is proposed as endpoint for biomarker and therapeutic studies. TRIAL REGISTRATION: clinicaltrials.gov NCT02782013 , May 25, 2016, retrospectively registered.

Standardized Haller and Asymmetry Index Combined for a More Accurate Assessment of Pectus Excavatum.

BACKGROUND: The measurement of the Haller index (HI) is not standardized, and HI does not consider the asymmetry of pectus excavatum. The aim of this study was to determine the most appropriate level for measuring the HI and to introduce the asymmetry index (AI) in order to respect the aspect of asymmetry. METHODS: Preoperative computer tomography scans of 43 patients with pectus excavatum were retrospectively analyzed by measuring both the HI and the AI at 3 different levels: (I) sternomanubrial junction; (II) caudal end of corpus sterni; and (III) tip of the xiphoid. The control group comprised 33 patients without chest wall deformity and a HI < 3.25. For each patient HI and AI were calculated according to a standardized protocol. A McNemar test was used for statistical analyses. RESULTS: The sensitivity of the HI was highest when measured at level II (p < 0.388), and the AI exhibited the highest sensitivity at level I. When combining both indices, the sensitivity of assessing pectus excavatum significantly increased compared with the use of HI at level II alone (p < 0.002). CONCLUSIONS: The measurement of the HI at level II represents the most valid standardized parameter for assessment of the severity of pectus excavatum. Asymmetry, on the other hand, is best assessed by the AI measured at level I. The combination of the standardized HI and AI not only provides a much more accurate description of pectus excavatum, but also improves the comparability of pectus excavatum patients in general.

Calibration of colloidal probes with atomic force microscopy for micromechanical assessment.

Mechanical assessment of biological materials and tissue-engineered scaffolds is increasingly focusing at lower length scale levels. Amongst other techniques, atomic force microscopy (AFM) has gained popularity as an instrument to interrogate material properties, such as the indentation modulus, at the microscale via cantilever-based indentation tests equipped with colloidal probes. Current analysis approaches of the indentation modulus from such tests require the size and shape of the colloidal probe as well as the spring constant of the cantilever. To make this technique reproducible, there still exist the challenge of proper calibration and validation of such mechanical assessment. Here, we present a method to (a) fabricate and characterize cantilevers with colloidal probes and (b) provide a guide for estimating the spring constant and the sphere diameter that should be used for a given sample to achieve the highest possible measurement sensitivity. We validated our method by testing agarose samples with indentation moduli ranging over three orders of magnitude via AFM and compared these results with bulk compression tests. Our results show that quantitative measurements of indentation modulus is achieved over three orders of magnitude ranging from 1 kPa to 1000 kPa via AFM cantilever-based microindentation experiments. Therefore, our approach could be used for quantitative micromechanical measurements without the need to perform further validation via bulk compression experiments.

Telephone health services in the field of rare diseases: a qualitative interview study examining the needs of patients, relatives, and health care professionals in Germany.

BACKGROUND: Rare diseases are, by definition, very serious and chronic diseases with a high negative impact on quality of life. Approximately 350 million people worldwide live with rare diseases. The resulting high disease burden triggers health information search, but helpful, high-quality, and up-to-date information is often hard to find. Therefore, the improvement of health information provision has been integrated in many national plans for rare diseases, discussing the telephone as one access option. In this context, this study examines the need for a telephone service offering information for people affected by rare diseases, their relatives, and physicians. METHODS: In total, 107 individuals participated in a qualitative interview study conducted in Germany. Sixty-eight individuals suffering from a rare disease or related to somebody with rare diseases and 39 health care professionals took part. Individual interviews were conducted using a standardized semi-structured questionnaire. Interviews were analysed using the qualitative content analysis, triangulating patients, relatives, and health care professionals. The fulfilment of qualitative data processing standards has been controlled for. RESULTS: Out of 68 patients and relatives and 39 physicians, 52 and 18, respectively, advocated for the establishment of a rare diseases telephone service. Interviewees expected a helpline to include expert staffing, personal contact, good availability, low technical barriers, medical and psychosocial topics of counselling, guidance in reducing information chaos, and referrals. Health care professionals highlighted the importance of medical topics of counselling-in particular, differential diagnostics-and referrals. CONCLUSIONS: Therefore, the need for a national rare diseases helpline was confirmed in this study. Due to limited financial resources, existing offers should be adapted in a stepwise procedure in accordance with the identified attributes.

Cost analysis of whole genome sequencing in German clinical practice.

OBJECTIVES: Whole genome sequencing (WGS) is an emerging tool in clinical diagnostics. However, little has been said about its procedure costs, owing to a dearth of related cost studies. This study helps fill this research gap by analyzing the execution costs of WGS within the setting of German clinical practice. METHODOLOGY: First, to estimate costs, a sequencing process related to clinical practice was undertaken. Once relevant resources were identified, a quantification and monetary evaluation was conducted using data and information from expert interviews with clinical geneticists, and personnel at private enterprises and hospitals. This study focuses on identifying the costs associated with the standard sequencing process, and the procedure costs for a single WGS were analyzed on the basis of two sequencing platforms-namely, HiSeq 2500 and HiSeq Xten, both by Illumina, Inc. In addition, sensitivity analyses were performed to assess the influence of various uses of sequencing platforms and various coverage values on a fixed-cost degression. RESULTS: In the base case scenario-which features 80 % utilization and 30-times coverage-the cost of a single WGS analysis with the HiSeq 2500 was estimated at €3858.06. The cost of sequencing materials was estimated at €2848.08; related personnel costs of €396.94 and acquisition/maintenance costs (€607.39) were also found. In comparison, the cost of sequencing that uses the latest technology (i.e., HiSeq Xten) was approximately 63 % cheaper, at €1411.20. CONCLUSIONS: The estimated costs of WGS currently exceed the prediction of a 'US$1000 per genome', by more than a factor of 3.8. In particular, the material costs in themselves exceed this predicted cost.

Hospital-related cost of sepsis: A systematic review.

OBJECTIVES: This article systematically reviews research on the costs of sepsis and, as a secondary aim, evaluates the quality of economic evaluations reported in peer-reviewed journals. METHODS: We systematically searched the MEDLINE, National Health Service (Abstracts of Reviews of Effects, Economic Evaluation and Health Technology Assessment), Cost-effectiveness Analysis Registry and Web of Knowledge databases for studies published between January 2005 and June 2015. We selected original articles that provided cost and cost-effectiveness analyses, defined sepsis and described their cost calculation method. Only studies that considered index admissions and re-admissions in the first 30 days were published in peer-reviewed journals and used standard treatments were considered. All costs were adjusted to 2014 US dollars. Medians and interquartile ranges (IQRs) for various costs of sepsis were calculated. The quality of economic studies was assessed using the Drummond 10-item checklist. RESULTS: Overall, 37 studies met our eligibility criteria. The median of the mean hospital-wide cost of sepsis per patient was $32,421 (IQR $20,745-$40,835), and the median of the mean ICU cost of sepsis per patient was $27,461 (IQR $16,007-$31,251). Overall, the quality of economic studies was low. CONCLUSIONS: Estimates of the hospital-related costs of sepsis varied considerably across the included studies depending on the method used for cost calculation, the type of sepsis and the population that was examined. A standard model for conducting cost improve the quality of studies on the costs of sepsis.

[Whole-genome sequencing in German clinical practice : Economic impacts of its use in selected areas of application]. / Ganzgenomsequenzierung in der deutschen Versorgung : Ökonomische Auswirkungen eines Einsatzes in ausgewählten Anwendungsgebieten.

BACKGROUND: The diagnostic use of whole-genome sequencing (WGS) is a growing issue in medical care. Due to limited resources in public health service, budget-impact analyses are necessary prior to implementation. OBJECTIVE: A budget-impact analysis for WGS of all newborns and diagnostic investigation of tumor patients in different oncologic indications were evaluated. METHODS: A cost analysis of WGS based on a quality-assured process chart for WGS at the German Cancer Research Center (DKFZ), Heidelberg, constitutes the basis for this evaluation. Data from the National Association of Statutory Health Insurance Funds and the Robert-Koch-Institute, Berlin, were used for calculations of specific clinical applications. RESULTS AND DISCUSSION: WGS in newborn screening leads to costs of € 2.85 bn and to an increase of total expenditure by 1.41%. Sequencing of all tumor patients would cost approximately € 0.84 bn, which corresponds to 0.42% of total expenditures. In all scenarios, the sole consideration of procedure costs results in increasing costs. However, in cost discussions potential savings (reduction of disease-related follow-up-costs, improved cost-effectiveness of medical measures etc.) should be considered. Such considerations are the subject of economic indication-specific evaluations. WGS has the potential to generate a large number of deterministic findings for which treatment options are limited. Hence, it is necessary to limit indications, in which WGS has proven medical evidence.

Cost-Effectiveness of Pharmacogenomic and Pharmacogenetic Test-Guided Personalized Therapies: A Systematic Review of the Approved Active Substances for Personalized Medicine in Germany.

BACKGROUND: The use of targeted therapies has recently increased. Pharmacogenetic tests are a useful tool to guide patient treatment and to test a response before administering medicines. Pharmacogenetic tests can predict potential drug resistance and may be used for determining genotype-based drug dosage. However, their cost-effectiveness as a diagnostic tool is often debatable. In Germany, 47 active ingredients are currently approved. A prior predictive test is required for 39 of these and is recommended for eight. The objective of this study was to review the cost-effectiveness (CE) of pharmacogenetic test-guided drug therapy and compare the application of drugs with and without prior genetic testing. METHODS: A systematic literature review was conducted to identify the CE and cost-utility of genetic tests. Studies from January 2000 until November 2015 were searched in 16 databases including Medline, Embase, and Cochrane. A quality assessment of the full-text publications was performed using the validated Quality of Health Economic Studies (QHES) instrument. RESULTS: In the majority of the included studies, the pharmacogenetic test-guided therapy represents a cost-effective/cost-saving treatment option. Only seven studies lacked a clear statement of CE or cost-savings, because of uncertainty, restriction to specific patient populations, or assumptions for comparative therapy. Moreover, the high quality of the available evidence was evaluated. CONCLUSION: Pharmacogenetic testing constitutes an opportunity to improve the CE of pharmacotherapy. The CE of targeted therapies depends on various factors including costs, prevalence of biomarkers, and test sensitivity and specificity. To guarantee the CE comparability of stratified drug therapies, national and international standards for evaluation studies should be defined.

Extra length of stay and costs because of health care-associated infections at a German university hospital.

BACKGROUND: Health care-associated infections (HAIs) can be associated with increased health care costs. We examined extra length of hospital stay (LOS) and associated per diem costs attributable to HAIs in a large academic medical center. METHODS: Data for analysis were acquired in a preinterventional phase of a prospective cohort study (ALERTS) conducted over 12 months in 27 general and 4 intensive care units at Jena University Hospital. HAIs were identified among patients hospitalized for ≥48 hours with at least 1 risk factor for HAI and new antimicrobial therapy; the diagnosis was confirmed by U.S. Centers for Disease Control and Prevention criteria. Extra LOS was estimated by multistate modeling, and associated extra costs were based on average per diem costs for clinical units sampled. RESULTS: Of a total of 22,613 patients hospitalized for ≥48 hours, 893 (3.95%) experienced 1,212 episodes of HAI during 12 months. The associated mean extra LOS ± SEM in general units was 8.45 ± 0.80 days per case and 8.09 ± 0.91 days for patients treated in both general and intensive care units. Additional costs attributable to HAIs were €5,823-€11,840 ($7,453-$15,155) per infected patient. CONCLUSION: HAIs generated substantial extra costs by prolonging hospitalization. Potential clinical and financial savings may be realized by implementing effective infection prevention programs.

Conformational analysis of oligosaccharides and polysaccharides using molecular dynamics simulations.

Complex carbohydrates usually have a large number of rotatable bonds and consequently a large number of theoretically possible conformations can be generated (combinatorial explosion). The application of systematic search methods for conformational analysis of carbohydrates is therefore limited to disaccharides and trisaccharides in a routine analysis. An alternative approach is to use Monte-Carlo methods or (high-temperature) molecular dynamics (MD) simulations to explore the conformational space of complex carbohydrates. This chapter describes how to use MD simulation data to perform a conformational analysis (conformational maps, hydrogen bonds) of oligosaccharides and how to build realistic 3D structures of large polysaccharides using Conformational Analysis Tools (CAT).

A systematic review of the cost-effectiveness of targeted therapies for metastatic non-small cell lung cancer (NSCLC).

BACKGROUND: Non-small cell lung cancer (NSCLC) imposes a substantial burden on patients, health care systems and society due to increasing incidence and poor survival rates. In recent years, advances in the treatment of metastatic NSCLC have resulted from the introduction of targeted therapies. However, the application of these new agents increases treatment costs considerably. The objective of this article is to review the economic evidence of targeted therapies in metastatic NSCLC. METHODS: A systematic literature review was conducted to identify cost-effectiveness (CE) as well as cost-utility studies. Medline, Embase, SciSearch, Cochrane, and 9 other databases were searched from 2000 through April 2013 (including update) for full-text publications. The quality of the studies was assessed via the validated Quality of Health Economic Studies (QHES) instrument. RESULTS: Nineteen studies (including update) involving the MoAb bevacizumab and the Tyrosine-kinase inhibitors erlotinib and gefitinib met all inclusion criteria. The majority of studies analyzed the CE of first-line maintenance and second-line treatment with erlotinib. Five studies dealt with bevacizumab in first-line regimes. Gefitinib and pharmacogenomic profiling were each covered by only two studies. Furthermore, the available evidence was of only fair quality. CONCLUSION: First-line maintenance treatment with erlotinib compared to Best Supportive Care (BSC) can be considered cost-effective. In comparison to docetaxel, erlotinib is likely to be cost-effective in subsequent treatment regimens as well. The insights for bevacizumab are miscellaneous. There are findings that gefitinib is cost-effective in first- and second-line treatment, however, based on only two studies. The role of pharmacogenomic testing needs to be evaluated. Therefore, future research should improve the available evidence and consider pharmacogenomic profiling as specified by the European Medicines Agency. Upcoming agents like crizotinib and afatinib need to be analyzed as well.

Vaccination of children with a live-attenuated, intranasal influenza vaccine - analysis and evaluation through a Health Technology Assessment.

BACKGROUND: Influenza is a worldwide prevalent infectious disease of the respiratory tract annually causing high morbidity and mortality in Germany. Influenza is preventable by vaccination and this vaccination is so far recommended by the The German Standing Committee on Vaccination (STIKO) as a standard vaccination for people from the age of 60 onwards. Up to date a parenterally administered trivalent inactivated vaccine (TIV) has been in use almost exclusively. Since 2011 however a live-attenuated vaccine (LAIV) has been approved additionally. Consecutively, since 2013 the STIKO recommends LAIV (besides TIV) for children from 2 to 17 years of age, within the scope of vaccination by specified indications. LAIV should be preferred administered in children from 2 to 6 of age. The objective of this Health Technology Assessment (HTA) is to address various research issues regarding the vaccination of children with LAIV. The analysis was performed from a medical, epidemiological and health economic perspective, as well as from an ethical, social and legal point of view. METHOD: An extensive systematic database research was performed to obtain relevant information. In addition a supplementary research by hand was done. Identified literature was screened in two passes by two independent reviewers using predefined inclusion and exclusion criteria. Included literature was evaluated in full-text using acknowledged standards. Studies were graded with the highest level of evidence (1++), if they met the criteria of European Medicines Agency (EMA)-Guidance: Points to consider on applications with 1. meta-analyses; 2. one pivotal study. RESULTS: For the medical section, the age of the study participants ranges from 6 months to 17 years. Regarding study efficacy, in children aged 6 months to ≤7 years, LAIV is superior to placebo as well as to a vac-cination with TIV (Relative Risk Reduction - RRR - of laboratory confirmed influenza infection approx. 80% and 50%, respectively). In children aged >7 to 17 years (= 18th year of their lives), LAIV is superior to a vaccination with TIV (RRR 32%). For this age group, no studies that compared LAIV with placebo were identified. It can be concluded that there is high evidence for superior efficacy of LAIV (compared to placebo or TIV) among children aged 6 months to ≤7 years. For children from >7 to 17 years, there is moderate evidence for superiority of LAIV for children with asthma, while direct evidence for children from the general population is lacking for this age group. Due to the efficacy of LAIV in children aged 6 months to ≤7 years (high evidence) and the efficacy of LAIV in children with asthma aged >7 to 17 years (moderate evidence), LAIV is also very likely to be efficacious among children in the general population aged >7 to 17 years (indirect evidence). In the included studies with children aged 2 to 17 years, LAIV was safe and well-tolerated; while in younger children LAIV may increase the risk of obstruction of the airways (e.g. wheezing). In the majority of the evaluated epidemiological studies, LAIV proved to be effective in the prevention of influenza among children aged 2-17 years under everyday conditions (effectiveness). The trend appears to indicate that LAIV is more effective than TIV, although this can only be based on limited evidence for methodological reasons (observational studies). In addition to a direct protective effect for vaccinated children themselves, indirect protective ("herd protection") effects were reported among non-vaccinated elderly population groups, even at relatively low vaccination coverage of children. With regard to safety, LAIV generally can be considered equivalent to TIV. This also applies to the use among children with mild chronically obstructive conditions, from whom LAIV therefore does not have to be withheld. In all included epidemiological studies, there was some risk of bias identified, e.g. due to residual confounding or other methodology-related sources of error. In the evaluated studies, both the vaccination of children with previous illnesses and the routine vaccination of (healthy) children frequently involve cost savings. This is especially the case if one includes indirect costs from a societal perspective. From a payer perspective, a routine vaccination of children is often regarded as a highly cost-effective intervention. However, not all of the studies arrive at consistent results. In isolated cases, relatively high levels of cost-effectiveness are reported that make it difficult to perform a conclusive assessment from an economic perspective. Based on the included studies, it is not possible to make a clear statement about the budget impact of using LAIV. None of the evaluated studies provides results for the context of the German healthcare setting. The efficacy of the vaccine, physicians' recommendations, and a potential reduction in influenza symptoms appear to play a role in the vaccination decision taken by parents/custodians on behalf of their children. Major barriers to the utilization of influenza vaccination services are a low level of perception and an underestimation of the disease risk, reservations concerning the safety and efficacy of the vaccine, and potential side effects of the vaccine. For some of the parents surveyed, the question as to whether the vaccine is administered as an injection or nasal spray might also be important. CONCLUSION: In children aged 2 to 17 years, the use of LAIV can lead to a reduction of the number of influenza cases and the associated burden of disease. In addition, indirect preventive effects may be expected, especially among elderly age groups. Currently there are no data available for the German healthcare setting. Long-term direct and indirect effectiveness and safety should be supported by surveillance programs with a broader use of LAIV. Since there is no general model available for the German healthcare setting, statements concerning the cost-effectiveness can be made only with precaution. Beside this there is a need to conduct health eco-nomic studies to show the impact of influenza vaccination for children in Germany. Such studies should be based on a dynamic transmission model. Only these models are able to include the indirect protective effects of vaccination correctly. With regard to ethical, social and legal aspects, physicians should discuss with parents the motivations for vaccinating their children and upcoming barriers in order to achieve broader vaccination coverage. The present HTA provides an extensive basis for further scientific approaches and pending decisions relating to health policy.

Sepsis survivors monitoring and coordination in outpatient health care (SMOOTH): study protocol for a randomized controlled trial.

BACKGROUND: Sepsis sequelae include critical illness polyneuropathy, myopathy, wasting, neurocognitive deficits, post-traumatic stress disorder, depression and chronic pain. Little is known howlong-term sequelae following hospital discharge are treated. The aim of our study is to determine the effect of a primary care-based, long-term program on health-related quality of life in sepsis survivors. METHODS/DESIGN: In a two-armed randomized multicenter interventional study, patients after sepsis (n = 290) will be assessed at 6, 12 and 24 months. Patients are eligible if severe sepsis or septic shock (ICD-10), at least two criteria of systemic inflammatory response syndrome (SIRS), at least one organ dysfunction and sufficient cognitive capacity are present. The intervention comprises 1) discharge management, 2) training of general practitioners and patients in evidence-based care for sepsis sequelae and 3) telephone monitoring of patients. At six months, we expect an improved primary outcome (health-related quality of life/SF-36) and improved secondary outcomes such as costs, mortality, clinical-, psycho-social- and process-of-care measures in the intervention group compared to the control group. DISCUSSION: This study evaluates a primary care-based, long-term program for patients after severe sepsis. Study results may add evidence for improved sepsis care management. General practitioners may contribute efficiently to sepsis aftercare. TRIAL REGISTRATION: U1111-1119-6345. DRKS00000741, CCT-NAPN-20875 (25 February 2011).

Genome sequencing: a systematic review of health economic evidence.

Recently the sequencing of the human genome has become a major biological and clinical research field. However, the public health impact of this new technology with focus on the financial effect is not yet to be foreseen. To provide an overview of the current health economic evidence for genome sequencing, we conducted a thorough systematic review of the literature from 17 databases. In addition, we conducted a hand search. Starting with 5 520 records we ultimately included five full-text publications and one internet source, all focused on cost calculations. The results were very heterogeneous and, therefore, difficult to compare. Furthermore, because the methodology of the publications was quite poor, the reliability and validity of the results were questionable. The real costs for the whole sequencing workflow, including data management and analysis, remain unknown. Overall, our review indicates that the current health economic evidence for genome sequencing is quite poor. Therefore, we listed aspects that needed to be considered when conducting health economic analyses of genome sequencing. Thereby, specifics regarding the overall aim, technology, population, indication, comparator, alternatives after sequencing, outcomes, probabilities, and costs with respect to genome sequencing are discussed. For further research, at the outset, a comprehensive cost calculation of genome sequencing is needed, because all further health economic studies rely on valid cost data. The results will serve as an input parameter for budget-impact analyses or cost-effectiveness analyses.

Influence of pharmacogenomic profiling prior to pharmaceutical treatment in metastatic colorectal cancer on cost effectiveness : a systematic review.

BACKGROUND: Metastatic colorectal cancer (mCRC) imposes a substantial health burden on individual patients and society. Furthermore, rising costs in oncology cause a growing concern about reimbursement for innovations in this sector. The promise of pharmacogenomic profiling and related stratified therapies in mCRC is to improve treatment efficacy and potentially save costs. Among other examples, the commonly used epidermal growth factor receptor (EGFR) antibodies cetuximab and panitumumab are only effective in patients with kirsten rat sarcoma viral oncogene homolog (KRAS) wild-type cancers. Hence, the adaptation of predictive biomarker testing might be a valid strategy for healthcare systems worldwide. OBJECTIVE: This study aims to review the clinical and economic evidence supporting pharmacogenomic profiling prior to the administration of pharmaceutical treatment in mCRC. Moreover, key drivers and areas of uncertainty in cost-effectiveness evaluations are analysed. METHODS: A systematic literature review was conducted to identify studies evaluating the cost effectiveness of predictive biomarkers and the result dependent usage of pharmaceutical agents in mCRC. RESULTS: The application of predictive biomarkers to detect KRAS mutations prior to the administration of EGFR antibodies saved treatment costs and was cost effective in all identified evaluations. However, because of the lack of data regarding cost-effectiveness analyses for predictive biomarker testing, e.g. for first-line treatment, definitive conclusions cannot be stated. Key drivers and areas of uncertainty in current cost-effectiveness analyses are, among others, the consideration of predictive biomarker costs, the characteristics of single predictive biomarkers and the availability of clinical data for the respective pharmaceutical intervention. Especially the cost effectiveness of uridine diphosphate-glucuronyl transferase 1A1 (UGT1A1) mutation analysis prior to irinotecan-based chemotherapy remains unclear. CONCLUSION: Pharmacogenomic profiling has the potential to improve the cost effectiveness of pharmaceutical treatment in mCRC. Hence, quantification of the economic impact of stratified medicine as well as cost-effectiveness analyses of pharmacogenomic profiling are becoming more important. Nevertheless, the methods applied in cost-effectiveness evaluations for the usage of predictive biomarkers for patient selection as well as the level of evidence required to determine clinical effectiveness are areas for further research. However, mCRC is one of the first indications in which stratified therapies are used in clinical practice. Thus, clinical and economic experiences could be helpful when adopting pharmacogenomic profiling into clinical practice for other indications.

Laparoscopic-assisted single-port appendectomy in children: it is a safe and cost-effective alternative to conventional laparoscopic techniques?

Aim. Laparoscopic-assisted single-port appendectomy (SPA), although combining the advantages of open and conventional laparoscopic surgery, is still not widely used in childhood. The aim of this study was to evaluate the safety and the cost effectiveness of SPA in children. Methods. After institutional review board approval, we retrospectively evaluated 262 children who underwent SPA. The appendix was dissected outside the abdominal cavity as in open surgery. For stump closure, we used two 3/0 vicryl RB-1 sutures. Results. We identified 146 boys (55.7%) and 116 girls (44.3%). Median age at operation was 11.4 years (range, 1.1-15.9). Closure of the appendiceal stump using two sutures (cost: USD 15) was successful in all patients. Neither a stapler (cost: USD 276) nor endoloops (cost: USD 89) were used. During a follow-up of up to 69 months (range, 30-69), six obese children (2.3%, body mass index >95th percentile) developed an intra-abdominal abscess after perforated appendicitis. No insufficiency of the appendiceal stump was observed by ultrasound. Five of them were treated successfully by antibiotics, one child required drainage. Conclusion. The SPA technique with conventional extracorporal closure of the appendiceal stump is safe and cost effective. In our unit, SPA is the standard procedure for appendectomy in children.

Cost-effectiveness of targeted therapy with cetuximab in patients with K-ras wild-type colorectal cancer presenting with initially unresectable metastases limited to the liver in a German setting.

BACKGROUND: In patients with metastases limited to the liver (liver-limited disease [LLD]), effective therapies such as monoclonal antibodies combined with chemotherapy may facilitate metastasis resection and improve long-term survival. OBJECTIVE: This study assessed the cost-effectiveness of bevacizumab and cetuximab in the treatment of patients with colorectal cancer presenting with initially unresectable liver metastases of the Kirsten rat sarcoma viral oncogene homolog (K-ras) wild type, from the perspective of German statutory health insurance. METHODS: The health-economic modeling approach presented here made indirect comparisons between available data on bevacizumab and cetuximab treatment outcomes using evidence synthesis techniques, extrapolating from the follow-up duration of identified clinical trials to a longer time horizon of up to 10 years and inferring costs and health outcomes based on modeled patient pathways. Expert opinion and Delphi panel methods were used for some assumptions, when evidence was missing. Probabilistic sensitivity analyses and different scenario analyses were applied to test for uncertainty around input parameters and assumptions. RESULTS: For the metastatic colorectal cancer LLD population with K-ras wild-type genotype, mean overall survival estimates were 37.7 months for first-line treatment with cetuximab plus FOLFIRI (irinotecan, leucovorin, fluorouracil) and 30.4 months for bevacizumab plus FOLFOX (oxaliplatin, leucovorin, fluorouracil). Corresponding discounted survival estimates were 2.88 life-years with cetuximab plus FOLFIRI versus 2.38 life-years with bevacizumab plus FOLFOX, an average gain of 0.50 discounted life-years. The incremental cost-effectiveness ratio of cetuximab plus FOLFIRI versus bevacizumab plus FOLFOX was €15,020 (year 2010 €) per life-year gained in the base case (with a 95% CI from the probabilistic sensitivity analysis of €3806-€24,660). Results were robust in different scenario analyses as well as in the probabilistic sensitivity analysis. CONCLUSIONS: First-line treatment with cetuximab plus FOLFIRI offers a cost-effective treatment option versus bevacizumab plus FOLFOX for the metastatic colorectal cancer LLD population with K-ras wild-type genotype in Germany. K-ras testing should be performed on all presenting cases of metastatic colorectal cancer to ensure access to this treatment option.