Filgotinib for Treating Moderately to Severely Active Ulcerative Colitis: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

The National Institute for Health and Care Excellence invited the manufacturer (Galapagos) of filgotinib (Jyseleca®), as part of the Single Technology Appraisal process, to submit evidence for the clinical effectiveness and cost effectiveness of filgotinib for treating moderately to severely active ulcerative colitis in adults who have had an inadequate response, loss of response or were intolerant to a previous biologic agent or conventional therapy. Kleijnen Systematic Reviews Ltd, in collaboration with Maastricht University Medical Centre+, was commissioned to act as the independent Evidence Review Group. This paper summarises the company submission, presents the Evidence Review Group's critical review on the clinical and cost-effectiveness evidence in the company submission, highlights the key methodological considerations and describes the development of the National Institute for Health and Care Excellence guidance by the Appraisal Committee. The company submission included one relevant study for the comparison of filgotinib versus placebo: the SELECTION trial. As there was no head-to-head evidence with any of the comparators, the company performed two separate network meta-analyses, one for the biologic-naïve population and one for the biologic-experienced population, and for both the induction and maintenance phases. The Evidence Review Group questioned the validity of the maintenance network meta-analysis because it assumed all active treatments to be comparators in this phase, which is not in line with clinical practice. The economic analysis used a number of assumptions that introduced substantial uncertainty, which could not be fully explored, for instance, the assumption that a risk of loss of response would be independent of health state and constant over time. Company and Evidence Review Group results indicate that at its current price, and disregarding confidential discounts for comparators and subsequent treatments, filgotinib dominates some comparators (golimumab and adalimumab in the company base case, all but intravenous and subcutaneous vedolizumab in the Evidence Review Group's base case) in the biologic-naïve population. In the biologic-experienced population, filgotinib dominates all comparators in both the company and the Evidence Review Group's base case. Results should be interpreted with caution as some important uncertainties were not included in the modelling. These uncertainties were mostly centred around the maintenance network meta-analysis, loss of response, health-related quality-of-life estimates and modelling of dose escalation. The National Institute for Health and Care Excellence recommended filgotinib within its marketing authorisation, as an option for treating moderately to severely active ulcerative colitis in adults when conventional or biological treatment cannot be tolerated, or if the disease has not responded well enough or has stopped responding to these treatments, and if the company provides filgotinib according to the commercial arrangement.

DNA and RNA Alterations Associated with Colorectal Peritoneal Metastases: A Systematic Review.

BACKGROUND: As colorectal cancer (CRC) patients with peritoneal metastases (PM) have a poor prognosis, new treatment options are currently being investigated for CRC patients. Specific biomarkers in the primary tumor could serve as a prediction tool to estimate the risk of distant metastatic spread. This would help identify patients eligible for early treatment. AIM: To give an overview of previously studied DNA and RNA alterations in the primary tumor correlated to colorectal PM and investigate which gene mutations should be further studied. METHODS: A systematic review of all published studies reporting genomic analyses on the primary tissue of CRC tumors in relation to PM was undertaken according to PRISMA guidelines. RESULTS: Overall, 32 studies with 18,906 patients were included. BRAF mutations were analyzed in 17 articles, of which 10 found a significant association with PM. For all other reported genes, no association with PM was found. Two analyses with broader cancer panels did not reveal any new biomarkers. CONCLUSION: An association of specific biomarkers in the primary tumors of CRC patients with metastatic spread into peritoneum could not be proven. The role of BRAF mutations should be further investigated. In addition, studies searching for potential novel biomarkers are still required.

Diagnostic Performance of Magnetic Resonance Imaging for Parathyroid Localization of Primary Hyperparathyroidism: A Systematic Review.

Accurate preoperative localization is crucial for successful minimally invasive parathyroidectomy in primary hyperparathyroidism (PHPT). Preoperative localization can be challenging in patients with recurrent and/or multigland disease (MGD). This has led clinicians to investigate multiple imaging techniques, most of which are associated with radiation exposure. Magnetic resonance imaging (MRI) offers ionizing radiation-free and accurate imaging, making it an attractive alternative imaging modality. The objective of this systematic review is to provide an overview of the diagnostic performance of MRI in the localization of PHPT. PubMed and Embase libraries were searched from 1 January 2000 to 31 March 2023. Studies were included that investigated MRI techniques for the localization of PHPT. The exclusion criteria were (1) secondary/tertiary hyperparathyroidism, (2) studies that provided no diagnostic performance values, (3) studies published before 2000, and (4) studies using 0.5 Tesla MRI scanners. Twenty-four articles were included in the systematic review, with a total of 1127 patients with PHPT. In 14 studies investigating conventional MRI for PHPT localization, sensitivities varied between 39.1% and 94.3%. When employing more advanced MRI protocols like 4D MRI for PHPT localization in 11 studies, sensitivities ranged from 55.6% to 100%. The combination of MR imaging with functional techniques such as 18F-FCH-PET/MRI yielded the highest diagnostic accuracy, with sensitivities ranging from 84.2% to 100% in five studies. Despite the limitations of the available evidence, the results of this review indicate that the combination of MR imaging with functional imaging techniques such as 18F-FCH-PET/MRI yielded the highest diagnostic accuracy. Further research on emerging MR imaging modalities, such as 4D MRI and PET/MRI, is warranted, as MRI exposes patients to minimal or no ionizing radiation compared to other imaging modalities.

The effectiveness of health education interventions on cervical cancer prevention in Africa: A systematic review.

Low levels of knowledge and awareness on cervical cancer play a role in limiting cervical cancer prevention uptake. This systematic review aimed to identify effective educational interventions to increase cervical cancer awareness, knowledge, and subsequently screening or vaccination uptake in African women. A literature search was conducted in Medline and EMBASE databases. We examined original, peer-reviewed English literature published between 2005 and 2020. Nineteen studies examining health education interventions' impact on awareness, knowledge, and screening or vaccination uptake in African women were included. Ten studies were controlled trials, nine performed pre- and post-measurements in one group. Most studies were published between 2015 and 2020 (86%), many were from Nigeria (47%). Studies were mostly set up in communities and schools. The most frequently used intervention was lectures, alone or combined with videos and practical demonstrations. Sixteen studies evaluated knowledge or awareness, and all showed a statistically significant improvement following the intervention. Of the ten studies that evaluated screening uptake, either as the single outcome or combined with knowledge or awareness, six found a significant rise in screening uptake after intervention. Educational interventions increased knowledge and awareness in African women, some boosted uptake of cervical cancer screening, especially when using peer health educators and culturally tailored methods. Innovative approaches such as self-collected HPV testing and mHealth also demonstrated a potential to increase uptake of screening. More research is needed to identify and analyse barriers to screening uptake, which can still be present even after a successful educational intervention.

Intraperitoneal drug delivery systems releasing cytostatic agents to target gastro-intestinal peritoneal metastases in laboratory animals: a systematic review.

For peritoneal metastases (PM), there are few curative treatment options, and they are only available for a select patient group. Recently, new therapies have been developed to deliver intraperitoneal chemotherapy for a prolonged period, suitable for a larger patient group. These drug delivery systems (DDSs) seem promising in the experimental setting. Many types of DDSs have been explored in a variety of animal models, using different cytostatics. This review aimed to provide an overview of animal studies using DDSs containing cytostatics for the treatment of gastro-intestinal PM and identify the most promising therapeutic combinations. The review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and Systematic Review Center for Laboratory Animal Experimentation (SYRCLE) guidelines. The 35 studies included revealed similar results: using a cytostatic-loaded DDS to treat PM resulted in a higher median survival time (MST) and a lower intraperitoneal tumor load compared to no treatment or treatment with a 'free' cytostatic or an unloaded DDS. In 65% of the studies, the MST was significantly longer and in 24% the tumor load was significantly lower in the animals treated with cytostatic-loaded DDS. The large variety of experimental setups made it impossible to identify the most promising DDS-cytostatic combination. In most studies, the risk of bias was unclear due to poor reporting. Future studies should focus more on improving the clinical relevance of the experiments, standardizing the experimental study setup, and improving their methodological quality and reporting.

Diagnostic Performance of Electronic Noses in Cancer Diagnoses Using Exhaled Breath: A Systematic Review and Meta-analysis.

Importance: There has been a growing interest in the use of electronic noses (e-noses) in detecting volatile organic compounds in exhaled breath for the diagnosis of cancer. However, no systematic evaluation has been performed of the overall diagnostic accuracy and methodologic challenges of using e-noses for cancer detection in exhaled breath. Objective: To provide an overview of the diagnostic accuracy and methodologic challenges of using e-noses for the detection of cancer. Data Sources: An electronic search was performed in the PubMed and Embase databases (January 1, 2000, to July 1, 2021). Study Selection: Inclusion criteria were the following: (1) use of e-nose technology, (2) detection of cancer, and (3) analysis of exhaled breath. Exclusion criteria were (1) studies published before 2000; (2) studies not performed in humans; (3) studies not performed in adults; (4) studies that only analyzed biofluids; and (5) studies that exclusively used gas chromatography-mass spectrometry to analyze exhaled breath samples. Data Extraction and Synthesis: PRISMA guidelines were used for the identification, screening, eligibility, and selection process. Quality assessment was performed using Quality Assessment of Diagnostic Accuracy Studies 2. Generalized mixed-effects bivariate meta-analysis was performed. Main Outcomes and Measures: Main outcomes were sensitivity, specificity, and mean area under the receiver operating characteristic curve. Results: This review identified 52 articles with a total of 3677 patients with cancer. All studies were feasibility studies. The sensitivity of e-noses ranged from 48.3% to 95.8% and the specificity from 10.0% to 100.0%. Pooled analysis resulted in a mean (SE) area under the receiver operating characteristic curve of 94% (95% CI, 92%-96%), a sensitivity of 90% (95% CI, 88%-92%), and a specificity of 87% (95% CI, 81%-92%). Considerable heterogeneity existed among the studies because of differences in the selection of patients, endogenous and exogenous factors, and collection of exhaled breath. Conclusions and Relevance: Results of this review indicate that e-noses have a high diagnostic accuracy for the detection of cancer in exhaled breath. However, most studies were feasibility studies with small sample sizes, a lack of standardization, and a high risk of bias. The lack of standardization and reproducibility of e-nose research should be addressed in future research.

Observed versus modelled lifetime overall survival of targeted therapies and immunotherapies for advanced non-small cell lung cancer patients - A systematic review.

Outcomes used for the effectiveness (median) and cost-effectiveness (mean) on overall survival (OS) are different and can vary from one another. Therefore, we compared median and mean OS gains of targeted therapies and immunotherapies for stage IIIB/IV Non-small cell lung cancer and explored underlying aspect. Eligible trials were searched in PubMed, survival curves were digitized, and parametric survival models fitted to model the mean OS. Twenty-seven trials were found for targeted therapies (n = 17) and immunotherapies (n = 10). Differences between median and mean OS gains in months ranged from -2.8 to 6.8 and -4.9 to 0.3 for two different subgroups of targeted therapies, and -2.4 to 11.4 for immunotherapies. The mean OS gain was substantially larger for most immunotherapy trials, due to relatively long survival. Median and mean OS gains did not differ for targeted therapies. Our findings imply a potential discrepancy between the estimates of effectiveness and cost-effectiveness of cancer treatments.

Growth, health, and motor development of 5-year-old children born after preimplantation genetic diagnosis.

OBJECTIVE: To evaluate the growth, health, and motor development of children born after preimplantation genetic diagnosis (PGD). DESIGN: Observational cohort study and comparison of 5-year-old children born after PGD to similar aged children born after IVF/intracytoplasmic sperm injection (ICSI) and children from families with a genetic disorder born after natural conception (NC). SETTING: University hospital. PATIENT(S): One hundred three children were included in the PGD group. The two control groups consisted of 90 children born after IVF/ICSI and 58 children born after NC. INTERVENTION(S): PGD. MAIN OUTCOME MEASURE(S): We measured height, weight, body circumferences, body mass index, and blood pressure and performed a dysmorphological and neurological examination. We also collected data about the children's medical history, health care consultations, and motor milestones. RESULT(S): The mean height, weight, and body mass index were comparable for all groups. Six (5.8%) PGD, four (4.4%) IVF/ICSI, and five (8.6%) NC children had a major congenital abnormality. The incidence of acute and chronic illnesses was similar in all groups. Motor milestones were achieved on time, but the IVF/ICSI group had a slightly younger mean sitting age. None of the children had severe neurological problems. CONCLUSION(S): Five-year-old children born after PGD show normal growth, health, and motor development when compared with children born after IVF/ICSI and NC children from families with a genetic disorder. TRIAL REGISTRATION NUMBER: NCT02149485.

European association for endoscopic surgery (EAES) consensus statement on single-incision endoscopic surgery.

BACKGROUND: Laparoscopic surgery changed the management of numerous surgical conditions. It was associated with many advantages over open surgery, such as decreased postoperative pain, faster recovery, shorter hospital stay and excellent cosmesis. Since two decades single-incision endoscopic surgery (SIES) was introduced to the surgical community. SIES could possibly result in even better postoperative outcomes than multi-port laparoscopic surgery, especially concerning cosmetic outcomes and pain. However, the single-incision surgical procedure is associated with quite some challenges. METHODS: An expert panel of surgeons has been selected and invited to participate in the preparation of the material for a consensus meeting on the topic SIES, which was held during the EAES congress in Frankfurt, June 16, 2017. The material presented during the consensus meeting was based on evidence identified through a systematic search of literature according to a pre-specified protocol. Three main topics with respect to SIES have been identified by the panel: (1) General, (2) Organ specific, (3) New development. Within each of these topics, subcategories have been defined. Evidence was graded according to the Oxford 2011 Levels of Evidence. Recommendations were made according to the GRADE criteria. RESULTS: In general, there is a lack of high level evidence and a lack of long-term follow-up in the field of single-incision endoscopic surgery. In selected patients, the single-incision approach seems to be safe and effective in terms of perioperative morbidity. Satisfaction with cosmesis has been established to be the main advantage of the single-incision approach. Less pain after single-incision approach compared to conventional laparoscopy seems to be considered an advantage, although it has not been consistently demonstrated across studies. CONCLUSIONS: Considering the increased direct costs (devices, instruments and operating time) of the SIES procedure and the prolonged learning curve, wider acceptance of the procedure should be supported only after demonstration of clear benefits.

Perinatal follow-up of children born after preimplantation genetic diagnosis between 1995 and 2014.

PURPOSE: We aim to evaluate the safety of PGD. We focus on the congenital malformation rate and additionally report on adverse perinatal outcome. METHODS: We collated data from a large group of singletons and multiples born after PGD between 1995 and 2014. Data on congenital malformation rates in live born children and terminated pregnancies, misdiagnosis rate, birth parameters, perinatal mortality, and hospital admissions were prospectively collected by questionnaires. RESULTS: Four hundred thirty-nine pregnancies in 381 women resulted in 364 live born children. Nine children (2.5%) had major malformations. This percentage is consistent with other PGD cohorts and comparable to the prevalence reported by the European Surveillance of Congenital Anomalies (EUROCAT). We reported one misdiagnosis resulting in a spontaneous abortion of a fetus with an unbalanced chromosome pattern. 20% of the children were born premature (< 37 weeks) and less than 15% had a low birth weight. The incidence of hospital admissions is in line with prematurity and low birth weight rate. One child from a twin, one child from a triplet, and one singleton died at 23, 32, and 37 weeks of gestation respectively. CONCLUSIONS: We found no evidence that PGD treatment increases the risk on congenital malformations or adverse perinatal outcome. TRIAL REGISTRATION NUMBER: NCT 2 149485.

Single-incision laparoscopic cholecystectomy versus conventional four-port laparoscopic cholecystectomy: a systematic review and meta-analysis.

BACKGROUND: Single-incision laparoscopic cholecystectomy (SILC) might maximize the advantages of laparoscopic cholecystectomy (LC) by reducing postoperative pain and improving cosmesis. However, the safety and feasibility of SILC has not yet been established. This study assesses safety, patient reported outcome measures and feasibility of SILC versus conventional LC. METHODS: Literature search for RCT's comparing SILC with conventional LC in gallstone-related disease was performed in PubMed and Embase. The conventional LC was defined as two 10-mm and two 5-mm ports. Study selection was done according to predefined criteria. Two reviewers assessed the risk of bias. Pooled outcomes were calculated for adverse events, pain, cosmesis, quality of life and feasibility using fixed-effect and random-effects models. RESULTS: Nine RCT's were included with total of 860 patients. No mortality was observed. More mild adverse events (RR 1.55; 95% CI 0.99-2.42) and significantly more serious adverse events (RR 3.00; 95% CI 1.05-8.58) occurred in the SILC group. Postoperative pain (MD -0.46; 95% CI -0.74 to -0.18) and cosmesis (SMD 2.38; 95% CI 1.50-3.26) showed significantly better results for the SILC group, but no differences were observed in quality of life. Operating time (MD 23.12; 95% CI 11.59-34.65) and the need for additional ports (RR 11.43; 95% CI 3.48-37.50) were significantly higher in the SILC group. No difference was observed in conversion to open cholecystectomy or hospital stay longer than 24 h. CONCLUSIONS: SILC does not provide any clear advantages over conventional LC except for less postoperative pain and improved cosmesis. It is questionable whether these advantages outweigh the higher occurrence of adverse events and shortcomings in feasibility. Considering considerable heterogeneity and low methodological quality of the studies it is advisable to perform well-designed RCT's in the future to address the safety and clinical benefits of SILC.

Sexual function after treatment for sacrococcygeal teratoma during childhood.

BACKGROUND: Children treated for sacrococcygeal teratoma (SCT) may suffer from sexual dysfunction later in life because of the extended pelvic surgery performed, however, structured evaluations have not been performed yet. METHODS: The Female Sexual Function Index (FSFI), the International Index of Erectile Function (IIEF) and the Body Image Questionnaire (BIQ) were sent to patients (≥18years) treated for SCT in the Dutch pediatric surgical centers after 1970. RESULTS: Forty-five of 76 patients returned the questionnaires; 28 women (median age 27.3years, range 18.3-41.0) and seven men (median age 22.0years, range 19.1-36.5) were eligible for analysis. The FSFI and IIEF results were compared to healthy controls. Female patients scored significantly lower on the desire (p=0.014), arousal (p=0.013) and lubrication domain (p=0.019). FSFI total-scores of female patients were significantly lower compared to controls [median 30.5 (IQR 28.6-31.4) vs. median 32.4 (IQR 30.6-33.45) p≤0.001] but were above the threshold value for sexual dysfunction. Males reported normal erectile function and penetration ability with normal ejaculation. Females had significant lower BIQ results compared to males; BIQ-cosmesis scores were moderately correlated to the FSFI-desire score (r=-0.37, p=0.028). CONCLUSION: SCT resection in girls may result in diminished sexual function at adult age with worse self-perceived body image. The possibility of sexual complaints should be integrated in the surveillance strategies for these patients.

Risk stratification by abbMEDS and CURB-65 in relation to treatment and clinical disposition of the septic patient at the emergency department: a cohort study.

BACKGROUND: Sepsis leads to high mortality, therefore risk stratification is important. The abbMEDS (abbreviated Mortality Emergency Department Sepsis) score assesses sepsis severity and predicts mortality. In community-acquired pneumonia, the CURB-65 (Confusion, Urea, Respiration, Blood pressure, Age) also provides support in clinical decisions regarding antibiotic treatment and clinical disposition. We investigated the predictive value and feasibility of the abbMEDS and CURB-65 in sepsis patients at the ED and the relationship between the scores and antibiotic treatment and clinical disposition (i.e. admission and type of ward). METHODS: In this retrospective cohort study, we included 725 sepsis patients at the ED. We investigated the value in predicting 28-day mortality and feasibility of both scores. We calibrated the abbMEDS. We further assessed the relationship between the three risk categories per score and antibiotic treatment (i.e. oral and intravenous narrow or broad-spectrum) and clinical disposition. RESULTS: Both abbMEDS and CURB-65 were good predictors of 28-day mortality (13.0%) (AUC 0.77 [95% CI 0.72 - 0.83] and 0.73 [95% CI 0.67 - 0.78], respectively) and feasible (complete score 92.7 and 93.9%, respectively). In the high risk category of the abbMEDS, all patients were admitted and treated with intravenous broad-spectrum antibiotics. In the high risk category of the CURB-65, 2.5% were not admitted and 4.4% received no antibiotics. CONCLUSION: Both abbMEDS and CURB-65 are good predictors of 28-day mortality in septic ED patients. The abbMEDS is well calibrated and matches current clinical decisions concerning antibiotic treatment and clinical disposition, while this is less so for the CURB-65. In the future, use of the abbMEDS at the ED may improve sepsis care when its value as a decision support tool can be confirmed.

Hippocampal GABA transporter distribution in patients with temporal lobe epilepsy and hippocampal sclerosis.

PURPOSE: To determine hippocampal expression of neuronal GABA-transporter (GAT-1) and glial GABA-transporter (GAT-3) in patients with temporal lobe epilepsy (TLE) and hippocampal sclerosis (HS). METHODS: Hippocampal sections were immunohistochemically stained for GABA-transporter 1 and GABA-transporter-3, followed by quantification of the immunoreactivity in the hilus by optical density measurements. GABA-transporter 3 positive hilar cells were counted and GABA-transporter protein expression in sections that included all hippocampal subfields was quantified by Western blot. RESULTS: The hilar GABA-transporter 1 expression of patients with severe hippocampal sclerosis was about 7% lower compared to that in the mild hippocampal sclerosis/control group (p<0.001). The hilar GABA-transporter 3 expression was about 5% lower in the severe hippocampal sclerosis group than in the mild hippocampal sclerosis/control group (non-significant). Also, severe hippocampal sclerosis samples contained 34% less (non-significant) GABA-transporter 3 positive cells compared to that of controls. Protein expression as assessed by Western blot showed that GABA-transporter 1 was equally expressed in mild and severe hippocampal sclerosis samples, whereas GABA-transporter 3 was reduced by about 62% in severe hippocampal sclerosis samples (p<0.0001). CONCLUSION: These data confirm that GABA-transporter expression is spatially and isoform-specific reduced and GABA-transporter 3 positive cell numbers are unchanged in hippocampal sclerosis. Implications for the use of GABAergic antiepileptic therapies in hippocampal sclerosis vs non-hippocampal sclerosis patients remain to be studied.

Randomized controlled trial of transoral incisionless fundoplication vs. proton pump inhibitors for treatment of gastroesophageal reflux disease.

OBJECTIVES: Transoral incisionless fundoplication (TIF) was developed in an attempt to create a minimally invasive endoscopic procedure that mimics antireflux surgery. The objective of this trial was to evaluate effectiveness of TIF compared with proton pump inhibition in a population consisting of gastroesophageal reflux disease (GERD) patients controlled with proton pump inhibitors (PPIs) who opted for an endoscopic intervention over lifelong drug dependence. METHODS: Patients with chronic GERD were randomized (2:1) for TIF or continuation of PPI therapy. American Society of Anesthesiologists >2, body mass index >35 kg/m(2), hiatal hernia >2 cm, and esophageal motility disorders were exclusion criteria. Primary outcome measure was GERD-related quality of life. Secondary outcome measures were esophageal acid exposure, number of reflux episodes, PPI usage, appearance of the gastroesophageal valve, and healing of reflux esophagitis. Crossover for the PPI group was allowed after 6 months. RESULTS: A total of 60 patients (TIF n=40, PPI n=20, mean body mass index 26 kg/m(2), 37 male) were included. At 6 months, GERD symptoms were more improved in the TIF group compared with the PPI group (P<0.001), with a similar improvement of distal esophageal acid exposure (P=0.228) compared with baseline. The pH normalization for TIF group and PPI group was 50% and 63%, respectively. All patients allocated for PPI treatment opted for crossover. At 12 months, quality of life remained improved after TIF compared with baseline (P<0.05), but no improvement in esophageal acid exposure compared with baseline was found (P=0.171) and normalization of pH was accomplished in only 29% in conjunction with deteriorated valve appearances at endoscopy and resumption of PPIs in 61%. CONCLUSION: Although TIF resulted in an improved GERD-related quality of life and produced a short-term improvement of the antireflux barrier in a selected group of GERD patients, no long-term objective reflux control was achieved.

Ocular hypertension and the risk of blindness.

PURPOSE: To estimate the risk of blindness in patients with ocular hypertension (OHT) using an appropriate model and current empirical data. DESIGN: A Markov model with data from a systematic literature review. METHODS: A Markov model with 3 health states was built: OHT, primary open-angle glaucoma (POAG), and unilateral blindness. Literature was searched for reports on conversion from OHT to POAG and progression from POAG to blindness, to estimate a range of annual conversion and progression probabilities. The model had a cycle length of 1 year. RESULTS: The 15-year risk estimates ranged from 3.1% to 9.4% in untreated, and from 0.9% to 8.6% in treated patients with OHT. The ranges were the result of differences in patient populations, treatments, and outcome definitions in currently available empirical data. CONCLUSIONS: The best estimates of the 15-year risk of unilateral blindness in patients with OHT, based on the currently available empirical data and an appropriate model, show that the risk is <10%.

Latanoprost versus timolol as first choice therapy in patients with ocular hypertension. A cost-effectiveness analysis.

PURPOSE: To determine the cost-effectiveness of ocular hypertension (OH) treatment initiated with latanoprost compared to timolol. METHODS: Two strategies for OH therapy are modelled, (1) 'starting with timolol' and (2) 'starting with latanoprost'. Therapy can be maintained or changed dependent on the achieved intraocular pressure (IOP) and side-effects. Adjustments of therapy to reach a target pressure involve monotherapy, combination therapy and laser. Four drugs are used: latanoprost, timolol, brimonidine and dorzolamide. Once the adjustments of therapy are completed, lifelong follow-up with IOP-dependent conversion to glaucoma and progression to blindness are modelled. Direct medical costs are assigned. The IOP-lowering effect of drugs is based on meta-analyses and applied by Monte Carlo simulation to a hypothetical cohort of patients with OH. The characteristics of the cohort, including the initial IOP distribution, are based on data of 1000 patients. RESULTS: The IOP decreased from 25,4 mm Hg (mean) to 16.7 (±0.017) mm Hg (strategy 1) and to 16.5 (±0.013) mm Hg (strategy 2). Costs per patient within 15 months of therapy were € 367 and € 469, respectively. Lifetime blindness and costs were 0.0334 years and € 3,514 (strategy 1) and 0.0318 years and € 4,397 (strategy 2). Incremental costs per year of vision saved for strategy (2) in comparison with strategy (1) amount to, given the uncertainties in the model, approximately € 537,000. CONCLUSION: For saving 1 year of vision, high costs are needed when OH therapy is initiated with latanoprost compared to timolol, when the cost price of latanoprost remains high.

The clinical impact of 2 different strategies for initiating therapy in patients with ocular hypertension.

PURPOSE: To assess the impact of 2 strategies for initiating therapy in ocular hypertension (OH) on drug use, intraocular pressure (IOP), and blindness caused by glaucoma. METHODS: Using a simulation model, initiating therapy with timolol (strategy 1) and with latanoprost (strategy 2) was simulated for a hypothetic cohort of ocular hypertension patients with an initial IOP distribution (data of 1000 patients). Adjustment of therapy within 15 months and a subsequent lifelong follow-up, with an IOP dependent conversion to glaucoma, were modeled. The IOP lowering effect of medication (based on a meta-analysis) was applied by Monte Carlo simulation. Therapy could be maintained or changed, depending on the achieved IOP and side effects. Four drugs (latanoprost, timolol, brimonidine, dorzolamide) were used as monotherapy or in combination. Glaucoma conversion rate was based on literature. RESULTS: Treatment goal was achieved in both strategies in 90% by monotherapy. This was 60% for patients with initial IOP's of 30 mm Hg. The originally prescribed medication was maintained in 66% (1) and in 77% (2). IOP decreased with approximately 34%, from 25.4 mm Hg (mean) to 16.7 mm Hg (1) and to 16.5 mm Hg (2) Blindness per person within 18.7 years of life expectancy was 0.0923 years (1) and 0.0870 years (2), which corresponds to approximately 1 month. The difference between strategies was 2 days spent in blindness per patient. CONCLUSIONS: The difference in clinical effects of the strategies is small. This is largely owing to the key concept of a target pressure, which underlies both strategies.

The cost-effectiveness of particle therapy in non-small cell lung cancer: exploring decision uncertainty and areas for future research.

PURPOSE: To review and synthesize all available evidence in order to explore the cost-effectiveness of particle therapy (carbon-ions, protons) compared to the best current treatments for non-small-cell lung cancer (NSCLC), and the value of additional research. The present study focuses on stage I NSCLC, as no data is available for more advanced stages. METHODS: A probabilistic decision-analytic Markov model was constructed to synthesize all available evidence. Comparative treatments were carbon-ions, protons, conventional radiotherapy (CRT) and stereotactic radiotherapy (SBRT) for inoperable stage I NSCLC; and carbon-ions and SBRT for operable stage I NSCLC. The expected value of perfect information (EVPI) was calculated to support research decisions. RESULTS: For inoperable stage I NSCLC, carbon-ion therapy costed euro 67.257 per quality-adjusted-life-year gained compared to SBRT. Both treatments dominated protons and CRT. Considerable uncertainty surrounded these results, resulting in a high EVPI. For operable stage I NSCLC SBRT dominated carbon-ion therapy. CONCLUSIONS: Due to the considerable uncertainty in stage I NSCLC, and the lack of data on more advanced stages, it is recommended not to adopt particle therapy as standard treatment in NSCLC yet. More evidence is needed to reduce the decision uncertainty and to support evidence-based treatment decisions. It might be worthwhile to invest in a particle facility for clinical research. Future research should also weigh the investment risk, value of information and costs of delay.

How costly is particle therapy? Cost analysis of external beam radiotherapy with carbon-ions, protons and photons.

PURPOSE: Particle therapy has potentially a better therapeutic ratio than photon therapy. However, investment costs are much higher. This study provides an estimation and comparison of the costs of these therapies. METHODS: Within an extensive analytical framework capital and operational costs, cost per fraction, and four tumor specific treatment costs are calculated for three facilities: combined carbon-ion/proton, proton-only, and photon. RESULTS: Capital costs for the combined, proton-only and photon facilities are: euro 138.6 million, euro 94.9 million, euro 23.4 million. Total costs per year are: euro 36.7 million, euro 24.9 million, euro 9.6 million. Cost per fraction is: euro 1128 (euro 877-1974), euro 743 (euro 578-1300), euro 233 (euro 190-407). Cost ratio particle/photon therapy is 4.8 for the combined and 3.2 for the proton-only facility. Particle treatment costs vary from euro 10,030 (c-ion: lung cancer) to euro 39,610 (proton: head & neck tumors). Cost difference between particle and photon therapies is relatively small for lung and prostate cancer, larger for skull-base chordoma and head & neck tumors. CONCLUSION: Investment costs are highest for the combined carbon-ion/proton facility and lowest for the photon facility. Cost differences become smaller when total costs per year and specific treatment costs are compared. Lower fractionation schedule of particle therapy might further reduce its costs.