Applying a cost-based pricing model for innovative cancer treatments subject to indication expansion: A case study for pembrolizumab and daratumumab.

BACKGROUND: Expanding the indication of already approved immuno-oncology drugs presents treatment opportunities for patients but also strains healthcare systems. Cost-based pricing models are discussed as a possibility for cost containment. This study focuses on two drugs, pembrolizumab (Keytruda) and daratumumab (Darzalex), to explore the potential effect of indication broadening on the estimated price when using the cost-based pricing (CBP) model proposed by Uyl-de Groot and Löwenberg (2018). METHODS: The model was used to calculate cumulative yearly prices, cumulative prices per indication, and non-cumulative indication-based prices using inputs such as research and development (R&D) costs, manufacturing costs, eligible patient population, and a profit margin. A deterministic stepwise analysis and scenario analysis were conducted to examine how sensitive the estimated price is to the different input assumptions. RESULTS: The yearly cumulative cost-based prices (CBPs) ranged from €52 to €885 for pembrolizumab per vial and €823 to €31,941 for daratumumab per vial. Prices were higher in initial years or indications due to smaller patient populations, decreased over time or after additional indications. Sensitivity analysis showed that the number of eligible patients had the most significant impact on the estimated price. In the scenario analysis the profit margin contributed most to a higher CBPs for both drugs. Lower estimates resulted from assumed lower R&D costs. DISCUSSION: The estimated CBPs are consistently lower than Dutch list prices for pembrolizumab (€2,861), mainly resulting from larger patient populations in registered indications. However, daratumumab's list prices fall within the range of modeled CBPs depending on the year or indication (€4,766). Both CBPs decrease over time or with additional indications. The number of eligible patients and initial R&D costs have the most significant influence on the CBPs. These findings contribute to the ongoing discussions on pharmaceutical pricing, especially concerning cancer drugs with expanding indications.

Long-term follow-up of patients with displaced scapular fractures managed surgically and non-operatively.

INTRODUCTION: Controversy remains on which patients with displaced scapula fractures benefit from surgery. This retrospective cohort study aims to compare and describe long-term patient-reported outcomes of patients with displaced scapula fractures treated both surgically and conservatively. METHODS: This study included patients with intra- and extra-articular scapula fractures, treated between 2010 and 2020 in a Swiss level 1 trauma centre. The decision to operate was based on standardized criteria for fracture displacement. Patients with isolated Bankart lesions (Ideberg 1) and process fractures (AO type 14-A) were excluded. Primary outcomes were functional patient reported measures (DASH score) and quality of life (EQ5D score). Secondary outcomes were complications, radiological union, satisfaction with treatment, pain and range of motion. RESULTS: Out of 486 cases, 74 patients had displaced scapula fractures. Forty patients were treated surgically and 34 were treated conservatively. Significantly more patients with intra-articular fractures and high-energy trauma were treated surgically. Fifty percent returned the questionnaires after a mean follow-up of 47 months (± SD 36). The mean DASH score of this group was 12 (SD 15.6), with a mean of 14.7 (SD 15.9) in the surgery group and 9.8 (SD 14.6) in the non-operative group (p = 0.7). Multivariate analysis did not show statistically significant correlating factors. No significant differences in quality of life were observed. Patients rated their treatment with a mean of 8.6/10 (SD 1.8). Among surgically treated patients, 19 underwent a deltoid sparing procedure with significant shorter time to union than those that underwent deltoid release (23 vs. 49 weeks, p<0.01). Complications occurred in 3/28 surgically treated patients and all three required a reoperation. CONCLUSION: In this cohort, functional results after conservative and surgical treatment were similar, despite more complex fractures and more intra-articular fractures being treated surgically. Osteosynthesis of both intra- and extra-articular scapula fractures is safe and leads to good functional results, furthermore, new minimal invasive techniques may lead to faster bone healing and return to work and sports.

The Qualitative Assessment of Two Translated Dutch Spirituality Scales for Children.

PURPOSE: This article describes the translation and qualitative assessment and small scale validation of two spirituality scales designed for children from English to Dutch and includes the translation and validation process and the results of the two most commonly used and best validated measurement instruments for spirituality in children: the Feeling Good, Living Life scale (FGLL) by Fisher (2004, 2009) and the Spirituality Sensitivity Scale for Children by Stoyles et al. (2012). DESIGN AND METHODS: The translation process was designed according to Beaton et al. (2000) and both the translation and the validation process followed the instructions of the Consensus-based Standards for the Selection of Health Measurement Instruments (COSMIN, 2018). The qualitative validation was done by a three-step test-interview eliciting the face validity of both questionnaires. RESULTS AND CONCLUSIONS: The results show that both instruments were reliably translated, are face valid with some minor alterations and structurally validated overall in the small-scale pilot. PRACTICE IMPLICATIONS: More attention from healthcare professionals and educators should be directed at using spiritual measuring instrument to develop the spiritual vocabulary of children. A larger study is needed to also confirm the cultural validity of the translated scales.

Results of plate fixation for humerus fractures in a large single-center cohort.

INTRODUCTION: This study aims to describe the results of plate fixation in one of the largest single-center cohorts that employs plate fixation as the golden standard. Additionally, risk factors related to a negative outcome were identified. MATERIALS AND METHODS: This was a retrospective cohort study of all patients treated for a humeral shaft fracture in a level-one trauma center between January 2010 and December 2017 with a mean follow-up of 1 year. RESULTS: Plate fixation was performed in 102 patients with a humeral shaft fracture. The mean age was 50 (SD 20) years with 54.9% (n = 56) being male. Forty-eight percent (n = 48) had an AO type-A, 34.3% (n = 35) type-B, and 18.7% (n = 19) type-C fracture. Deep surgical site infections and non-union occurred in 1% (n = 1) and 3.9% (n = 4) of patients, respectively. Revision of the implant was performed in 15.7% (n = 16) mainly due to implant-related complaints. Only one patient developed radial nerve palsy after surgery. The median duration to radiological fracture healing and full-weight bearing was 18 (range 7-65) weeks and 14 (range 6-56) weeks, respectively. Risk factors for negative outcome included higher age, osteoporosis, open and higher AO class fractures, performing surgery during out-office hours, and the use of LCP 3.5-mm plate and an anterolateral approach. CONCLUSION: Plate fixation for humeral shaft fractures has low risks of complications. It should be emphasized that the complications can be further minimized with a greater surgical expertise and by refraining from performing a surgery during out-office hours.

Field and laboratory findings following the large-scale use of intermediate type infectious bursal disease vaccines in Denmark.

Following a period of clinical outbreaks of very virulent infectious bursal disease virus (vvIBDV) in Denmark, the histological bursal lesion score (HBLS) was used on a national scale to screen broiler flocks vaccinated with intermediate IBD vaccines for lesions indicative of IBDV challenge. High lesion scores were detected in a high percentage of healthy and well performing flocks despite the lack of other indications of the presence of vvIBDV. RT-PCR and subsequent sequencing showed the frequent presence of H253Q and H253N IBDV strains that were genetically close to the sequence of the intermediate vaccines with a relative risk ratio of 13.0 (P < 0.0001) in intermediate vaccine A or B vaccinated flocks compared to unvaccinated flocks. The relevance of these H253Q and H253N strains was tested under experimental conditions using a protocol derived from the European Pharmacopoeia for safety of live IBD vaccines. The results confirmed the higher pathogenicity for the bursa of these strains compared to intermediate vaccines as well as the negative effect on antibody response to a Newcastle disease (ND) vaccination performed at the peak of the bursa damage. The efficacy of the ND vaccination was still 100% showing that the H253N and H253Q IBDV strains would be considered as safe vaccine viruses. In conclusion, the use of the HBLS to screen commercial broiler flocks vaccinated with intermediate IBD vaccines for the presence of vvIBDV does not seem to be a reliable method due to the frequent occurrence of H253N and H253Q strains in those flocks. For screening of IBD vaccinated flocks for the presence of vvIBDV or other field strains, the RT-PCR with subsequent sequencing seems to be most suitable.

[Stroke mimicking acute peripheral vertigo: how to avoid misdiagnosis - importance of alarm symptoms and assessment of eye movements]. / Draaiduizeligheid: gewoon beroerd of een beroerte?

Identifying the occurrence of stroke in patients with isolated vertigo is difficult for general practitioners (GPs) as well as for physicians working in the Emergency Department. Three patients with acute vestibular syndrome are presented in this clinical lesson. The importance of an adequate neuro-otological examination is emphasised. However, many GPs lack knowledge of the nystagmus and the head impulse test. Alternative strategies for GPs are discussed.

[Motion sickness in motion: from carsickness to cybersickness]. / Bewegingsziekten in beweging.

- Motion sickness is not a disorder, but a normal response to a non-normal situation in which movement plays a central role, such as car travel, sailing, flying, or virtual reality.- Almost anyone can suffer from motion sickness, as long as at least one of the organs of balance functions. If neither of the organs of balance functions the individual will not suffer from carsickness, seasickness, airsickness, nor from cybersickness. - 'Cybersickness' is a form of motion sickness that is stimulated by artificial moving images such as in videogames. Because we are now exposed more often and for longer periods of time to increasingly realistic artificial images, doctors will also encounter cases of motion sickness more often. - The basis for motion sickness is the vestibular system, which can be modulated by visual-vestibular conflicts, i.e. when the movements seen by the eyes are not the same as those experienced by the organs of balance.- Antihistamines can be effective against motion sickness in everyday situations such as car travel if taken before departure, but the effectiveness of medication for motion sickness is limited.

Acute cerebellitis in adults: a case report and review of the literature.

BACKGROUND: Acute cerebellitis is a rare disease with the majority of cases described in children. Little is known about the clinical characteristics and outcome in adults. CASE PRESENTATION: A 37-year-old Caucasian woman presented with headache, nausea, and photophobia, and was diagnosed as having a migraine attack. Two days later, she subsequently returned with aggravated headache, dysarthria and horizontal nystagmus. Magnetic resonance imaging (MRI) showed a swollen cerebellum and hydrocephalus and the patient was diagnosed with acute cerebellitis. Cerebrospinal fluid (CSF) examination showed an elevated leukocyte count and protein. Blood serology showed the presence of immunoglobulin M and immunoglobulin G for both Epstein-Barr virus and cytomegalovirus. The patient was treated with dexamethasone and discharged to a rehabilitation center, where she fully recovered. We searched the literature for adult cases of acute cerebellitis. Including our patient, we identified 35 patients with a median age of 36 years. The etiology was unknown in 34% of cases. The most common clinical presentation consisted of headache, nausea/vomiting and ataxia. Six patients presented with only headache and nausea and subsequently returned with cerebellar signs. In 9 cases, the cerebellitis was complicated by hydrocephalus. Half of the patients ended up with neurological sequelae, while follow-up MRI was abnormal in 71%. CONCLUSION: Acute cerebellitis in adults is a rare disorder which mainly presents with headache, nausea/vomiting and ataxia. To diagnose cerebellitis, imaging of the brain (preferably MRI) is required and CSF examination may be necessary to narrow the differential diagnosis. The treatment depends on the widely diverse etiology, and treatment with steroids is recommended in the case of cerebellar oedema and hydrocephalus. Neurosurgical intervention may be necessary to prevent brain herniation.

The Role of Spirituality in Lifestyle Changing Among Patients with Chronic Cardiovascular Diseases: A Literature Review of Qualitative Studies.

Chronic cardiovascular diseases (CVD) are diseases with marked morbidity. Patients are often advised to change their lifestyle to prevent complications and impairment of their diseases. Compliance, however, is influenced by multiple factors. Initial studies show that spirituality is an important aspect in health behavior and lifestyle changing, but to health professionals like nurses this is unknown. The aim of this review is to investigate and synthesize evidence about the role of spirituality in lifestyle changing in patients with chronic CVD. A comprehensive search was conducted in electronic databases Academic Search Premier, E-journals, Medline and PubMed, published between the years 2000-2015. After selection based on pre-set inclusion criteria, studies were retrieved and evaluated on quality using the criteria of the QOREC. Twelve studies with a qualitative empirical design and mixed methods were included. This review shows that spirituality, is related to the self-management of patients with chronic diseases. For instance, lifestyle changes are experienced as a continuous inner battle. Religion gives strength, but is also experienced as a struggle. Feelings of guilt and becoming a victim influence patients' experience. For effectively advising patients with CVD on lifestyle changes, nurses cannot ignore this factor but further investigation is required.

Drug-drug interactions in pediatric oncology patients.

BACKGROUND: Drug-drug interactions (DDIs) can negatively affect pharmacotherapy. However, pediatric DDI studies are scarce. We undertook an exploratory study to investigate prevalence and clinical relevance of DDIs between cytostatic and noncytostatic drugs in outpatient pediatric oncology patients. PROCEDURE: After informed consent and inclusion, the following information was collected: currently prescribed noncytostatic and cytostatic drugs, comorbidities, and use of over-the-counter (OTC) drugs, complementary and alternative medicines (CAMs), and dietary supplements. All medication was screened for DDIs according to two databases: Micromedex® Solutions and the Dutch drug database G-Standard. The researcher presented DDIs with an associated potential for adverse outcome and a proposal for intervention to three independent experts. If the experts considered a DDI to be potentially clinically relevant and requiring intervention, the physician was notified. RESULTS: Seventy-three patients were included (median age 8.9 years). A total of 67 different DDIs were counted (66 in Micromedex® Solutions, 14 in G-Standard, and 13 DDIs in both databases). The medication reviews resulted in 35 interventions related to 11 different DDIs. The majority of DDIs concerned noncytostatic drugs (25/35) and one third occurred between cytostatic and noncytostatic drugs (10/35). The use of QTc-interval-prolonging drugs resulted in one intervention. The use of OTC drugs, CAM, or dietary supplements did not lead to DDIs. CONCLUSIONS: This study resulted in a selection of 11 potentially clinically relevant DDIs for 73 outpatients in our pediatric oncology department. Interventions were formulated in close collaboration between physicians and clinical pharmacists. Future research should focus on assessing DDIs concerning QTc-interval prolongation.

An Ocular Protein Triad Can Classify Four Complex Retinal Diseases.

Retinal diseases generally are vision-threatening conditions that warrant appropriate clinical decision-making which currently solely dependents upon extensive clinical screening by specialized ophthalmologists. In the era where molecular assessment has improved dramatically, we aimed at the identification of biomarkers in 175 ocular fluids to classify four archetypical ocular conditions affecting the retina (age-related macular degeneration, idiopathic non-infectious uveitis, primary vitreoretinal lymphoma, and rhegmatogenous retinal detachment) with one single test. Unsupervised clustering of ocular proteins revealed a classification strikingly similar to the clinical phenotypes of each disease group studied. We developed and independently validated a parsimonious model based merely on three proteins; interleukin (IL)-10, IL-21, and angiotensin converting enzyme (ACE) that could correctly classify patients with an overall accuracy, sensitivity and specificity of respectively, 86.7%, 79.4% and 92.5%. Here, we provide proof-of-concept for molecular profiling as a diagnostic aid for ophthalmologists in the care for patients with retinal conditions.

Vertex Corrections for Positive-Definite Spectral Functions of Simple Metals.

We present a systematic study of vertex corrections in a homogeneous electron gas at metallic densities. The vertex diagrams are built using a recently proposed positive-definite diagrammatic expansion for the spectral function. The vertex function not only provides corrections to the well known plasmon and particle-hole scatterings, but also gives rise to new physical processes such as the generation of two plasmon excitations or the decay of the one-particle state into a two-particle-one-hole state. By an efficient Monte Carlo momentum integration we are able to show that the additional scattering channels are responsible for a reduction of the bandwidth, the appearance of a secondary plasmon satellite below the Fermi level, and a substantial redistribution of spectral weights. The feasibility of the approach for first-principles band-structure calculations is also discussed.

Discovery of new methylation markers to improve screening for cervical intraepithelial neoplasia grade 2/3.

BACKGROUND: Assessment of DNA promoter methylation markers in cervical scrapings for the detection of cervical intraepithelial neoplasia (CIN) and cervical cancer is feasible, but finding methylation markers with both high sensitivity as well as high specificity remains a challenge. In this study, we aimed to identify new methylation markers for the detection of high-grade CIN (CIN2/3 or worse, CIN2+) by using innovative genome-wide methylation analysis (MethylCap-seq). We focused on diagnostic performance of methylation markers with high sensitivity and high specificity considering any methylation level as positive. RESULTS: MethylCap-seq of normal cervices and CIN2/3 revealed 176 differentially methylated regions (DMRs) comprising 164 genes. After verification and validation of the 15 best discriminating genes with methylation-specific PCR (MSP), 9 genes showed significant differential methylation in an independent cohort of normal cervices versus CIN2/3 lesions (p < 0.05). For further diagnostic evaluation, these 9 markers were tested with quantitative MSP (QMSP) in cervical scrapings from 2 cohorts: (1) cervical carcinoma versus healthy controls and (2) patients referred from population-based screening with an abnormal Pap smear in whom also HPV status was determined. Methylation levels of 8/9 genes were significantly higher in carcinoma compared to normal scrapings. For all 8 genes, methylation levels increased with the severity of the underlying histological lesion in scrapings from patients referred with an abnormal Pap smear. In addition, the diagnostic performance was investigated, using these 8 new genes and 4 genes (previously identified by our group: C13ORF18, JAM3, EPB41L3, and TERT). In a triage setting (after a positive Pap smear), sensitivity for CIN2+ of the best combination of genes (C13ORF18/JAM3/ANKRD18CP) (74 %) was comparable to hrHPV testing (79 %), while specificity was significantly higher (76 % versus 42 %, p ≤ 0.05). In addition, in hrHPV-positive scrapings, sensitivity and specificity for CIN2+ of this best-performing combination was comparable to the population referred with abnormal Pap smear. CONCLUSIONS: We identified new CIN2/3-specific methylation markers using genome-wide DNA methylation analysis. The diagnostic performance of our new methylation panel shows higher specificity, which should result in prevention of unnecessary colposcopies for women referred with abnormal cytology. In addition, these newly found markers might be applied as a triage test in hrHPV-positive women from population-based screening. The next step before implementation in primary screening programs will be validation in population-based cohorts.

Hypoglycin A Concentrations in Maple Tree Species in the Netherlands and the Occurrence of Atypical Myopathy in Horses.

BACKGROUND: Atypical myopathy (AM) in horses is caused by the plant toxin hypoglycin A, which in Europe typically is found in the sycamore maple tree (Acer pseudoplatanus). Owners are concerned about whether their horses are in danger if they graze near maple trees. HYPOTHESIS/OBJECTIVES: To measure hypoglycin A in the most common maple tree species in the Netherlands, and to determine whether concentration of toxin is a predictor of AM in horses. METHODS: A total of 278 samples of maple tree leaves, sprouts, and seeds were classified by species. Mean concentrations of hypoglycin A were compared for the type of sample, the season and the occurrence of AM in the pasture (non-AM versus AM). Statistical analysis was performed using generalized a linear model (SPPS22). RESULTS: Almost all Acer pseudoplatanus samples contained hypoglycin A, with concentrations differing significantly among sources (P < .001). Concentrations were significantly higher in seeds from the AM group than in seeds from the non-AM group (856 ± 677 and 456 ± 358 mg/kg, respectively; P = .039). In sprouts and leaves this was not the case. Acer platanoides and Acer campestre samples did not contain detectable concentrations of hypoglycin A. CONCLUSIONS AND CLINICAL IMPORTANCE: Acer platanoides and campestre seem to be safe around paddocks and pastures, whereas almost all Acer pseudoplatanus samples contained hypoglycin A. In all AM cases, Acer pseudoplatanus was found. Despite significantly higher concentration of hypoglycin A in seeds of pastures where AM has occurred, individual prediction of AM cannot be made by measuring these concentrations because of the high standard deviation.

Comparing the effectiveness and costs of Bevacizumab to Ranibizumab in patients with Diabetic Macular Edema: a randomized clinical trial (the BRDME study).

BACKGROUND: The effectiveness of ranibizumab in the treatment of diabetic macular edema has been proven with large clinical trials. For bevacizumab only two clinical trials have been published and a head-to-head comparison is lacking to date. However, if proved non-inferior to ranibizumab, use of the off-label bevacizumab could reduce costs enormously without a loss in visual acuity. A cost-effectiveness study has been designed to substantiate this hypothesis. AIM: To compare the effectiveness and costs of 1.25 mg of bevacizumab to 0.5 mg ranibizumab given as monthly intravitreal injections during 6 months in patients with diabetic macular edema. It is hypothesized that bevacizumab is non-inferior to ranibizumab regarding its effectiveness. DESIGN: This is a randomized, controlled, double masked, clinical trial in 246 patients in seven academic trial centres in The Netherlands. OUTCOMES: The primary outcome measure is the change in best-corrected visual acuity (BCVA) in the study eye from baseline to month 6. Secondary outcomes are the proportions of patients with a gain or loss of 15 letters or more or a BCVA of 20/40 or more at 6 months, the change in leakage on fluorescein angiography and the change in foveal thickness by optical coherence tomography at 6 months, the number of adverse events in 6 months, and the costs per quality adjusted life-year of the two treatments.

Pick-up and drop transfer of diamond nanosheets.

Nanocrystalline diamond (NCD) is a promising material for electronic and mechanical micro- and nanodevices. Here we introduce a versatile pick-up and drop technique that makes it possible to investigate the electrical, optical and mechanical properties of as-grown NCD films. Using this technique, NCD nanosheets, as thin as 55 nm, can be picked-up from a growth substrate and positioned on another substrate. As a proof of concept, electronic devices and mechanical resonators are fabricated and their properties are characterized. In addition, the versatility of the method is further explored by transferring NCD nanosheets onto an optical fiber, which allows measuring its optical absorption. Finally, we show that NCD nanosheets can also be transferred onto two-dimensional crystals, such as MoS2, to fabricate heterostructures. Pick-up and drop transfer enables the fabrication of a variety of NCD-based devices without requiring lithography or wet processing.

Drug-drug interactions in patients treated for cancer: a prospective study on clinical interventions.

BACKGROUND: Drug-drug interactions (DDIs) are of major concern in oncology, since cancer patients typically take many concomitant medications. Retrospective studies have been conducted to determine the prevalence of DDIs. However, prospective studies on DDIs needing interventions in cancer patients have not yet been carried out. Therefore, a prospective study was designed to identify DDIs leading to interventions among ambulatory cancer patients receiving anticancer treatment. PATIENTS AND METHODS: Patients starting with a new treatment regimen with i.v. or oral anticancer medication were asked to participate. The patients' medication was checked for DDIs by using drug interaction software. An expert team of clinical pharmacologists evaluated the relevance of these identified DDIs. If a DDI was qualified as potentially clinically relevant, an intervention was proposed to the treating (hemato)oncologist. Several variables were studied as determinants for performing an intervention. Descriptive statistics and uni- and multivariate logistic regression analyses were carried out. RESULTS: In this study, 302 patients were included. A total of 603 DDIs were identified by the drug interaction software and judged by the expert team. Of all 603 DDIs, 120 DDIs were considered potentially clinically relevant. These 120 DDIs, present in a total of 81 patients, resulted in a clinical intervention already executed by the (hemato)oncologist in 39 patients (13%), while an additional intervention was proposed by a clinical pharmacologist in 42 patients (14%). The number of comorbidities and the number of 'over-the-counter' drugs were identified as determinants. CONCLUSIONS: Clinical interventions on DDIs are frequently required among patients starting with anticancer therapy. Structured screening for these potentially clinically relevant DDIs, by (hemato)oncologists in close collaborations with clinical pharmacologists, should take place before the start and during anticancer treatment. CLINICAL TRIALS NUMBER: This study was registered at the Dutch Trial Registry under number NTR3760.