The CHOICES Study: Facility Level Comparative Cost, Resource Utilization, and Outcomes Analysis of Myomectomy Compared to Transcervical Fibroid Ablation.

PURPOSE: The CHOICES study compared short-term resource utilization, facility costs, and perioperative patient outcomes between transcervical fibroid ablation (TFA) with the Sonata® system and myomectomy through a case-matched comparative trial design. This is the first facility-level comparative study conducted for TFA. PATIENTS AND METHODS: The study enrolled 88 patients from 4 centers equally divided among the two cohorts. The TFA arm consisted of 44 women who had enrolled in the SONATA Pivotal IDE trial, whereas the myomectomy arm included 44 patients who were identified through retrospective case-matching to the enrolled SONATA patients at the same 4 centers. RESULTS: TFA had a significantly lower mean operating room duration (90 minutes) and length of stay (5.2 hours) than myomectomy (143 minutes and 45.8 hours, respectively). The average total mean facility costs for TFA procedure ($7,563) were significantly lower than those associated with myomectomy ($11,425; p=0.002). TFA mean facility costs were also compared with other stratifications of myomectomy (inpatient or outpatient and surgical route). TFA facility costs were significantly lower than that associated with inpatient, abdominal, or laparoscopic myomectomy (all p<0.001). CONCLUSION: TFA using the Sonata system has a significantly shorter operating room time and length of stay than myomectomy for the treatment of symptomatic uterine fibroids. All procedure, anesthesia, laboratory, pathology, and pharmacy costs were significantly higher for myomectomy as compared to TFA. TFA was also associated with significantly lower facility procedure-related costs compared to myomectomy, including inpatient, abdominal, or laparoscopic myomectomy.

Applicability of drug response metrics for cancer studies using biomaterials.

Bioengineers have built models of the tumour microenvironment (TME) in which to study cell-cell interactions, mechanisms of cancer growth and metastasis, and to test new therapies. These models allow researchers to culture cells in conditions that include features of the in vivo TME implicated in regulating cancer progression, such as extracellular matrix (ECM) stiffness, integrin binding to the ECM, immune and stromal cells, growth factor and cytokine depots, and a three-dimensional geometry more representative of the in vivo TME than tissue culture polystyrene (TCPS). These biomaterials could be particularly useful for drug screening applications to make better predictions of efficacy, offering better translation to preclinical models and clinical trials. However, it can be challenging to compare drug response reports across different biomaterial platforms in the current literature. This is, in part, a result of inconsistent reporting and improper use of drug response metrics, and vast differences in cell growth rates across a large variety of biomaterial designs. This study attempts to clarify the definitions of drug response measurements used in the field, and presents examples in which these measurements can and cannot be applied. We suggest as best practice to measure the growth rate of cells in the absence of drug, and follow our 'decision tree' when reporting drug response metrics. This article is part of a discussion meeting issue 'Forces in cancer: interdisciplinary approaches in tumour mechanobiology'.

An omentum-inspired 3D PEG hydrogel for identifying ECM-drivers of drug resistant ovarian cancer.

Ovarian cancer (OvCa) is a challenging disease to treat due to poor screening techniques and late diagnosis. There is an urgent need for additional therapy options, as patients recur in 70% of cases. The limited availability of clinical treatment options could be a result of poor predictions in early stage drug screens on standard tissue culture polystyrene (TCPS). TCPS does not capture the mechanical and biochemical cues that cells experience in vivo, which can impact how cells will respond to a drug. Therefore, an in vitro model that captures some of the microenvironment features that the cells experience in vivo could provide better insights into drug responses. In this study, we formed 3D multicellular tumor spheroids (MCTS) in microwells and encapsulated them in 3D omentum-inspired hydrogels. SKOV-3 MCTS were resistant to Paclitaxel in our 3D hydrogels compared to a monolayer on TCPS. Toward clinical application, we tested cells from patients [ovarian carcinoma ascites spheroids (OCAS)] who had been treated with Paclitaxel, and drug responses predicted by using the 3D omentum-inspired hydrogels demonstrated the lack of the Paclitaxel response of these samples. Additionally, we observed the presence of collagen production around the encapsulated SKOV-3 MCTS, but not significantly on TCPS. Our results demonstrated that our 3D omentum-inspired hydrogel is an improved in vitro drug testing platform to study the OvCa drug response for patient-derived cells and helped us identify collagen 3 as a potential driver of Paclitaxel resistance in 3D.

Cost-effectiveness of fractional exhaled nitric oxide (FeNO) measurement in predicting response to omalizumab in asthma.

Purpose: To use a modeled analysis to examine the cost-effectiveness of utilizing fractional exhaled nitric oxide (FeNO) as a biomarker to aid in the identification of omalizumab responders in patients with moderate-to-severe allergic asthma. Omalizumab is a biological drug used to treat asthma in adults and children 12 years and older. Patients and methods: We conducted a decision analysis in which two alternative strategies for predicting omalizumab response were assessed: 1) testing response via a 12-week trial of omalizumab and 2) using FeNO measurement to screen patients for likely omalizumab response prior to initiating a 12-week trial of omalizumab. In the standard of care arm, trial omalizumab responders continue on to receive 12 months of continuous omalizumab therapy. In the FeNO measurement predictor arm, patients with FeNO measurements >19.5 ppb are started on a trial of omalizumab. Trial omalizumab responders in this arm are then also tracked for 12 months of continuous omalizumab therapy. Results: Per-patient costs during the trial and initial treatment periods total $10,943 for FeNO + omalizumab and $13,703 for omalizumab only. The expected cost per responder during the trial period is $4,326 for FeNO + omalizumab and $7,786 for omalizumab only. Conclusion: Use of FeNO measurement to identify omalizumab responders decreases the expected per-patient cost by nearly 50% during the trial period and continues to show cost savings through the initial treatment period of 12 months. Our analysis may serve as a model for policy and clinical practice regarding the use of FeNO to determine omalizumab response and has widespread implications for health care payers, who may choose to require FeNO measurement and prespecify a minimum FeNO value to determine patient eligibility for omalizumab trial.

Comparative cost-effectiveness analysis of the subacromial spacer for irreparable and massive rotator cuff tears.

PURPOSE: There is ongoing debate regarding the optimal surgical treatment of irreparable rotator cuff tears (IRCT). This study aimed to assess within the Italian health care system the cost-effectiveness of subacromial spacer as a treatment modality for patients with IRCT. METHODS: An expected-value decision analysis was created comparing costs and outcomes of patients undergoing arthroscopic subacromial spacer implantation, rotator cuff repair (RCR), total shoulder arthroplasty, and conservative treatment for IRCTs. A broad literature search provided input data to extrapolate and inform treatment success and failure rates, costs, and health utility states for these outcomes. The primary outcome assessed was an incremental cost-effectiveness ratio (ICER) of subacromial spacer implantation versus shoulder arthroplasty, RCR, and conservative treatment. RESULTS: Subacromial spacer is favorable over both arthroscopic partial repair and shoulder arthroplasty since it costs less than both options and increases effectiveness by 0.06 and 0.10 quality-adjusted life years (QALYs), respectively. While conservative treatment is the least costly management strategy, subacromial spacer results in a gain of 0.05 QALYs for the additional cost of 522 €, resulting in an ICER of 10,440 €/QALY gain, which is below the standard willingness to pay ratio of $50,000 USD. Strategies with an ICER of less than 50,000 USD are considered to be cost-effective. CONCLUSIONS: Based on the available evidence and reasonably conservative assumptions, subacromial spacer is likely to provide a safe, effective, and cost-effective option for patients with massive IRCTs. Furthermore, this cost-effectiveness analysis may ultimately serve as a guide for development of health care system and insurer policy as well as clinical practice.

Potential mortality and cost reduction in adult severe sepsis and septic shock through the use of an innovative fluid delivery device.

BACKGROUND: While early fluid resuscitation has been shown to significantly improve health and economic metrics in septic shock, providers are often unable to achieve fluid delivery guidelines using current techniques. PURPOSE: To examine expected clinical and economic consequences of more consistent achievement of fluid resuscitation guidelines through use of a novel fluid delivery technology. PATIENTS AND METHODS: A decision analytic model was developed to compare expected costs and outcomes associated with the standard technique vs a novel, faster technique for rapid fluid resuscitation in adult patients with severe sepsis or septic shock. RESULTS: Use of an innovative fluid delivery device (LifeFlow) resulted in lower expected mortality compared to standard intravenous fluid delivery methods (reduction of 10 fewer deaths per 500 cases). Compared to standard methods, use of the innovative rapid fluid delivery device also resulted in lower expected hospital costs (US$1,569,131 cost reduction per 500 cases), a lower required use of mechanical ventilation (24% vs 31%), decreased average length of stay (11 vs 13 days), decreased average intensive care unit length of stay (2 vs 3 days), and decreased use of vasopressors (17% vs 21%). A sensitivity analysis showed that utilization of the rapid fluid delivery device is more cost-effective than standard methods, even under the most conservative assumptions. CONCLUSION: Based on existing data supporting the importance of early, controlled fluid resuscitation in septic shock patients, the analytical model developed in this study demonstrated the benefit of a novel device that facilitates earlier fluid bolus completion and better adherence to sepsis bundles.

Cost-Effectiveness Analysis of Monitoring Fractional Exhaled Nitric Oxide (FeNO) in the Management of Asthma.

PURPOSE: Current asthma guidelines combine treatment, follow-up, and reevaluation to manage asthma control, reduce impairment, and decrease risk of morbidity in patients. Clinical use of biomarkers, such as fractional exhaled nitric oxide (FeNO), along with standard management can provide clinicians with improved ability to recognize airway inflammation, optimize drug therapy, and potentially increase asthma control. Our objective is to examine the impact of FeNO monitoring on the cost effectiveness of asthma management compared with management without FeNO. Sensitivity analyses further examine the impact of FeNO monitoring on patients with varying levels of severity and exacerbations. DESIGN AND METHODS: A decision-tree analysis of estimated outcomes and costs associated with annual management of asthma was utilized to simulate asthma management and treatment cost scenarios, comparing estimated 12-month costs and outcomes using the following treatment alternatives: (1) current standard of care (SOC) or (2) FeNO utilized in conjunction with the current SOC. Costs were estimated from the perspective of the health care payer; cost effectiveness was estimated as cost per quality-adjusted life year (QALY). RESULTS: FeNO in conjunction with SOC guidelines has decreased expected per-patient annual expenditure ($2,228) and increased expected per-patient annual QALYs (0.844) compared with SOC alone ($2,637 and 0.767). FeNO monitoring with SOC resulted in decreased annual costs and increased annual QALYs compared with SOC alone, and this difference was consistent through all one-way sensitivity analyses. CONCLUSION: Our analysis revealed that FeNO monitoring to guide asthma management is cost effective and could result in increased QALYs and decreased health care costs associated with asthma management.

Comparative Study of Multicellular Tumor Spheroid Formation Methods and Implications for Drug Screening.

Improved in vitro models are needed to better understand cancer progression and bridge the gap between in vitro proof-of-concept studies, in vivo validation, and clinical application. Multicellular tumor spheroids (MCTS) are a popular method for three-dimensional (3D) cell culture, because they capture some aspects of the dimensionality, cell-cell contact, and cell-matrix interactions seen in vivo. Many approaches exist to create MCTS from cell lines, and they have been used to study tumor cell invasion, growth, and how cells respond to drugs in physiologically relevant 3D microenvironments. However, there are several discrepancies in the observations made of cell behaviors when comparing between MCTS formation methods. To resolve these inconsistencies, we created and compared the behavior of breast, prostate, and ovarian cancer cells across three MCTS formation methods: in polyNIPAAM gels, in microwells, or in suspension culture. These methods formed MCTS via proliferation from single cells or passive aggregation, and therefore showed differential reliance on genes important for cell-cell or cell-matrix interactions. We also found that the MCTS formation method dictated drug sensitivity, where MCTS formed over longer periods of time via clonal growth were more resistant to treatment. Toward clinical application, we compared an ovarian cancer cell line MCTS formed in polyNIPAAM with cells from patient-derived malignant ascites. The method that relied on clonal growth (PolyNIPAAM gel) was more time and cost intensive, but yielded MCTS that were uniformly spherical, and exhibited the most reproducible drug responses. Conversely, MCTS methods that relied on aggregation were faster, but yielded MCTS with grapelike, lobular structures. These three MCTS formation methods differed in culture time requirements and complexity, and had distinct drug response profiles, suggesting the choice of MCTS formation method should be carefully chosen based on the application required.

Complementary, Semiautomated Methods for Creating Multidimensional PEG-Based Biomaterials.

Tunable biomaterials that mimic selected features of the extracellular matrix (ECM) such as its stiffness, protein composition, and dimensionality are increasingly popular for studying how cells sense and respond to ECM cues. In the field, there exists a significant trade-off for how complex and how well these biomaterials represent the in vivo microenvironment versus how easy they are to make and how adaptable they are to automated fabrication techniques. To address this need to integrate more complex biomaterials design with high-throughput screening approaches, we present several methods to fabricate synthetic biomaterials in 96-well plates and demonstrate that they can be adapted to semiautomated liquid handling robotics. These platforms include (1) glass bottom plates with covalently attached ECM proteins and (2) hydrogels with tunable stiffness and protein composition with either cells seeded on the surface or (3) laden within the three-dimensional hydrogel matrix. This study includes proof-of-concept results demonstrating control over breast cancer cell line phenotypes via these ECM cues in a semiautomated fashion. We foresee the use of these methods as a mechanism to bridge the gap between high-throughput cell-matrix screening and engineered ECM-mimicking biomaterials.

Costs and benefits of bundled community-based screening for carotid artery stenosis, peripheral artery disease, and abdominal aortic aneurysm.

PURPOSE: Perform an initial formal assessment of the costs and benefits of bundled cardiovascular screening. Primarily, determine the relative importance of data uncertainties to the integrity ofmodeled outcomes associated with bundled screening for carotid artery stenosis (CAS), peripheral artery disease (PAD), and abdominal aortic aneurysm (AAA); secondarily, establish parameters around potential costs and outcomes benefits of this screening bundle. DESIGN: A decision-analysis framework composed of four decision tree submodels with transition probabilities specific to four age- and gender-specific subgroups. Model transition probabilities for each of the four submodels are based on the prevalence of all possible combinations of the presence or absence of moderate CAS, significant CAS, PAD, and AAA, and the likelihood of appropriate or inappropriate medical follow-up. METHODOLOGY: Evaluates a hypothetical self-funded employer with 10,000 beneficiaries and who is considering whether to provide bundled cardiovascular health screenings. Screenings would be performed in addition to any other medical screenings commonly performed by physicians to assess cardiovascular risk. Determine costs and catastrophic events (death, myocardial infarction, stroke, other cardiovascular-related events, amputation events) for these self-funded hypothetical beneficiaries aged ≥ 50 years and < 65 years. RESULTS: The model predicts approximately $54 million in health care costs over 10 years for the control cohort and $51 million for the screening cohort, representing a 5.2% reduction in 10-year health care spending due to screening. CONCLUSION: This initial analysis predicts robust cost and health benefits associated with the decision to provide bundled cardiovascular health screening to a self-funded employer's beneficiaries aged ≥ 50 years and < 65 years. Further analyses are necessary to better quantify the magnitude of the cost and health benefits.

Exhaled nitric oxide as a tool in managing and monitoring difficult-to-treat asthma.

Most patients diagnosed with asthma maintain control reasonably well and do not experience asthma exacerbations; however, on average, 30% of patients achieve suboptimal control, have severe or difficult-to-treat asthma, and are relatively nonresponsive to the same medications that achieve and maintain asthma control for most patients. This small patient population of difficult-to-treat or severe asthma accounts for 80% of asthma medical costs. This study was designed to determine the potential U.S. payer cost savings resulting from an asthma specialist incorporating fractionated exhaled nitric oxide (FE(NO)) as an asthma management or monitoring tool to guide treatment of difficult-to-treat asthma patients. We present an annual medical resource use scenario typical of a difficult-to-treat asthma patient as well as five hypothetical scenarios of annual medical resource use for a difficult-to-treat asthma patient being managed with regular FE(NO) measurements in addition to current standard asthma management guidelines. We used the most conservative estimate of the potential asthma cost savings when FE(NO) measurement is used for difficult-to-treat asthma. The most likely clinical scenario assumes a 5% reduction in hospitalization and emergency department costs only. The inclusion of FE(NO) measurements to the asthma management strategy would essentially reach parity with the current standard of care, despite the additional cost of FE(NO) MEASUREMENTS: Additional scenarios were examined, all showed cost and use reduction across all medical resource usage categories. Use of exhaled NO measurement to guide asthma management, maintenance, and control in difficult-to-treat asthma would almost certainly result in cost savings to the payer.

Increasing proportions of tyrosine hydroxylase-immunoreactive interneurons colocalize with choline acetyltransferase or vasoactive intestinal peptide in the developing rat cerebral cortex.

Cortical interneurons are critical for information processing, and their dysfunction has been implicated in neurological disorders. One subset of this diverse cell population expresses tyrosine hydroxylase (TH) during postnatal rat development. Cortical TH-immunoreactive neurons appear at postnatal day (P) 16. The number of TH cells sharply increases between P16 and P20 and subsequently decreases to adult values. The absence of apoptotic markers in these cells suggests that the reduction in cell number is not due to cell death but is due to a decline in TH production. Cortical TH cells lack all additional catecholaminergic enzymes, and many coexpress GABA and calretinin, but little else is known about their phenotype or function. Because interneurons containing choline acetyltransferase (ChAT) or vasoactive intestinal peptide (VIP) share characteristics with cortical TH neurons, the coexpression of TH with ChAT or VIP was examined throughout the neocortex at P16, P20, and P30. The proportions of TH cell profiles double-labeled for ChAT or VIP significantly increased between P16 and P30. Based on their proximity to blood vessels, intrinsic cholinergic and VIPergic cells have been hypothesized to regulate cortical microcirculation. Labeling with the gliovascular marker aquaporin-4 revealed that at least half of the TH cells were apposed to microvessels at these ages, and many of these cells contained ChAT or VIP. Cortical TH neurons did not coproduce nitric oxide synthase. These results suggest that increasing proportions of cortical TH neurons express ChAT or VIP developmentally and that a subset of these TH neurons may regulate local blood flow.