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The impact of the Oncotype Dx (ODX) breast cancer assay on adjuvant chemotherapy (ACT) treatment decisions has been evaluated in many previous studies. However, it can be difficult to interpret the collective findings, which were conducted in diverse settings with limited sample sizes. We conducted a systematic review and meta-analysis to synthesize the results and provide insights about ODX utility. Studies, identified from PubMed, Embase, ASCO, and SABCS, were included if patients had ER+, node −, early-stage breast cancer, reported use of ODX to inform actual ACT decisions. Information was summarized and pooled according to: (1) distribution of ODX recurrence scores (RS), (2) impact of ODX on ACT recommendations, (3) impact of ODX on ACT use, and (4) proportion of patients following the treatment suggested by the ODX RS. A total of 23 studies met inclusion criteria. The distribution of RS categories was 48.8 % low, 39.0 % intermediate, and 12.2 % high (21 studies, 4,156 patients). ODX changed the clinical-pathological ACT recommendation in 33.4 % of patients (8 studies, 1,437 patients). In patients receiving ODX, receipt of ACT were: 28.2 % overall, 5.8 % low, 37.4 % intermediate, and 83.4 % high. High RS patients were significantly more likely to follow the treatment suggested by ODX versus low RS patients RR: 1.07 (1.01–1.14). The pooled results are consistent with most individual studies to date. The increased proportion of intermediate scores relative to original estimates may have implications for the clinical utility and cost impacts of testing. In addition, low versus high RS patients were significantly more likely to follow the ODX results, suggesting a tendency toward less aggressive treatment, despite a high ODX RS. Finally, there was a lack of studies on the impact of ODX on ACT use versus standard approaches, suggesting that additional studies are warranted.

In the United States the increasing number of Food and Drug Administration (FDA)-approved, innovative, and potentially effective commercial cancer therapies pose a significant financial burden on public and private payers. Chimeric antigen receptor (CAR) T cells are prototypical of this challenge. In 2017 and 2018, tisagenlecleucel (Kymriah, Novartis) and axicabtagene ciloleucel (Yescarta, Kite) were approved by the FDA for use after showing groundbreaking results in relapsed/refractory B-cell malignancies. In 2020 and 2021, four further submissions to the FDA are expected for CAR T-cell therapies for indolent and aggressive B-cell malignancies and plasma cell myeloma. Yet, with marketed prices of over $350,000 per infusion for the two FDA-approved therapies and similar price tags expected for the coming products, serious concerns are raised over value and affordability. In this review we summarize recent, peer-reviewed cost-effectiveness studies of tisagenlecleucel and axicabtagene ciloleucel in the United States; discuss key issues concerning the health plan budget impact of CAR T-cell therapy; and review policy, payment and scientific approaches that may improve the value and affordability of CAR T-cell therapy.

Prior studies have shown the promise of ultrasound-based approaches to measure knee laxity during clinical laxity assessments. However, a majority of these approaches involve manually measuring the change in the joint gap and/or bone motion before and after applying an external load. These manual measurements make determining changes in kinematics throughout a set of assessments, across many subjects, and/or across many time points impractical. Therefore, the objectives of this study were: (1) to develop an ultrasound-based approach to continuously measure bone motion using optical flow, and (2) to compute the errors in measuring knee kinematics during clinical laxity assessments using this approach. Our approach using optical flow allows users to select points along the bone(s) of interest in the first ultrasound frame to automatically define unique regions of interest to track the bone’s motion in successive ultrasound frames. We employed this approach to measure tibiofemoral kinematics using ultrasound B-mode cine loops of five human cadaver knees during anterior, posterior, varus, and valgus clinical laxity assessments. We computed errors in these kinematics compared to those measured using bone-pin-mounted optical motion capture markers. We found the maximum root-mean-square errors of ultrasound-measured kinematics using optical flow to be 1.1 mm and 0.9° for the anterior-posterior and varus-valgus laxity assessments, respectively, when simulating loading rates of clinical laxity assessments. In conclusion, our results demonstrate that our ultrasound-based approach using optical flow is a broadly translatable approach to accurately measure knee kinematics during clinical laxity assessments.

Low-dose computed tomography (LDCT) of the chest for lung cancer screening of heavy smokers was given a 'B' rating by the U.S. Preventive Services Task Force (USPSTF) in 2013, and gained widespread insurance coverage in the U.S. in 2015. Lung cancer screening has since had low uptake. However, for those that do choose to screen, little is known about patient motivations for completing screening in real-world practice. To explore the motivations for screening-eligible patients to screen for lung cancer. Semi-structured qualitative interviews were conducted with 20 LDCT screen-completed men and women who were members of an integrated mixed-model healthcare system in Washington State. From June to September 2015, participants were recruited and individual interviews performed about motivations to screen for lung cancer. Audio-recorded interviews were transcribed and analyzed using inductive content analysis by three investigators. Four primary themes emerged as motivations for completing LDCT lung cancer screening: 1) trust in the referring clinician; 2) early-detection benefit; 3) low or limited harm perception; and 4) friends or family with advanced cancer. Participants in our study were primarily motivated to screen for lung cancer based on perceived benefit of early-detection, absence of safety concerns, and personal relationships. Our findings provide new insights about patient motivations to screen, and can potentially be used to improve lung cancer screening uptake and shared decision-making processes.

Ligaments and tendons undergo nonuniform deformation during movement. While deformations can be imaged, it remains challenging to use such information to infer regional tissue loading. Shear wave tensiometry is a promising noninvasive technique to gauge axial stress and is premised on a tensioned beam model. However, it is unknown whether tensiometry can predict regional stress in a nonuniformly loaded structure. The objectives of this study were to (1) determine whether regional shear wave speed tracks regional axial stress in nonuniformly loaded fibrous soft tissues, and (2) determine the sensitivity of regional axial stress and shear wave speed to nonuniform load distribution and fiber alignment. We created a representative set of 12,000 dynamic finite element models of a fibrous soft tissue with probabilistic variations in fiber alignment, stiffness, and aspect ratio. In each model, we applied a randomly selected nonuniform load distribution, and then excited a shear wave and tracked its regional propagation. We found that regional shear wave speed was an excellent predictor of the regional axial stress (RMSE = 0.57 MPa) and that the nature of the regional shear wave speed-stress relationship was consistent with a tensioned beam model (R2 = 0.99). Variations in nonuniform load distribution and fiber alignment did not substantially alter the wave speed-stress relationship, particularly at higher loads. Thus, these findings suggests that shear wave tensiometry could provide a quantitative estimate of regional tissue stress in ligaments and tendons.

Purpose Following total knee arthroplasty (TKA), high tibial forces, large differences in tibial forces between the medial and lateral compartments, and anterior translation of the contact locations of the femoral component on the tibial component during passive flexion indicate abnormal knee function. Because the goal of kinematically aligned TKA is to restore native knee function without soft tissue release, the objectives were to determine how well kinematically aligned TKA limits high tibial forces, differences in tibial forces between compartments, and anterior translation of the contact locations of the femoral component on the tibial component during passive flexion. Methods Using cruciate retaining components, kinematically aligned TKA was performed on thirteen human cadaveric knee specimens with use of manual instruments without soft tissue release. The tibial forces and tibial contact locations were measured in both the medial and lateral compartments from 0° to 120° of passive flexion using a custom tibial force sensor. Results The average total tibial force (i.e. sum of medial + lateral) ranged from 5 to 116 N. The only significant average differences in tibial force between compartments occurred at 0° of flexion (29 N, p  = 0.0008). The contact locations in both compartments translated posteriorly in all thirteen kinematically aligned TKAs by an average of 14 mm ( p  < 0.0001) and 18 mm ( p  < 0.0001) in the medial and lateral compartments, respectively, from 0° to 120° of flexion. Conclusions After kinematically aligned TKA, average total tibial forces due to the soft tissue restraints were limited to 116 N, average differences in tibial forces between compartments were limited to 29 N, and a net posterior translation of the tibial contact locations was observed in all kinematically aligned TKAs during passive flexion from 0° to 120°, which are similar to what has been measured previously in native knees. While confirmation in vivo is warranted, these findings give surgeons who perform kinematically aligned TKA confidence that the alignment method and surgical technique limit high tibial forces, differences in tibial forces between compartments, and anterior translation of the tibial contact locations during passive flexion.

The evaluation of in vivo muscle-tendon loads is fundamental to understanding the actuation of normal and pathological human walking. However, conventional techniques for measuring muscle-tendon loads in the human body are too invasive for use in gait analysis. Here, we demonstrate the use of noninvasive measures of shear wave propagation as a proxy for Achilles tendon loading during walking. Twelve healthy young adults performed isometric ankle plantarflexion on a dynamometer. Achilles tendon wave speed, tendon moment arms, tendon cross-sectional area and ankle torque were measured. We first showed that the linear relationship between tendon stress and wave speed squared can be calibrated from isometric tasks. There was no significant effect of knee angle, ankle angle or loading rate on the subject-specific calibrations. Calibrated shear wave tensiometers were used to estimate Achilles tendon loading when walking at speeds ranging from 1 to 2 m/s. Peak tendon stresses during pushoff increased from 41 to 48 MPa as walking speed was increased, and were comparable to estimates from inverse dynamics. The tensiometers also detected Achilles tendon loading of 4 to 7 MPa in late swing. Late swing tendon loading was not discernible in the inverse dynamics estimates, but did coincide with passive stretch of the gastrocnemius muscle-tendon units. This study demonstrates the capacity to use calibrated shear wave tensiometers to evaluate tendon loading in locomotor tasks. Such technology could prove beneficial for identifying the muscle actions that underlie subject-specific movement patterns.

In 2013, the American Society for Radiation Oncology (ASTRO) issued a Choosing Wisely recommendation against the routine use of intensity modulated radiotherapy (IMRT) for whole breast irradiation. We evaluated IMRT use and subsequent impact on Medicare expenditure in the period immediately preceding this recommendation to provide a baseline measure of IMRT use and associated cost consequences. SEER records for women ≥66 years with first primary diagnosis of Stage I/II breast cancer (2008-2011) were linked with Medicare claims (2007-2012). Eligibility criteria included lumpectomy within 6 months of diagnosis and radiotherapy within 6 months of lumpectomy. We evaluated IMRT versus conventional radiotherapy (cRT) use overall and by SEER registry (12 sites). We used generalized estimating equations logit models to explore adjusted odds ratios (OR) for associations between clinical, sociodemographic, and health services characteristics and IMRT use. Mean costs were calculated from Medicare allowable costs in the year after diagnosis. Among 13,037 women, mean age was 74.4, 50.5% had left-sided breast cancer, and 19.8% received IMRT. IMRT use varied from 0% to 52% across SEER registries. In multivariable analysis, left-sided breast cancer (OR 1.75), living in a big metropolitan area (OR 2.39), living in a census tract with ≤$90,000 median income (OR 1.75), neutral or favorable local coverage determination (OR 3.86, 1.72, respectively), and free-standing treatment facility (OR 3.49) were associated with receipt of IMRT (p<0.001). Mean expenditure in the year after diagnosis was $8,499 greater (p<0.001) among women receiving IMRT versus cRT. We found highly variable use of IMRT and higher expenditure in the year after diagnosis among women treated with IMRT (vs. cRT) with early-stage breast cancer and Medicare insurance. Our findings suggest a considerable opportunity to reduce treatment variation and cost of care while improving alignment between practice and clinical guidelines.

While the value of individual biosimilars is evident, little is known about the value of a biosimilar portfolio beyond the cost savings between biosimilars and originators. Stakeholders may consider the value of a manufacturer's biosimilar portfolio, especially when negotiating portfolio-based contracts or other rebate programs. However, little is known about what other types of value, in addition to financial benefits, decision-makers perceive regarding a manufacturer with a biosimilar portfolio compared to those without one. The objective of this integrative literature review was to describe a conceptual framework consisting of themes that may help define the value of a biosimilar portfolio. An integrative literature review was conducted using Excerpta Medica Database (Embase) and Medical Literature Analysis and Retrieval System Online (MEDLINE). Grey literature searches of search engines, journals not indexed in Embase or MEDLINE, healthcare payers, health technology assessment bodies, value frameworks, and non-pharmaceutical industry analogs were also conducted. Eligible studies reported on the value of a biosimilar portfolio in decision-making by stakeholders. Apart from the literature, insights were gained from clinical experience and observation. No studies investigating biosimilar portfolio value were identified; however, several themes were identified that may help define the value of a biosimilar portfolio: Manufacturing; procurement, inventory, and storage; administration; education; and transaction costs. Several non-pharmaceutical industry analogs were identified: Product line length and single-supplier versus multiple-supplier procurement. Several themes were identified through other sources: Science credibility and research. Based on these themes, we developed a conceptual framework for biosimilar portfolio value. To our knowledge, this is the first study to systematically assess and create a framework for biosimilar portfolio value. The conceptual framework described here could be tested to quantify the clinical and economic value associated with a biosimilar portfolio.

The T16 project has produced a uniformly detrended and systematics-corrected set of 83,717,159 TESS Cycle 1 full-frame image (FFI) light curves for stars observed by TESS in its primary mission down to T = 16 mag, enabling sensitive transit searches beyond the official TESS pipelines. While most existing TESS planet searches focus on relatively bright targets, planet occurrence rates suggest that a substantial number of planets should exist around fainter stars. We therefore use the T16 light curves to conduct a semiautomated search for transiting exoplanets across the full Cycle 1 FFI sample, resulting in 11,554 planet candidates orbiting stars down to the 16th magnitude in the TESS band, with orbital periods between 0.5 and 27 days. Of these, 10,091 are new planet candidates, and 411 are single-transit events, for which we do not attempt to determine orbital parameters. The remaining 1052 candidates are previously known TESS candidates. We validate our pipeline through Magellan/Planet Finder Spectrograph radial-velocity follow-up measurements on one of our candidate hosts, TIC 183374187, a metal-poor thick-disk star, confirming the signal as a newly identified hot Jupiter, which we call TIC 183374187 b. This detection demonstrates our pipeline’s ability to identify real, previously undiscovered, transiting planets. Overall, this work shows that large-scale, machine learning–assisted transit searches of TESS FFIs can significantly expand the census of transiting planet candidates, in particular around faint stars, providing a rich target set for future validation and follow-up efforts. Our findings more than double the number of known TESS exoplanet candidates.