Clinical benefit, reimbursement outcomes, and prices of FDA-approved cancer drugs reviewed through Project Orbis in the USA, Canada, England, and Scotland: a retrospective, comparative analysis.

BACKGROUND: Project Orbis is a global initiative that aims to streamline regulatory review processes across international regulators in the USA, Canada, Australia, UK, Israel, Brazil, Singapore, and Switzerland to bring promising cancer drugs to patients earlier. We explored the clinical benefit, time to regulatory approval and health technology assessment recommendations, reimbursement outcomes, and monthly treatment prices of cancer drugs reviewed through this initiative. METHODS: For this retrospective, comparative analysis, we identified cancer drug approvals reviewed through Project Orbis in the USA, Canada, and the UK between May 1, 2019, and Nov 1, 2023. Approvals of cancer drugs reviewed Project Orbis were extracted from the Food and Drug Administration (FDA) Oncology Centre of Excellence and all other FDA approvals from the Drugs@FDA database. The co-primary outcomes were time of regulatory review, time from regulatory approval to health technology assessment recommendation (England, Scotland, and Canada), reimbursement outcomes, clinical benefit (defined as median gains in progression-free survival and overall survival) between cancer drug approvals reviewed by Project Orbis and other FDA approval processes, and monthly treatment prices. The Wilcoxon rank-sum and Fisher's Exact tests were used to examine statistical significance between approvals reviewed through Project Orbis and other FDA approvals during the same period. FINDINGS: Between May 1, 2019 and Nov 1, 2023, 81 (33%) of 244 cancer drugs approved by the FDA were reviewed through Project Orbis. The median overall survival gains were 4·1 months (IQR 3·3-5·1) compared with 2·7 months (2·1-3·9) for other FDA approvals. Similarly, progression-free survival gains were 2·6 months (IQR 1·7-4·9) for Project Orbis compared with 2·6 months (0·6-5·1) for other FDA approvals. Neither overall survival (p=0·11) nor progression-free survival (p=0·44) gains were significantly different between the two cohorts of approvals. Of the 14 UK Medicines and Healthcare products Regulatory Agency (MHRA) approvals reviewed by the Scottish Medicines Consortium (SMC), the agency gave positive recommendations for all 14 (100%). Of the 15 MHRA approvals reviewed by the National Institute for Health and Care Excellence (NICE), the agency gave positive recommendations for six (40%). Of the 49 approvals reviewed by the Canadian Agency for Drugs and Technologies in Health (CADTH), the agency conditionally recommended 44 (90%). The time between regulatory approval to NICE recommendation increased from a median of 137 days (IQR 102-172) in 2021 to 302 days (184-483) in 2023, SMC recommendation increased from 185 days (in 2021 for one drug only) to 368 days (IQR 313-476) in 2023, and CADTH decision increased from 97 days (in 2020 for one drug only) to 202 days (IQR 153-304) in 2023. The median monthly price of approvals reviewed through Project Orbis was US$20 000 per month (IQR 13 000-37 000). INTERPRETATION: Clinical outcomes of Project Orbis were no different than other FDA approvals during the same time, and access, after a successful health technology assessment, was considerably delayed or absent, raising questions about whether Project Orbis participation translates into faster patient access to medicines with high clinical benefit and sustainable costs. Although future challenges might benefit from regulatory harmonisation, the advantages are currently unclear. FUNDING: None.

Assessing patient burden and benefit: A decade of cabozantinib clinical trials.

Drug development is complex and costly. Clinical trial participants take on risks, making it essential to maximize trial efficiency and maintain participant safety. Identifying periods of excessive burden during drug development can inform trial design, ensure patient benefit and prevent harm. This study aims to examine all published clinical trials for cabozantinib to assess patient benefit and burden over time. We conducted a retrospective cross-sectional review of interventional clinical trials of cabozantinib for solid cancer treatment. We searched PubMed/MEDLINE, Embase, Cochrane (CENTRAL) and ClinicalTrials.gov. We extracted adverse event rates, median progression-free survival (PFS), median overall survival and objective response rate (ORR) for each included trial. We calculated frequencies of trial characteristics, cumulative grade 3-5 adverse event rates and cumulative ORRs. Out of 1735 studies, 54 publications were included that involved 6372 participants and 21 cancers. Of the 54 studies in our sample, 31 (57.41%) were single-arm trials and 23 (42.60%) had negative results. Trials among and within various indications had conflicting results over time. Cumulative risk to participants increased over time, and clinical benefit decreased. The findings suggest that the risk profile of cabozantinib increased from 2011 to 2016 and has remained elevated but stable while benefit has decreased over time. The use of non-randomized and single-arm trials is concerning, and more methodologically rigorous trials are needed. The results of trials for different indications are inconsistent, and empirical administration may reduce the drug's efficacy.

How Can (or Why Should) Process Engineering Aid the Screening and Discovery of Solid Sorbents for CO2 Capture?

ConspectusAdsorption using solid sorbents is emerging as a serious contender to amine-based liquid absorption for postcombustion CO2 capture. In the last 20+ years, significant efforts have been invested in developing adsorption processes for CO2 capture. In particular, significant efforts have been invested in developing new adsorbents for this application. These efforts have led to the generation of hundreds of thousands of (hypothetical and real) adsorbents, e.g., zeolites and metal-organic frameworks (MOFs). Identifying the right adsorbent for CO2 capture remains a challenging task. Most studies are focused on identifying adsorbents based on certain adsorption metrics. Recent studies have demonstrated that the performance of an adsorbent is intimately linked to the process in which it is deployed. Any meaningful screening should thus consider the complexity of the process. However, simulation and optimization of adsorption processes are computationally intensive, as they constitute the simultaneous propagation of heat and mass transfer fronts; the process is cyclic, and there are no straightforward design tools, thereby making large-scale process-informed screening of sorbents prohibitive.This Account discusses four papers that develop computational methods to incorporate process-based evaluation for both bottom-up (chemistry to engineering) screening problems and top-down (engineering to chemistry) inverse problems. We discuss the development of the machine-assisted adsorption process learning and emulation (MAPLE) framework, a surrogate model based on deep artificial neural networks (ANNs) that can predict process-level performance by considering both process and material inputs. The framework, which has been experimentally validated, allows for reliable, process-informed screening of large adsorbent databases. We then discuss how process engineering tools can be used beyond adsorbent screening, i.e., to estimate the practically achievable performance and cost limits of pressure vacuum swing adsorption (PVSA) processes should the ideal bespoke adsorbent be made. These studies show what conditions stand-alone PVSA processes are attractive and when they should not be considered. Finally, recent developments in physics-informed neural networks (PINNS) enable the rapid solution of complex partial differential equations, providing tools to potentially identify optimal cycle configurations. Ultimately, we provide areas where further developments are required and emphasize the need for strong collaborations between chemists and chemical engineers to move rapidly from discovery to field trials, as we do not have much time to fulfill commitments to net-zero targets.

Financial conflicts of interest among presenters, panellists and moderators at haematology and oncology FDA workshops.

OBJECTIVE: To assess the characteristics and financial conflicts of interest of presenters, panellists and moderators at haematology and oncology workshops held jointly with or hosted by the US FDA. SETTING: We included information on all publicly available haematology or oncology FDA workshop agendas held between 1 January 2018 and 31 December 2022. EXPOSURE: General and research payments reported on Open Payments, industry funding to patient advocacy organizations reported on their webpages or 990 tax forms and employment in both pharmaceutical and regulatory settings. RESULTS: Among physicians eligible for payments, 78% received at least one payment from the industry between 2017 and 2021. The mean general payment amount was $82,170 for all years ($16,434 per year) and the median was $14,906 for all years ($2981 per year). Sixty-nine per cent of patient advocacy speakers were representing organizations that received financial support from the pharmaceutical industry. Among those representing regulatory agencies or pharmaceutical companies, 16% had worked in both settings during their careers. CONCLUSIONS AND RELEVANCE: Our findings in this cross-sectional study show a majority of US-based physician presenters at haematology and oncology workshops held jointly with members of the US FDA have some financial conflict of interest with the pharmaceutical industry. These findings support the need for clear disclosures and suggest that a more balanced selection of presenters with fewer conflicts may help to limit bias in discussions between multiple stakeholders.

Evidence base for yearly respiratory virus vaccines: Current status and proposed improved strategies.

Annual vaccination is widely recommended for influenza and SARS-CoV-2. In this essay, we analyse and question the prevailing policymaking approach to these respiratory virus vaccines, especially in the United States. Every year, licensed influenza vaccines are reformulated to include specific strains expected to dominate in the season ahead. Updated vaccines are rapidly manufactured and approved without further regulatory requirement of clinical data. Novel vaccines (i.e. new products) typically undergo clinical trials, though generally powered for clinically unimportant outcomes (e.g. lab-confirmed infections, regardless of symptomatology or antibody levels). Eventually, the current and future efficacy of influenza and COVID-19 vaccines against hospitalization or death carries considerable uncertainty. The emergence of highly transmissible SARS-CoV-2 variants and waning vaccine-induced immunity led to plummeting vaccine effectiveness, at least against symptomatic infection, and booster doses have since been widely recommended. No further randomized trials were performed for clinically important outcomes for licensed updated boosters. In both cases, annual vaccine effectiveness estimates are generated by observational research, but observational studies are particularly susceptible to confounding and bias. Well-conducted experimental studies, particularly randomized trials, are necessary to address persistent uncertainties about influenza and COVID-19 vaccines. We propose a new research framework which would render results relevant to the current or future respiratory viral seasons. We demonstrate that experimental studies are feasible by adopting a more pragmatic approach and provide strategies on how to do so. When it comes to implementing policies that seriously impact people's lives, require substantial public resources and/or rely on widespread public acceptance, high evidence standards are desirable.

A novel framework to assess haematology and oncology registration trials: The THEOREMM project.

BACKGROUND: Methodological limitations affect a significant number of oncology and haematology trials, raising concerns about the applicability of their results. For example, a suboptimal control arm or limited access to best care upon progression may skew the trial results toward a benefit in the experimental arm. Beyond the fact that such limitations do not prevent drugs reaching the market, other assessment tools, such as those developed by professional societies-ESMO-MCBS and ASCO Value Framework-do not integrate these important shortcomings. METHODS: We propose creating a novel framework with the scope of assessing registration cancer clinical trials in haematology and oncology (randomized or single arm)-that is trials leading to a marketing authorization. The main steps of the methods are (1) assembling a scientific board; (2) defining the scope, goal and methods through pre-specified, pre-registered and protocolized methodology; (3) preregistration of the protocol; (4) conducting a scoping review of limitations and biases affecting oncology trials and assessing existing scores or methods; (5) developing a list of features to be included and assessed within the framework; (6) assessing each feature through a questionnaire sent to highly cited haematologists and oncologists involved in clinical trials; and (7) finalizing the first version of framework. RESULTS: Not applicable. CONCLUSIONS: Our proposal emerged in response to the lack of consideration for key limitations in current trial assessments. The goal is to create a framework specifically designed to assess single trials leading to marketing authorization in the field of oncology and haematogy.

The importance of falsification endpoints in observational studies of vaccination to prevent severe disease: A critique of a harm-benefit analysis of BNT162b2 vaccination of 5- to 11-year-olds.

We explore one systematic review and meta-analysis of both observational and randomized studies examining COVID-19 vaccines in 5- to 11-year-olds, which reported substantial benefits associated with vaccinating this age group. We discuss the limitations of the individual studies that were used to estimate vaccination benefits. The review included five observational studies that evaluated vaccine effectiveness (VE) against COVID-19 severe disease or hospitalization. All five studies failed to adequately assess differences in underlying health between vaccination groups. In terms of vaccination harms, looking only at the randomized studies, a significantly higher odds of adverse events was identified among the vaccinated compared with the unvaccinated. Observational studies are at risk of overestimating the effectiveness of vaccines against severe disease if healthy vaccinee bias is present. Falsification endpoints can provide valuable information about underlying healthy vaccinee bias. Studies that have not adequately ruled out bias due to better health among the vaccinated or more vaccinated should be viewed as unreliable for estimating the VE of COVID-19 vaccination against severe disease and mortality. Existing systematic reviews that include observational studies of the COVID-19 vaccine in children may have overstated or falsely inferred vaccine benefits due to unidentified or undisclosed healthy vaccinee bias.

Identification of Reaction Network Hypotheses for Complex Feedstocks from Spectroscopic Measurements with Minimal Human Intervention.

In this work, we detail an automated reaction network hypothesis generation protocol for processes involving complex feedstocks where information about the species and reactions involved is unknown. Our methodology is process agnostic and can be utilized in any reactive process with spectroscopic measurements that provide information on the evolution of the components in the mixture. We decompose the mixture spectra to obtain spectroscopic signatures of the individual components and use a 1-D convolutional neural network to automatically identify functional groups indicated by them. We employ atom-atom mapping to automatically recover reaction rules that are applied on candidate molecules identified from chemistry databases through fingerprint similarity. The method is tested on synthetic data and on spectroscopic measurements of lab-scale batch hydrothermal liquefaction (HTL) of biomass to determine the accuracy of prediction across datasets of varying complexities. Our methodology is able to identify reaction network hypotheses containing reaction networks close to the ground truth in the case of synthetic data, and we are also able to recover candidate molecules and reaction networks close to the ones reported in the previous literature studies for biomass pyrolysis.

Long COVID clinics and services offered by top US hospitals: an empirical analysis of clinical options as of May 2023.

BACKGROUND: The economic and health burden of COVID-19 has transformed the healthcare system in the US. Hospitals have adapted to the heterogeneity in long COVID symptoms, and the sheer number of people affected by this condition, by building long COVID centers and programs. OBJECTIVE: We sought to describe characteristics, services, and clinical trials of long COVID centers at top US hospitals. DESIGN: Cross-sectional analysis. PARTICIPANTS: Long COVID treatment programs or centers at top US hospitals. EXPOSURES: Frequency of long COVID centers, eligibility for being treated, the services they provide, specialist to whom the patients may be referred, and the long COVID clinical trials in which these hospitals participate. FINDINGS: Most top hospitals in the US (n = 43/50; 86%) offer long COVID services. 65% (28/43) did not describe the services provided. 12 (28%) required a referral from a primary care physician. The most common services were meeting with a team member (n = 20; 47%), ordering lab and/or radiology services (n = 8; 18.6%), and administering a physical exam (n = 7; 16%). 7 (16%) centers/programs treated only adults; 5 (12%) treated both adults and children, and 31 (72%) did not specify. The most common specialists described were psychology (n = 25; 58%), neurology (n = 25; 58%), and pulmonary (n = 24; 56%). Sixty-three trials (of 134 long COVID clinical trials) had at least one top hospital listed as a study site. The median number of clinical trials that each hospital sponsored or was a study site was 2 (interquartile range: 1, 3). CONCLUSIONS AND RELEVANCE: We find that services offered at long COVID clinics at top hospitals in the US often include meeting with a team member and referrals to a wide range of specialists. The diversity in long COVID services offered parallels the diversity in long COVID symptoms, suggesting a need for better consensus in developing and delivering treatment.

The Ethical Obligation for Research During Public Health Emergencies: Insights From the COVID-19 Pandemic.

In times of crises, public health leaders may claim that trials of public health interventions are unethical. One reason for this claim can be that equipoise-i.e. a situation of uncertainty and/or disagreement among experts about the evidence regarding an intervention-has been disturbed by a change of collective expert views. Some might claim that equipoise is disturbed if the majority of experts believe that emergency public health interventions are likely to be more beneficial than harmful. However, such beliefs are not always justified: where high quality research has not been conducted, there is often considerable residual uncertainty about whether interventions offer net benefits. In this essay we argue that high-quality research, namely by means of well-designed randomized trials, is ethically obligatory before, during, and after implementing policies in public health emergencies (PHEs). We contend that this standard applies to both pharmaceutical and non-pharmaceutical interventions, and we elaborate an account of equipoise that captures key features of debates in the recent pandemic. We build our case by analyzing research strategies employed during the COVID-19 pandemic regarding drugs, vaccines, and non-pharmaceutical interventions; and by providing responses to possible objections. Finally, we propose a public health policy reform: whenever a policy implemented during a PHE is not grounded in high-quality evidence that expected benefits outweigh harms, there should be a planned approach to generate high-quality evidence, with review of emerging data at preset time points. These preset timepoints guarantee that policymakers pause to review emerging evidence and consider ceasing ineffective or even harmful policies, thereby improving transparency and accountability, as well as permitting the redirection of resources to more effective or beneficial interventions.

Eventual success rate and predictors of success for oncology drugs tested in phase I trials.

Previous estimates of the likelihood of a drug tested in phase I trials obtaining FDA clearance are out of date. In the intervening years, newer pharmaceuticals have been developed, resulting in new delivery systems and lines of therapies. We sought to explore and update these estimates by comprehensively searching drugs tested in phase I trials and to determine the factors associated with later receiving FDA approval. In a cross-sectional analysis, we searched for anti-tumor drugs tested in phase I trials and published in scientific journals or presented at hematology/oncology conferences. For each drug, we searched PubMed for phase II and phase III studies testing the drug for the same indication tested in phase I studies. We found 51 drug approvals; four were withdrawn. The probability of a drug tested in 2015 being approved by 2021 was 6.2%. Drugs tested as monotherapy were more likely to receive approval than drugs tested in combination, and monoclonal antibodies were more likely to receive approval than drugs of other mechanisms. In adjusted models, response rates higher than 40% in phase I studies, demonstrating an improvement in overall survival (OS) in phase III studies, and drugs tested as monotherapy were associated with receiving FDA approval. When looking at all drugs tested during a single year, most drugs were not approved, and among those that are approved, almost 8% are withdrawn. Response rates higher than 40%, testing a drug as monotherapy, and demonstrating an improvement in OS were associated with receiving FDA approval.

Time-to-event surrogate end-points in multiple myeloma randomised trials from 2005 to 2019: A surrogacy analysis.

Use of surrogate end-points such as progression-free survival (PFS) and other time-to-event (TTE) end-points is common in multiple myeloma (MM) clinical trials. This systematic review characterises all published randomised controlled trials (RCTs) in MM using PFS or other TTE end-points between 2005 and 2019 and assesses strength of surrogacy of PFS for overall survival (OS). The association between OS hazard ratios (HRs) and PFS HRs was evaluated with linear regression, and the coefficient of determination with Pearson's correlation. We identified 88 RCTs of which 67 (76%) used PFS as the primary/co-primary end-point. One trial indicated whether progression was biochemical or clinical. Of the variance in OS, 39% was due to variance in PFS. Correlation between PFS and OS was weak (0.62, 95% confidence interval [CI] 0.38-0.78). In newly diagnosed MM, 43% of the variance in OS was due to changes in PFS. The correlation between PFS and OS was weak (0.65, 95% CI 0.30-0.84). In relapsed/refractory MM, 58% of the variance in OS was due to changes in PFS. Correlation between PFS and OS was medium (0.76, 95% CI 0.42-0.91). We demonstrate that PFS and progression characteristics are characterised poorly in MM trials and that PFS is a poor surrogate for OS in MM.

Additional considerations before using a ctDNA-guided approach for informing adjuvant chemotherapy in colorectal cancer.

BACKGROUND: The DYNAMIC trial investigated the use of circulating tumor DNA (ctDNA) to guide adjuvant treatment decisions in stage II colon cancer. Despite the DYNAMIC trial's assertion that a ctDNA-guided approach could minimize the use of adjuvant treatment without compromising recurrence-free survival (RFS), we raised concerns regarding the trial's methodology and the practical implications of its findings in a Debate article. Here, we expand upon these concerns in a response to a correspondence by the authors of the DYNAMIC trial. MAIN BODY: We dispute the choice of a large non-inferiority margin in the DYNAMIC trial, simply because an 8.5 percentage points decrease in recurrence-free survival could result in significant harm to patients. We challenge the authors' comparisons of the DYNAMIC trial outcomes with observational studies. Such comparison is subject to selection bias and changes over time that limit their relevance. The prognostic role of ctDNA do not automatically imply that more treatment in patients with ctDNA positivity would improve outcomes, which we highlight. In real-world settings, we anticipate a potential rise in chemotherapy use due to clinicians utilizing ctDNA alongside existing clinicopathologic factors, rather than using ctDNA as an entire replacement. Lastly, a key concern in DYNAMIC was an 350% higher use of oxaliplatin in the ctDNA arm compared with standard management (9.5% versus 2.7%, respectively), which poses a risk for long-term neuropathy. CONCLUSION: We look forward improvements in patient selection in the adjuvant setting, but we maintain our reservations about the DYNAMIC trial and the real-life implementation of its results. As an alternative to exploring de-escalation strategies with large margins non-inferiority trials, we propose that superiority trials in stage II patients could be a more effective strategy.

Persistent challenges with treating multiple myeloma early.

Over the past decade, 2 strategies have advanced the treatment of patients with multiple myeloma and its precursor diseases. First, the definition has changed to include patients without end organ damage, who previously would not have been treated. Second, there is widespread enthusiasm for treating high-risk, smoldering multiple myeloma. In this commentary, we explore the evidence supporting these therapeutic expansions. Although early treatment adds cost and therapeutic burden, it remains unknown whether survival and health-related quality of life are improved by early treatment. Herein, we consider the implications of diagnostic expansion in multiple myeloma.

COVID-19 vaccine induced myocarditis in young males: A systematic review.

BACKGROUND: Myocarditis is a rare but significant adverse event associated with COVID-19 vaccination, especially for men under 40. If the risk of myocarditis is not stratified by pertinent risk factors, it may be diluted for high-risk and inflated for low-risk groups. We sought to assess how the risk of myocarditis is reported in the literature. METHODS: In accordance with PRISMA standards, we reviewed primary publications in PubMed, Embase, Google Scholar and MedRxiv (through 3/2022) and included studies that estimated the incidence of myocarditis/pericarditis after receiving either the BNT162b2 (Pfizer), mRNA-1273 (Moderna) or Ad26COVS1 (Janssen) vaccine. The main outcome was the percentage of studies using 4, 3, 2, 1 or 0 stratifiers (i.e. sex, age, dose number and manufacturer) when reporting the highest risk of myocarditis. Secondary outcomes included the incidence of myocarditis in males after dose 1 and 2 of the BNT162b2 (Pfizer) or mRNA-1273 (Moderna) vaccine. RESULTS: The 29 included studies originated in North America, Europe, Asia, or were Worldwide. Of them, 28% (8/29) used all four stratifiers, and 45% (13/29) used 1 or 0 stratifiers. The highest incidence of myocarditis ranged from 8.1-39 cases per 100,000 persons (or doses) in studies using four stratifiers. Six studies reported an incidence greater than 15 cases per 100,000 persons (or doses) in males aged 12-24 after dose 2 of an mRNA-based vaccine. CONCLUSIONS: Only one in four articles reporting myocarditis used four stratifiers, and men younger than 40 receiving a second dose of an mRNA vaccine are at greatest risk.

The definition of long COVID used in interventional studies.

INTRODUCTION: There has been little consensus for a specific definition of long COVID, though several organizations have created varying ones. We sought to examine the definition of long COVID used in ongoing clinical trials. METHODS: We searched 'long COVID' and related terms on both PubMed and clinicaltrials.gov for randomized studies that either included patients with long COVID or had a persistent or long-term COVID-related outcome and abstracted long COVID definition components. RESULTS: Of the 92 studies, a laboratory-only confirmed diagnosis of COVID-19 was stipulated in 54.3% (n = 50) studies. We found eight different time durations specified for how long symptoms needed to have occurred, ranging from 4 to 52 weeks, with 12 weeks being the most common (34.8%; n = 32). 35.9% (n = 33) did not specify a time duration. There were 57 different symptoms specified in total, with a median of one symptom identified per study (range 0-32). 8.7% of trials adhered to NICE or WHO definitions. CONCLUSION: Standardized definitions of long COVID should be applied in studies assessing this condition to unify and harmonize research on this topic.

Post-progression treatment in cancer randomized trials: a cross-sectional study of trials leading to FDA approval and published trials between 2018 and 2020.

BACKGROUND: Suboptimal treatment upon progression may affect overall survival (OS) results in oncology randomized controlled trials (RCTs). We aim to assess the proportion of trials reporting post-progression treatment. METHODS: This cross-sectional analysis included two concurrent analyses. The first one examined all published RCTs of anti-cancer drugs in six high impact medical/oncology journals between January 2018 and December 2020. The second studied all US Food and Drug Administration (FDA) approved anti-cancer drugs during the same period. Included trials needed to study an anti-cancer drug in the advanced or metastatic setting. Data abstracted included the tumor type, characteristics of trials, and reporting and assessment of post-progression treatment. RESULTS: There were 275 published trials and 77 US FDA registration trials meeting inclusion criteria. Assessable post-progression data were reported in 100/275 publications (36.4%) and 37/77 approvals (48.1%). Treatment was considered substandard in 55 publications (n = 55/100, 55.0%) and 28 approvals (n = 28/37, 75.7%). Among trials with assessable post-progression data and positive OS results, a subgroup analysis identified substandard post-progression treatment in 29 publications (n = 29/42, 69.0%) and 20 approvals (n = 20/26, 76.9%). Overall, 16.4% of publications (45/275) and 11.7% of registration trials (9/77) had available post-progression data assessed as appropriate. CONCLUSION: We found that most anti-cancer RCTs do not report assessable post-progression treatment. When reported, post-progression treatment was substandard in most trials. In trials reporting positive OS results and with assessable post-progression data, the proportion of trials with subpar post-progression treatment was even higher. Discrepancies between post-progression therapy in trials and the standard of care can limit RCT results' applicability. Regulatory rules should enforce higher requirements regarding post-progression treatment access and reporting.

Umbrella review of basket trials testing a drug in tumors with actionable genetic biomarkers.

BACKGROUND: The utilization of basket trials in oncology has gained popularity because of the drive for precision medicine and the increasing ease of genetically profiling tumors. However, it is unknown if this has translated into patient benefit, either through higher response rates because of precision treatment or because of increasing options for less-common tumor types that are less represented in oncology drug trials. We sought to characterize basket studies for oncology drugs targeting a genetic biomarker, determine the responses for various tumor types and genetic biomarkers, and test for correlation between the number of participants in each tumor basket and the incidence of the respective tumor. METHODS: We conducted a retrospective cross-sectional review of oncology basket trials on Embase or clinicaltrials.gov with published data. We included studies that reported on oncology drugs that target a genetic biomarker. We examined the response for basket trial participants, stratified by tumor type and genetic biomarker and the correlation between the number of participants in each tumor basket and the incidence of the respective tumor. RESULTS: The overall response rate for all 25 included trials was 23%. The response for each genetic biomarker ranged from 0 to 69%, and for half of the genetic biomarkers, the response rate ranged from 0 to 100%, depending on tumor type. There is low correlation between the number of participants in each tumor basket and the incidence of the respective tumor (66.41 + -0.20x, R2 = 0.003, p = 0.75). CONCLUSION: While there has been an increase in the number of published basket trials and individuals included in these trials, the response rate is low, but varies widely, depending on tumor type and genetic biomarker.

Current Utilization of Electron Microscopy in the Pediatric Pathology Setting: A Survey by the SPP Practice Committee.

BACKGROUND: Electron microscopy (EM), once an important component in diagnosing pediatric diseases, has experienced a decline in its use. To assess the impact of this, pediatric pathology practices were surveyed regarding EM services. METHODS: The Society of Pediatric Pathology Practice Committee surveyed 113 society members from 74 hospitals. Settings included 36 academic tertiary, 32 free-standing children's, and 6 community hospitals. RESULTS: Over 60% maintained in-house EM services and had more than 2 pathologists interpreting EM while reporting a shortage of EM technologists. Freestanding children's hospitals had the most specimens (100-200 per year) and more diverse specimen types. Hospitals with fewer than 50 yearly specimens often used reference laboratories. Seventeen had terminated all in-house EM services. Challenges included decreasing caseloads due to alternative diagnostic methods, high operating costs, and shortages of EM technologists and EM-proficient pathologists. Kidney, liver, cilia, heart, and muscle biopsies most often required EM. Lung/bronchoalveolar lavage, tumor, skin, gastrointestinal, nerve, platelet, and autopsy samples less commonly needed EM. CONCLUSIONS: The survey revealed challenges in maintaining EM services but demonstrated its sustained value in pediatric pathology. Pediatric pathologists may need to address the centralization of services and training to preserve EM diagnostic proficiency among pathologists who perform ultrastructural interpretations.

Chaotic advection in a recirculating flow: Effect of a fluid multiple-flexible-solid interaction.

This paper deals with chaotic advection due to a two-way interaction between flexible elliptical-solids and a laminar lid-driven cavity flow in two dimensions. The present Fluid multiple-flexible-Solid Interaction study involves various number N(= 1-120) of equal-sized neutrally buoyant elliptical-solids (aspect ratio ß = 0.5) such that they result in the total volume fraction Φ = 10 % as in our recent study on single solid, done for non-dimensional shear modulus G ∗ = 0.2 and Reynolds number R e = 100. Results are presented first for flow-induced motion and deformation of the solids and later for chaotic advection of the fluid. After the initial transients, the fluid as well as solid motion (and deformation) attain periodicity for smaller N ≤ 10 while they attain aperiodic states for larger N > 10. Adaptive material tracking (AMT) and Finite-Time Lyapunov Exponent (FTLE)-based Lagrangian dynamical analysis revealed that the chaotic advection increases up to N = 6 and decreases at larger N(= 6-10) for the periodic state. Similar analysis for the transient state revealed an asymptotic increase in the chaotic advection with increasing N ≤ 120. These findings are demonstrated with the help of two types of chaos signatures: exponential growth of material blob's interface and Lagrangian coherent structures, revealed by the AMT and FTLE, respectively. Our work, which is relevant to several applications, presents a novel technique based on the motion of multiple deformable-solids for enhancement of chaotic advection.