Trial Data Research Articles

CTNI-41. LONG-TERM SURVIVAL AND PATTERNS OF PROGRESSION IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA TREATED WITH OR WITHOUT TUMOR TREATING FIELDS (TTFIELDS) IN A REAL-WORLD SETTING

Abstract BACKGROUND Tumor Treating Fields therapy (TTFields) is an FDA-approved locoregional treatment for patients with newly diagnosed glioblastoma (ndGBM). Previous trial data showed the addition of TTFields to standard TMZ-based therapy to significantly improve overall survival (OS), but real-world data is lacking, particularly with long follow-up duration. Here, we report real-world survival and patterns of progression for patients with ndGBM treated with or without TTFields. METHODS Patients diagnosed with GBM and treated with standard of care therapy at the Medical College of Wisconsin between March 2015–March 2023 were included. Progression-free survival (PFS) and OS outcomes were assessed, and compared across groups who received or did not receive TTFields therapy during maintenance treatment. Patterns of disease progression were analyzed via anatomic assessment. Patients were followed through March 1, 2024. RESULTS A total of 210 patients (TTFields: n=110/52.4%; No-TTFields: n=100/47.6%) were included for analysis. Median age was 60 and 63 years for the TTFields and No-TTFields groups, respectively, with each group 43% female. Other baseline characteristics were consistent across groups. Median TTFields duration was 6.8 months (range: 1–94). OS was significantly improved for the TTFields group vs No-TTFields group (median OS: 21.6 months [18.4–24.8] vs 17.7 months [15.0–20.8]; HR 0.73 [95% CI: 0.54–0.99, P=0.042]). Median PFS was 12.1 months (10.3–14.4) vs 9.6 months (8.5–12.8) with HR 0.77 (95% CI: 0.58–1.02; P=0.071). 5-year OS was 17% (10–28) for the TTFields group, and 11% (5–22) for No-TTFields group. Patients treated with TTFields exhibited a higher rate of non-local progression compared with the No-TTFields group (28% vs 15%, [P=0.044]). CONCLUSIONS Analysis of patients from a large institutional dataset reveals an association between TTFields use and long-term survival benefit. Higher incidence of non-local patterns of progression among TTFields users is consistent with pivotal trial findings.

TMOD-33. DOES PRE-CLINICAL DRUG ACTIVITY PREDICT PHASE II CLINICAL EFFICACY IN GLIOBLASTOMA? A DETAILED ANALYSIS

Abstract Despite decades of research, there are fewer than six FDA-approved therapies for glioblastoma (GBM). The drug approval process relies on studies establishing pre-clinical activity, most commonly using murine models, followed by in human studies establishing safety and then efficacy. Although murine models for GBM have allowed for insights into tumor biology, their utility in assessing the efficacy of novel anti-cancer therapies remains highly debated. Here, we sought to establish whether there was any relationship between drug activity in preclinical models and phase 2 clinical trial outcomes. Using ClinicalTrials.gov (NIH), all phase 2 trials in glioblastoma up to December 2023 were queried and downloaded. Trials that were never started, had not yet started, were withdrawn, not completed, or contained indications beyond glioblastoma were excluded. Studies examining anti-tumor effects of an investigational agent with or without bevacizumab, temozolomide, or radiation therapy in glioblastoma were included, and studies examining alternative dosing strategies, various medical devices, or drug combinations, were excluded. The corresponding preclinical studies were identified via literature review for each clinical trial. Data including the progression free and overall survival benefit, mouse models used, and sample sizes were extracted from each study. 659 trials between 1994 and 2023 were included for analysis. Of these, 272 (41%) were for monotherapies, examining 90 unique small molecules. Preclinical endpoints included murine survival and tumor weight. In comparing mouse survival and tumor size to progression free and overall survival in humans, our preliminary analysis did not reveal any clear correlation. The correlation between preclinical and clinical drug response in GBM remains uncertain. Future work will examine whether mouse genotype, immune status, or GBM cell line used affected the degree of concordance with human clinical trial data. Our analysis suggests that further investigation into preclinical models of GBM, and standardized reporting of preclinical models, are needed.

Clinical practice guidelines for the care of patients with a chronic subdural haematoma: multidisciplinary recommendations from presentation to recovery

Introduction A chronic subdural haematoma (cSDH) is an encapsulated collection of fluid and blood degradation products in the subdural space. It is increasingly common, affecting older people and those living with frailty. Currently, no guidance exists to define optimal care from onset of symptoms through to recovery. This paper presents the first consensus-built recommendations for best practice in the care of cSDH, co-designed to support each stage of the patient pathway. Methods Guideline development was led by a multidisciplinary Steering Committee with representation from diverse clinical groups, professional associations, patients, and carers. Literature searching to identify relevant evidence was guided by core clinical questions formulated through facilitated discussion with specially convened working groups. A modified Delphi exercise was undertaken to build consensus on draft statements for inclusion in the guideline using survey methodology and an in-person meeting. The proposed guideline was subsequently endorsed by the Society for British Neurological Surgeons, Neuroanaesthesia and Critical Care Society, Association of Anaesthetists, British Association of Neuroscience Nurses, British Geriatric Society, and Centre for Perioperative Care. Results We identified that high quality evidence was generally lacking in the literature, although randomised controlled trial (RCT) data were available to inform specific recommendations on aspects of surgical technique and use of corticosteroids. The final guideline represents the outcome of synthesising available evidence, consensus-built expert opinion and patient involvement. The guideline comprises 67 recommendations across eight major themes, covering: presentation and diagnosis, neurosurgical triage and shared decision-making, non-operative management, perioperative management (including anticoagulation), timing of surgery, intraoperative and postoperative care, rehabilitation and recovery. Conclusions We present the first multidisciplinary guideline for the care of patients with cSDH. The recommendations reflect a paradigm shift in the care of cSDH, recognising and formalising the need for multidisciplinary and collaborative clinical management, communication and decision-making delivered effectively across secondary and tertiary care.

Diving into hot topics of salivary gland carcinoma management—an EORTC young and early career investigator survey

IntroductionRecently, the ASCO and ESMO guidelines on salivary gland carcinomas (SGCs) have been released. However, several crucial points lack strong recommendations due to low or intermediate quality of evidence. To better address these “grey zones” in the guidelines, we conducted a survey among the European Organization for Research and Treatment of Cancer (EORTC) Head and Neck Cancer Group (HNCG) members on behalf of the EORTC young and early career investigators.Materials and methodsThe survey included 29 questions addressing diagnostic and therapeutic issues related to SGC patients and was shared among 539 members of the EORTC HNCG. Responses were collected from December 2022 to March 2023. The primary aim was to evaluate the decision-making criteria guiding physicians in areas with low evidence in SGC guidelines.ResultsWith a response rate of 19%, the survey received input from 102 respondents, mainly medical oncologists (45%). Among those with pathological high-risk features, 35% and 30% of respondents opted for chemoradiotherapy (CRT) in the definitive and adjuvant settings, respectively. For patients with R0 resection of highly aggressive SGC at the pT1–2 stage, 37% proposed a close follow-up, while 38% proposed adjuvant lymph-node field RT. In cases of pT3–4 stage, 48% proposed adjuvant lymph-node field RT in all cases, and 44% proposed it based only on risk factors. The most important factors guiding the decision to give adjuvant RT after salvage surgery for locoregional relapse include previous radiotherapy, margin status, and the presence of extranodal extension. When faced with combined positivity to HER2 and AR, responses regarding the choice of first-line palliative treatment were heterogeneous.ConclusionsInternational guidelines lack strong recommendations in several fields of SGC diagnosis and treatment due to insufficient high-quality data, resulting in heterogeneity in physicians’ treatment decision (e.g., adjuvant lymph-node field RT and their low concordance with guidelines, such as the use of concomitant CRT). The survey demonstrated the need for prospective clinical trial data to address these gaps in the future.

Long-Term Adverse Effects and Complications After Prostate Cancer Treatment

Due to the often indolent nature of prostate cancer (PCA), treatment decisions must weigh the risks and benefits of cancer control with those of treatment-associated morbidities. To characterize long-term treatment-related adverse effects and complications in patients treated for PCA compared to a general population of older males. This cohort study used a novel approach linking data from 2 large PCA prevention clinical trials (the Prostate Cancer Prevention Trial and the Selenium and Vitamin-E Cancer Prevention Trial) with Medicare claims records. This analysis included patients with PCA who had been treated with prostatectomy or radiotherapy compared with an untreated control group. Multivariable Cox regression was used, with a time-varying covariate for the occurrence of PCA treatment, adjusted for age, race, and year of time-at-risk initiation, and stratified by study and intervention arm. Data analyses were performed from September 21, 2022, to March 18, 2024. Prostatectomy and radiotherapy occurring after a PCA diagnosis, identified from trial data or Medicare claims records. Ten potential PCA treatment-related complications identified from Medicare claims data. The study sample comprised 29 196 participants (mean [SD] age at time-at-risk initiation, 68.7 [4.8] years). Of these, 3946 participants had PCA, among whom 655 were treated with prostatectomy and 1056 with radiotherapy. The 12-year hazard risk of urinary or sexual complications was 7.23 times greater for those with prostatectomy (95% CI, 5.96-8.78; P < .001) and 2.76 times greater for radiotherapy (95% CI, 2.26-3.37; P < .001) compared to untreated participants. Moreover, among participants treated with radiotherapy, there was a nearly 3-fold greater hazard risk of bladder cancer than in the untreated (hazard ratio [HR], 2.78; 95% CI, 1.92-4.02; P < .001), as well as an approximately 100-fold increased hazard risk of radiation-specific outcomes including radiation cystitis (HR, 131.47; 95% CI, 52.48-329.35; P < .001) and radiation proctitis (HR, 87.91; 95% CI, 48.12-160.61; P < .001). The incidence per 1000 person-years of any 1 of the 10 treatment-related complications was 124.26 for prostatectomy, 62.15 for radiotherapy, and 23.61 for untreated participants. This cohort study found that, even after accounting for age-related symptoms and disease, PCA treatment was associated with higher rates of complications in the 12 years after treatment. Given the uncertain benefit of PCA treatment for most patients, these findings highlight the importance of patient counseling before PCA screening and treatment and provide a rationale for pursuing opportunities for cancer prevention.

Handling missing data in longitudinal clinical trials: three examples from the pediatric psychology literature.

Researchers by default tend to choose complex models when analyzing nonindependent response variable data, this may be particularly applicable in the analysis of longitudinal trial data, possibly due to the ability of such models to easily address missing data by default. Both maximum-likelihood (ML) estimation and multiple imputation (MI) are well-known to be acceptable methods for handling missing data, but much of the recently published quantitative literature has addressed questions regarding the research designs and circumstances under which one should be chosen over the other. The purpose of this article is threefold. First, to clearly define the assumptions underlying three common longitudinal trial data analysis models for continuous dependent variable data: repeated measures analysis of covariance (RM-ANCOVA), generalized estimating equation (GEE), and a longitudinal linear mixed model (LLMM). Second, to clarify when ML or MI should be chosen, and to introduce researchers to an easy-to-use, empirically well-validated, and freely available missing data multiple imputation program: BLIMP. Third, to show how missing longitudinal trial data can be handled in the three data analysis models using three popular statistical analysis software packages (SPSS, Stata, and R) while keeping the published quantitative research in mind.

Spatial analysis with unoccupied aircraft systems data in wheat breeding yield trials

AbstractAn important aspect of reliable cultivar development is good field trial evaluations. Unoccupied aircraft systems (UAS also known as drones or UAVs) are a popular high‐throughput phenotyping tool that has been used to successfully evaluate plant stress and other canopy characteristics in a field. In precision agriculture applications, UAS imagery has been used to identify spatial variability in field settings. Here, we use UAS spectral imagery to improve field trial spatial analysis, better control spatial variability, and reduce errors for more reliable selections. UAS imagery data were collected across 47 breeding trials planted in an augmented complete block design (ACBD) or alpha‐lattice replicated designs from 2020 through 2023. Trials were evaluated using three spatial analysis strategies: linear models incorporating block effect, row‐column effect, or 2D splines. UAS‐derived spectral reflectance indices (SRI) were combined with each model as covariates. Modeling strategies were used across all trials and evaluated for autocorrelation, model fitness, and coefficient of variation (CV). Akaike information criterion (AIC) was used to assess model fitness. For spatial analysis trials, SRIs significantly lowered model AIC by an average of 38.4 for alpha‐lattice trials and 69.1 for ACBD trials. CV scores were also lowered when SRIs were utilized, with average CV values being 2.6 lower for alpha‐lattice and 2.1 for ACBD trials. This study highlights the potential for SRIs to improve the analyses of field breeding trials despite extreme environmental variables and climate conditions, improving experiment reliability and changing the way breeders plan and implement breeding experiments.

A study of feature importance for king salmon health classification with feature selection

King salmon is important for aquaculture in New Zealand, contributing significant economic value. Fish health is a priority for the industry, and the change in the health status of king salmon needs to be accurately detected at the earliest possible stage. Many factors affect the health of king salmon, such as temperature. Identifying the key features that influence health prediction is a crucial step toward achieving this goal. This study utilizes trial data collected by the Cawthron Institute, which includes diverse information on king salmon, such as blood biochemistry and hematology. We explore the data by employing statistical methods and feature selection techniques in machine learning to identify the most relevant features for king salmon health prediction, aiming to classify individuals as healthy or unhealthy with a small number of features. The results show that although the most efficient feature selection techniques on different datasets vary, overall, feature selection approaches can successfully identify relevant and informative features for king salmon health classification. Through the incorporation of a few selected features, the learned classifiers could still achieve statistically equal or better classification performance. This study not only contributes to the understanding of the health indicators of king salmon but also provides crucial insights into health prediction, which will be beneficial to the improvement of the health of king salmon, leading to the development of more effective management strategies for aquaculture.

Amyloid-beta antibody treatment in Alzheimer's disease : An update on recent data and outlook on implementation in clinical routine.

Amyloid-beta (Aβ) antibody treatment has emerged as apromising approach for the treatment of Alzheimer's disease (AD), targeting the accumulation of Aβ plaques, which are ahallmark of the disease. This review provides an update on recent clinical trial data, highlighting the efficacy and safety of various antibodies targeting Aβ. Recent trials have demonstrated that certain Aβ antibodies can reduce amyloid plaques and slow cognitive decline in patients with early AD. Key findings from trials of drugs are discussed, including their mechanisms of action, dosing regimens, and observed side effects. The potential for Aβ antibody therapy to be integrated into routine clinical practice is also explored. While Aβ antibody therapy represents asignificant advancement in AD treatment, ongoing research is needed to optimize their use and understand their long-term impact. This review underscores the importance of personalized medicine in AD and the need for continued innovation in therapeutic strategies.

Safety of Simultaneous vs Sequential mRNA COVID-19 and Inactivated Influenza Vaccines

Limited randomized clinical trial data exist on the safety of simultaneous administration of COVID-19 and influenza vaccines. To compare the reactogenicity, safety, and changes in health-related quality of life (HRQOL) after simultaneous vs sequential receipt of messenger RNA (mRNA) COVID-19 vaccine and quadrivalent inactivated influenza vaccine (IIV4). This randomized, placebo-controlled clinical trial was conducted between October 8, 2021, and June 14, 2023, at 3 US sites. Participants were nonpregnant persons aged 5 years or older with the intention of receiving both influenza and mRNA COVID-19 vaccines. Intramuscular administration in opposite arms of either IIV4 or saline placebo simultaneously with mRNA COVID-19 vaccine at visit 1. Those who received placebo at visit 1 received IIV4 and those who received IIV4 at visit 1 received placebo 1 to 2 weeks later at visit 2. The primary composite reactogenicity outcome was the proportion of participants with fever, chills, myalgia, and/or arthralgia of moderate or greater severity within 7 days after vaccination visits 1 and/or 2, using a 10% noninferiority margin. Secondary outcomes were solicited reactogenicity events and unsolicited adverse events (AEs) for 7 days after each visit separately and HRQOL after visit 1, assessed by the EuroQol 5-Dimension 5-Level (EQ-5D-5L) Index. Serious AEs (SAEs) and AEs of special interest (AESIs) were assessed for 121 days. Outcomes were compared between groups. A total of 335 persons (mean [SD] age, 33.4 [15.1] years) were randomized (169 to the simultaneous group and 166 to the sequential group); 211 (63.0%) were female, and 255 (76.1%) received bivalent BNT162b2 mRNA COVID-19 vaccine. The proportion with the primary composite reactogenicity outcome in the simultaneous group (25.6% [n = 43]) was noninferior to the proportion in the sequential group (31.3% [n = 52]) (site-adjusted difference, -5.6 percentage points [pp]; 95% CI, -15.2 to 4.0 pp). Respective proportions in each group were similar after each visit separately (visit 1, 40 [23.8%] vs 47 [28.3%]; visit 2, 5 [3.0%] vs 9 [5.4%]). No significant group differences in participants with AEs (21 [12.4%] vs 16 [9.6%]), SAEs (1 [0.6%] vs 1 [0.6%]), and AESIs (19 [11.2%] vs 9 [5.4%]) were observed in the simultaneous vs sequential groups, respectively. Among participants with severe reactogenicity, the mean (SD) EQ-5D-5L Index score decreased from 0.92 (0.08) to 0.92 (0.09) prevaccination to 0.81 (0.09) to 0.82 (0.12) postvaccination. In this randomized clinical trial assessing simultaneous vs sequential administration of mRNA COVID-19 and IIV4 vaccines, reactogenicity was comparable in both groups. These findings support the option of simultaneous administration of these vaccines. ClinicalTrials.gov Identifier: NCT05028361.

Design of CONQUEST, a novel, randomized, placebo-controlled, Phase 2b platform clinical trial to investigate new treatments for patients with early active systemic sclerosis with interstitial lung disease.

Safe, effective therapies are urgently needed for patients with systemic sclerosis. However, clinical trial recruitment is challenging given the limited number of people with systemic sclerosis and further restrictions imposed by eligibility criteria. Innovative approaches are needed to accelerate development of new therapies. This article describes the rationale and trial design for CONQUEST (NCT06195072), a novel platform clinical trial sponsored by the Scleroderma Research Foundation, a not-for-profit organization. CONQUEST is a multicentre, double-blind, randomized, placebo-controlled, Phase 2b platform trial evaluating the efficacy, safety and pharmacodynamics of multiple investigational products to treat early active systemic sclerosis with interstitial lung disease versus placebo. The primary objective is to evaluate change from baseline to Week 52 in forced vital capacity (mL). Secondary objectives include evaluating changes from baseline to Week 52 in high-resolution computed-tomography-assessed lung involvement and dyspnoea, and overall treatment response (measured using the revised composite response index in diffuse systemic sclerosis score in participants with diffuse cutaneous systemic sclerosis). Patients will be enrolled across more than 150 centres in over 25 countries. Recruitment started on 15 April 2024. As the first platform clinical trial in the rheumatology field, CONQUEST aims to meaningfully accelerate the development of new therapies for early active systemic sclerosis. Depending on regimen-specific results, trial data could be used to plan and design a Phase 3 trial or may be used alone or together with another registrational trial to establish substantial evidence of effectiveness and safety. The first molecules to be studied, amlitelimab and nerandomilast, both have a strong scientific rationale to modify underlying disease processes in systemic sclerosis. Platform Clinical Study for Conquering Scleroderma (CONQUEST); NCT06195072; https://www.clinicaltrials.gov/study/NCT06195072.

Drug Efficacy Estimation for Follow-on Companion Diagnostic Devices Through External Studies.

A therapeutic product is usually not suitable for all patients but for only a subpopulation. The safe and effective use of such a therapeutic product requires the co-approval of a companion diagnostic device which can be used to identify suitable patients. While the first-of-a-kind companion diagnostic device is often developed in conjunction with its intended therapeutic product and simultaneously validated through a randomized clinical trial, there remains room for the innovation of new and improved follow-on companion diagnostic devices designed for the same therapeutic product. However, conducting a new randomized trial or a bridging study for the follow on companion devices may be unethical, expensive or unpractical. Hence, there arises a need for an external study to evaluate the concordance between the FDA-approved comparator companion diagnostic device (CCD) and the subsequent follow-on companion diagnostic devices (FCD), indirectly validating the latter. In this article, we introduce a novel external study design, referred to as the targeted treatment design, as an extension of the existing concordance design. Additionally, we present corresponding statistical analysis methods. Our approach combines the CCD randomized trial data and the FCD external study data, enabling the estimation of drug efficacy within the FCD+ and FCD- subpopulations-the parameters crucial for the validation of the FCD. Theoretical results and simulation studies validate the proposed methods and we further illustrate the proposed methods through an application in a real example of non-small-cell lung cancer.

Impact of Structural Severity on Outcomes in Knee Osteoarthritis: An Analysis of Data from Phase 2 and Phase 3 Lorecivivint Clinical Trials.

Developing knee osteoarthritis (OA) treatments is challenging due to assessing pain and joint structure outcomes within a highly heterogeneous disease. Lorecivivint (LOR), an intra-articular (IA) CLK/DYRK inhibitor, modulates Wnt and inflammatory pathways. This review analysis of LOR 0.07 mg trial data aims to describe the potential impact of baseline joint structure on OA pain response. Two Phase 2 and two Phase 3 trials enrolled knee OA patients with Kellgren-Lawrence (KL) Grades 2-3 and Pain Numeric Rating Scale (NRS [0-10]) ≥4 to ≤ 8 in target knee. Cumulative frequency distribution plots by KL grade summarized the percentages of patients with medial joint space width (medial JSW) < 3 mm. Osteoarthritis Research Society International Joint Space Narrowing grades and treatment responses in trials capturing Pain NRS were similarly summarized. Pain outcome changes were estimated using baseline adjusted ANCOVA. Compared with phase 2 trials, the phase 3 trials had an increased proportion of patients with baseline medial JSW < 3 mm. LOR demonstrated beneficial treatment effects vs placebo in KL 2 subgroups, which were found to have higher proportions of baseline medial JSW > 3 mm, apart from one Phase 3 trial with advanced structural knee OA. Baseline medial JSWs were heterogeneous across trials despite KL inclusion criteria. LOR demonstrated greater symptomatic improvements in patients with less structurally advanced disease, indicative of an association between OA structural damage and pain. Early treatment interventions may improve outcomes and provide insight for future OA trial inclusion criteria development. OA-02, NCT02536833; OA-04, NCT03122860; OA-10, NCT04385303; OA-11, NCT03928184.

Clinical and economic benefits of patients undergoing lobectomy with the use of powered vascular staplers—based on China’s real-world data

Background Endoscopic surgery is widely performed with an increasing use of powered vascular staplers (PVS). However, few studies have examined PVS use in China, most of which have focused on clinical effects; fewer studies have examined the economic benefits of PVS. This study evaluated the clinical and economic benefits of the PVS compared to standard-of-care (SOC) staplers in lobectomy using results from a single-arm, multicenter clinical trial conducted in China and actual clinical use in a hospital collected in a real healthcare setting. Methods Patients with lung cancer undergoing thoracoscopic lobectomy were included in the study. The clinical and economic benefits of powered vascular stapler have been evaluated from a hospital’s perspective based on parameters such as bleeding occurrence, hospitalization time, secondary thoracotomy, and hospitalization costs. To compare the bleeding associated with use of PVS and SOC stapler in clinical use, PVS single-arm multi-center clinical trial data is used for the intervention group, and sampling data from hospitals is used for the control group. To ensure the outcome indicators between the two groups are comparable, we set the same inclusion criteria for the two groups of data and then used propensity score matching (PSM) to match two groups of patients according to the baseline characteristics. Results The results show that bleeding incidence in patients with SOC stapler group is 17.33% from hospital sampling data. In contrast, in the PVS group, it is 4.00%, and these rates are statistically different (P = 0.0167). Considering converted to open thoracic surgery, the rate of the SOC stapler group is 5.78% and that of the PVS group is 4.00%. These rates are not statistically different (P = 0.6166). Regarding hospitalization days, the length of the SOC stapler group is 18.97 days, while that in the PVS group is 12.38 days, and these data are statistically different (P = 0.0002). As patients in the PVS group have reduced bleeding, they will require less resource use from blood transfusion, drug services and surgical services. If PVS is used for transection of vessel, it can reduce the bleeding incidence by 13.33% and save 75.47 CNY in blood transfusion costs, 571.36 CNY in drug costs, and 183.38 CNY in surgical service costs per patient. From these three aspects, the hospital saves per patient 830.21 CNY. Conclusions Compared with the SOC stapler group, the PVS group has a lower bleeding incidence and shorter hospital days for lobectomy. In terms of blood transfusion costs, drug costs and surgical service costs, the hospital saves per patient 830.21 CNY.

The R.O.A.D. to precision medicine

We propose a novel framework that addresses the deficiencies of Randomized clinical trial data subgroup analysis while it transforms ObservAtional Data to be used as if they were randomized, thus paving the road for precision medicine. Our approach counters the effects of unobserved confounding in observational data through a two-step process that adjusts predicted outcomes under treatment. These adjusted predictions train decision trees, optimizing treatment assignments for patient subgroups based on their characteristics, enabling intuitive treatment recommendations. Implementing this framework on gastrointestinal stromal tumors (GIST) data, including genetic sub-cohorts, showed that our tree recommendations outperformed current guidelines in an external cohort. Furthermore, we extended the application of this framework to RCT data from patients with extremity sarcomas. Despite initial trial indications of universal treatment necessity, our framework identified a subset of patients who may not require treatment. Once again, we successfully validated our recommendations in an external cohort.

Histiocytosis Advancements Parallel Ophthalmic Innovations. The LXXXI Edward Jackson Memorial Lecture

PurposeTo highlight innovations in ophthalmic oncology through histiocytosis advancements. DesignPerspective and retrospective review. MethodsThe literature outlining the recent advancements in histiocytosis and ocular oncology were reviewed and combined with trial data and personal recollection. Intersections between these two fields were discussed. ResultsThe understanding of genetic mutations in disease—both in which cells they occur and the timing of mutation development—has expanded in tandem for the fields of ophthalmic oncology and histiocytosis. Similarly, advancements in diagnostic and treatment technology in one field can help patients in the other. For example, in one study, cell-free DNA testing reliably detected mutations in 14 of 18 (78%) patients with suspected histiocytosis. This technique has also been used in ophthalmic oncology as an alternative to invasive biopsy to avoid the risk of tumor externalization, vision impairment, and other side effects. These and other advancements, have allowed both fields to utilize targeted agents to successfully treat diseases with an actionable mutation; or deliver more targeted chemotherapy via the intraarterial technique. ConclusionsThe explosion of molecular genetics technology and targeted therapies has revolutionized cancer treatment, including histiocytosis and ophthalmic oncology. Recent progress in both fields has shown how these seemingly disparate areas have many intersections, and this speaks to the collaborative spirit that is inherent in clinical research.

Incorporating external controls in the design of randomized clinical trials: a case study in solid tumors

BackgroundThe use of historical external control data in clinical trials has grown in interest and needs when considering the design of future trials. Hybrid control designs can be more efficient to achieve the same power with fewer patients and limited resources. The literature is sparse on appropriate statistical methods which can account for the differences between historical external controls and the control patients in a study. In this article, we illustrate the analysis framework of a clinical trial if a hybrid control design was used after determining an RCT may not be feasible.MethodsWe utilize two previously completed RCTs in nonsquamous NSCLC and a nationwide electronic health record derived de-identified database as examples and compare 5 analysis methods on each trial, as well as a set of simulations to determine operating characteristics of such designs.ResultsIn single trial estimation, the Case Weighted Adaptive Power Prior provided estimated treatment hazard ratios consistent with the original trial’s conclusions with narrower confidence intervals. The simulation studies showed that the Case Weighted Adaptive Power Prior achieved the highest power (and well controlled type-1 error) across all 5 methods with consistent study sample size.ConclusionsBy following the proposed hybrid control framework, one can design a hybrid control trial transparently and accounting for differences between control groups while controlling type-1 error and still achieving efficiency gains from the additional contribution from external controls.

Acquired Hemophilia A: A Narrative Review and Management Approach in the Emicizumab Era

Acquired Hemophilia A (AHA) is a rare bleeding disorder caused by inhibitory autoantibodies to factor VIII (FVIII). The goals of treatment are two-fold, namely immunosuppressive therapy (IST) to eradicate the inhibitor and hemostatic management to control bleeding. Emicizumab, a bispecific antibody that acts as a factor VIIIa (FVIIIa) mimetic, has seen growing use in AHA following its approval for congenital hemophilia A (cHA). This review provides an overview of the epidemiology, pathophysiology, diagnosis, and treatment of AHA. Registry, trial, and case series data are assimilated and summarized with an emphasis on a standardized approach that integrates the use of emicizumab. With recent registry data suggesting the need to focus on immunosuppression-related mortality in AHA, we provide treatment recommendations in an algorithmic format that have become the standard of care at our institution. These recommendations are intended to minimize hemostatic product usage and potential toxicity related to IST, while reducing morbidity and re-hospitalization rates for bleeding. The proposed treatment algorithm, which includes key interventions by phase of therapy, can be readily implemented at centers that have rapid access to plasma FVIII activity using a one-stage assay. A case is presented to illustrate the proposed diagnostic and management considerations.

Leveraging single-dose human papillomavirus vaccination dose-efficiency to attain cervical cancer elimination in resource-constrained settings.

In low- and middle-income countries, resource constraints remain a critical factor limiting access to cervical cancer preventive measures. The option of single-dose immunization could help improve access to human papillomavirus vaccination and attain cervical cancer elimination. With simulation models adapted to country-specific data and scenarios for single-dose protection derived from International Agency for Research on Cancer India vaccine trial data, we estimated the expected impact of single-dose vaccination in India, Rwanda, and Brazil, three countries with varying profiles of cervical cancer risk and vaccination timelines. In combination with single-dose vaccination, we explored different resource reallocation strategies based on dose efficiency, elimination attainment, and cervical cancer cases prevented, with the existing 2-dose program as a comparator. Assuming lifelong single-dose protection, switching from 2-dose to 1-dose vaccination and reallocating resources to female catch-up could prevent 467-1336, 94-194, and 15-207 additional cervical cancer cases (per 100 000 women born) in cohorts aged 11-30 years in India, Rwanda, and Brazil, respectively. Resource reallocation to improve the current routine coverage could help eliminate cervical cancer in India and across all Brazilian states but not in Rwanda. For each country, we found a dose-efficient reallocation strategy (or a combination of strategies) together with 1-dose vaccination that could prevent more cervical cancers vs 2-dose vaccination, even in the worst-case scenario of single-dose protection. Adopting single-dose vaccination with resource reallocation is a resource-efficient approach to enhance progress toward cervical cancer elimination. The overall impact of vaccination can be maximized by fine-tuning resource reallocation to a country's needs.

Disseminated Superficial Actinic Porokeratosis: A Systematic Treatment Review.

Disseminated superficial actinic porokeratosis (DSAP) is a disorder of keratinization characterised by small, brown plaques with elevated keratotic rims, typically occurring on sun exposed areas. DSAP poses a risk for malignant transformation, emphasising the need for effective management strategies. The aim of this study was to review the current reported management options for DSAP. This systematic review was based on a comprehensive search of databases (Cochrane, PubMed, Medline, Embase, Emcare, ProQuest, Web of Science, CINAHL) from inception to 15 March 2024. Studies reporting management of DSAP were included irrespective of study design. Of 923 citations, 61 studies were included, predominantly comprising case reports and retrospective case series. A limited number of randomized and open-label trials were identified. Various treatment modalities were reported, including topical and systemic agents, photodynamic therapy, and laser therapy. Multiple management options are available for DSAP, including topical and systemic agents, photodynamic therapy and laser treatments. However, these approaches vary in their balance between efficacy and toxicity. Currently, there is a paucity of high-quality clinical trial data to guide treatment decisions. Further studies are required to determine the most effective and safe management strategies for DSAP. PROSPEROREGISTRATION: CRD42024514558.