Reports Of Clinical Trials Research Articles

Causes and risk factors for early death in adult patients with acute promyelocytic leukemia: a real-life experience

IntroductionEarly Death (ED) remains challenging in newly diagnosed acute promyelocytic leukemia (APL), especially in developing countries. The clinical and laboratory profile at diagnosis were evaluated and causes and risk factors were investigated in adult APL patients. MethodA retrospective real-life analysis of 141 medical records was performed of patients diagnosed with APL between 2007 and 2018, whether they were treated with the IC-APL 2006 protocol or not. Risk factors were assessed by univariate and multivariate analysis. Main resultsOverall, 112 patients were included in the study. ED occurred in 22.3% of cases, surpassing clinical trial reports, with non-protocol-eligible patients presenting notably higher rates (60%), potentially due to their clinical status. Hemorrhage (60%) and infection (33.3%) were the leading causes of ED. Univariate analysis associated ED to the ECOG score; white blood cell (WBC) count; body mass index; levels of hemoglobin, albumin, uric acid, and creatinine, aPTT and INR and FLT3 mutations. Multivariate analysis identified ECOG score ≥2 and elevated WBC count as independent risk factors. ConclusionED remains a substantial challenge in APL, especially in real-world settings with hemorrhage and infection being the leading causes. ECOG status and WBC count emerged as independent risk factors, while age and platelet count lacked a 30-day prognostic correlation. Evaluating prognostic enhancement tools in controlled trials and real-life settings is pivotal to improving APL outcomes.

Guidelines for reporting pediatric and child health clinical trial protocols and reports: study protocol for SPIRIT-Children and CONSORT-Children

BackgroundDespite the critical importance of clinical trials to provide evidence about the effects of intervention for children and youth, a paucity of published high-quality pediatric clinical trials persists. Sub-optimal reporting of key trial elements necessary to critically appraise and synthesize findings is prevalent. To harmonize and provide guidance for reporting in pediatric controlled clinical trial protocols and reports, reporting guideline extensions to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) and Consolidated Standards of Reporting Trials (CONSORT) guidelines specific to pediatrics are being developed: SPIRIT-Children (SPIRIT-C) and CONSORT-Children (CONSORT-C).MethodsThe development of SPIRIT-C/CONSORT-C will be informed by the Enhancing the Quality and Transparency of Health Research Quality (EQUATOR) method for reporting guideline development in the following stages: (1) generation of a preliminary list of candidate items, informed by (a) items developed during initial development efforts and child relevant items from recent published SPIRIT and CONSORT extensions; (b) two systematic reviews and environmental scan of the literature; (c) workshops with young people; (2) an international Delphi study, where a wide range of panelists will vote on the inclusion or exclusion of candidate items on a nine-point Likert scale; (3) a consensus meeting to discuss items that have not reached consensus in the Delphi study and to “lock” the checklist items; (4) pilot testing of items and definitions to ensure that they are understandable, useful, and applicable; and (5) a final project meeting to discuss each item in the context of pilot test results. Key partners, including young people (ages 12–24 years) and family caregivers (e.g., parents) with lived experiences with pediatric clinical trials, and individuals with expertise and involvement in pediatric trials will be involved throughout the project. SPIRIT-C/CONSORT-C will be disseminated through publications, academic conferences, and endorsement by pediatric journals and relevant research networks and organizations.DiscussionSPIRIT/CONSORT-C may serve as resources to facilitate comprehensive reporting needed to understand pediatric clinical trial protocols and reports, which may improve transparency within pediatric clinical trials and reduce research waste.Trial RegistrationThe development of these reporting guidelines is registered with the EQUATOR Network: SPIRIT-Children (https://www.equator-network.org/library/reporting-guidelines-under-development/reporting-guidelines-under-development-for-clinical-trials-protocols/#35) and CONSORT-Children (https://www.equator-network.org/library/reporting-guidelines-under-development/reporting-guidelines-under-development-for-clinical-trials/#CHILD).

Kisspeptin and its Current Clinical Status- A Systematic Review.

Kisspeptin was initially known as metastin for its role in suppressing metastasis in melanoma and breast cancer. Later, based on its ability to stimulate GPR54, its importance in maintaining an intact hypothalamic-pituitary-ovarian axis was recognised, which is the basis for the widespread application of the drug in several conditions such as secondary amenorrhea, regulation of puberty onset, ovarian function, trophoblast invasion, fertility regulation, parturition, and lactation. This systematic study aims to evaluate the current status of kisspentin in clinical trials. The keywords 'kisspeptin' or 'metastin' were used in the clinicaltrials.gov website and Clinical Trial Registry of India (CTRI) to find eligible clinical trials or records carried out without time constraints until February 26, 2023. A total of 33 records were identified through clinical trial databases. All records were screened, and four trials were rejected as they failed to meet the inclusion criteria. Finally, 29 (87.9%) reports of interventional clinical trials with kisspeptin were reviewed. Kisspeptin can be viewed as a multipurpose drug with considerably fewer side effects due to its effects simulating normal physiological processes in our body.

The effects of insufficient sleep and adequate sleep on cognitive function in healthy adults

Study objectivesAlthough sleep affects a range of waking behaviors, the majority of studies have focused on sleep loss with relatively little attention on sustained periods of adequate sleep. The goal of this study was to use an experimental design to examine the effect of both of these sleep patterns on cognitive performance in healthy adults. MethodsThis study used a randomized crossover design. Participants who regularly slept 7-9 hours/night completed two 6-week intervention conditions, adequate sleep (maintenance of habitual bed/wake times) and insufficient sleep (reduction in sleep of 1.5 hours relative to adequate sleep), separated by a 2-6weeks (median=43days) washout period. Cognitive functioning was evaluated at baseline and endpoint of each intervention using the NIH Toolbox Cognition Battery. General linear models contrasted scores following each condition to the baseline of the first condition; the baseline of the second condition was included to evaluate practice effects. ResultsSixty-five participants (age 35.9 ± 4.9years, 89% women, 52% non-White race/ethnicity) completed study procedures. There was improvement in performance on the List Sorting Working Memory task after the adequate sleep condition that exceeded practice effects. Cognitive performance after insufficient sleep did not reach the level expected with practice and did not differ from baseline. A similar pattern was found on the Flanker Inhibitory Control and Attention task. ConclusionsThese findings contribute to our understanding of the complex interplay between sleep and cognition and demonstrate that consistent, stable sleep of at least 7 hours/night improves working memory and response inhibition in healthy adults. Clinical Trial RegistrationThe manuscript reports on data from two clinical trials: Impact of Sleep Restriction on Performance in Adults (URL: https://clinicaltrials.gov/ct2/show/NCT02960776, ID Number: NCT02960776) and Impact of Sleep Restriction in Women (URL: https://clinicaltrials.gov/ct2/show/NCT02835261, ID Number: NCT02835261).

Biomedical Natural Language Inference on Clinical trials using the BERT-based Models

Clinical trials are crucial in experimental medicine as they assess the safety and efficiency of new treatments. Due to its unstructured and plain language nature, clinical text data often presents challenges in understanding the relationships between various elements like disease, symptoms, diagnosis, and treatment. This task is challenging as the Multi-evidence Natural Language Inference for Clinical Trial Data (NLI4CT) requires intricate reasoning involving textual and numerical elements. It involves integrating information from one or two Clinical Trial Reports (CTRs) to validate hypotheses, demanding a multi-faceted approach. To address these problems, we use BERT-base models’ ability to predict entailment or contradiction labels and compare the use of transformer-based feature extraction and pre-trained models. We utilize seven pre-trained models, including six BERT-based and one T5-based model: BERT-base uncased, BioBERT-base-cased-v1.1-mnli, DeBERTa-v3-base-mnli-fever-anli, DeBERTa-v3-base-mnli-fever-docnli-ling-2c, DeBERTa-large-mnli, BioLinkBERT-base, and Flan-T5-base. We achieve an F1-score of 61% on both DeBERTa-v3-base-mnli-fever-anli and DeBERTa-large-mnli models and 95% faithfulness on the BioLinkBERT-base model.

Insights into the statistical quality of randomized clinical trial reports submitted to the British Journal of Dermatology.

Insights into the statistical quality of randomized clinical trial reports submitted to the British Journal of Dermatology.

Pomegranate (Punica granatum L.) and Its Rich Ellagitannins as Potential Inhibitors in Ulcerative Colitis.

Ulcerative colitis, an immune-mediated inflammatory disease of the gastrointestinal tract, places a significant financial burden on patients and the healthcare system. Recently, reviews of the pomegranate and the abundant medicinal applications of its ellagitannins, as well as its pharmacological action, phytochemicals, metabolism, and pharmacokinetics, have been completed. However, summaries on their anti-ulcerative colitis effects are lacking. Numerous preclinical animal investigations and clinical human trial reports demonstrated the specific therapeutic effects of pomegranate and the effect of its ellagitannins against ulcerative colitis. According to the literature collected by Sci-finder and PubMed databases over the past 20 years, this is the first review that has compiled references regarding how the rich ellagitannins found in pomegranate have altered the ulcerative colitis. It was suggested that the various parts of pomegranates and their rich ellagitannins (especially their primary components, punicalagin, and ellagic acid) can inhibit oxidant and inflammatory processes, regulate the intestinal barrier and flora, and provide an anti-ulcerative colitis resource through dietary management.

Cefiderocol and Sulbactam-Durlobactam against Carbapenem-Resistant Acinetobacter baumannii.

Infections caused by carbapenem-resistant Acinetobacter baumannii (CRAB) remain a clinical challenge due to limited treatment options. Recently, cefiderocol, a novel siderophore cephalosporin, and sulbactam-durlobactam, a bactericidal β-lactam-β-lactamase inhibitor combination, have been approved by the Food and Drug Administration for the treatment of A. baumannii infections. In this review, we discuss the mechanisms of action of and resistance to cefiderocol and sulbactam-durlobactam, the antimicrobial susceptibility of A. baumannii isolates to these drugs, as well as the clinical effectiveness of cefiderocol and sulbactam/durlobactam-based regimens against CRAB. Overall, cefiderocol and sulbactam-durlobactam show an excellent antimicrobial activity against CRAB. The review of clinical studies evaluating the efficacy of cefiderocol therapy against CRAB indicates it is non-inferior to colistin/other treatments for CRAB infections, with a better safety profile. Combination treatment is not associated with improved outcomes compared to monotherapy. Higher mortality rates are often associated with prior patient comorbidities and the severity of the underlying infection. Regarding sulbactam-durlobactam, current data from the pivotal clinical trial and case reports suggest this antibiotic combination could be a valuable option in critically ill patients affected by CRAB infections, in particular where no other antibiotic appears to be effective.

Drug Development for Leukemia : Comprehensive Analysis of Clinical Trial Success Rates Presented at the American Society Hematology (ASH) Annual Meetings

Introduction: Slow progress in drug development is an ongoing issue even more critical for oncologic drugs, which have lower likelihood for approval than other therapeutic areas. Early clinical trials are frequently conducted and few eventually lead to drug approvals. We analyzed success rates of anti-leukemic drugs presented at the annual ASH meetings to identify rates of progression to advanced development and factors associated with clinical trial (CT) success. Methods: Our eligibility criteria included ASH meetings abstracts reporting CT assessing investigational anti-leukemic drugs conducted in the United States from 2011 to 2015. We searched ClinicalTrials.gov, PubMed, and Food and Drug Administration (FDA) websites to track the transition at each clinical phase (from Phase 1 to Phase 3), regulatory history, and publication as full-length manuscripts. We assessed the success rate (number of CT approved by FDA divided by the total number of CT) by study, drug and outcomes features using chi-square or Fisher's exact test. To verify the correlation between the impact factor (IF) of the journal in which the CT was published with the success of the study, the FDA-approval status (No vs Yes) was considered ordinal variable and the Pearson correlation coefficient was calculated. Results: Among the 3,929 abstracts for leukemia reviewed, 488 were main CT reports. Based on our eligibility criteria, 235 abstracts were identified including Phase 1 (121), Phase 2 (100), and Phase 3 (14) CT. Of these CT abstracts, only 45 (19.1%) eventually led to FDA approval. Among the unsuccessful studies, 37 (15.7%) progressed to the next one or two phases, and 153 (65.1%) did not transition any phase forward. Abstracts in acute myeloid leukemia (AML, 47%) and chronic lymphocytic leukemia (CLL, 30.2%) were the most common, followed by acute lymphocytic leukemia (ALL, 15.6%) and chronic myeloid leukemia (CML, 6.5%). Investigational New Drug (IND) combined with FDA-approved regimens (41.7%) or as monotherapy (40.9%) were the most commonly investigated therapy modalities. Combinations of multiple IND (9.8%) and new uses for FDA-approved drugs or regimens (7.7%) were evaluated less frequently. The overall success rate of CT was 6%. Although CML and ALL were the least studied types of leukemia, they had the highest approval success rates, 47% and 24.4%, respectively (p<0.001). Monotherapy INDs were more frequently approved by FDA (32.3%) than when combined with FDA-approved drugs (11.2%, p<0.001). FDA approval was also more frequent for advanced CT phase (p<0.001) and more recent (by year) presentation of the abstract (p=0.008). Tumor status (untreated vs relapsed and/or refractory [R/R] vs untreated and R/R) and the age of the patients included in the CT (adults including older adults vs older adults only vs pediatric vs adults and pediatric) were not significantly associated with approval rates (p>0.05). CT including drugs and regimens that led to FDA approval were published in journals with higher impact factors (R=0.368, p=0.0002), such as Lancet Oncology (24.1%), Blood (17.2%), Lancet Haematology (13.8%), and New England Journal of Medicine (13.8%). Blood was the journal that published the highest number of unsuccessful CT (15.3%). During the study period, CT assessing Enasidenib as monotherapy for R/R AML with IDH2 mutation, Ponatinib for CML and Philadelphia chromosome (Ph+) ALL, and Venetoclax for R/R CLL transitioned directly from Phase 2 to FDA approval. Conclusion: CT success rates for hematologic malignancies improved modestly over the last years. The high investment in CT for AML and CLL management has not resulted in increased approval rates proportional to reported CT.

Harnessing 3D-CT Simulation and Planning for Enhanced Precision Surgery: A Review of Applications and Advancements in Lung Cancer Treatment.

The clinical application of three-dimensional computed tomography (3D-CT) technology has rapidly expanded in the last decade and has been applied to lung cancer surgery. Two consecutive reports of large-scale prospective clinical trials from Japan and the United States have brought a paradigm shift in lung cancer surgery and may have led to a rapid increase in sublobar lung resections. Sublobar resection, especially segmentectomy, requires a more precise understanding of the anatomy than lobectomy, and preoperative 3D simulation and intraoperative navigation support it. The latest 3D simulation software packages are user-friendly. Therefore, in this narrative review, we focus on recent attempts to apply 3D imaging technologies, particularly in the sublobar resection of the lung, and review respective research and outcomes. Improvements in CT accuracy and the use of 3D technology have advanced lung segmental anatomy. Clinical applications have enabled the safe execution of complex sublobar resection through a minimally invasive approach, such as video-assisted thoracoscopic surgery and robotic surgery. However, currently, many facilities still render 3D images on two-dimensional monitors for usage. In the future, it will be challenging to further spread and advance intraoperative navigation through the application of 3D output technologies such as extended reality.

Adverse Event Reporting in Randomized Clinical Trials for Multiple Myeloma

Cancer treatment can result in burdensome toxic effects that profoundly affect patient quality of life. In seeking to emphasize the efficacy of tested treatments, clinical trial reports may use subjective or minimizing terms to describe adverse events (AEs). To evaluate patterns of AE reporting in multiple myeloma (MM) randomized clinical trials (RCTs) published between 2015 and early 2023. For this cohort study, the PubMed, Embase, and Cochrane Central Register of Controlled Trials databases were searched to assess the prevalence of minimizing terms in MM RCTs published between January 1, 2015, and March 1, 2023. Minimizing terms were defined as subjective terms used to favorably describe the safety profile of the intervention. The terms searched included convenient, manageable, acceptable, expected, well-tolerated, tolerable, favorable, and safe. Final data analysis was performed on July 21, 2023. The primary outcome was the occurrence of at least 1 minimizing term in an article. Univariate logistic regression analyses were performed to evaluate the association between the presence of at least 1 minimizing term and the actual incidence of grade 3 or 4 AEs, serious AEs, or grade 5 AEs. Of the 65 RCTs included, 56 (86%) used minimizing terms when describing treatment-emergent AEs. The most frequently used minimizing terms were well-tolerated or tolerable in 29 trials (45%), manageable in 18 (28%), and acceptable in 16 (25%). Grade 3 or 4 AE rate in the examined RCTs ranged from 23% to 94%, with a median of 75% (IQR, 59%-82%). A univariate regression analysis demonstrated no association between the use of minimizing terms and grade 3 or 4 AE rates (odds ratio [OR], 1.35 [95% CI, 0.88-2.10] per 10% AE rate increase; P = .17) or grade 5 AE rates (OR, 3.16 [95% CI, 0.27-12.7] per 10% AE rate increase; P = .45). These findings suggest that trial investigators and sponsors regularly use minimizing terms to describe toxic effects in MM trials, and use of this terminology may not reflect actual AE rates in these studies. Instead of using these terms, trial investigators should highlight event rates and patient-reported outcomes, to allow clinicians and patients to better evaluate the true tolerability of AEs.

Trends in the Development of Antibody-Drug Conjugates for Cancer Therapy.

In cancer treatment, the first-generation, cytotoxic drugs, though effective against cancer cells, also harmed healthy ones. The second-generation targeted cancer cells precisely to inhibit their growth. Enter the third-generation, consisting of immuno-oncology drugs, designed to combat drug resistance and bolster the immune system's defenses. These advanced therapies operate by obstructing the uncontrolled growth and spread of cancer cells through the body, ultimately eliminating them effectively. Within the arsenal of cancer treatment, monoclonal antibodies offer several advantages, including inducing cancer cell apoptosis, precise targeting, prolonged presence in the body, and minimal side effects. A recent development in cancer therapy is Antibody-Drug Conjugates (ADCs), initially developed in the mid-20th century. The second generation of ADCs addressed this issue through innovative antibody modification techniques, such as DAR regulation, amino acid substitutions, incorporation of non-natural amino acids, and enzymatic drug attachment. Currently, a third generation of ADCs is in development. This study presents an overview of 12 available ADCs, reviews 71 recent research papers, and analyzes 128 clinical trial reports. The overarching objective is to gain insights into the prevailing trends in ADC research and development, with a particular focus on emerging frontiers like potential targets, linkers, and drug payloads within the realm of cancer treatment.

Aloe Vera: A Potential Herb for Periodontitis Management

Background:: The Aloe Vera plant has been used in India for several decades for the treatment of periodontal disease. The plant has been considered to have antimicrobial and antiinflammatory properties, but it is still used for the treatment of periodontitis inflammation. Objective:: The study's goal was to assess the function of Aloe vera in the treatment of periodontitis. The article summarized numerous clinical research studies, clinical trials reports, patent reports, and safety data in addition to the mechanism of action to provide an overview of Aloe Vera’s usefulness in the treatment of periodontitis. Methods:: The information for their review articles was acquired by using Google Scholar and PubMed as search engines, as well as a number of publishers, including Springer Nature, Bentham Science, Taylor & Francis, and Elsevier. ClinicalTrials.gov.in was referred to study the clinical trials data, and Google Patents was used as a search engine for collecting patent reports. Results:: Aloe Vera is useful for Periodontitis prevention and treatment due to its antiinflammatory, antibacterial, and antioxidant features. Aloe Vera can be used as an alternative to treat periodontitis and its related physiological effects such as gingivitis and mucositis, and various pre-clinical and clinical studies have been summarized that have demonstrated that using Aloe Vera significantly improved the mentioned parameters. Conclusion:: Aloe Vera is an herb that may be used to treat periodontitis and its associated negative effects. However, more preclinical and clinical research, might contribute to raising awareness and managing periodontitis.

ClinicalRisk: A New Therapy-related Clinical Trial Dataset for Predicting Trial Status and Failure Reasons.

Clinical trials aim to study new tests and evaluate their effects on human health outcomes, which has a huge market size. However, carrying out clinical trials is expensive and time-consuming and often ends in no results. It will revolutionize clinical practice if we can develop an effective model to automatically estimate the status of a clinical trial and find out possible failure reasons. However, it is challenging to develop such a model because of the lack of a benchmark dataset. To address these challenges, in this paper, we first build a new dataset by extracting the publicly available clinical trial reports from ClinicalTrials.gov. The associated status of each report is treated as the status label. To analyze the failure reasons, domain experts help us manually annotate each failed report based on the description associated with it. More importantly, we examine several state-of-the-art text classification baselines on this task and find out that the unique format of the clinical trial protocols plays an essential role in affecting prediction accuracy, demonstrating the need for specially designed clinical trial classification models.

Cost-effectiveness of terlipressin for hepatorenal syndrome: the United States hospital perspective

BackgroundHepatorenal syndrome (HRS) is characterized by severely reduced renal perfusion that precipitates rapid morbidity and mortality. Terlipressin is the only US Food and Drug Administration-approved treatment to improve kidney function for adults with HRS with a rapid reduction in kidney function. Prior to the approval of terlipressin, unapproved vasoconstrictive agents used in HRS treatment were octreotide/midodrine and norepinephrine with albumin.MethodsA cohort decision-tree model representing a US hospital perspective assessed the clinical outcomes and direct medical costs (based primarily on hospital charges) of treating HRS with terlipressin + albumin (ALB) versus midodrine/octreotide (MID/OCT)+ALB, or norepinephrine (NorEp)+ALB. Treatment efficacy was defined by clinical response (complete/HRS reversal, partial, or no response) based on change of serum creatinine derived from published clinical trial reports. The proportions of patients with complete response were: terlipressin + ALB (36.2%), NorEp + ALB (19.1%), and MID/OCT + ALB (3.1%). Model outcomes included utilization of HRS-related healthcare resources (hospital and intensive care, outpatient and emergency department, dialysis, and transplantations), adverse events, and HRS-related mortality. Outcomes were assessed for the initial hospitalization in the base case and at 30, 60, and 90 days post-discharge.ResultsTotal costs incurred over the initial hospitalization with terlipressin + ALB were lower vs NorEp + ALB, primarily due to higher ICU costs with NorEp + ALB ($7,433 vs $61,897). TER + ALB was associated with higher total costs vs MID/OCT + ALB due to higher pharmacy costs with terlipressin + ALB. The cost per complete response achieved of terlipressin + ALB ($451,605) was half that of NorEp + ALB ($930,571) and one-tenth that of MID/OCT + ALB ($4,942,123).ConclusionsHRS patients treated with terlipressin experienced better clinical outcomes and a lower cost per treatment response vs other unapproved treatments. ICU days and pharmacy costs were key cost drivers distinguishing the treatment groups. These outcomes suggest that terlipressin is cost-effective on the basis of total cost per response achieved.

Using public clinical trial reports to probe non-experimental causal inference methods

BackgroundNon-experimental studies (also known as observational studies) are valuable for estimating the effects of various medical interventions, but are notoriously difficult to evaluate because the methods used in non-experimental studies require untestable assumptions. This lack of intrinsic verifiability makes it difficult both to compare different non-experimental study methods and to trust the results of any particular non-experimental study.MethodsWe introduce TrialProbe, a data resource and statistical framework for the evaluation of non-experimental methods. We first collect a dataset of pseudo “ground truths” about the relative effects of drugs by using empirical Bayesian techniques to analyze adverse events recorded in public clinical trial reports. We then develop a framework for evaluating non-experimental methods against that ground truth by measuring concordance between the non-experimental effect estimates and the estimates derived from clinical trials. As a demonstration of our approach, we also perform an example methods evaluation between propensity score matching, inverse propensity score weighting, and an unadjusted approach on a large national insurance claims dataset.ResultsFrom the 33,701 clinical trial records in our version of the ClinicalTrials.gov dataset, we are able to extract 12,967 unique drug/drug adverse event comparisons to form a ground truth set. During our corresponding methods evaluation, we are able to use that reference set to demonstrate that both propensity score matching and inverse propensity score weighting can produce estimates that have high concordance with clinical trial results and substantially outperform an unadjusted baseline.ConclusionsWe find that TrialProbe is an effective approach for probing non-experimental study methods, being able to generate large ground truth sets that are able to distinguish how well non-experimental methods perform in real world observational data.

Disparities in Clinical Trial Enrollment and Reporting in Rectal Cancer: A Systematic Review and Demographic Comparison to the National Cancer Database.

Cancer care guidelines based on clinical trial data in homogenous populations may not be applicable to all rectal cancer patients. The aim of this study was to evaluate whether patients enrolled in rectal cancer clinical trials (CTs) are representative of United States (U.S.) rectal cancer patients. Prospective rectal cancer CTs from 2010 to 2019 in the United States were systematically reviewed. In trials with multiple arms reporting separate demographic variables, each arm was considered a separate CT group in the analysis. Demographic variables considered in the analysis were age, sex, race/ethnicity, facility location throughout the United States, rural vs urban geography, and facility type. Participant demographics from trial and the National Cancer Database (NCDB) participants were compared using chi-squared goodness of fit and one-sample t-test where applicable. Of 50 CT groups identified, 42 (82%) studies reported mean or median age. Trial participants were younger compared to NCDB patients (P < .001 all studies). All but three trials had fewer female patients than NCDB (48.2% female, P < .001). Less than half the CT groups reported on race or ethnicity. Eighteen out of 22 trials (82%) had a smaller percentage of Black patients and 4 out of 8 (50%) trials had fewer Hispanic or Spanish origin patients than the NCDB. No CTs reported comorbidities, socioeconomic factors, or education. CT primary sites were largely at academic centers and in urban areas. The present study supports the need for improved demographic representation and transparency in rectal cancer clinical trials.

Inter-rater reliability of the extended Composite Quality Score (CQS-2).

To establish the inter-rater reliability of the Composite Quality Score (CQS-2) and to test the null hypothesis that it did not differ significantly from that of the first CQS version (CQS-1). Four independent raters were selected to rate 45 clinical trial reports using CQS-1 and CQS-2. The raters remained unaware of each other's participation in this study until all rating had been completed. Each rater received only one rating template at a time in a random sequence for CQS-1 and CQS-2 rating. Raters completed each template and sent these back to the principal investigator. Each rater received their next template 2 weeks after submission of the completed previous template. The inter-rater reliabilities for the overall appraisal score of the CQS-1 and the CQS-2 were established by using the Brennan-Prediger coefficient (BPC). The coefficients of both CQS versions were compared by using the two-sample z-test. During secondary analysis, the BPCs for every criterion and each corroboration level for both CQS versions were established. The BPC for the CQS-1 was 0.85 (95% CI: 0.64-1.00) and for the CQS-2 it was 1.00 (95% CI: 0.94-1.00), suggesting a very high inter-rater reliability for both. The difference between the two CQS versions was statistically not significant (p = 0.17). The null hypothesis was accepted. The CQS-2 is still under development, This study shows that it is associated with a very high inter-rater reliability, which did not statistically significantly differ from that of the CQS-1. The promising results of this study warrant further investigation in the applicability of the CQS-2 as an appraisal tool for prospective controlled clinical therapy trials.

PSMA-targeted therapy for non-prostate cancers.

Radioligand therapy (RLT) agents are demonstrating a crucial role in the clinical approach to aggressive malignancies such as metastatic castrate-resistant prostate cancer (m-CRPC). With the recent FDA approval of prostate-specific membrane antigen (PSMA)-targeted RLT for m-CRPC, the field has broadened its gaze to explore other cancers that express PSMA in the tumor parenchyma or tumor neovasculature. In this review article, we discuss current progress in the clinical use of PSMA RLTs in non-prostate cancers such salivary gland cancers, renal cell carcinoma, high grade glioma, and soft tissue sarcoma. We highlight early reports in small case series and clinical trials indicating promise for PSMA-targeted RLT and highlighting the importance of identifying patient cohorts who may most benefit from these interventions. Further study is indicated in non-prostate cancers investigating PSMA RLT dosimetry, PSMA PET/CT imaging as a biomarker, and assessing PSMA RLT safety and efficacy in these cancers.

Consistency between Treatment Effects on Clinical and Brain Atrophy Outcomes in Alzheimer’s Disease Trials

BackgroundLongitudinal changes in volumetric MRI outcome measures have been shown to correlate well with longitudinal changes in clinical instruments and have been widely used as biomarker outcomes in clinical trials for Alzheimer’s disease (AD). While instances of discordant findings have been noted in some trials, especially the recent amyloid-removing therapies, the overall relationship between treatment effects on brain atrophy and clinical outcomes, and how it might depend on treatment target or mechanism, clinical instrument or imaging variable is not yet clear.ObjectiveTo systematically assess the consistency and therapeutic class-dependence of treatment effects on clinical outcomes and on brain atrophy in published reports of clinical trials conducted in mild cognitive impairment (MCI) and/or AD.DesignQuantitative review of the published literature. The consistency of treatment effects on clinical and brain atrophy outcomes was assessed in terms of statistical agreement with hypothesized equal magnitude effects (e.g., 30% slowing of both) and nominal directional concordance, as a function of therapeutic class.SettingInterventional randomized clinical trials.ParticipantsMCI or AD trial participants.InterventionTreatments included were those that involved ingestion or injection of a putatively active substance into the body, encompassing both pharmacological and controlled dietary interventions.MeasurementsEach trial included in the analysis reported at least one of the required clinical outcomes (ADAS-Cog, CDR-SB or MMSE) and at least one of the required imaging outcomes (whole brain, ventricular or hippocampal volume).ResultsData from 35 trials, comprising 185 pairwise comparisons, were included. Overall, the 95% confidence bounds overlapped with the line of identity for 150/185 (81%) of the imaging-clinical variable pairs. The greatest proportion of outliers was found in trials of anti-amyloid antibodies that have been shown to dramatically reduce the level of PET-detectable amyloid plaques, for which only 13/33 (39%) of observations overlapped the identity line. A Deming regression calculated using all data points yielded a slope of 0.54, whereas if data points from the amyloid remover class were excluded, the Deming regression line had a slope of 0.92. Directional discordance of treatment effects was also most pronounced for the amyloid-removing class, and for comparisons involving ventricular volume.ConclusionOur results provide a frame of reference for the interpretation of clinical and brain atrophy results from future clinical trials and highlight the importance of mechanism of action in the interpretation of imaging results.