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Epilepsia Sep 2023The Salzburg criteria for nonconvulsive status epilepticus (NCSE) and the American Clinical Neurophysiology Society (ACNS) Standardized Critical Care EEG Terminology...
OBJECTIVE
The Salzburg criteria for nonconvulsive status epilepticus (NCSE) and the American Clinical Neurophysiology Society (ACNS) Standardized Critical Care EEG Terminology 2021 include a diagnostic trial with intravenous (IV) antiseizure medications (ASMs) to assess electroencephalographic (EEG) and clinical response as a diagnostic criterion for definite NCSE and possible NCSE. However, how to perform this diagnostic test and assessing the EEG and clinical responses have not been operationally defined.
METHODS
We performed a Delphi process involving six experts to standardize the diagnostic administration of IV ASM and propose operational criteria for EEG and clinical response.
RESULTS
Either benzodiazepines (BZDs) or non-BZD ASMs can be used as first choice for a diagnostic IV ASM trial. However, non-BZDs should be considered in patients who already have impaired alertness or are at risk of respiratory depression. Levetiracetam, valproate, lacosamide, brivaracetam, or (if the only feasible drug) fosphenytoin or phenobarbital were deemed appropriate for a diagnostic IV trial. The starting dose should be approximately two thirds to three quarters of the full loading dose recommended for treatment of status epilepticus, with an additional smaller dose if needed. ASMs should be administered during EEG recording under supervision. A monitoring time of at least 15 min is recommended. If there is no response, a second trial with another non-BDZ or BDZs may be considered. A positive EEG response is defined as the resolution of the ictal-interictal continuum pattern for at least three times the longest previously observed spontaneous interval of resolution (if any), but minimum of one continuous minute. For a clinical response, physicians should use a standardized examination before and after IV ASM administration. We suggest a definite time-locked improvement in a focal deficit or at least one-step improvement on a new dedicated one-domain 10-level NCSE response scale.
SIGNIFICANCE
The proposed standardized approach of a diagnostic IV ASM trial further refines the ACNS and Salzburg diagnostic criteria for NCSE.
Topics: Humans; Administration, Intravenous; Benzodiazepines; Electroencephalography; Phenobarbital; Status Epilepticus; Clinical Trials as Topic
PubMed: 37350392
DOI: 10.1111/epi.17694 -
International Journal of Molecular... Jul 2023Radiopharmaceuticals are rapidly developing as a field, with the successful use of targeted beta emitters in neuroendocrine tumors and prostate cancer serving as... (Review)
Review
Radiopharmaceuticals are rapidly developing as a field, with the successful use of targeted beta emitters in neuroendocrine tumors and prostate cancer serving as catalysts. Targeted alpha emitters are in current development for several potential oncologic indications. Herein, we review the three most prevalently studied conjugated/chelated alpha emitters (actinium, lead, and astatine) and focus on contemporary clinical trials in an effort to more fully appreciate the breadth of the current evaluation. Phase I trials targeting multiple diseases are now underway, and at least one phase III trial (in selected neuroendocrine cancers) is currently in the initial stages of recruitment. Combination trials are now also emerging as alpha emitters are integrated with other therapies in an effort to create solutions for those with advanced cancers. Despite the promise of targeted alpha therapies, many challenges remain. These challenges include the development of reliable supply chains, the need for a better understanding of the relationships between administered dose and absorbed dose in both tissue and tumor and how that predicts outcomes, and the incomplete understanding of potential long-term deleterious effects of the alpha emitters. Progress on multiple fronts is necessary to bring the potential of targeted alpha therapies into the clinic.
Topics: Humans; Male; Alpha Particles; Prostatic Neoplasms; Radiopharmaceuticals; Clinical Trials as Topic
PubMed: 37511386
DOI: 10.3390/ijms241411626 -
Nature Medicine Jan 2024Neoadjuvant immunotherapy plus chemotherapy improves event-free survival (EFS) and pathologic complete response (0% residual viable tumor (RVT) in primary tumor (PT) and...
Neoadjuvant immunotherapy plus chemotherapy improves event-free survival (EFS) and pathologic complete response (0% residual viable tumor (RVT) in primary tumor (PT) and lymph nodes (LNs)), and is approved for treatment of resectable lung cancer. Pathologic response assessment after neoadjuvant therapy is the potential analog to radiographic response for advanced disease. However, %RVT thresholds beyond pathologic complete response and major pathologic response (≤10% RVT) have not been explored. Pathologic response was prospectively assessed in the randomized, phase 3 CheckMate 816 trial (NCT02998528), which evaluated neoadjuvant nivolumab (anti-programmed death protein 1) plus chemotherapy in patients with resectable lung cancer. RVT, regression and necrosis were quantified (0-100%) in PT and LNs using a pan-tumor scoring system and tested for association with EFS in a prespecified exploratory analysis. Regardless of LN involvement, EFS improved with 0% versus >0% RVT-PT (hazard ratio = 0.18). RVT-PT predicted EFS for nivolumab plus chemotherapy (area under the curve = 0.74); 2-year EFS rates were 90%, 60%, 57% and 39% for patients with 0-5%, >5-30%, >30-80% and >80% RVT, respectively. Each 1% RVT associated with a 0.017 hazard ratio increase for EFS. Combining pathologic response from PT and LNs helped differentiate outcomes. When compared with radiographic response and circulating tumor DNA clearance, %RVT best approximated EFS. These findings support pathologic response as an emerging survival surrogate. Further assessment of the full spectrum of %RVT in lung cancer and other tumor types is warranted. ClinicalTrials.gov registration: NCT02998528 .
Topics: Humans; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase III as Topic; Lung Neoplasms; Neoadjuvant Therapy; Nivolumab; Pathologic Complete Response; Progression-Free Survival; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 37903504
DOI: 10.1038/s41591-023-02660-6 -
BMJ Open Jul 2023Venous congestion is a pathophysiological state where high venous pressures cause organ oedema and dysfunction. Venous congestion is associated with worse outcomes,...
INTRODUCTION
Venous congestion is a pathophysiological state where high venous pressures cause organ oedema and dysfunction. Venous congestion is associated with worse outcomes, particularly acute kidney injury (AKI), for critically ill patients. Venous congestion can be measured by Doppler ultrasound at the bedside through interrogation of the inferior vena cava (IVC), hepatic vein (HV), portal vein (PV) and intrarenal veins (IRV). The objective of this study is to quantify the association between Doppler identified venous congestion and the need for renal replacement therapy (RRT) or death for patients with septic shock.
METHODS AND ANALYSIS
This study is a prespecified substudy of the ANDROMEDA-SHOCK 2 (AS-2) randomised control trial (RCT) assessing haemodynamic resuscitation in septic shock and will enrol at least 350 patients across multiple sites. We will include adult patients within 4 hours of fulfilling septic shock definition according to Sepsis-3 consensus conference. Using Doppler ultrasound, physicians will interrogate the IVC, HV, PV and IRV 6-12 hours after randomisation. Study investigators will provide web-based educational sessions to ultrasound operators and adjudicate image acquisition and interpretation. The primary outcome will be RRT or death within 28 days of septic shock. We will assess the hazard of RRT or death as a function of venous congestion using a Cox proportional hazards model. Sub-distribution HRs will describe the hazard of RRT given the competing risk of death.
ETHICS AND DISSEMINATION
We obtained ethics approval for the AS-2 RCT, including this observational substudy, from local ethics boards at all participating sites. We will report the findings of this study through open-access publication, presentation at international conferences, a coordinated dissemination strategy by investigators through social media, and an open-access workshop series in multiple languages.
TRIAL REGISTRATION NUMBER
NCT05057611.
Topics: Adult; Humans; Cohort Studies; Hyperemia; Randomized Controlled Trials as Topic; Sepsis; Shock, Septic; Ultrasonography, Doppler; Multicenter Studies as Topic
PubMed: 37487682
DOI: 10.1136/bmjopen-2023-074843 -
Journal of the National Cancer Institute Sep 2023Relapse-free survival (RFS) has been considered a primary endpoint to assess the effects of immunotherapy in the adjuvant setting among patients with early-stage... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Relapse-free survival (RFS) has been considered a primary endpoint to assess the effects of immunotherapy in the adjuvant setting among patients with early-stage disease. However, it is not clear whether RFS is a valid surrogate endpoint for overall survival (OS) in this clinical context.
METHODS
Phase II or III clinical trials of adjuvant immunotherapy that reported hazard ratios on OS and RFS were identified. We used a weighted regression analysis at the arm and trial levels to assess the efficacy of RFS as a surrogate for OS, quantified by the weighted coefficient of determination (R2). Strong correlations (R2 ≥ 0.7) at the arm and trial levels indicated valid surrogacy. The surrogate threshold effect was also evaluated.
RESULTS
Fifteen high-quality randomized clinical trials involving 13 715 patients were included. At the arm level, moderate and strong associations were observed between RFS2-year and OS3-year (R2 = 0.58, 95% confidence interval [CI] = 0.25 to 0.92) and RFS3-year and OS5-year (R2 = 0.72, 95% CI = 0.38 to 1.00), respectively. At the trial level, a moderate association was observed between effect of treatment on RFS and OS (R2 = 0.63, 95% CI = 0.33 to 0.94). The surrogate threshold effect for RFS was 0.86. Consistent results were confirmed in several sensitivity analyses based on different trial phases, experimental arms, cancer types, and treatment strategies.
CONCLUSIONS
Our meta-analysis failed to find a clinically strong association between RFS and OS in randomized clinical trials of adjuvant immunotherapy. Our findings challenge the use of RFS as the primary efficacy endpoint and suggest the use of OS in this clinical context.
Topics: Humans; Proportional Hazards Models; Biomarkers; Regression Analysis; Immunotherapy; Disease-Free Survival; Randomized Controlled Trials as Topic
PubMed: 37389446
DOI: 10.1093/jnci/djad125 -
Contemporary Clinical Trials Jun 2024Since the 1950s, randomized clinical trials (RCTs) have served as the gold standard for confirming the benefits of a new drug. Accordingly, phase 3 trials, the last... (Review)
Review
BACKGROUND
Since the 1950s, randomized clinical trials (RCTs) have served as the gold standard for confirming the benefits of a new drug. Accordingly, phase 3 trials, the last steps in the evaluation process for a new drug, have been recommended to all be RCTs. Nevertheless, single-arm phase 3 trials still appear to be in use.
METHODS
We performed a PubMed search to identify the use of a single-arm design in phase 3 trials, excluding only non-English articles. Three categories were distinguished: past use of an RCT, of any other trial design, or no previous trial; and according to diagnosis (oncology, infection, others).
RESULTS
A total of 176 single-arm phase 3 trials (19 oncology, 43 infections and 114 others) were identified by the search, with exponential growth since 1994, in parallel with that of RCTs. Among them, 64 (36%) were preceded by an RCT, 58 (33%) by a non-randomized trial, and 54 (31%) had no previous trial, with no main influence of the diagnosis setting. Justification of the design was reported in 30 (18%) of those trials, with ethical concerns comprising one-third of those justifications. This was similar in the 14 single-arm phase 2-3 trials, with about one-third in each group, and 17% justification of a non-comparative design.
CONCLUSION
The use of a single-arm phase 3 trial is heterogeneous, ranging from first trials up to confirmatory trials after a previously conducted RCT. Justification for these single-arm designs as confirmatory evidence should be more clearly reported, along with potential sources of bias.
Topics: Humans; Research Design; Clinical Trials, Phase III as Topic; Randomized Controlled Trials as Topic; Non-Randomized Controlled Trials as Topic
PubMed: 38508234
DOI: 10.1016/j.cct.2024.107506 -
Heart, Lung & Circulation Sep 2023Current pharmacological options for hypertrophic cardiomyopathy (HCM) are not disease-specific; while it treats symptoms, mavacamten targets the underlying pathology. We... (Review)
Review
BACKGROUND
Current pharmacological options for hypertrophic cardiomyopathy (HCM) are not disease-specific; while it treats symptoms, mavacamten targets the underlying pathology. We aim to assess the efficacy and safety of mavacamten, a first-in-class cardiac myosin inhibitor, in symptomatic obstructive HCM.
METHODS
This systematic review of the literature followed the PRISMA guidelines. Title/abstract and topics were searched using the following term: "mavacamten". The electronic research literature databases included the Cochrane Library, MedLine, and clinicaltrials.gov from July to August 2022. Primary efficacy endpoint was to assess clinical response at the end of treatment compared with baseline, defined as, at least one New York Heart Association (NYHA) class reduction. Two secondary endpoints from baseline were determined. The first was defined as improvement in mixed venous oxygen pressure (pVO). The second was defined as reduction of the post-exercise left ventricular outflow tract (LVOT) gradient.
RESULTS
We included in our analyses data from four studies that met our review eligibility criteria. There were three randomised placebo-controlled clinical trials and one non-randomised open-label clinical trial. All four studies showed a reduction in NYHA class from mavacamten use. Three out of four studies demonstrated >1 NYHA functional class improvement ranging from 34% to 80%, while only one study showed a smaller percentage of patients remaining at class 3. Three out of four studies measured pVO as an outcome, and all three studies noticed an increase in peak oxygen consumption after mavacamten treatment. Additionally, three out of four studies measured post-exercise LVOT gradient reduction as an outcome and all three found significant reduction in the post-exercise LVOT gradient after treatment. The most commonly observed adverse side effects were atrial fibrillation and decreased left ventricular ejection fraction, but all participants recovered without long-term sequelae and only one patient dropped out of the trial.
CONCLUSIONS
Mavacamten has a greater efficacy than placebo in the treatment of HCM. It also showed promising tolerability and efficacy profiles in the treatment of HCM in adults. The three endpoints used in the evaluation of studies were reduction in NYHA class, increase in pVO, and post-exercise LVOT gradient reduction. Mavacamten showed greater reduction in NYHA, larger effects on increase of pVO, and significant reduction of the LVOT gradient. Mavacamten was also found to be well tolerated, like the placebo. The side effect profile was limited for the majority of individuals taking mavacamten. In the future, authors recommended dose-optimisation studies, and studies that evaluate mavacamten both in comparison to, and in conjunction with other current treatments.
Topics: Adult; Humans; Cardiomyopathy, Hypertrophic; Heart; Stroke Volume; Ventricular Function, Left; Clinical Trials as Topic
PubMed: 37453852
DOI: 10.1016/j.hlc.2023.05.019 -
Pharmacological Research Dec 2023Breast cancer (BC) remains the foremost cause of cancer mortality globally, with neutrophils playing a critical role in its pathogenesis. As an essential tumor... (Review)
Review
Breast cancer (BC) remains the foremost cause of cancer mortality globally, with neutrophils playing a critical role in its pathogenesis. As an essential tumor microenvironment (TME) component, neutrophils are emerging as pivotal factors in BC progression. Growing evidence has proved that neutrophils play a Janus- role in BC by polarizing into the anti-tumor (N1) or pro-tumor (N2) phenotype. Clinical trials are evaluating neutrophil-targeted therapies, including Reparixin (NCT02370238) and Tigatuzumab (NCT01307891); however, their clinical efficacy remains suboptimal. This review summarizes the evidence regarding the close relationship between neutrophils and BC, emphasizing the critical roles of neutrophils in regulating metabolic and immune pathways. Additionally, we summarize the existing therapeutic approaches that target neutrophils, highlighting the challenges, and affirming the rationale for continuing to explore neutrophils as a viable therapeutic target in BC management.
Topics: Female; Humans; Breast Neoplasms; Neutrophils; Treatment Outcome; Tumor Microenvironment; Clinical Trials as Topic
PubMed: 37972723
DOI: 10.1016/j.phrs.2023.106996 -
Chinese Clinical Oncology Feb 2024The management of resectable non-small cell lung cancer (NSCLC) has relied on surgery and adjuvant chemotherapy for the past two decades, but is now radically changing... (Review)
Review
BACKGROUND AND OBJECTIVE
The management of resectable non-small cell lung cancer (NSCLC) has relied on surgery and adjuvant chemotherapy for the past two decades, but is now radically changing through the introduction of immunotherapy and targeted drugs. This review was conducted to summarize recent developments and highlight future directions.
METHODS
A literature search for randomized phase 2/3 trials on the treatment of early-stage NSCLC was performed based on PubMed and the content on major oncology congresses during the last 3 years.
KEY CONTENT AND FINDINGS
Perioperative strategies with 3-4 cycles of neoadjuvant chemoimmunotherapy and 1 year of adjuvant programmed cell death (ligand) 1 [PD-(L)1] blockade combine the efficacy of purely adjuvant [effective for both stage II and stage III tumors with event-free survival hazard ratios (HR) of approximately 0.70] and the purely neoadjuvant strategies (effective only for stage III with a lower EFS HR of approximately 0.50), show benefit across the entire spectrum of PD-L1 tumor expression levels, and significantly improve overall survival, as the NADIM-2 and Keynote-671 studies recently showed. Once approved, they will probably dominate the landscape of management for resectable NCSLC based on two main advantages: first, compared to purely adjuvant treatments, like those of the IMpower010 and Keynote-091 trials, they allow for evaluation of response in the surgical specimen and permit adjustment of the postoperative management accordingly; second, compared to the purely neoadjuvant treatment of Checkmate-816, their postoperative component appears to additionally improve the outcome of patients failing to achieve a pathologic complete remission (pCR). Further improvements in the near future will likely include intensified postoperative therapy for non-pCR patients, e.g., with addition of chemotherapy, antibody-drug conjugates, or next-generation immunotherapeutics; broader use of circulating tumor DNA assays for improved monitoring of minimal residual disease; as well as routine availability of further tyrosine kinase inhibitors (TKI) against oncogenic drivers beyond classic EGFR mutations, like adjuvant alectinib for tumors with ALK fusions, whose approval is expected soon based on the recent success of the ALINA trial, and adjuvant selpercatinib for tumors with RET fusions, if the ongoing LIBRETTO-432 trial is also positive. The availability of both TKI and neoadjuvant chemoimmunotherapy in the routine setting renders molecular tumor profiling imperative for potentially resectable tumors already at initial diagnosis.
CONCLUSIONS
Perioperative immunotherapy is becoming the dominant treatment paradigm for resectable NSCLC, while increasing use of targeted drugs for actionable alterations necessitates upfront molecular profiling of early tumors for patient selection.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Neoadjuvant Therapy; Immunotherapy; Chemotherapy, Adjuvant; Clinical Trials, Phase II as Topic; Randomized Controlled Trials as Topic
PubMed: 38372058
DOI: 10.21037/cco-23-137 -
BMJ Open Aug 2023Insomnia is the most prevalent sleep disorder, with few effective pharmacotherapies. Anecdotal reports and recent preclinical research suggest that cannabinol (CBN), a...
Cannabinol (CBN; 30 and 300 mg) effects on sleep and next-day function in insomnia disorder ('CUPID' study): protocol for a randomised, double-blind, placebo-controlled, cross-over, three-arm, proof-of-concept trial.
OBJECTIVE
Insomnia is the most prevalent sleep disorder, with few effective pharmacotherapies. Anecdotal reports and recent preclinical research suggest that cannabinol (CBN), a constituent of derived from delta-9-tetrahydrocannabinol, could be an effective treatment. Despite this, the isolated effects of CBN on sleep have yet to be systematically studied in humans.
METHODS
The present protocol paper describes a randomised, double-blind, placebo-controlled, single-dose, three-arm, cross-over, proof-of-concept study which investigates the effects of CBN on sleep and next-day function in 20 participants with clinician-diagnosed insomnia disorder and an Insomnia Severity Index Score ≥15. Participants receive a single fixed oral liquid dose of 30 mg CBN, 300 mg CBN and matched placebo, in random order on three treatment nights; each separated by a 2-week wash-out period. Participants undergo overnight sleep assessment using in-laboratory polysomnography and next-day neurobehavioural function tests. The primary outcome is wake after sleep onset minutes. Secondary outcomes include changes to traditional sleep staging, sleep-onset latency and absolute spectral power during non-rapid eye movement (NREM) sleep. Tertiary outcomes include changes to sleep spindles during NREM sleep, arousal indices, absolute spectral power during REM sleep and subjective sleep quality. Safety-related and exploratory outcomes include changes to next-day simulated driving performance, subjective mood and drug effects, postural sway, alertness and reaction time, overnight memory consolidation, pre and post-sleep subjective and objective sleepiness; and plasma, urinary, and salivary cannabinoid concentrations. The study will provide novel preliminary data on CBN efficacy and safety in insomnia disorder, which will inform larger clinical trials.
ETHICS AND DISSEMINATION
Human Research Ethics Committee approval has been granted by Bellberry (2021-08-907). Study findings will be disseminated in a peer-reviewed journal and at academic conferences.
TRIAL REGISTRATION NUMBER
NCT05344170.
Topics: Humans; Sleep Initiation and Maintenance Disorders; Cannabinol; Sleep; Polysomnography; Sleep Latency; Randomized Controlled Trials as Topic
PubMed: 37612115
DOI: 10.1136/bmjopen-2022-071148