Upcoming Clinical Trials Research Articles

An Overview of Pharmacological Profile of Flavonoids as Potential Molecules of Therapeutic Importance

Abstract: A growing number of research investigations have shown the multiple health benefits of flavonoids derived from plants, leading to interest in the field. Many recent studies have concentrated on flavonoids effects on human health. Flavonoids are effective against a wide spectrum of bacteria, viruses, and other pathogens. Numerous flavonoids have been demonstrated to possess antioxidative, free radical scavenging, hepatoprotective, antiinflammatory, anticancer, and coronary heart disease preventive properties. Some of novel flavonoids having therapeutic potential as new medication have been identified which include hesperetin-5′-O-β-rhamnoglucoside, Resveratrol, Astragalin (AST) Desmodinosides A-E: New Flavonoid C-glycosides, Apigenin, Luteolin, and Baicalein, rutin, hyperoside etc. Some recent developments including clinical trials of a few of the flavonoids discussed in the review provide a novel library of pharmacologically potential molecules which provides a paradigm for the treatment of several ailments such as SARS-CoV-2, Alzheimer's disease, diabetes, angina pectoris, Hepatitis C virus and Sickle cell disease (SCD) etc. The present review aims at updating recent flavonoid advancements for various pharmacological actions, from conventional therapeutic implications to upcoming clinical trials. We encourage researchers to focus on flavonoids for a variety of medicinal applications since the industrial acceptance of these compounds will determine the future growth of this field.

Transcriptome-based classification to predict FOLFIRINOX response in a real-world metastatic pancreatic cancer cohort

Pancreatic ductal adenocarcinoma (PDAC) is often diagnosed at metastatic stage and typically treated with fluorouracil, leucovorin, irinotecan and oxaliplatin (FOLFIRINOX). Few patients benefit from this treatment. Molecular subtypes are prognostic in particularly resectable PDAC and might predict treatment response. This study aims to correlate molecular subtypes in metastatic PDAC with FOLFIRINOX responses using real-world data, providing assistance in counselling patients. We collected 131 RNA-sequenced metastatic biopsies and applied a network-based meta-analysis using published PDAC classifiers. Subsequent survival analysis was performed using the most suitable classifier. For validation, we developed an immunohistochemistry (IHC) classifier using GATA6 and keratin-17 (KRT17), and applied it to 86 formalin-fixed paraffin-embedded samples of advanced PDAC. Lastly, GATA6 knockdown models were generated in PDAC organoids and cell lines. We showed that the PurIST classifier was the most suitable classifier. With this classifier, classical tumors had longer PFS and OS than basal-like tumors (PFS: 216 vs. 78 days, p = 0.0002; OS: 251 vs. 195 days, p = 0.049). The validation cohort showed a similar trend. Importantly, IHC GATA6low patients had significantly shorter survival with FOLFIRINOX (323 vs. 746 days, p = 0.006), but no difference in non-treated patients (61 vs. 54 days, p = 0.925). This suggests that GATA6 H-score predicts therapy response. GATA6 knockdown models did not lead to increased FOLFIRINOX responsiveness. These data suggest a predictive role for subtyping (transcriptomic and GATA6 IHC), though no direct causal relationship was found between GATA6 expression and chemoresistance. GATA6 immunohistochemistry should be seamlessly added to current diagnostics and integrated into upcoming clinical trials.

Present and Future Surgical Options for Tricuspid Regurgitation.

Tricuspid regurgitation, once considered a relatively benign condition, has now gathered significant attention due to new evidence showing its impact on both short- and long-term follow-up. While surgical intervention remains the established standard approach for treating severe tricuspid regurgitation, current guidelines provide Class I indication for intervention in only a limited set of scenarios. This review delves into the present and future perspectives of surgical tricuspid regurgitation management, examining aspects such as disease prognosis, surgical indications, outcomes, and a comprehensive overview of past and upcoming clinical trials.

Characterization of Phenotypic Variability in Becker Muscular Dystrophy for Clinical Practice and Towards Trial Readiness: A Two-Years Follow up Study.

Becker muscular dystrophy (BMD) is a dystrophinopathy due to in-frame mutations in the dystrophin gene (DMD) which determines a reduction of dystrophin at muscle level. BMD has a wide spectrum of clinical variability with different degrees of disability. Studies of natural history are needed also in view of up-coming clinical trials. From an initial cohort of 32 BMD adult subjects, we present a detailed phenotypic characterization of 28 patients, then providing a description of their clinical natural history over the course of 12 months for 18 and 24 months for 13 of them. Each patient has been genetically characterized. Baseline, and 1-year and 2 years assessments included North Star Ambulatory Assessment (NSAA), timed function tests (time to climb and descend four stairs), 6-minute walk test (6MWT), Walton and Gardner-Medwin Scale and Medical Research Council (MRC) scale. Muscle magnetic resonance imaging (MRI) was acquired at baseline and in a subgroup of 9 patients after 24 months. Data on cardiac function (electrocardiogram, echocardiogram, and cardiac MRI) were also collected. Among the clinical heterogeneity, a more severe involvement is often observed in patients with 45-X del, with a disease progression over two years. The 6MWT appears sensitive to detect modification from baseline during follow up while no variation was observed by MRC testing. Muscle MRI of the lower limbs correlates with clinical parameters.Our study further highlights how the phenotypic variability of BMD adult patients makes it difficult to describe an uniform course and substantiates the need to identify predictive parameters and biomarkers to stratify patients.

Facioscapulohumeral Muscular Dystrophy European Patient Survey: Assessing Patient Reported Disease Burden and Preferences in Clinical Trial Participation.

Facioscapulohumeral muscular dystrophy (FSHD) is a genetic disorder characterized by progressive muscle weakness leading to permanent disability. There are no curative treatments, however, there are several upcoming clinical trials testing new therapies in FSHD. This study aimed to explore the disease burden and patient preferences of people with FSHD to ensure that clinical trials can be designed to include outcome measures that are relevant and important to patients. A survey was developed with a steering committee clinicians and physiotherapists with relevant experience in the disease, patient representatives, a registry expert and industry consultants. Themes of the survey included; participant demographics, disease progression and impact on function, factors encouraging or discouraging clinical trial participation, and positive outcomes of a clinical trial. 1147 participants responded to the online survey, representing 26 countries across Europe and a range of disease severities. The study highlighted the key symptoms causing concern for FSHD patients - muscle weakness and mobility issues - reflecting what participants want targeted for future therapies. The need for clear information and communication throughout clinical trials was emphasised. Factors most encouraging trial participation included access to new investigational therapies, access to trial results and benefits for the FSHD community. Factors most discouraging trial participation included travel related issues and fear of side effects. The results from this study identify the patient reported burden of FSHD and should provide researchers and industry with areas of therapeutic research that would be meaningful to patients, as well as supporting the development of patient centric outcome measures in clinical trials.

The future of coronary artery bypass grafting.

Coronary artery bypass grafting has evolved considerably since it was introduced approximately 50 years ago, with continuously improved patient outcomes as a result of this growth. The most up-to-date evidence on topics such as graft patency, grafting strategy, approaches to graft harvesting, minimally invasive coronary artery bypass grafting, and postoperative pharmacotherapy may lead to changes in current accepted practice. In addition, several unanswered questions in the field of coronary artery bypass grafting may benefit from further investigation and, if resolved, might advance the field and change practice. Current or upcoming clinical trials seek to answer these unanswered questions and may generate data that yields improved outcomes and quality of life for all patients after coronary artery bypass grafting. In addition, cutting edge clinical trials designed specifically for women and racial and ethnic minorities who have had poorer outcomes and have traditionally been underrepresented in cardiovascular surgery research, have recently been launched that may change the way that a large portion of the coronary artery bypass grafting population is treated in the future.

Advances in familial hypercholesterolemia.

Familial hypercholesterolemia (FH), a semi-dominant genetic disease affecting more than 25 million people worldwide, is associated with severe hypercholesterolemia and premature atherosclerotic cardiovascular disease. Over the last decade, advances in data analysis, screening, diagnosis and cardiovascular risk stratification has significantly improved our ability to deliver precision medicine for these patients. Furthermore, recent updates on guideline recommendations and new therapeutic approaches have also proven to be highly beneficial. It is anticipated that both ongoing and upcoming clinical trials will offer further insights for the care and treatment of FH patients.

Audiovisual gamma stimulation for the treatment of neurodegeneration.

Alzheimer's disease (AD) is the most common type of neurodegenerative disease and a health challenge with major social and economic consequences. In this review, we discuss the therapeutic potential of gamma stimulation in treating AD and delve into the possible mechanisms responsible for its positive effects. Recent studies reveal that it is feasible and safe to induce 40Hz brain activity in AD patients through a range of 40Hz multisensory and noninvasive electrical or magnetic stimulation methods. Although research into the clinical potential of these interventions is still in its nascent stages, these studies suggest that 40Hz stimulation can yield beneficial effects on brain function, disease pathology, and cognitive function in individuals with AD. Specifically, we discuss studies involving 40Hz light, auditory, and vibrotactile stimulation, as well as noninvasive techniques such as transcranial alternating current stimulation and transcranial magnetic stimulation. The precise mechanisms underpinning the beneficial effects of gamma stimulation in AD are not yet fully elucidated, but preclinical studies have provided relevant insights. We discuss preclinical evidence related to both neuronal and nonneuronal mechanisms that may be involved, touching upon the relevance of interneurons, neuropeptides, and specific synaptic mechanisms in translating gamma stimulation into widespread neuronal activity within the brain. We also explore the roles of microglia, astrocytes, and the vasculature in mediating the beneficial effects of gamma stimulation on brain function. Lastly, we examine upcoming clinical trials and contemplate the potential future applications of gamma stimulation in the management of neurodegenerative disorders.

Progression of cognitive dysfunction in NPC survivors with radiation-induced brain necrosis: A prospective cohort

Background and purposeThe evidence of longitudinal changes in cognition in nasopharyngeal carcinoma (NPC) survivors with radiation-induced brain necrosis (RIBN) after radiotherapy (RT) remained insufficient. We aimed to estimate the clinical progression rate of cognitive decline and identify patients with differential decline rates. Materials and methodsBased on an ongoing prospective cohort study, NPC patients aged ≥18 years old and diagnosed with RIBN were included in this current analysis if they finished the time frame of 3-year follow-up and had at least twice cognition assessments. The Chinese version of the Montreal Cognitive Assessment (MoCA) was used to assess the cognitive state. Linear mixed-effect models were used to analyze the annual progression rates of MoCA total and seven sub-items scores. ResultsAmong 134 patients in this study, the transition probability from normal to mild/moderate cognitive dysfunction were 14.2 % (19/134) and 1.49 % (2/134) respectively during the median follow-up time of 2.35 years. The total MoCA score declined by −0.569 (SE 0.208) points annually (p = 0.008). Patients with ≤6 years of duration from RT to RIBN have higher annual progression rate of total scores [−0.851 (SE 0.321), p = 0.013; p for interaction = 0.041]. ConclusionOur findings of the annual decline rate of cognition in NPC patients with RIBN from a 3-year longitudinal data, particularly for those who developed RIBN rapidly after RT, have important implications for the upcoming clinical trials designed to prevent or decrease cognitive decline in NPC patients with RIBN, regarding the selection of study patients and the calculation of sample size.

Blazing a trail for the clinical use of rapamycin as a geroprotecTOR.

Treatment with rapamycin, an inhibitor of the mechanistic Target Of Rapamycin Complex One (mTORC1) protein kinase, has been repeatedly demonstrated to extend lifespan and prevent or delay age-related diseases in diverse model systems. Concerns over the risk of potentially serious side effects in humans, including immunosuppression and metabolic disruptions, have cautiously limited the translation of rapamycin and its analogs as a treatment for aging associated conditions. During the last decade, we and others have developed a working model that suggests that while inhibition of mTORC1 promotes healthy aging, many of the negative side effects of rapamycin are associated with "off-target" inhibition of a second mTOR complex, mTORC2. Differences in the kinetics and molecular mechanisms by which rapamycin inhibits mTORC1 and mTORC2 suggest that a therapeutic window for rapamycin could be exploited using intermittent dosing schedules or alternative rapalogs that may enable more selective inhibition of mTORC1. However, the optimal dosing schedules and the long-term efficacy of such interventions in humans are unknown. Here, we highlight ongoing or upcoming clinical trials that will address outstanding questions regarding the safety, pharmacokinetics, pharmacodynamics, and efficacy of rapamycin and rapalogs on several clinically oriented outcomes. Results from these early phase studies will help guide the design of phase 3 clinical trials to determine whether rapamycin can be used safely to inhibit mTORC1 for the treatment and prevention of age-related diseases in humans.

Anemia and Red Blood Cell Transfusion in Aneurysmal Subarachnoid Hemorrhage.

Anemia is very common in aneurysmal subarachnoid hemorrhage (aSAH), with approximately half of the aSAH patient population developing moderate anemia during their hospital stay. The available evidence (both physiologic and clinical) generally supports an association of anemia with unfavorable outcomes. Although aSAH shares a number of common mechanisms of secondary insult with other forms of acute brain injury, aSAH also has specific features that make it unique: an early phase (in which early brain injury predominates) and a delayed phase (in which delayed cerebral ischemia and vasospasm predominate). The effects of both anemia and transfusion are potentially variable between these phases, which may have unique considerations and possibly different risk-benefit profiles. Data on transfusion in this population are almost exclusively limited to observational studies, which suffer from significant heterogeneity and risk of bias. Overall, the results are conflicting, with the balance of the studies suggesting that transfusion is associated with unfavorable outcomes. The transfusion targets that are well established in other critically ill populations should not be automatically applied to patients with aSAH because of the unique disease characteristics of this population and the limited representation of aSAH in the clinical trials that established these targets. There are two upcoming clinical trials evaluating transfusion in aSAH that should help clarify specific transfusion targets. Until then, it is reasonable to base transfusion decisions on the current guidelines and use an individualized approach incorporating physiologic and clinical data when available.

Opţiuni terapeutice în schizofrenia ultrarezistentă. Intervenţii nonfarmacologice (II)

Clozapine-resistant or ultra-resistant schizophrenia represents a challenge for clinicians, given the lack of recommendations in all the major treatment guidelines regarding the next steps once clozapine has failed or cannot be tolerated. The first part of this narrative review investigated the pharmacological arsenal available to the clinician to deal with cases of clozapine-resistant schizophrenia. In the present section of the analysis, the results of research that explored the efficacy and tolerability of nonpharmacological methods for this type of schizophrenia will be presented. Ongoing or upcoming clinical trials in patients with ultra-resistant schizophrenia will also be reviewed. Searching electronic databases and clinical trial archives identified seven reports on the effects of psychotherapy and 15 reports on neuromodulation techniques that aimed at ameliorating psychotic symptoms and functionality in clozapine-resistant schizophrenia. A number of six ongoing clinical trials targeting this type of schizophrenia are also presented. In conclusion, based on the data analyzed, cognitive-behavioral therapy for psychosis, cognitive-behavioral therapy, and occupational therapy benefit from moderate-quality data to support their efficacy as add-ons to clozapine in these patients. Except for electroconvulsive therapy, the evidence for other neuromodulation techniques is, at least for now, insufficient to recommend them in ultra-resistant cases. It is necessary to carry out good quality and long-term clinical studies in order to confirm the usefulness of these adjuvant treatments.

Non-invasive Angiographic-based Fractional Flow Reserve: Technical Development, Clinical Implications, and Future Perspectives

New non- and less-invasive techniques have been developed to overcome the procedural and operator related burden of the fractional flow reserve (FFR) for the assessment of potentially significant stenosis in the coronary arteries. Virtual FFR-techniques can obviate the need for the additional flow or pressure wires as used for FFR measurements. This review provides an overview of the developments and validation of the virtual FFR-algorithms, states the challenges, discusses the upcoming clinical trials, and postulates the future role of virtual FFR in the clinical practice.

Mechanical Circulatory Support for Complex High-risk Percutaneous Coronary Intervention

Technological and procedural innovations presently permit the safe and effective performance of increasingly complex percutaneous coronary interventions, while new mechanical circulatory support devices offer circulatory and ventricular support to patients with severely reduced left ventricular systolic function and deranged cardiovascular hemodynamics. Together, these advances now permit the application of complex percutaneous coronary interventions to higher-risk patients who might otherwise be left untreated. Increasing observational data support the use of mechanical circulatory support in appropriate complex and high-risk patients as part of a larger multidisciplinary heart team treatment plan. In-progress and upcoming randomized clinical trials may provide higher-quality evidence to better guide management decisions in the near future.

Abstract P3-03-28: Clinicopathological Risk Factors of Brain Metastasis in Breast Cancer Patients: A Systematic Review and Meta-analysis

Abstract BACKGROUND: Breast cancer brain metastasis (BCBM) has an incidence rate of 5.1% among Breast Cancer (BC) patients. In BCBM, cancerous cells come from a primary tumor that implant and grow in the brain leading to potentially lethal neurologic symptoms and signs. With more clinical options and therapeutics strategies becoming available, a multi-disciplinary approach for treatment is needed in order to best meet BCBM patients’ needs, however, systematic guidelines for the screening of high-risk asymptomatic patients are still lacking and the BCBM diagnoses are performed only after symptoms manifestation. Therefore, understanding the clinical and pathologic drivers of BCBM aids in improving medical interventions by guiding future research directions. This study aims to determine the clinicopathological risk factors of brain metastasis (BM) among BC patients. METHODS: Retrospective cohort studies on the clinicopathological characteristics of BM versus non-BM (NBM) patients were retrieved through reputable search databases. Review Manager version 5.4.1 was used for statistical analyses. In the presence of heterogeneities, a pragmatic approach was undertaken to employ both random-effects (RE) and fixed-effect (FE) meta-analyses. The statistical significance of the pooled effect estimates was examined by the Z-test. Interstudy variations and heterogeneities were estimated using Cochran’s Q-statistic with P < 0.05 indicating a statistically significant heterogeneity. The risk of bias and the quality of studies were assessed at a study level using ROBINS-I tool. RESULTS: A total of four (4) retrospective cohort studies were included in the analyses. Random-effects meta-analyses with i2 < 50% (P > 0.05) had shown significant association (P < 0.05) on the increased incidences of BCBM development for HER2+ expression [OR: 2.43, 95% CI: 1.88 – 3.12, P < 0.00001] and for pre-menopausal status [OR: 1.77, 95% CI: 1.13 – 2.76, P = 0.01]. Fixed-effect meta-analyses had shown significant association (P < 0.05) on the decreased incidence of BCBM development for TNBC disease [OR: 0.66; 95% CI: 0.47 – 0.92; P = 0.02]. The risk of bias was low to moderate in the majority of studies. CONCLUSION: HER2 positivity and pre-menopausal status are risk factors for increased BCBM development while the absence of regional lymph node metastases and ILC findings are less likely to progress to BCBM. Higher T and N categories, higher histological grade, ER negativity, and PR negativity may be associated with higher risks of BCBM while lower T categories, HER2 negativity, and TNBC may likely be associated to less BCBM development. More powerful relevant and upcoming randomized clinical trials with larger sample sizes among BCBM patients versus non-BM patients must be made exploring certainty on the clinicopathological factors contributing to BM among BC patients. Keyword/s: risk factors, breast cancer, brain metastasis Citation Format: Korina Blanca C. Garcia, April Ann A. Lubay. Clinicopathological Risk Factors of Brain Metastasis in Breast Cancer Patients: A Systematic Review and Meta-analysis [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-03-28.

Effectiveness and safety of Inclisiran in hyperlipidemia treatment: An overview of systematic reviews.

This paper aimed to comprehensively evaluate the effectiveness and safety of Inclisiran in treating hyperlipidemia through an overview of systematic reviews (SRs). The Cochrane Library, EMBASE, PubMed, CNKI, WANGFANG database, VIP database, ClinicalTrials.gov, and ICRT were searched electronically to collect SRs and meta-analysis of Inclisiran in hyperlipidemia treatment from the establishment of the database till May 2022. Two researchers independently screened the relevant literature, then the assessment of multiple systematic reviews tool was made into assess the methodological quality of the included studies. Data extracted were used to perform the study through RevMan5.3 software. The grading of recommendations assessment, development, and evaluation tool was used to grade the quality of the evidence of the outcomes included in the SRs. Prospero ID: CRD 42022326845. A total of 10 relevant SRs were included, involving 7 randomized controlled trials. The assessment results of the assessment of multiple systematic reviews tool suggested that the quality of the SRs included needed to be improved. The reduced level of low-density lipoprotein cholesterol of the experimental group was lower than the control group, and the difference in the amount of effectiveness was statistically significant (MD = -50.13, 95%CI: -56.2 to -44.06, P < .00001). The grading of recommendations assessment, development, and evaluation results showed that out of 27 outcomes, 8 were high-quality, 3 were of medium quality, 6 were of low quality, and 10 were of the most inferior quality. 300mg Inclisiran with 2 injections a year has the best therapeutic effect, which can significantly reduce low-density lipoprotein cholesterol and total cholesterol, and increase high-density lipoprotein cholesterol levels in patients with hyperlipidemia. Inclisiran has a favorable safety profile, with no significant difference in the incidence of adverse reactions compared to a placebo. Most of the adverse effects were associated with the reaction on the injection site.

The role of neurofilament light in genetic frontotemporal lobar degeneration.

Genetic frontotemporal lobar degeneration caused by autosomal dominant gene mutations provides an opportunity for targeted drug development in a highly complex and clinically heterogeneous dementia. These neurodegenerative disorders can affect adults in their middle years, progress quickly relative to other dementias, are uniformly fatal and have no approved disease-modifying treatments. Frontotemporal dementia, caused by mutations in the GRN gene which encodes the protein progranulin, is an active area of interventional drug trials that are testing multiple strategies to restore progranulin protein deficiency. These and other trials are also examining neurofilament light as a potential biomarker of disease activity and disease progression and as a therapeutic endpoint based on the assumption that cerebrospinal fluid and blood neurofilament light levels are a surrogate for neuroaxonal damage. Reports from genetic frontotemporal dementia longitudinal studies indicate that elevated concentrations of blood neurofilament light reflect disease severity and are associated with faster brain atrophy. To better inform patient stratification and treatment response in current and upcoming clinical trials, a more nuanced interpretation of neurofilament light as a biomarker of neurodegeneration is now required, one that takes into account its relationship to other pathophysiological and topographic biomarkers of disease progression from early presymptomatic to later clinically symptomatic stages.

Impact of the COVID-19 pandemic on clinical trials: a cross-sectional questionnaire study in China.

The number of Chinese clinical trials has continued to grow throughout the coronavirus disease 2019 (COVID-19) pandemic, but we know little about clinical trial team members' perceptions and attitudes toward the impacts of the pandemic. This study aimed to assess the impact of the COVID-19 pandemic on clinical trials in China from the perspective of research staff to provide a deeper understanding and some recommendations for the ongoing and upcoming clinical trials during the pandemic. A nationwide cross-sectional questionnaire was distributed to respondents throughout mainland China between September 2021 and October 2021. The participants assessed the impact of the COVID-19 pandemic on clinical trials based on a 5-point Likert-type scale, and exploratory factor analysis (EFA) was used to confirm the factor structure. Descriptive statistical analysis and the Mann-Whitney test were used to discover the differences between different groups. A total of 2,393 questionnaires from 272 hospitals were collected in mainland China. Factor analysis resulted in 4 factors, with a cumulative explained variance of 64.93%, as follows: subject enrollment, patient care, study supplies and data management, and research milestones and quality management. The research team members, predominantly represented by clinical research coordinators (CRCs), basically agreed with all but 3 preset scenarios of the impact of COVID-19 on clinical trials. Most respondents did not agree that the pandemic was associated with more serious adverse events (SAEs), missed reports of safety events, or any increase of unscheduled unblinding. In addition, significant differences were revealed in different age, gender, and role groups of respondents based on their views on the impact of the pandemic. The current pandemic situation has had a negative impact on clinical trials, especially in terms of subject recruitment and protocol compliance, yet research team members feel confident that some of the effective measures proposed in the study can moderate the negative impact.

CDK 4/6 inhibitors for the treatment of meningioma.

Meningiomas are the most common non-metastatic brain tumors, and although the majority are relatively slow-growing and histologically benign, a subset of meningiomas are aggressive and remain challenging to treat. Despite a standard of care that includes surgical resection and radiotherapy, and recent advances in meningioma molecular grouping, there are no systemic medical options for patients with meningiomas that are resistant to standard interventions. Misactivation of the cell cycle at the level of CDK4/6 is common in high-grade or molecularly aggressive meningiomas, and CDK4/6 has emerged as a potential target for systemic meningioma treatments. In this review, we describe the preclinical evidence for CDK4/6 inhibitors as a treatment for high-grade meningiomas and summarize evolving clinical experience with these agents. Further, we highlight upcoming clinical trials for patients meningiomas, and discuss future directions aimed at optimizing the efficacy of these therapies and selecting patients most likely to benefit from their use.

Emerging Therapies and Novel Targets for TDP-43 Proteinopathy in ALS/FTD.

Nuclear clearance and cytoplasmic mislocalization of the essential RNA binding protein, TDP-43, is a pathologic hallmark of amyotrophic lateral sclerosis, frontotemporal dementia, and related neurodegenerative disorders collectively termed "TDP-43 proteinopathies." TDP-43 mislocalization causes neurodegeneration through both loss and gain of function mechanisms. Loss of TDP-43 nuclear RNA processing function destabilizes the transcriptome by multiple mechanisms including disruption of pre-mRNA splicing, the failure of repression of cryptic exons, and retrotransposon activation. The accumulation of cytoplasmic TDP-43, which is prone to aberrant liquid-liquid phase separation and aggregation, traps TDP-43 in the cytoplasm and disrupts a host of downstream processes including the trafficking of RNA granules, local translation within axons, and mitochondrial function. In this review, we will discuss the TDP-43 therapy development pipeline, beginning with therapies in current and upcoming clinical trials, which are primarily focused on accelerating the clearance of TDP-43 aggregates. Then, we will look ahead to emerging strategies from preclinical studies, first from high-throughput genetic and pharmacologic screens, and finally from mechanistic studies focused on the upstream cause(s) of TDP-43 disruption in ALS/FTD. These include modulation of stress granule dynamics, TDP-43 nucleocytoplasmic shuttling, RNA metabolism, and correction of aberrant splicing events.