Delay Disease Progression Research Articles

Pulmonary thromboembolism in children with Duchenne Musculary Dystrophy: A Case Report

Objectives: To describe a clinical case of pulmonary thromboembolism (PE) in a child with Duchenne muscular dystrophy. Methods: A detailed description of the clinical picture and a review of the patients medical record were carried out, in addition to a discussion based on a literature review. Discussion: PTE is not common in children and in 95% of cases it is secondary to an underlying cause or disease, with Duchennes disease being a predisposing condition due to the hypercoagulable state. Diagnosis in the pediatric population is not supported by tests validated as for adults; in this case, CT angiography was the exam of choice with sensitivity and specificity above 90%. In addition to diagnosis, a risk classification is essential, and supports the therapeutic choice. Therefore, lowrisk patients receive anticoagulation, while high-risk patients receive thrombolytic therapy; in patients with contraindications to these drugs, surgical intervention may be necessary. Correct identification and early management are essential to delay disease progression and prevent sequelae, as well as avoid unnecessary invasive approaches. Conclusion: Due to the difficulty in diagnosing pulmonary thromboembolism in children, a detailed clinical investigation is essential, through the discussion of differential diagnoses and assessment of risk factors, since other diseases can mimic this clinical condition, which can present with signs and nonspecific symptoms.

Does Antioxidant Superoxide Dismutase levels Decline with Advanced primary Knee Osteoarthritis in Synovial Fluid ? A Pilot Study

Abstract Introduction: Osteoarthritis (OA) is a progressive, degenerative disease that leads to joint pain, tenderness, stiffness, locking, effusion, reduced motion, swelling, crepitus, and disability. The pain in OA is the most significant clinical feature and impacts function, mobility, quality of life, and the reason for medical advice. Methods: Fifty individuals with primary knee OA in the age range of 45–90 years were chosen at random for the research (N=50). The American College of Rheumatology's diagnostic criteria were employed to diagnose osteoarthritis, and a visual analogue scale was utilized to score the severity of pain. Knee OA was graded using the Kellgren-Lawrence (K-L) radiographic assessment method. The antioxidant levels of superoxide dismutase in the synovial fluid were measured by using a spectrophotometric assay. Results: Grades 1, 2, 3, and 4 have SOD activity values of 1.43±0.55, 1.44±0.72, 0.92±0.52, and 0.87 ±0.52 U/ml, respectively, in synovial fluid. Synovial fluid SOD activity was higher in grades 1 & 2 of KOA as compared to grades 3 &4 and the difference was statistically significant (p<0.05). Conclusions: There was a link between K-L grade and synovial antioxidant activity level. In the late stages of knee osteoarthritis, the antioxidant enzyme (SOD) activity was reduced.According to the results of this study, regular antioxidant supplementation to early osteoarthritis patients may delay disease progression by improving the antioxidant status of the knee, which neutralises free radicals and thus prevents cartilage damage.

COGNITIVE STATUS AND HEALTH CARE UTILIZATION IN AN EMERGENCY DEPARTMENT: EARLY RESULTS OF A LONGITUDINAL PILOT STUDY

Abstract Many people living with Alzheimer’s disease and related dementias (ADRD) never receive a formal disease diagnosis. This compromises wellbeing and increases health services utilization and care costs. Wider screening and assessment for ADRD may increase access to supportive care, improve allocation of medical care, and foster interventions that prevent or delay disease progression. A sample of Medicare-enrolled individuals 65+ (n=60) consecutively presenting to the Oregon Health & Science University (OHSU) emergency department (ED) in Portland, Oregon consented to the study and were administered the TICS, a validated tool for telephone-based assessments of cognition, post-discharge from the ED. Study participants were asked about their physical health via the modified Cumulative Illness Rating Scale (M-CIRS), and their cognitive health via the PROMIS Cognitive Measure Questions on Mental Clarity. Care utilization patterns were measured via review of participants’ electronic health records (EHR) for three years prior to study enrollment focusing on total hospitalizations, ED visits, and primary care (PC) visits.Medicare-enrolled adults 65+ recently discharged from the ED were a feasible population to perform a cognitive assessment. The study enrollment rate was 24.2% (n=60). Enrollment was limited to patients with their PC affiliated with the OHSU health system, which excluded the majority (792, 73.8%) of ED patients Medicare-enrolled, 65+ from our study (1,072). This study provides preliminary evidence to support focusing on older ED patients to administer cognitive assessments, linking outcomes to the EHR, and ultimately providing a platform for future research on impacts of under-diagnosed ADRD on population-level health outcomes and care utilization.

The role of oxidative stress in neurodegenerative diseases and potential antioxidant therapies.

The central nervous system (CNS) is essential for homeostasis and controls the physiological functions of the body. However, the biochemical characteristics of the CNS make it especially vulnerable to oxidative damage (OS). This phenomenon compromises correct CNS functioning, leading to neurodegeneration and neuronal death. OS plays a crucial role in the physiopathology of neurodegenerative diseases. It is involved in multiple mechanisms of nucleic acid, protein, and lipid oxidation, thereby contributing to progressive brain damage. These mechanisms include mitochondrial dysfunction; excessive production of reactive oxygen and nitrogen species; deficiency of antioxidant defenses; protein oligomerization; cytokine production and inflammatory response; blood-brain barrier abnormalities; and proteasome dysfunction. All these dysfunctions are involved in the pathogenesis ofneurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, Huntington's disease, or amyotrophic lateral sclerosis. A curative treatment is currently not available. Research is focused on the search for therapies that reduce oxidative damage and delay disease progression. In the recent years, researchers have focused their attention on the effects of antioxidant therapies.

Anti-α-synuclein c-terminal antibodies block PFF uptake and accumulation of phospho-synuclein in preclinical models of Parkinson's disease

Parkinson's disease (PD), a neurodegenerative disease affecting dopaminergic (DA) neurons, is characterized by decline of motor function and cognition. Dopaminergic cell loss is associated with accumulation of toxic alpha synuclein aggregates. As DA neuron death occurs late in the disease, therapeutics that block the spread of alpha synuclein may offer functional benefit and delay disease progression. To test this hypothesis, we generated antibodies to the C terminal region of synuclein with high nanomolar affinity and characterized them in in vitro and in vivo models of spread. Interestingly, we found that only antibodies with high affinity to the distal most portion of the C-terminus robustly reduced uptake of alpha synuclein preformed fibrils (PFF) and accumulation of phospho (S129) alpha synuclein in cell culture. Additionally, the antibody treatment blocked the spread of phospho (S129) alpha synuclein associated-pathology in a mouse model of synucleinopathy. Blockade of neuronal PFF uptake by different antibodies was more predictive of in vivo activity than their binding potency to monomeric or oligomeric forms of alpha synuclein. These data demonstrate that antibodies directed to the C-terminus of the alpha synuclein have differential effects on target engagement and efficacy. Furthermore, our data provides additional support for the development of alpha synuclein antibodies as a therapeutic strategy for PD patients.

Time-lagged relationships between a decade of air pollution exposure and first hospitalization with Alzheimer's disease and related dementias

Alzheimer's disease and related dementias (ADRD) poses substantial health challenges among an aging population. One of the primary challenges in studying ADRD is that biological processes underlying these ailments begin decades prior to diagnosis. Previous studies indicate a relationship between ADRD and air pollution exposure to both fine particulate matter (PM2.5) and nitrogen dioxide (NO2) but are limited in their interpretation because they consider exposure measurements at a single time point. Our retrospective cohort study considered 27 + million Medicare enrollees in the United States followed up to 17 years and matched with highly accurate annual air pollution exposure measurements for PM2.5, NO2, and summer ozone. We applied distributed lag models and estimated the lagged associations between air pollution and odds of first hospitalization with ADRD. We found significantly increased odds due to overall PM2.5 and NO2 exposure and time-lagged exposure 10 and 8 years prior to admission, respectively. Furthermore, we found the connection between air pollution exposure and increased odds of first hospitalization with ADRD exists at air pollution levels below current National Ambient Air Quality Standards set by the US Environmental Protection Agency, with the steepest increase in odds occurring at low concentrations of PM2.5. Our findings are the first to show that air pollution exposures from as many as 10 years prior to the admission are related to increased odds of hospitalizations with ADRD. As there are no clear treatments available for ADRD, identifying modifiable risk factors such as air pollution exposure may make significant contributions towards prevention or delayed disease progression.

Proton Pump Inhibitors: Promising Role in the Prophylaxis and Symptom Control of Acute Exacerbations of Chronic Obstructive Pulmonary Disease

Abstract Chronic Obstructive Pulmonary Disease (COPD), the third leading cause of death worldwide and the fifth-ranked cause of chronic disability is usually associated with significant concomitant chronic diseases, Gastroesophageal Reflux Disease (GERD) being the commonest. Exacerbations of COPD (AECOPD) are episodes of worsening of symptoms, the frequency of which increases with the severity of COPD. AECOPD is triggered mainly by respiratory infections, bacterial or viral or both. Human rhinoviruses (HRV) are the top viral pathogen in triggering AECOPD, and experimental infection has provided significant new evidence in establishing a causal relationship between virus infections and AECOPD. Proton pump inhibitors (PPI), the most potent acid suppressants, are commonly prescribed for isolated GERD or GERD complicating COPD. There has been a breakthrough in Pulmonary Medicine in that PPI, in addition to their well proven role in acid suppression, has emerged as a promising interventional tool in the prophylaxis and symptom control of AECOPD. This efficacy is not limited to patients with COPD complicated by GERD, since PPI also independently and significantly reduced the risk of developing frequent AECOPD in those with COPD alone, delaying disease progression and improving clinical outcomes. Although the studies conducted so far regarding effectiveness of PPI had promising results, current evidence is insufficient to determine to what extent their long-term use is safe. Large scale multi-center studies are warranted to assess their long-term safety profile and clinical outcomes. The objective of this study is to identify a possible role of PPI in prophylaxis and symptom control of AECOPD.

KEYNOTE-991: pembrolizumab plus enzalutamide and androgen deprivation for metastatic hormone-sensitive prostate cancer.

Current treatment for patients with metastatic hormone-sensitive prostate cancer (mHSPC) delays disease progression and improves survival, but resistance is inevitable. Additional therapies that prolong survival are needed. Androgen deprivation therapy (ADT) combined with next-generation hormonal agents, such as enzalutamide, is standard-of-care for men with mHSPC. Emerging evidence suggests potential synergism between enzalutamide and the PD-1 inhibitor pembrolizumab in prostate cancer. The phase III randomized, placebo-controlled, double-blind KEYNOTE-991 trial will investigate the efficacy and safety of pembrolizumab versus placebo in combination with enzalutamide when initiating ADT in participants with mHSPC naive to next-generation hormonal agents. Approximately 1232 patients will be randomly assigned 1:1 to receive pembrolizumab 200mg every 3weeksor placebo every 3 weeks, both with enzalutamide 160mg once daily and ADT. Dual primary end points are overall survivaland radiographic progression-free survival. Secondary end points include time to first subsequent therapy, time to symptomatic skeletalrelated event, objective response rateand safety and tolerability. Clinical Trial Registration: NCT04191096 (ClinicalTrials.gov).

Characterisation of pupillary responses to alternating blue and orange light exposures in a fMRI protocol

AbstractBackgroundThe non‐image forming (NIF) functions of light are diverse and include stimulation of cognition and alertness, sleep regulation and pupil diameter modulation. Previous work indicated that exposure to blue‐enriched light as well as pupil size variations are associated with higher locus coeruleus (LC) activity. Given the central role of LC structure and function in the earliest stages of Alzheimer’s disease neuropathology, light exposure may constitute a promising stimulation technique to delay disease progression. Prior to addressing light impact on the LC, here, we aimed at characterising the pupil responses to light during fMRI protocol, to determine its quality in assessing NIF effects of light.MethodPupil diameter was continuously recorded in 11 healthy subjects (20‐30yr, 7 women) with an infrared eyetracker device while they were administered a 15‐min auditory oddball task in a 7T MRI scanner. Participants were concomitantly exposed to pseudo‐randomly alternating 30s blocks of blue‐enriched (4,000K; 200µW/cm2) and orange (589nm; 6x1013photons/cm2/s) lights. Statistics consisted in generalized linear mixed models seeking effects of light condition on pupil response, with subjects as random intercept and controlling for age, sex and BMI.ResultBlue light condition was associated with a significantly smaller pupil diameter as compared to the orange condition, (main effect of light condition: F(2,270)=571.22;p<.0001; Fig1). Moreover, the impact of the light condition on pupil size did not significantly change over the 15min‐protocol (light condition x block repetition interaction: F(12,240)=1.21 ; p=.28), suggesting that time‐in‐protocol and prior light blocks did not influence pupil constriction.ConclusionWe report preliminary results confirming that blue‐enriched light triggers a stronger pupil response than longer wavelength light and showing that the protocol induces a stable response in time even when using short alternating light exposures. These findings support the validity of the protocol to assess NIF responses to light in fMRI in healthy participants, including over the LC. Being able to stimulate the LC holds important implications for possibly delaying Alzheimer’s disease progression. We now aim to include more participants, including older individuals, and to extend to other cognitive tasks to assess the generalization of the present findings to other cognitive domains and age‐ranges.

Outcomes of thoracic endovascular aortic repair for uncomplicated type B dissections based on chronicity.

The long-term results of thoracic endovascular aortic repair (TEVAR) for uncomplicated type B aortic dissection (uTBAD) have been associated with improved aorta-specific survival and delayed disease progression compared with medical therapy alone. In 2020, the Society for Vascular Surgery (SVS) and Society for Thoracic Surgeons (STS) reported new reporting standards and classification for TBAD. We assessed the effectiveness of TEVAR in the treatment of uTBAD stratified by the updated classification using the Vascular Quality Initiative database. The Vascular Quality Initiative registry was queried for patients who had undergone TEVAR for uTBAD from August 2014 to November 2020. We analyzed the outcomes stratified by the SVS/STS reporting standards. The cohort was then grouped and compared using the updated chronicity classification (hyperacute,<24hours; acute, 1-14days; subacute, 15-90days; and chronic, >90days) and univariable methods (χ2, analysis of variance), multivariable logistic regression, and survival analysis (Kaplan-Meier, Cox regression). Of 1476 TEVARs, 121 (8.2%) were for hyperacute, 833 (56.4%) for acute, 316 (21.4%) for subacute, and 206 (14.0%) for chronic uTBAD. The rates of in-hospital stroke for hyperacute and acute uTBAD were significantly higher than was the rate for chronic uTBAD. The rate of spinal cord ischemia (SCI) was significantly higher for hyperacute and subacute uTBAD than for chronic uTBAD but not for acute vs chronic uTBAD. After multivariable adjustment, no significant difference was found in the 30-day mortality between the four groups. However, the adjusted stroke risk was more than sixfold higher for hyperacute uTBAD than for chronic uTBAD (odds ratio [OR], 6.78; 95% confidence interval [CI], 1.83-25.17; P= .004) and more than threefold higher for acute than for chronic uTBAD (OR, 3.42; 95% CI, 1.04-11.24; P= .043). The adjusted risk of SCI was also significantly higher for hyperacute and subacute than for chronic uTBAD (OR, 19.17; 95% CI, 2.42-151.90; P= .005; and OR, 8.64; 95% CI, 1.11-67.21; P= .039, respectively) but not for acute vs chronic uTBAD (OR, 6.95; 95% CI, 0.93-51.88; P= .059). The risk of postoperative reintervention was threefold higher for hyperacute vs chronic uTBAD (OR, 3.02; 95% CI, 1.19-7.69; P= .02). The Kaplan-Meier survival estimates revealed that the 1-year survival rate for hyperacute, acute, subacute, and chronic uTBAD was 83.2%, 87.2%, 92.3%, and 92.9%, respectively (P= .010). However, no significant differences were found in the hazard of 1-year mortality after adjustment for potential confounders. Using the updated SVS/STS chronicity classification, we found an increased risk of perioperative stroke, SCI, and the need for reintervention after TEVAR for uTBAD in the hyperacute periods compared with the chronic period. The updated classification should be incorporated into all future study designs for TEVAR trials. We would recommend avoiding TEVAR for uTBAD in the hyperacute phase.

Lifetime clinical benefits of lecanemab in early Alzheimer’s disease using simulation modeling

AbstractBackgroundAlzheimer’s disease (AD) is a progressive, neurodegenerative disease and imposes a substantial societal burden. Treatment strategies that slow disease progression may improve health outcomes and reduce burden. Lecanemab is a humanized IgG1 monoclonal antibody that preferentially targets soluble aggregated Aβ species. In the phase 2b BAN2401‐G000‐201 trial, lecanemab reduced clinical decline as measured by key global and cognitive scales at 18 months.MethodsA validated disease simulation model was used to assess lifetime health outcomes of lecanemab for patient with early AD (MCI due to AD and mild AD dementia) based on BAN2401‐G000‐201 trial data and published literature. The model captures the pathophysiology and management of AD, with the aim of evaluating the effects of disease modification on disease progression and translating them into meaningful health outcomes.ResultsLecanemab treatment was projected to delay disease progression, resulting in an increase in patient’s expected time in the early AD stages while reducing the time in more severe states. A 26% slowing of clinical decline on CDR‐SB in patients treated with lecanemab corresponded to a 7%, 13%, and 10% reduction in the proportion of patients progressing to mild, moderate, and severe AD dementia, respectively, over a lifetime horizon compared to the standard of care (SoC). Similarly, the estimated mean time to advance to mild, moderate, and severe AD dementia extended for lecanemab treatment by 2.51, 3.13, and 2.34 years, respectively. Scenario analyses indicated the potential lifetime impact of lecanemab was greater at earlier, younger onset AD. The incremental mean times for transition to mild and moderate AD dementia were 3.29 and 3.38 years, respectively, in younger adults (baseline mean age 65 vs. 71.5 years) with MCI due to AD only. Compared with SoC, lecanemab treatment improved patient’s quality of life over lifetime with additional 0.75 quality‐adjusted life‐years per patient (4.97 vs. 4.22).ConclusionsThe findings suggest that lecanemab treatment in early AD may have large health impacts by slowing disease progression to more severe stages of AD and reducing patient, caregiver, and public health burden. Predicted long‐term health outcomes provide a foundation for healthcare decision‐makers to understand the potential clinical and socioeconomic value of lecanemab.

Activating mitofusins interrupts mitochondrial degeneration and delays disease progression in SOD1 mutant amyotrophic lateral sclerosis.

Mitochondrial involvement in neurodegenerative diseases is widespread and multifactorial. Targeting mitochondrial pathology is therefore of interest. The recent development of bioactive molecules that modulate mitochondrial dynamics (fusion, fission and motility) offers a new therapeutic approach for neurodegenerative diseases with either indirect or direct mitochondrial involvement. Here, we asked: (1) Can enhanced mitochondrial fusion and motility improve secondary mitochondrial pathology in superoxide dismutase1 (SOD1) mutant amyotrophic lateral sclerosis (ALS)? And: (2) What is the impact of enhancing mitochondria fitness on in vivo manifestations of SOD1 mutant ALS? We observed that small molecule mitofusin activators corrected mitochondrial fragmentation, depolarization and dysmotility in genetically diverse ALS patient reprogrammed motor neurons and fibroblasts, and in motor neurons, sensory neurons and fibroblasts from SOD1 G93A mice. Continuous, but not intermittent, pharmacologic mitofusin activation delayed phenotype progression and lethality in SOD1 G93A mice, reducing neuron loss and improving neuromuscular connectivity. Mechanistically, mitofusin activation increased mitochondrial motility, fitness and residency within neuromuscular synapses; reduced mitochondrial reactive oxygen species production; and diminished apoptosis in SOD1 mutant neurons. These benefits were accompanied by improved mitochondrial respiratory coupling, despite characteristic SOD1 mutant ALS-associated downregulation of mitochondrial respiratory complexes. Targeting mitochondrial dysdynamism is a promising approach to alleviate pathology caused by secondary mitochondrial dysfunction in some neurodegenerative diseases.

The Importance of Early Identification for Parkinson's Disease Patients with Postural Instability and Gait Disturbance.

More and more evidence-based medicine has proved that Parkinson's disease (PD) patients of tremor-dominant (TD) and postural instability and gait difficulty (PIGD) subtype express great individual differences and heterogeneity. Early identification of different subtypes may be an important way to delay disease progression and improve patients' prognosis. The study aimed to compare the spectrum of motor symptoms (MS) and nonmotor symptoms (NMS) between TD and PIGD dominant in the early and middle stages of PD, and determine predictive factors that are associated with different motor subtypes. 292 PD patients in this study were divided into TD-PD and PIGD-PD, and the clinical characteristics between different motor subtypes were compared based on scales related to sleep, mood, and autonomic function. Univariate and multivariate ordered logistic regression analyses were used to analyze the independent influencing factors of disease severity between different motor subtypes. Through the establishment of binary logistic regression model, the potential independent risk factors for distinguishing TD-PD and PIGD-PD were studied. Compared with TD subtype, patients with PIGD subtype have longer course of disease, higher disease severity, and higher daily dosage of levodopa. The severity of nontremor motor symptoms in PIGD-PD is greater than that of TD subtype. Only PIGD score was independently associated with disease severity for the two motor subtypes. Meanwhile, high scores (LED, total UPDRS, PIGD score, gastrointestinal, thermoregulatory, RBDSQ) and low tremor scores were the potential independent risk factors for distinguishing PIGD-PD from TD-PD. Specific nonmotor symptoms (RBD, gastrointestinal function and thermoregulation function) were associated with the PIGD subtype. Prompt detection and early treatment of NMSs related to the PIGD subtype based on the treatment of motor symptoms may improve patient outcomes.

Genomic Evolution of Patients with Myelodysplastic Syndrome after Hypomethylating Agent Failure

Background: Hypomethylating agents (HMAs), such as azacitidine and decitabine, are the current standard of care for patients with myelodysplastic syndrome (MDS). Though HMAs improve cytopenias and delay progression of disease, most patients eventually lose response to these agents and have poor survival afterwards. This poses significant treatment challenges after HMA failure (HMA-F) and an increased risk of transformation to acute myeloid leukemia. The genomic evolution of patients with MDS at the time of HMA-F has not been previously described. Here, we assess the genomic changes of MDS patients at the time of HMA-F and their effects on the outcomes of MDS patients at the time of HMA-F. Methods: We retrospectively evaluated all patients with MDS seen at a single tertiary cancer center from July 2017 to July 2021 and identified those who were previously untreated and later developed HMA-F. Bone marrow (BM) data was assessed at diagnosis and at the time of HMA-F. Genomic DNA was extracted from whole BM aspirate samples and subject to 81-gene target PCR-based sequencing using a next-generation sequencing platform. Survival data was updated in May 2022. The Kaplan-Meier method and Cox proportional hazards model were used for time-to-event data analysis. The number of metaphases for each unique karyotypic aberration combinations were used to compute the proportions of cytogenetic clones. All the analysis was performed in R 4.0.3. Results: Out of 799 untreated MDS patients, 147 patients (32%) developed HMA-F with a median follow-up time of 44.0 months from diagnosis. Paired cytogenetic and molecular data were available in 128 and 75 patients, respectively. The median overall survival (mOS) since diagnosis (hazard ratio (HR) 1.65, p=0.033) and HMA-F (HR 1.95, p=0.004, Figure A) was inferior for individuals with decreasing number of clones at the time of HMA-F with no statistically significant differences in the time to HMA-F. Gain and/or loss of cytogenetic abnormalities at the time of HMA-F resulted in a shorter mOS (HR 2.35, p<0.001), time to HMA-F (HR 1.65, p=0.033) and mOS since HMA-F (HR 2.89, p<0.001). A change in the dominant cytogenetic clone by the number of metaphases at the time of HMA-F resulted in inferior mOS since diagnosis (HR 2.28, p<0.001), time to HMA-F (HR 1.89, p=0.005), and mOS since HMA-F (HR 2.45, p<0.001). Interestingly, most patients who had gain and/or loss of karyotypic abnormalities and a change in the dominant cytogenetic clone had mutations in TP53. Regarding mutations, there were no statistically significant differences in mOS and time to HMA-F by the gain and/or loss of new mutations at the time of HMA-F. However, the change of the dominant mutation by variant allele frequency resulted in improved mOS from diagnosis (HR 0.47, p=0.02), time to HMA-F (HR 0.46, p=0.02), and mOS since HMA-F (HR 0.55, p=0.072, Figure B). Of note, most TP53-mutated patients had no changes in mutations at the time of HMA-F. Conclusions: Patients with HMA-F MDS have poorer outcomes with a decreasing number of cytogenetic clones, gain and/or loss of karyotypic aberrations, or a change in the dominant clone by the number of metaphases at the time of HMA-F. However, the gain or loss of mutations on next-generation sequencing appear to have no impact on survival outcomes, though a change in the dominant mutation by variant allele frequency appears to be protective. Further understanding of the underlying biology of HMA-F MDS is warranted with an urgent need for therapeutic interventions after failure of HMA therapy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Real-World Treatment (Tx) Patterns and Clinical Outcomes Among Patients (Pts) with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) Who Received at Least 2 Prior Lines of Therapy Including Bruton Tyrosine Kinase Inhibitor (BTKi) and/or B-Cell Lymphoma 2 Inhibitor (BCL2i)

Background: Real-world evidence highlighting the tx landscape and outcomes among pts with CLL/SLL who have received ≥3 lines (3L+) of systemic therapy that include a prior BTKi and/or BCL2i are limited. The objective of this study was to describe pt characteristics, tx patterns, and overall survival (OS) among these pts. Methods: This was a retrospective study using de-identified, electronic health records from the Flatiron Health database from 01/01/2011 to 02/28/2022. The study population included US pts aged ≥ 18 years with CLL/SLL who received ≥ 2 prior lines of therapy (LOT) including a BTKi (cohort 1) or both a BTKi and a BCL2i (cohort 2) and who initiated a subsequent LOT. For cohorts 1 and 2, respectively, the index date was defined as the start of 3L+ therapy after discontinuation of a BTKi and discontinuation of a BTKi and a BCL2i. Pts with any other primary cancers (except nonmelanoma skin cancer) within 12 months before the index date or during the follow-up period were excluded from the analytic cohorts. Descriptive analyses were conducted to examine pt characteristics and tx patterns. Time to discontinuation (TTD), time to next tx (TTNT), and OS for the index LOT were assessed using Kaplan-Meier (KM) method. TTD was defined as the time between index therapy start date and end date. TTNT was defined as the time between start of index therapy and start of subsequent LOT. Results: The study sample included 405 pts in cohort 1 and 57 pts in cohort 2, with a median follow-up of 18 and 11 months, respectively. The majority of pts (percent in cohort 1 and cohort 2) were aged ≥ 65 years (80.2% and 78.9%), male (60.2% and 50.9%), White (76% and 78.9%), and treated in the community setting (93.6% and 94.7%). Approximately 70% of pts in cohort 1 began their index LOT in 2018 or later, whereas 79% of pts in cohort 2 began their index LOT in 2019 or later. Pts in both cohorts were largely well functioning, with ECOG PS score ≤ 1 in 83.7% of cohort 1 and 68.0% of cohort 2. Disease transformation was reported among 8.9% of pts in cohort 1 and 14.0% of pts in cohort 2. Pts in cohort 1 received a median of 2 prior LOTs, whereas those in cohort 2 received a median of 3 prior LOTs. The most common txs observed in cohort 1 in the index LOT were BTKi monotherapy (20.0%), chemotherapy + anti-CD20 mAb (19.0%), BCL2i monotherapy (13.3%), and BCL2i + anti-CD20 mAb (13.1%). The most common txs observed in cohort 2 in the index LOT were BCL2i + anti-CD20 mAb (19.3%), phosphatidylinositol-3-kinase inhibitor monotherapy (17.5%), chemotherapy + anti-CD20 mAb (14.0%), and BCL2i monotherapy (12.3%). Median (95% CI) KM estimate of TTD for index therapy was 13.2 (11.1‒17.5) months and 7.1 (5.0‒11.8) months for cohorts 1 and 2, respectively. For pts who received a subsequent LOT after index therapy, the median (95% CI) KM estimate of TTNT was 11.3 (9.1‒12.6) months for cohort 1 and 6.6 (3.6‒10.1) months for cohort 2. The median (95% CI) OS was 33.1 (28.3‒40.0) months (Figure 1) and 16.6 (11.0‒27.5) months (Figure 2), and the 12-month OS estimate was 76.5% and 57.5%, for cohorts 1 and 2, respectively. Conclusions: The study findings highlight a significant unmet need in pts with 3L+ CLL/SLL. Real-world tx patterns observed in this study are reflective of a heterogenous tx landscape without the presence of a standard of care. The results indicate that pts receive similar txs as used in earlier LOTs. This rechallenging results in suboptimal disease control as indicated by short TTNT, TTD, and estimated OS. Study findings suggest that disease prognosis worsens among pts who were heavily pretreated (i.e., cohort 2, which received prior BTKi and BCL2i), despite the relatively small sample size. Although response and disease progression data were not captured in the Flatiron database, this study sufficiently demonstrates the need for newer and more effective options in the CLL/SLL tx landscape, which can delay disease progression while ensuring better disease control. Overall, these findings are generalizable to pts with CLL/SLL treated in the community setting in the US. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Functional Role of Histone Variant macroH2A1 (H2AFY) in Acute Myeloid Leukemia (AML)

Histone variants can replace replication-coupled histones in the nucleosome. Among core histones, the H2A family exhibits highest sequence divergence resulting in the largest number of variants. Dysregulated expression of macrohistone (macroH2A) variants has been reported in different cancers. Their role in normal hematopoiesis and hematopoietic cancers remained so far poorly understood. We found high expression of macrohistone H2AFY (macroH2A1) in hematopoietic stem and progenitor cells (HSPCs) and primary AML as compared to differentiated hematopoietic cells. To assess for the functional dependency of human AML cells on macroH2A1, we performed in vitro CRISPR-Cas9 negative selection competition assays. Genetic inactivation of H2AFY in 4/9 AML cell lines (Molm-13, MV4;11, THP-1, OCI-AML3) resulted in outcompetition of H2AFY-deleted cells against non-deleted competitors. To confirm these findings in vivo, we performed xenotransplantation experiments. Genetic inactivation of H2AFY in human AML cells resulted in delayed leukemia development in recipient mice (median survival for NT-control: 35.5 days vs. H2AFY-KO: 44.0 days; p=0.002). To validate the functional impact of macroH2A1 on leukemic stem cells (LSCs), we generated a novel conditional knockout mouse model for H2AFY [B6(Cg)-H2afytm1Flh/J (H2afy flox/flox)]. Here, isolated lineage-depleted H2afy+/+, Mx1-Cre+ and H2afyfl/fl, Mx1-Cre+ bone marrow cells (Lin-BMCs) were retrovirally infected with MLL-AF9-GFP (MA9) and transplanted into sub-lethally irradiated recipient mice. Following establishment of leukemia, we transplanted 1x105 leukemic cells and inactivated H2afy in the leukemic cells by pIpC injection on day 7, 9 and 11 post-transplantation. Genetic deletion of H2afy resulted in delayed disease progression (median survival +/+: 83.5 days vs. -/-: 162.0 days, p=0.0013) and reduction of disease penetrance to 61%. Organ infiltration by leukemic cells led to disease development in a limited number of H2afy-/- recipient mice. Isolated H2afy-/- leukemic cells showed a decreased in proliferation and an increased in differentiation. Importantly, 37% of H2afy-/- recipient mice that developed AML showed only partial excision of H2afy, indicating selection of partially excised clones. Long-term survivors without leukemia development showed no molecular evidence for counterselection. Irrespective of the time of disease development and survival, immunophenotypic analysis of (Lin-cKit+Sca-1-FcγR+CD34+GFP+) LGMPs revealed decreased numbers of LSCs following H2afy-deletion (+/+: 2631/106 BMC; -/-: 727/106 BMC; p=0.0002). To assess for the functional consequences of H2afy-deletion on the LSC pool, we performed limiting dilution assays. When transplanting 1x105, 1x104, 1x103 and 1x102 H2afy+/+ or -/- leukemic cells into sub-lethally irradiated recipients, LGMP frequency in H2afy-deficient cells was significantly reduced (1/1 vs. 1/29928; p=1.25e-19). The reduction of LGMP frequency correlated with reduced plating efficiency and increased differentiation. Consistently, primary human AML cells showed impaired colony forming capacity following H2afy deletion (mean colony number NT-control: 60.0±17.1 vs. H2afy-KD: 30.1±8.9; p=0.0023). To assess for the impact of H2afy deletion on normal HSPCs, we performed competitive repopulation assays. Immunophenotypic abundance of HSPC in H2afy+/+ vs. -/- animals revealed comparable numbers in all relevant subpopulations. Serial competitive transplantation of H2afy+/+ and -/- BMC into primary and secondary recipient animals showed no competitive disadvantage or lack of self-renewal capacity of H2afy-/- cells. Likewise, colony formation of healthy human donor CD34+ cells was not impaired following depletion of H2AFY by RNAi. Transcriptome analysis of LGMP populations indicated increased of myeloid cell development and loss of LSC signatures in H2afy-deficient LGMPs. Likewise, ATAC-seq of H2afy+/+ and -/- LGMP population revealed profound changes in the chromatin structure and a strong correlation between chromatin accessibility and mRNA expression. Together, our results provide first evidence for a critical function of H2afy (macroH2A1) in models of AML while being dispensable for normal HSPC function. Experiments to assess for the mechanistic consequences of H2afy deletion on chromatin are currently under way.

An Updated Safety and Efficacy Analysis of Venetoclax Plus Daratumumab and Dexamethasone in an Expansion Cohort of a Phase 1/2 Study of Patients with t(11;14) Relapsed/Refractory Multiple Myeloma

Background: Multiple myeloma (MM) is a plasma cell malignancy with no cure. Current therapies delay disease progression, prolong survival, and minimize symptoms but most patients (pts) eventually relapse or become refractory (RR). Therefore, there is an unmet need for new therapies. The combination of daratumumab (D), an anti-CD38 antibody, bortezomib (V), a proteasome inhibitor (PI) and dexamethasone (d), are approved for the treatment of MM in pts who have received ≥1 prior line of MM therapy. Venetoclax (Ven) is a potent and selective oral BCL-2 inhibitor with demonstrated anti-myeloma activity in pts with t(11;14) RRMM. This Phase 1/2 (3-part) study is investigating the combination of VenDd +/- V in RRMM. In parts 1 and 2, VenDd (in pts with t(11;14) RRMM) and VenDVd (in pts with RRMM irrespective of t(11;14) status) displayed tolerable safety profile and high overall response rate (ORR) (Bahlis N et al. J Clin Oncol 2021). Part 3 further evaluates VenDd and DVd in pts with t(11;14) RRMM with a previously reported overall response rate of 72.7%, 100% and 31.3% in the Ven400Dd, Ven800Dd, and DVd arms respectively (Blood (2021) 138 (Supplement 1): 817). Updated results of Part 3 are presented here. Methods: Part 3 of this Phase 1/2, multicenter, dose-escalation and expansion study (NCT03314181) is evaluating the safety and efficacy of VenDd and DVd in pts with t(11;14) RRMM. Pts (≥ 18 years) with confirmed t(11;14) RRMM with measurable disease per International Myeloma Working Group (IMWG) criteria and who had received ≥1 prior line of MM therapy including an immunomodulatory agent (IMiD) and were non-refractory to PIs or anti-CD38 Ab were enrolled in this study. Pts were randomized 1:1 to receive VenDd or DVd treatment. Treatments in Part 3 were as follows: VenDd cycles (C) were 28-day: daily, oral Ven (400 mg or 800 mg) + D (1800 mg SC [Cycle, C1, 2: Days 1, 8, 15, 22; C3-6: Days 1, 15; C7+: Day 1]) + d (40 mg total weekly); DVd C1 - 8 were 21-day, C9+ were 28-day: D (1800 mg SC [C1 - 3: Days 1, 8, 15; C4 - 8: Day 1; C9+: Day 1]) + V (1.3mg/m2 [C1 - 8: Days 1, 4, 8 and 11]) + d (20 mg [C1 - 3: Days 1, 2, 4, 5, 8, 9, 11, 12 ,15; C4 - 8: Days 1, 2, 4, 5, 8, 9, 11,12; C9+: Day 1]). Results: As of 31 May 2022, enrollment into Part 3 has completed with 21, 10 and 24 t(11;14) pts enrolled in the Ven400Dd, Ven800Dd and DVd arms, respectively. The median age (range) was Ven400Dd: 61 (31 - 88); Ven800Dd: 57 (53 - 84); and DVd: 70 (51 - 80) years. Median prior lines of therapy (range) were 1 (1 - 6) in Ven400Dd; 1 (1 - 4) in Ven800Dd; and 2 (1 - 4) in DVd. Pts with ISS I/II/III (%) disease was Ven400Dd: 38.1/28.6/4.8; Ven800Dd: 40.0/20.0/30.0; and DVd: 25.0/25.0/16.7. Pts with ECOG performance status of grade 0/1/2 (%) were Ven400Dd: 52.4/42.9/4.8; Ven800Dd: 60.0/40.0/0; DVd: 33.3/58.3/8.3. Prior PI/IMiD/anti-CD38Ab (%) exposure was Ven400Dd: 85.7/95.2/0; Ven800Dd: 100/100/10; DVd: 87.5/95.8/4.2. The most common adverse events (AEs) included (Ven400Dd/Ven800Dd/DVd; %): insomnia (52.4/60.0/29.2), fatigue (47.6/50.0/37.5), diarrhea (33.3/50.0/33.3), and nausea (28.6/30.0/20.8). Grade ≥3 AEs were mainly hematologic toxicities. The most frequent serious AE was pneumonia (4.8/10.0/4.2). There were one (Ven800Dd) and three (DVd) pts with an SAE of pyrexia. There was one and three pts with an SAE of upper respiratory tract infection in the Ven800Dd and DVd arms respectively. There were four deaths (one in Ven800Dd and three in DVd arm) reported in part 3 of this study; all occurred following ≥1 post-study MM treatment. The median treatment exposure at the time of data cut was 12.0, 12.0, and 6.9 months for the Ven400Dd, Ven800Dd, and DVd arms, respectively. The ORR was 95%, 100%, and 62% for the Ven400Dd, Ven800Dd, and DVd arms. The ORR for the combined Ven arms was 98%. The preliminary rate of very good partial response or better (≥VGPR) was 86%, 100%, and 38% for the Ven400Dd, Ven800Dd, and DVd arms, respectively. The preliminary 24-month progression-free survival (PFS) rate was 94% (95% CI 63.2, 99.1), 83% (95% CI 27.3, 97.5) and 47% (95% CI 20.6, 70.2) in the Ven400Dd, Ven800Dd, and DVd arms, respectively (Figure). Conclusion: The updated results from part 3 of this randomized, phase 1/2 study of t(11;14) RRMM pts treated with VenDd vs DVd continue to demonstrate a tolerable safety profile and responses have deepened compared to our prior presentation. VenDd demonstrated deep responses that appear to be durable; data are not mature and follow-up is ongoing. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

BRD9 Facilitates Oncogenic Nrf2 Pathway and Dampens Venetoclax Sensitivity By Remodeling Chromatin Accessibility in Chronic Lymphocytic Leukemia

Bromodomain-containing protein 9 (BRD9) functions as a key component of the chromatin remodeling complex in regulation of gene transcription, which is widely implicated in tumorigenicity. Although venetoclax has transformed the paradigm of CLL treatment, some patients are still unable to achieve or maintain clinical remission, indicating the medical need of novel therapeutic target or combinatory regimen. Hence, this study was performed to explore the regulatory mechanism and potential clinical utility of BRD9 in CLL. At first, aberrantly elevated BRD9 expression was frequently observed in CLL patients (n=94) than healthy donors (n=17) both in mRNA and protein level (donors vs. CLL patients, 0.94 ± 0.41 vs. 10.96 ± 2.01, p=0.03). Furthermore, BRD9 overexpression was identified as the independent prognostic factor in CLL (HR=3.55, p<0.001). The exceptionally upregulation of BRD9 was intensely correlated with inferior prognosis in CLL patients, including overall survival (HR=3.246, p=0.02) and time to first treatment (HR=2.326, p=0.005). To investigate the functional significance of BRD9 in CLL, stable BRD9 knockdown cells using lentiviral shRNAs were established. The suppression of BRD9 remarkably impeded cell proliferation, increased cell apoptosis and induced G1/S phase blockage in CLL. What's more, I-BRD9, a selective inhibitor of BRD9, resulted in a defective proliferation in CLL primary cells in a time- and dose-dependent manner. We subsequently performed pre-clinical investigations of I-BRD9 in orthotopic CLL xenograft murine model. Notably, I-BRD9 treatment showed obviously reduced leukemia burden and manifested splenomegaly to a lesser extent than control (Figure 1A), which was further confirmed by H&E and Ki67 staining of spleen. Additionally, I-BRD9 could significantly prolong the lifespan (p=0.02) and delay disease progression of the CLL xenograft mice (p<0.01). Also, a reduction of CLL cells in bone marrow and spleen drawn from I-BRD9 treated mice was corroborated by using flow cytometry. To decipher the specific contribution of BRD9 in CLL pathogenesis, ATAC-seq and CHIP-seq were employed to monitor BRD9-deficent and control cells. Knockdown of BRD9 diminished global ChIP signal and chromatin accessibility near transcriptional start sites. Integrated analysis of mRNA expression profiles of RNA-seq and differential signals of CHIP-seq, Nrf2 was selected as a candidate target for further investigation. The expression of Nrf2 and downstream targets (like HO-1, NOQ1 and SOD1) were significantly decreased in BRD9-silencing CLL cells (p<0.01). Furthermore, the existence of BRD9 binding site was identified in a 2kb region upstream of the NFE2L2 (encoding Nrf2) promoter through constructing truncations (p<0.05). In addition, the enrichment of H3K27ac modification in the binding site was further substantiated by CHIP-qPCR (p<0.01). The inhibitor of histone acetyltransferase reduced the enrichment of BRD9 in this region, indicating that BRD9 bound to NFE2L2 through recognizing the acetylated histone marks. What's more, the Hi-C data suggested a looping of the transcription factor complexes among the labeled regions which showed divergent CHIP signals between shControl and shBRD9 (Figure 1B). The GO analysis of differentially expressed genes obtained from RNA-seq demonstrated a mainly enrichment in apoptotic pathway, which prompted us to investigate the role of BRD9 in venetoclax sensitivity. Following venetoclax addition, CLL cells with BRD9 silenced presented markedly reduced viability than control cells, indicating BRD9 inhibition could potentially drive a therapeutic vulnerability to the venetoclax (p<0.05). Besides, supplementing I-BRD9 with venetoclax strikingly alleviated malignant proliferation and enhanced apoptosis on CLL primary cells than single agent (all combination index<0.6, p<0.05). Western blotting assays suggested the involvement of Nrf2/ARE signaling in venetoclax sensitivity induced by BRD9 inhibition. Taking all these data together, our study firstly credentials the oncogenic role of BRD9 in CLL leukemogenesis, suggesting the therapeutic synergy of combinatory venetoclax/I-BRD9 treatment for clinical utility. Targeting BRD9 displays promising clinical application in the context of extensive use of venetoclax in CLL patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Early selexipag initiation and long-term outcomes: insights from randomised controlled trials in pulmonary arterial hypertension.

Further understanding of when to initiate therapies in pulmonary arterial hypertension (PAH) is important to improve long-term outcomes. Post hoc analyses of GRIPHON (NCT01106014) and exploratory analyses of TRITON (NCT02558231) suggested benefit of early selexipag initiation on long-term outcomes, despite no additional benefit versus initial double combination on haemodynamic and functional parameters in TRITON. Post hoc analyses investigated the effect of early selexipag initiation on disease progression and survival in a large, pooled PAH cohort. Data from newly diagnosed (≤6 months) PAH patients from GRIPHON and TRITON were pooled. Patients on active therapy with selexipag (pooled selexipag group) were compared with those on control therapy with placebo (pooled control group). Disease progression end-points were defined as per the individual studies. Hazard ratios (HR) and 95% CI for time to first disease progression event up to end of double-blind treatment (selexipag/placebo) +7 days and time to all-cause death up to end of study were estimated using Cox regression models. The pooled dataset comprised 649 patients, with 44% on double background therapy. Selexipag reduced the risk of disease progression by 52% versus control (HR: 0.48; 95% CI: 0.35-0.66). HR for risk of all-cause death was 0.70 (95% CI: 0.46-1.10) for the pooled selexipag versus control group. Sensitivity analyses accounting for the impact of PAH background therapy showed consistent results, confirming the appropriateness of data pooling. These post hoc, pooled analyses build on previous insights, further supporting selexipag use within 6 months of diagnosis, including as part of triple therapy, to delay disease progression.

Early renal structural changes and potential biomarkers in diabetic nephropathy.

Diabetic nephropathy is one of the most serious microvascular complications of diabetes mellitus, with increasing prevalence and mortality. Currently, renal function is assessed clinically using albumin excretion rate and glomerular filtration rate. But before the appearance of micro-albumin, the glomerular structure has been severely damaged. Glomerular filtration rate based on serum creatinine is a certain underestimate of renal status. Early diagnosis of diabetic nephropathy has an important role in improving kidney function and delaying disease progression with drugs. There is an urgent need for biomarkers that can characterize the structural changes associated with the kidney. In this review, we focus on the early glomerular and tubular structural alterations, with a detailed description of the glomerular injury markers SMAD1 and Podocalyxin, and the tubular injury markers NGAL, Netrin-1, and L-FABP in the context of diabetic nephropathy. We have summarized the currently studied protein markers and performed bioprocess analysis. Also, a brief review of proteomic and scRNA-seq method in the search of diabetic nephropathy.