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Background: Treatment of advanced CCA has changed dramatically over the past five years with the advent of molecularly targeted therapy, now approved in the 2nd line and beyond. However, real ...world utilization of molecular profiling and targeted therapy is still unknown and these data are critical to empower treatment decision-making. Methods: In 2019, the Cholangiocarcinoma Foundation (CCF) and Ciitizen (a wholly owned subsidiary of Invitae Corporation) collaboratively launched a registry platform that directly consents patients and collects comprehensive medical records. De-identified data including clinical characteristics, molecular testing, interventions, and outcomes are extracted and standardized for research use. The data is longitudinal with regularly planned updates; registry participants can be re-engaged to obtain additional data and communicate tailored insights. Results: We quantified the rate of molecular testing, the presence of targetable biomarkers, and the utilization and outcomes on matched targeted therapies for 372 individuals with CCA. 328 (88.2%) individuals had molecular testing, with the identified targetable mutations and matched therapies reported. Of 328 individuals who had molecular testing, 111 (33.8%) individuals had one or more targetable mutations (116 mutations total). Only 46% (51) of individuals with targetable mutations received targeted therapy. Of the 54% (60) individuals with targetable mutations that did not receive any matched therapy, the majority (61.7%, 37) were in early disease or first line of treatment and therefore not yet eligible for targeted therapy. These individuals will be informed that based on their molecular profile, a targeted therapy may be an option, and suggest they discuss with their treating physician. Conclusions: A novel prospectively-maintained database registry for CCA has been formed in collaboration between a patient advocacy organization (CCF) and industry (Invitae). Prevalence of actionable biomarkers was higher than historically expected and may reflect patient utilization bias of the registry platform. Molecular profiling and access to targeted therapeutics remains suboptimal at this time in CCA. Future directions for the registry include identifying and targeting disparities in care and supporting biopharmaceutical development and regulatory decisions. Table: see text
INTRODUCTION Chronic Lymphocytic Leukemia (CLL) is a hematological malignancy characterized by a progressive accumulation of abnormal monoclonal B lymphocytes. The treatment landscape for CLL has ...undergone significant changes with the introduction of novel targeted agents, notably BTK inhibitors (BTKis). While BTKis have contributed to advancements in CLL management, the class effect of cardiac-related toxicity has emerged in several clinical trials, particularly associated with the first generation BTKi ibrutinib. Our study utilizes a real-world registry dataset to quantify cardiotoxic adverse events (CT AEs) across treatment classes, and explores resulting changes in the treatment journey and disease course for CT AEs associated with ibrutinib. METHODS 766 participants with CLL from the Leukemia and Lymphoma Society (LLS) registry had data extracted from collected medical records via the Invitae CiitizenⓇ platform, a patient-centric platform that leverages the HIPAA right-of-access to organize clinical data into a standardized, research-ready format using machine learning and human clinician review. Lines of therapy (LOTs) were generated using a proprietary logic-based algorithm, and defined as “ibrutinib” if they contained ibrutinib, “2nd-generation” if they contained a 2nd-generation BTKi (e.g. acalabrutinib), or “CD20” if they contained a CD20-targeting monoclonal antibody (e.g. rituximab). Categories were not mutually exclusive (e.g. LOT containing ibrutinib and rituximab counted as both “ibrutinib” and “CD20”). If the medical record stated that AEs resulted from only one medication in the LOT, the AE was assigned to that medication; if it was unclear which medication in a LOT caused the AE, that LOT and AE were excluded from analysis. A proprietary logic-based algorithm was used to calculate endpoints. Statistical significance was assessed using chi-square, with Bonferroni correction applied for multiple comparisons. RESULTS Out of 766 patients in the cohort, 411 received a total of 703 LOTs, of which 228 contained ibrutinib, 91 contained 2nd-generation BTKis, 358 contained CD20s, and 71 contained neither BTKis nor CD20s (“Other”). Ibrutinib-containing LOTs had a statistically significantly higher rate of at least one CT AE (21.5%; 49/228) as compared to LOTs containing 2nd-generation BTKis (5.5%; 5/91; p=0.002), CD20s (2.8%; 10/358; p<0.00001), or Other (8.5%; 6/71; p=0.005). The 49 individuals with an ibrutinib-associated cardiac AE experienced a total of 57 events, which were then characterized for timing, pre-existing cardiac comorbidities, treatment setting, and treatment impact ( Table 1). Ibrutinib CT AEs were not significantly concentrated in any numerical LOT, with a 22.5% (34/151) frequency in 1L, 28.6% (16/56) in 2L, and 22.6% (7/31) in 3+L settings. Individuals with a pre-existing cardiac comorbidity were neither more likely to experience an ibrutinib-associated CT AE, nor more likely to have a treatment impact if they did have a CT AE. Atrial fibrillation was more likely to result in a dose reduction, treatment hold, or discontinuation than hypertension (60% (12/20) vs. 18.2% (4/22), p=0.008); other differences were not statistically significant. We next explored outcomes and subsequent treatments for ibrutinib-containing LOTs that did or did not have any associated CT AE ( Table 2). Outcomes for LOTs associated with a CT AE were not statistically significantly different for ToT, TtNT, CRR, or ORR (see table 2). While the overall distribution of subsequent classes of therapy was similar for those who did or did not experience a CT AE, we note that for those who had treatment discontinued as a result of the CT AE, only 2/11 switched to a 2nd gen BTKi (the remainder switched to a BCL2i-containing regimen), suggesting a potential trend towards out-of-class switching. CONCLUSION Our data support the established higher rate of CT AEs associated with ibrutinib compared to 2nd-generation BTKis or non-BTKi LOTs. However, in this dataset the presence of an ibrutinib-associated CT AE did not significantly alter either the patient's treatment journey or disease course overall. Future analyses will characterize the real-world incidence and impact of other types of AEs at the level of individual medications, LOTs, and medication classes.
INTRODUCTION Therapeutic options for Chronic Lymphocytic Leukemia (CLL) have advanced significantly over time, resulting in a heterogeneous treatment landscape. Insights into the depth of treatment ...response can be gained through highly-sensitive detection of residual cancer cells using measurable (also known as minimal) residual disease (MRD) testing. Initially, MRD testing was limited to prognostic use within clinical trials. However, in recent years it has expanded into various clinical settings, although the extent of real-world use is not well established. METHODS 766 individuals with CLL enrolled in the Leukemia and Lymphoma Society (LLS) registry had their medical records collected and data extracted via the Invitae Ciitizen® platform, a patient-centric platform that leverages HIPAA right-of-access to organize clinical data into a standardized, research-ready format, using a combination of machine learning and human clinician review. Proprietary logic-based algorithms were used to characterize lines of therapy (LOTs), MRD testing methods, outcomes and duration of therapy. Descriptive findings are reported below. RESULTS Of the 766 CLL participants, 117 (15%) received a total of 311 MRD tests (mean=3 tests/person, median=2, max=16). 67 individuals had one or more MRD negative results (134 negative results total) and 78 individuals had one or more MRD positive results (177 positive results total). 56/117 (47.9%) patients had one or more MRD tests as part of a clinical trial, for a total of 132/311 (42.2%) MRD tests performed during a trial. Total MRD tests included 260 (83.6%) evaluated by flow cytometry, 8 (2.6%) by next generation sequencing (NGS), with the remainder not having documented methods (43; 13.8%). Since 2014, when MRD testing was integrated as a prognostic indicator in clinical trials, there has been increasing use of MRD testing ( Figure 1) within this cohort, as assessed by percentage of individuals receiving one or more tests per year. Interestingly, there is a peak of percentage tested in a clinical trial setting in 2017, after which a continued increase in those tested outside of a clinical trial setting shifts the overall proportion down. We also note the appearance of NGS testing in 2018. The 117 individuals who were MRD tested received 40 unique LOTs (e.g., “obinutuzumab, venetoclax”). We then quantified the MRD outcomes as either “achieved MRD-negative” or “did not achieve MRD-negative” for the most commonly-used therapies (n≥5) ( Table 1). Ibrutinib and acalabrutinib monotherapies had the lowest proportion of MRD-negative outcomes (1/15 and 0/6, respectively), whereas obinutuzumab-venetoclax +/- ibrutinib combination therapies had the highest proportion of MRD-negative outcomes (4/5 and 17/17, respectively). In order to assess the impact of MRD outcome on treatment patterns, the duration of therapy following a MRD-positive and negative test were evaluated. Therapy continued a mean duration of 691 days (n=126, median=488) after a MRD-positive test and 419 days (n=66, median=230) after a MRD negative test. CONCLUSION In this real-world dataset of 766 individuals with CLL, we detect an increasing rate of MRD testing since 2014. Notably, this usage is not limited to the clinical trial setting, underscoring the growing significance of MRD testing as a more general tool for evaluating disease control. Exploration of which LOTs achieve proportionally more MRD-negative statuses highlights that venetoclax-containing fixed-duration regimens as well as venetoclax monotherapy have higher rates of MRD-negativity. Conversely, BTK monotherapies ibrutinib and acalabrutinib were associated with the lowest percentage of MRD-negative outcomes. Finally, we find that the duration of therapy from the time of MRD testing is shorter when the result is MRD-negative, suggesting that MRD testing as a component of outcomes assessment used in the real-world setting may be useful in deciding when to discontinue therapy. This aligns with ongoing clinical trials investigating fixed duration therapies and the use of MRD-negative status as an outcome measure to assess depth of remission. Future studies on larger datasets will explore how MRD testing is integrated into clinical practice and its impact on treatment decisions.
STXBP1-related disorders are among the most common genetic epilepsies and neurodevelopmental disorders. However, the longitudinal epilepsy course and developmental end points, have not yet been ...described in detail, which is a critical prerequisite for clinical trial readiness. Here, we assessed 1281 cumulative patient-years of seizure and developmental histories in 162 individuals with STXBP1-related disorders and established a natural history framework. STXBP1-related disorders are characterized by a dynamic pattern of seizures in the first year of life and high variability in neurodevelopmental trajectories in early childhood. Epilepsy onset differed across seizure types, with 90% cumulative onset for infantile spasms by 6 months and focal-onset seizures by 27 months of life. Epilepsy histories diverged between variant subgroups in the first 2 years of life, when individuals with protein-truncating variants and deletions in STXBP1 (n = 39) were more likely to have infantile spasms between 5 and 6 months followed by seizure remission, while individuals with missense variants (n = 30) had an increased risk for focal seizures and ongoing seizures after the first year. Developmental outcomes were mapped using milestone acquisition data in addition to standardized assessments including the Gross Motor Function Measure-66 Item Set and the Grasping and Visual-Motor Integration subsets of the Peabody Developmental Motor Scales. Quantification of end points revealed high variability during the first 5 years of life, with emerging stratification between clinical subgroups. An earlier epilepsy onset was associated with lower developmental abilities, most prominently when assessing gross motor development and expressive communication. We found that individuals with neonatal seizures or early infantile seizures followed by seizure offset by 12 months of life had more predictable seizure trajectories in early to late childhood compared to individuals with more severe seizure presentations, including individuals with refractory epilepsy throughout the first year. Characterization of anti-seizure medication response revealed age-dependent response over time, with phenobarbital, levetiracetam, topiramate and adrenocorticotropic hormone effective in reducing seizures in the first year of life, while clobazam and the ketogenic diet were effective in long-term seizure management. Virtual clinical trials using seizure frequency as the primary outcome resulted in wide range of trial success probabilities across the age span, with the highest probability in early childhood between 1 year and 3.5 years. In summary, we delineated epilepsy and developmental trajectories in STXBP1-related disorders using standardized measures, providing a foundation to interpret future therapeutic strategies and inform rational trial design.
Dravet syndrome is a severe form of childhood epilepsy characterized by frequent temperature-sensitive seizures and delays in cognitive development. In the majority (80%) of cases, Dravet syndrome is ...caused by mutations in the SCN1A gene, encoding the voltage-gated sodium channel Na
1.1, which is abundant in the central nervous system. Dravet syndrome can be caused by either gain-of-function mutation or loss of function in Na
1.1, making it necessary to characterize each novel mutation. Here we use a combination of patch-clamp recordings and immunocytochemistry to characterize the first known NH
-terminal amino acid duplication mutation found in a patient with Dravet syndrome, M72dup. M72dup does not significantly alter rate of fast inactivation recovery or rate of fast inactivation onset at any measured membrane potential. M72dup significantly shifts the midpoint of the conductance voltage relationship to more hyperpolarized potentials. Most interestingly, M72dup significantly reduces peak current of Na
1.1 and reduces membrane expression. This suggests that M72dup acts as a loss-of-function mutation primarily by impacting the ability of the channel to localize to the plasma membrane.
Genetic screening of a patient with Dravet syndrome revealed a novel mutation in SCN1A. Of over 700 SCN1A mutations known to cause Dravet syndrome, M72dup is the first to be identified in the NH
-terminus of Na
1.1. We studied M72dup using patch-clamp electrophysiology and immunocytochemistry. M72dup causes a decrease in membrane expression of Na
1.1 and overall loss of function, consistent with the role of the NH
-terminal region in membrane trafficking of Na
1.1.
Dravet syndrome is a severe form of childhood epilepsy characterized by frequent temperature-sensitive seizures and delays in cognitive development. In the majority (80%) of cases, Dravet syndrome is ...caused by mutations in the SCN1A gene, encoding the voltage-gated sodium channel Na
V
1.1, which is abundant in the central nervous system. Dravet syndrome can be caused by either gain-of-function mutation or loss of function in Na
V
1.1, making it necessary to characterize each novel mutation. Here we use a combination of patch-clamp recordings and immunocytochemistry to characterize the first known NH
2
-terminal amino acid duplication mutation found in a patient with Dravet syndrome, M72dup. M72dup does not significantly alter rate of fast inactivation recovery or rate of fast inactivation onset at any measured membrane potential. M72dup significantly shifts the midpoint of the conductance voltage relationship to more hyperpolarized potentials. Most interestingly, M72dup significantly reduces peak current of Na
V
1.1 and reduces membrane expression. This suggests that M72dup acts as a loss-of-function mutation primarily by impacting the ability of the channel to localize to the plasma membrane.
NEW & NOTEWORTHY
Genetic screening of a patient with Dravet syndrome revealed a novel mutation in SCN1A. Of over 700 SCN1A mutations known to cause Dravet syndrome, M72dup is the first to be identified in the NH
2
-terminus of Na
V
1.1. We studied M72dup using patch-clamp electrophysiology and immunocytochemistry. M72dup causes a decrease in membrane expression of Na
V
1.1 and overall loss of function, consistent with the role of the NH
2
-terminal region in membrane trafficking of Na
V
1.1.
Summary
Objective
The Epilepsy Genetics Initiative (EGI) was formed in 2014 to create a centrally managed database of clinically generated exome sequence data. EGI performs systematic research‐based ...reanalysis to identify new molecular diagnoses that were not possible at the time of initial sequencing and to aid in novel gene discovery. Herein we report on the efficacy of this approach 3 years after inception.
Methods
One hundred sixty‐six individuals with epilepsy who underwent diagnostic whole exome sequencing (WES) were enrolled, including 139 who had not received a genetic diagnosis. Sequence data were transferred to the EGI and periodically reevaluated on a research basis.
Results
Eight new diagnoses were made as a result of updated annotations or the discovery of novel epilepsy genes after the initial diagnostic analysis was performed. In five additional cases, we provided new evidence to support or contradict the likelihood of variant pathogenicity reported by the laboratory. One novel epilepsy gene was discovered through dual interrogation of research and clinically generated WES.
Significance
EGI's diagnosis rate of 5.8% represents a considerable increase in diagnostic yield and demonstrates the value of periodic reinterrogation of whole exome data. The initiative's contributions to gene discovery underscore the importance of data sharing and the value of collaborative enterprises.
Abstract only
Renal interstitial fibrosis is characterized by renal fibroblast proliferation. This process involves renal tubular epithelial cells adopting a fibroblast morphology through ...epithelial‐to‐mesenchymal transition (EMT). EMT produces phenotypic changes such as epithelial cell adherins junction loss and de novo α‐smooth muscle actin (SMA) expression. TGF‐ß1 has been shown to stimulate EMT. Identifying agents that inhibit TGF‐ß1 induced EMT may prevent patient progression towards chronic renal failure (CRF). Previous work from our laboratory has shown that 4‐phenylbuterate (4‐PBA), a histone deacetylase inhibitor (HDACi), inhibited EMT. In this study, we hypothesized that a broad spectrum HDACi, vorinastat, would inhibit TGF‐ß1 induced EMT and apoptosis in human proximal tubular epithelium (hPTE). We tested vorinastat and 4‐PBA on TGF‐ß1 induced EMT in hPTE. TGF‐ß1 induced EMT was inhibited by both 1mM 4‐PBA and 5μM vorinastat as shown by cadherin junction preservation and reduced de novo α‐SMA expression. Vorinastat was also shown to prevent TGF‐ß1‐induced decrease of E‐cadherin and increase of type I collagen transcript levels. Further, 4‐PBA and vorinastat inhibited TGF‐ß1 induced apoptosis in hPTE. These findings suggest that HDACi prevent EMT and apoptosis induced by TGFß1 and may reduce the progression of patients with chronic kidney disease towards CRF.
Funding, CIHR OSO‐115895.
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