Prolonged Peak Research Articles

Abstract PO1-04-02: ACE-Breast-03: A phase 2 study of ARX788, a novel next-generation anti-HER antibody-drug conjugate in HER2-positive metastatic breast cancer patients previously treated with trastuzumab deruxtecan

Abstract Background: HER2 overexpression and/or amplification confers aggressive tumor behavior and decreased survival in patients with breast cancer. Targeting of HER2 is a validated therapeutic strategy, and trastuzumab deruxtecan (T-DXd) has emerged as a preferred treatment in the second-line setting. However, effective treatment following progression on T-DXd remains a major unmet medical need. ARX788 is a next-generation antibody-drug conjugate (ADC) using a technology platform whereby a HER2-specific monoclonal antibody is conjugated to amberstatin 269 (AS269), a potent cytotoxic tubulin inhibitor. Site-specificity, high homogeneity, and stable covalent conjugation of ARX788 leads to the slow release and prolonged peak of serum pAF-AS269, which may contribute to the lower systemic toxicity and increased targeted delivery of payload to tumor cells, at a lower effective dose compared with other HER2 ADCs. Methods: ACE-Breast-03 (NCT04829604) is a global, phase 2 study designed to assess anticancer activity and safety in approximately 40 patients with unresectable or metastatic HER2 positive breast cancer who have been previously treated with T-DXd. Eligibility criteria include measurable disease by RECIST v1.1, radiographically stable brain metastases, no more than three prior lines of treatment in the metastatic setting, and HER2 positivity as determined by central review. If recently progressed on T-DXd or trastuzumab emtansine (T-DM1), a new biopsy for HER2 status is required. Patients will be administered 1.5 mg/kg of ARX788 every three weeks. Efficacy will be assessed using RECIST v1.1 at nine-week intervals after starting ARX788 until progression or start of new cancer treatment. Objective response rate is the primary endpoint, with disease control rate, progression-free survival, overall survival, best overall response, duration of response, and time to response as additional endpoints. The safety and tolerability profile will also be evaluated. PK analysis will determine serum concentrations of ARX788, total antibody, and pAF-AS269. Potential predictive and/or prognostic biomarkers will be analyzed for exploratory purposes. Descriptive statistics will be used to evaluate anticancer activity, safety, and tolerability. The study is currently recruiting patients. Citation Format: Kashif Ali, Laila Agrawal, Anu Thummala, Kevin Kalinsky, Sami Ali, Sibel Blau, Margaret Block, Michael Danso, Denise Yardley, Jay Andersen, Adrienne Gropper-Waks, Priya Jayachandran, Igor Makhlin, Petros Nikolinakos, Joyce O'Shaughnessy, Sandra Aung, Colin Hessel, Hope Rugo, William Gradishar, Debu Tripathy. ACE-Breast-03: A phase 2 study of ARX788, a novel next-generation anti-HER antibody-drug conjugate in HER2-positive metastatic breast cancer patients previously treated with trastuzumab deruxtecan [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-04-02.

Bilateral Pattern Electroretinogram Abnormalities in Patients with Herpes Zoster Keratitis and Conjunctivitis.

Herpes zoster ophthalmicus (HZO) results from the reactivation of varicella zoster virus (VZV) in the ophthalmic branch of the trigeminal nerve. The inflammation caused by VZV involves multiple tissues in the eyes. Our goal is to evaluate pattern electroretinogram (PERG) changes and their relationship with corneal sub-basal nerve changes in patients with HZO. Twenty-two patients with herpes zoster keratitis or conjunctivitis and 20 healthy volunteers were recruited for this cross-sectional study. A PERG test was performed on both eyes of HZO patients and one eye of the healthy controls. In vivo confocal microscopy (IVCM) was also performed on both eyes of the HZO patients to detect corneal nerve damage. Our results showed changes in the PERG parameters in both eyes of HZO patients compared to the healthy controls. Affected eyes showed delayed N95 peak time and decreased P50 and N95 amplitude compared to the unaffected eyes (p < 0.05, respectively). Both affected and unaffected eyes in HZO patients showed delayed P50 peak time and decreased N95 amplitude (p < 0.05, respectively) compared to controls. In HZO patients, no significant differences in each PERG parameter were found between eyes with and without corneal lesions or between eyes with and without increased Langham's cells in the corneal epithelial sub-basal layer. The IVCM images showed decreased total nerve length and number at the sub-basal layer of the epithelial cornea in affected eyes compared to unaffected eyes (p < 0.05). No significant correlation was found between total nerve length and PERG changes. Our results showed that VZV-affected eyes without central cornea involvement displayed reduced N95 amplitude and prolonged P50 peak time in bilateral eyes compared to the healthy controls. Larger studies are needed to further explore the effect of HZO on the electrophysiological response of the eye and the posterior segment.

A Comprehensive Study on the Diagnostic Value of Multi-Slice Computed Tomography for Peripancreatic Infection in Elderly With Severe Acute Pancreatitis.

This study investigated the diagnostic efficacy of multi-slice spiral computed tomography (MSCT) perfusion imaging in evaluating peripancreatic infection in elderly patients with severe acute pancreatitis (SAP). A retrospective analysis was conducted on the clinical data of 110 elderly SAP patients treated at our hospital from March 2018 to August 2019. The study correlated MSCT perfusion imaging characteristics with peripancreatic infection in elderly SAP patients. Additionally, receiver operating characteristic (ROC) curves were constructed to assess the diagnostic performance of MSCT perfusion imaging parameters in evaluating peripancreatic infection in elderly SAP patients. The results indicated that among all 110 elderly SAP patients, the incidence rate of peripancreatic infection was 20.91%, with a mortality rate of 0.91%. MSCT perfusion imaging revealed that after peripancreatic infection in elderly SAP patients, there was a decrease in pancreatic density, local enlargement of the pancreas, blurring of the pancreatic margins, and associated ascites. Compression/narrowing/occlusion of the splenic vein was observed in 22 patients, compression/narrowing/occlusion of the superior mesenteric vein in 17 patients, thickening/thrombosis of the portal vein in 19 patients, and collateral circulation in 21 patients. Compared to elderly SAP patients without peripancreatic infection, those with the infection showed prolonged peak times, reduced peak heights, and decreased blood flow. ROC analysis indicated that the combination of the three parameters (peak time, peak height, and blood flow) had higher specificity and area under the curve (AUC) than single parameters, with no significant difference in sensitivity between the combination and single parameters. In conclusion, combining the three key MSCT perfusion imaging parameters (peak time, peak height, and blood flow) can significantly enhance the predictive efficacy for the risk of peripancreatic infection in elderly SAP patients.

Sensitivity and specificity of the uniform field electroretinogram in glaucoma detection in comparison to the pattern electroretinogram.

To determine the ability of the photopic negative response (PhNR) of the uniform field electroretinogram (UF-ERG) to identify early glaucomatous changes in comparison to the checkerboard and bar stimuli of the pattern electroretinogram (PERG). Forty-nine glaucoma patients were classified into two groups: glaucoma-suspect (23 eyes) and early to moderate glaucoma (30 eyes), based on their clinical examination and the results of standard automated perimetry. Thirty patients (30 eyes) with intraocular pressures (IOP) of 21mmHg or less, with no history of reported high IOP, were included as controls. PERG and UF-ERG recordings were obtained on a Diagnosys D-341 Attaché-Envoy System. Visual field testing was done only for glaucoma-suspect and glaucoma patients. All three tests (PERG bar stimulus, PERG checkerboard stimulus and PhNR) displayed significantly prolonged peak times for glaucoma and glaucoma-suspect patients, with delays ranging from 7.8 to 14.8%, depending on the test. The PERG bar stimulus also showed a significantly lower N95 amplitude for both glaucoma groups (with reductions of 26.0% and 33.0% for glaucoma-suspect and glaucoma groups, respectively). The PERG checkerboard N95 amplitude component had high sensitivity for detecting glaucoma patients but a low specificity (97% and 37%, respectively; AUC = 0.61). Overall, the PhNR peak time showed the highest sensitivity and specificity (77% and 90%, respectively; AUC = 0.87). PERG bar stimuli and the PhNR of the UF-ERG can be used in the clinical setting to detect glaucoma-related changes in glaucoma-suspect and glaucoma patients. However, our data confirm that the PhNR peak time has the best combined sensitivity and specificity.

RETINAL AGING IN COMPANION DOGS

Abstract Companion dogs cohabit with humans in approximately 45% of US households. They experience similar environmental exposures and lifestyles to their human companions, and have shown sensory, cognitive, and neurological decline with aging. The relationship between age and retinal neurologic function in dogs has not been described. The aim of this study was to determine associations between age and retinal full-field electroretinographic measures in companion dogs, an important translational model species for human neurologic aging. Healthy adult companion dogs with no ophthalmic abnormalities were included (n=54, 18 male, 36 female, median weight 25.7kg, median age 89 months). Unilateral full-field light-adapted and dark-adapted electroretinography (ERG) was performed using a handheld device, with mydriasis and topical anesthesia. Standard least squares effect leverage models were used with log transformed data to determine the cross-sectional effect of age, sex, and bodyweight on ERG amplitudes and peak times. Age and sex were significantly associated with ERG outcome variables, more consistently with ERG amplitude than peak time; age had the largest and most significant effect leverage on outcomes (significantly affecting 3/9 peak time and 8/10 amplitude outcome variables). Younger and female dogs had higher ERG amplitudes. Body weight had no significant effect on any outcome. Our finding that aged companion dogs have reduced ERG amplitudes and prolonged peak times mirror ERG findings in aging humans. Because dogs have a shorter lifespan compared with humans, they may act as a sentinel species to monitor for emerging risk factors for age-related neurologic decline.

Ankle biomechanics of the three-step layup in a basketball player with chronic ankle instability

At present, the effects of chronic ankle instability (CAI) on the biomechanics of the ankle joint in the three-step layup of basketball players are not clear. This work aims to thoroughly investigate the impact of CAI on the biomechanical characteristics of the ankle during the execution of a three-step layup in basketball players. Thirty male basketball players were stratified into distinct groups—namely, a CAI group and a non-CAI group—comprising 15 individuals each, based on the presence or absence of CAI. Demographic attributes, including age, weight, height, and the Cumberland Ankle Instability Tool (CAIT) score, were subjected to rigorous statistical examination within both athlete cohorts. The research employed four Whistler 9281CA 3D force measuring platforms (Switzerland), recording at 1000 Hz, in conjunction with eight camera motion analysis systems (USA), functioning at a frequency of 200 Hz. The study recorded maximal plantarflexion angle, inversion angle, dorsiflexion angle, and peak ankle dorsiflexion moment across the subjects during the distinct phases of push-off, landing, and the ensuing landing period. The findings notably exhibited that within the context of the one-foot push-off phase, the maximum ankle inversion angle was notably diminished in the CAI group as contrasted with the non-CAI group, demonstrating statistical significance (t = − 3.006, P < 0.01). The CAI group exhibited a lesser alteration in ankle inversion angle compared to the non-CAI group. Notably, during the one-foot landing period, the CAI group demonstrated a significantly greater maximum ankle inversion angle in contrast to the non-CAI group (t = 8.802, P < 0.001). Furthermore, the CAI group displayed a substantially larger maximum dorsiflexion angle at the ankle joint compared to the non-CAI group (t = 2.265, P < 0.05). Additionally, the CAI group exhibited a prolonged peak time for ankle dorsiflexion moment as compared to the non-CAI group (t = − 2.428, P < 0.05). Collectively, the findings elucidated a reduction in the maximum ankle joint inversion angle during the one-foot push-off phase in individuals with CAI. Furthermore, increased maximum inversion angle and maximum dorsiflexion angle of the ankle joint were observed during the one-foot landing period, alongside a lengthening of the peak time of ankle dorsiflexion moment. These results contribute valuable insights into the selection of training methodologies for basketball players afflicted by CAI.

Clot Waveform Analysis for Hemostatic Abnormalities.

Clot waveform analysis (CWA) observes changes in transparency in a plasma sample based on clotting tests such as activated partial thromboplastin time (APTT), prothrombin time (PT), and thrombin time (TT). Evidence indicates that not only an abnormal waveform but also peak times and heights in derivative curves of CWA are useful for the evaluation of hemostatic abnormalities. Modified CWA, including the PT with APTT reagent, dilute PT (small amount of tissue factor [TF]-induced clotting factor IX [FIX] activation; sTF/FIXa), and dilute TT, has been proposed to evaluate physiological or pathological hemostasis. We review routine and modified CWA and their clinical applications. In CWA-sTF/FIXa, elevated peak heights indicate hypercoagulability in patients with cancer or thrombosis, whereas prolonged peak times indicate hypocoagulability in several conditions, including clotting factor deficiency and thrombocytopenia. CWA-dilute TT reflects the thrombin burst, whereas clot-fibrinolysis waveform analysis reflects both hemostasis and fibrinolysis. The relevance and usefulness of CWA-APTT and modified CWA should be further investigated in various diseases.

Age-associated changes in electroretinography measures in companion dogs.

To determine the association between age and retinal full-field electroretinographic (ERG) measures in companion (pet) dogs, an important translational model species for human neurologic aging. Healthy adult dogs with no significant ophthalmic abnormalities were included. Unilateral full-field light- and dark-adapted electroretinography was performed using a handheld device, with mydriasis and topical anaesthesia. Partial least squares effect screening analysis was performed to determine the effect of age, sex, body weight and use of anxiolytic medication on log-transformed ERG peak times and amplitudes; age and anxiolytic usage had significant effects on multiple ERG outcomes. Mixed model analysis was performed on data from dogs not receiving anxiolytic medications. In dogs not receiving anxiolytics, median age was 118months (interquartile range 72-140months, n = 77, 44 purebred, 33 mixed breed dogs). Age was significantly associated with prolonged peak times of a-waves (dark-adapted 3 and 10cds/m2 flash p < 0.0001) and b-waves (cone flicker p = 0.03, dark-adapted 0.01cds/m2 flash p = 0.001). Age was also significantly associated with reduced amplitudes of a-waves (dark-adapted 3cds/m2 flash p < 0.0001, 10cds/m2 flash p = 0.005) and b-waves (light-adapted 3cds/m2 flash p < 0.0001, dark-adapted 0.01cds/m2 flash p = 0.0004, 3cds/m2 flash p < 0.0001, 10cds/m2 flash p = 0.007) and flicker (light-adapted 30Hz 3cds/m2 p = 0.0004). Within the Golden Retriever breed, these trends were matched in a cross-sectional analysis of 6 individuals that received no anxiolytic medication. Aged companion dogs have slower and reduced amplitude responses in both rod- and cone-mediated ERG. Consideration of anxiolytic medication use should be made when conducting ERG studies in dogs.

Astrocytic control of extracellular GABA drives circadian timekeeping in the suprachiasmatic nucleus

The hypothalamic suprachiasmatic nucleus (SCN) is the master mammalian circadian clock. Its cell-autonomous timing mechanism, a transcriptional/translational feedback loop (TTFL), drives daily peaks of neuronal electrical activity, which in turn control circadian behavior. Intercellular signals, mediated by neuropeptides, synchronize and amplify TTFL and electrical rhythms across the circuit. SCN neurons are GABAergic, but the role of GABA in circuit-level timekeeping is unclear. How can a GABAergic circuit sustain circadian cycles of electrical activity, when such increased neuronal firing should become inhibitory to the network? To explore this paradox, we show that SCN slices expressing the GABA sensor iGABASnFR demonstrate a circadian oscillation of extracellular GABA ([GABA]e) that, counterintuitively, runs in antiphase to neuronal activity, with a prolonged peak in circadian night and a pronounced trough in circadian day. Resolving this unexpected relationship, we found that [GABA]e is regulated by GABA transporters (GATs), with uptake peaking during circadian day, hence the daytime trough and nighttime peak. This uptake is mediated by the astrocytically expressed transporter GAT3 (Slc6a11), expression of which is circadian-regulated, being elevated in daytime. Clearance of [GABA]e in circadian day facilitates neuronal firing and is necessary for circadian release of the neuropeptide vasoactive intestinal peptide, a critical regulator of TTFL and circuit-level rhythmicity. Finally, we show that genetic complementation of the astrocytic TTFL alone, in otherwise clockless SCN, is sufficient to drive [GABA]e rhythms and control network timekeeping. Thus, astrocytic clocks maintain the SCN circadian clockwork by temporally controlling GABAergic inhibition of SCN neurons.

Association of Cord Ferritin Levels with Brain Stem Evoked Response Audiometry in Newborns.

Iron is an important nutrient and it plays a pivotal role in myelin formation and neurotransmitter synthesis, thus contributing to normal neurological activity. Ferritin is a reliable indicator of the tissue iron stores and in-utero stores can be well measured by cord ferritin levels. The objective of this study was to evaluate the effects of umbilical cord ferritin levels (CFL) on the brain stem evoked response audiometry (BERA) This prospective observational study was conducted in a tertiary care centre of North India with a sample size of 100 inborn neonates. After evaluation of the umbilical cord ferritin levels the study cohort was divided into Group A( UCF<75ng/ml) and Group B(UCF>75ng/dl). All subjects were subjected to BERA. A detailed analysis of CFL and BERA was done and statistically analysed. Neonates in group B had significantly prolonged absolute peak latency of wave I, III and V and interpeak latency of wave III-V when compared to group A. The Pearson correlation also showed negative correlation of CFL with absolute peak latency of wave I, III, and V and interpeak latency of wave III-V. Among the maternal and neonatal variables, highly significant correlation was noted between absolute latency of wave I, III and V, CFL and cord hematocrit. The Pearson correlation showed negative correlation of absolute peak latency of wave I, III and V with maternal haemoglobin (Hb), neonatal birth weight, CFL,s and cord hematocrit values. A negative Pearson correlation was noted between interpeak latency of wave III-V with neonatal birth weight and cord hematocrit level, interpeak latency of wave I-V with neonatal birth weight and between interpeak latency of wave I-III with cord hematocrit values. CFL's significantly affect the absolute peak latency of wave I, III and V and it also affects the interpeak latency of wave III-V. This may be attributed to slow conduction time secondary to altered myelination. CFL's should be considered as a routine protocol in neonates to detect early compromises in the process of myelination and brain maturation.

Immunoregulatory Roles of TGF-β and IL-4 during Mouse-adapted SARS-CoV-2 Infection

Abstract Severe COVID-19 is due to a dysregulated immune response; however, the mechanisms preventing recovery of airway function are unclear. Cytokines regulate the quality of inflammation, and drive both anti-viral and disease tolerance mechanisms. There was a mostly monocytic infiltration in the lungs with alveolar thickening and consolidation 3 days post-infection with mouse-adapted SARS-CoV-2 (CMA3p20) at the peak of weight loss. Based on the cytokine profiles observed in human and animal studies, we targeted IL-4 and TGF-β as potentially regulatory cytokines, and quantified changes using flow cytometry. Neutralizing TGF-β, which regulates inflammatory cytokine production, significantly increased cellular infiltration of the lung. Neutralization of TGF-β particularly affected inflammatory monocyte (Ly6C+) recruitment, with a slight decrease in alveolar macrophages (CD11c-int). Neutralizing IL-4 prolonged weight loss to 4 dpi but visibly improved resolution of alveolar thickening on 7 dpi, suggesting that IL-4 is protecting from prolonged peak pathology, but delaying resolution. Neutralizing IL-4 also increased the fraction of polymorphonuclear cells and Tregs, as well as improving the ratio of type II to type I alveolar epithelial cells in the lungs compared to the isotype group. To begin to understand mechanisms connecting IL-4 to epithelial repair, we are studying the quality of the monocyte response and found alternatively activated macrophages with Ym1 staining in activated macrophages in the alveoli of infected mice in an IL-4 dependent manner. In order to improve therapeutics for severe COVID-19, it will be important to determine the cellular mechanisms linking regulatory cytokines to epithelial repair. R01AI135061 (RS, LPC), R01AI166668 (RR, MGO), R01AI131634 (MCS, HGF)

BS-452758-1 SUPPRESSION-REPLACEMENT GENE THERAPY REVERSE REMODELS THE INTRACELLULAR CALCIUM HANDLING DISEASE PHENOTYPE OF TNNT2-MEDIATED HYPERTROPHIC CARDIOMYOPATHY

Hypertrophic cardiomyopathy (HCM), characterized by otherwise unexplained left ventricular hypertrophy, has a prevalence of 1:500. Pathogenic variants in TNNT2-encoded cardiac troponin T causes a thin filament subtype of sarcomeric HCM. A key cellular feature of the pathological remodeling in TNNT2-mediated HCM involves dysregulation of intracellular calcium handling in ventricular cardiomyocytes (CMs). To develop a TNNT2 “suppression-replacement (SupRep)” gene therapy to reverse the intracellular calcium perturbations associated with thin filament, sarcomeric HCM using induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs) derived from a patient with TNNT2-R288P-mediated HCM. Custom-designed TNNT2 targeting shRNAs were tested for knockdown (KD) efficiency using TSA201 cells and RT-qPCR. A dual-component SupRep TNNT2 gene therapy was created by cloning into a single construct a custom-designed TNNT2 shRNA that produced greatest KD (suppression) and a “shRNA-immune” (shIMM) TNNT2 cDNA (replacement). Patient-specific TNNT2-R288P and CRISPR/Cas9 variant-corrected isogenic control (IC) iPSC-CMs were generated from a patient with HCM. The intracellular calcium indicator, Fluo-4, was used to detect intracellular free calcium. Our lead TNNT2-shRNA had an 80% KD efficiency of TNNT2. TNNT2-R288P iPSC-CMs treated with TNNT2-SupRep showed a similar KD efficiency. Compared to the IC iPSC-CMs, the TNNT2-R288P iPSC-CMs showed increased irregular events (30.4% vs. 10.9%, p<0.0001), prolonged calcium transient duration 90 (CTD90, 1.01 ± 0.03 s vs. 0.89 ± 0.02 s, p<0.0001) and prolonged peak to 90% decay time (0.57 ± 0.02 s vs. 0.49 ± 0.01 s, p=0.0012). Compared to untreated cells, transfection with TNNT2-SupRep gene therapy, the TNNT2-R288P iPSC-CMs showed a decrease in irregular events (30.4% vs. 14%, p<0.0001), shortened CTD90 (1.01 ± 0.03 s vs. 0.91 ± 0.01 s, p=0.003), and shortened peak to 90% decay time (0.57 ± 0.02 s vs. 0.50 ± 0.02 s, p=0.02). There was no significant difference in irregular events, CTD90, or peak to 90% decay time between TNNT2-R288P iPSC-CMs treated with TNNT2-SupRep and IC iPSC-CMs. Here, we provide the first proof-of-principle SupRep gene therapy for TNNT2-mediated HCM. TNNT2-SupRep gene therapy almost fully restored the impaired intracellular calcium handling properties of TNNT2-R288P patient-derived iPSC-CMs back to the normal state achieved by the CRISPR/Cas9 gene-edited cure.

Analysis of APTT Based Clot Waveform Parameters in Various Clinical Conditions – A Study at A Tertiary Care Center

Various coagulation tests like Prothrombin Time (PT) and Activated Partial Thromboplastin Time (APTT) are estimated by automated coagulation analyzers. The newer fully automated analyzers generate clot wave forms aPTT-CWA for these parameters are derived. In this study, the objective was to analyze clot wave form characteristics morphology and its first and second derivative values in cases with abnormal APTT. ACL TOP 300 generated curves for APTT in a total 125 patients with 20 normal controls are included. First derivative, second derivative, morphology of curve: sigmoid, biphasic, prolonged pre-coagulation phase, second derivative morphology like early and late shoulder, biphasic peak, delayed deceleration were the analyzed parameters. Wave clot forms of 125 patients were included in this study. Patients (M:F - 2.2:1, mean age: 46.9 ± 20 years). A spectrum of clinical conditions was Covid (20%), liver disease (23%), polytrauma (10.4%), cardiac diseases (8.8%), sepsis/DIC (7.2%), thromboembolism (7.2%), renal diseases (6.4%), bacterial infections (4%), dengue (4%), snake bite (1.6%) and factor deficiency (1.6%). Liver and heart disease showed a significant difference in acceleration and deceleration peaks followed by sepsis, dengue, polytrauma and sepsis/DIC. Deceleration peak was prolonged in patients of Covid (p&lt;0.05). Sepsis and liver diseases showed prolonged first derivative peak (p&lt;0.05). CWA is very easily available on all automated coagulation analyzers. It is inexpensive with fast turn round time. Both quantitative as well as qualitative informations such as velocity, acceleration of clot formation and wave pattern details were recorded. Our study highlights importance of quantitative and qualitative CWA parameters acquired by performing APTT test for the automated analyzers.

Neuromuscular Disorders (Neuropathy and Myopathy) Associated with Late Onset of Stills Disease (P9-5.021)

<h3>Objective:</h3> NA <h3>Background:</h3> Adult-onset Still’s disease (AOSD) is a rare inflammatory disorder characterized by a classical triad of spiking fever, arthritis, and evanescent rash. Neurological involvement in AOSD is quite infrequent with reported prevalence less than 10%. <h3>Design/Methods:</h3> 52-year-old male with medical history of AOSD, obstructive sleep apnea and bipolar disorder presented to neurology clinic for muscle fatigue and weakness. Patient was diagnosed with AOSD based on Yamaguchi criteria. <h3>Results:</h3> Physical examination was notable for reduced sensation to light touch and pinprick in four toes bilaterally excluding 5th toe. Normal muscle tone, strength, and reflexes were noted. Cranial nerve examination was normal. Extended myositis panel was negative. Patient underwent MRI of the pelvis which showed mild to moderate myositis to the gluteal muscles and anterior compartments in bilateral thighs. Patient underwent EMG which demonstrated mildly prolonged peak latency with normal amplitude in sensory nerve action potential (SNAP) in right median nerve. Mildly slowed conduction velocity with normal distal latency and normal amplitude was also noted on compound muscle action potential (CMAP) in right median nerve. EMG of right lower extremity demonstrated increased recruitment of small amplitude short duration polyphasic MUAPs observed in the vastus lateralis and tibialis anterior muscles. The EMG findings were consistent with non-irritable myopathy. Given rest of the myositis work up was unremarkable, the presentation was likely related to neurological manifestations of ASOD. Patient was continued on prednisone ands weekly Tocilizumab. <h3>Conclusions:</h3> AOSD is a rare disorder pathophysiology for which is not completely understood. Neurological manifestation in AOSD have been reported occasionally including aseptic meningitis, cranial nerve palsy, encephalitis, and cerebral infarction. Case report of Parkinsonian symptoms associated with AOSD have also been reported. We here report myositis during the course of AOSD which has not been previously reported and hope to enhance information regarding the spectrum of neurological involvement in AOSD <b>Disclosure:</b> Dr. Khosa has nothing to disclose. Dr. Khosa has nothing to disclose. Dr. Mishra has nothing to disclose. Dr. Trikamji has nothing to disclose. Dr. Freundlich has nothing to disclose.

Role of 3 Tesla Magnetic Resonance Imaging in the Assessment of Infiltrative Cardiomyopathies.

The aim of the present study was to assess the role of 3 Tesla (3T) magnetic resonance imaging (MRI) in the assessment of infiltrative cardiomyopathy (ICM). Cardiac MRI was performed on a 3T MRI machine for 15 patients who had clinical or echocardiographic signs of infiltrative cardiomyopathy. Each scan was assessed on a set of anatomical and functional parameters. The patterns of left ventricular (LV) late gadolinium enhancement (LGE) were also analyzed. Bi-atrial dilatation was noted in 14 patients, consistent with a restrictive phenotype. All 15 patients had diastolic dysfunction with reduced LV diastolic ventricular filling and prolonged peak filling times. Eleven patients had a decreased peak filling rate. Twelve patients had systolic dysfunction with reduced ejection fraction (EF). Ten patients had contractile dysfunction in the form of global LVhypokinesia. On delayed contrast imaging, four patients showed no abnormal LGE. Two patients showed diffuse subendocardial enhancement. Two patients showed patchy subendocardial enhancement. Six patients showed patchy mid-myocardial enhancement. One patient showed diffuse mid-myocardial enhancement. Three patients showed patchy subepicardial enhancement. Two patients showed patchy transmural enhancement. Three patients showed reversed myocardial nulling. All 15 patients received a provisional diagnosis of infiltrative cardiomyopathy on the basis of cardiac MRI findings. Sarcoidosis was given as a probable cause in four patients, amyloidosis in three patients, an infectious cause in two patients, and drug-induced cardiomyopathy in one patient. In five patients, no obvious cause could be identified. Infiltrative cardiomyopathies, although relatively uncommon, pose significant challenges in diagnosis and treatment. Cardiac MRI has become the gold standard for non-invasive diagnosis of all infiltrative cardiomyopathies.

Visual pathway function in untreated individuals with major depression.

Major depression (MD) is the one of the most debilitating diseases, affecting millions of people all around the world. To establish visual pathway function in untreated individuals with MD. In 29 untreated, newly diagnosed, ophthalmologically asymptomatic individuals (58 eyes) with MD (mean age: 47.3 years) and in 29 (58 eyes) of age-, sexand refractive error-matched healthy controls (mean age: 46.8 years), the following examinations were performed: 1) best corrected distance visual acuity (BCDVA); 2) intraocular pressure (IOP); 3) and 4) biomicroscopy of anterior and posterior segment of eye; 5) macular structure (SD-OCT-Zeiss); and 6) pattern visual evoked potentials (PVEPs) measurements according to the International Society for Clinical Electrophysiology of Vision (ISCEV) standard (ISCEV-standard PVEPs). An analysis of correlation between the parameters of PVEPs and the depression severity (Hamilton Depression Rating Scale (HAMD)) was performed. To estimate the diagnostic power of PVEPs test, a receiver operating characteristics (ROC) curve was used. Data were analyzed with the significance level of p < 0.05. In the study group and in healthy control, the clinical results and macular structure were normal and not different. In the MD group, in PVEPs test (check size: 1°4'and 0°16'), a significant decrease of amplitudes of P100 (AP100), associated with prolonged P100 peak time (PTP100; check size: 0°16', p < 0.004) were detected. The most frequent abnormality in PVEPs examination in the MD group was AP100 reduction (in 69% of individuals) detected using stimulation check size 0°16'. The statistically significant positive correlation between PTP100 (check size: 0°16') and HAMD score was found in severe MD (p = 0.03). The analysis of ROC curve revealed the highest sensitivity of 0.759 and specificity of 1.0 for AP100 (0°16'). The area under the curve (AUC) was 0.841 (p < 0.001). In individuals with newly diagnosed, ophthalmologically asymptomatic and untreated MD, a dysfunction of visual pathway is present without other signs of ocular pathology. The visual pathway dysfunction measured with ISCEV PVEPs has a potential value to be an objective biomarker of MD.

Different visual evoked potentials in neuromyelitis optica spectrum disorder-related optic neuritis and idiopathic demyelinating optic neuritis: a prospective longitudinal analysis

BackgroundTo investigate different visual evoked potential (VEP) patterns in neuromyelitis optica spectrum disorder-related optic neuritis (NMOSD-ON) and idiopathic demyelinating optic neuritis (IDON).MethodsThis was a longitudinal, prospective, case-control study. Eighty-four Chinese patients with acute optic neuritis were enrolled, including 26 NMOSD-ON patients and 58 IDON patients. All the patients underwent best-corrected visual acuity (BCVA) and full-field pattern reversal VEP recordings at the onset, 1 month, 3 months, and 6 months.ResultsWithin 15′ checks, the NMOSD-ON patients had more severe VEP amplitude reduction at 6 months (2.39 ± 4.63 μV vs. 6.96 ± 8.88 μV, P = 0.034). However, the IDON patients showed more frequently normal VEP response at 3 months (24.0% vs. 4.5%, P = 0.017), and only prolonged P100 peak latency with normal amplitude (L) at 6 months (30.0% vs. 57.8%, P = 0.048). Within 60′ checks, no significant difference in VEP parameters between the two groups was found at each follow-up (P > 0.05). ConclusionsThe NMOSD-ON patients showed more severe axonal damage and worse axonal recovery than the IDON patients. VEP elicited by smaller check size was more sensitive to visual pathway abnormality in NMOSD-ON.

273TiP ACE-Breast-03: A phase II study patients with HER2-positive metastatic breast cancer whose disease is resistant or refractory to T-DM1, and/or T-DXd, and/or tucatinib-containing regimens treated with ARX788

The HER2 receptor is an oncogenic driver that is overexpressed on 15-20% of breast cancers. HER2+ targeted therapy has improved survival in both early and advanced disease, but new treatments are needed for recurrent and refractory disease. ARX788 is a next-generation ADC using a HER2-specific monoclonal antibody conjugated with Amberstatin269, a potent cytotoxic tubulin inhibitor (DAR=2). Site-specific, highly homogenous, and stable covalent conjugation leads to slow release and prolonged peak of serum pAF-AS269, with lower systemic toxicity, increased targeted delivery, and lower effective dose.

HPLC-MS/MS analysis of primary alkaloids in rat plasma after oral administration of “Nux vomica - Glycyrrhiza glabra decoction”: A pharmacokinetic study

Ethnopharmacological relevanceDecoction is the most common form of administering traditional Chinese medicine (TCM). During the preparation of decoction, the high temperature and complex chemical environment result in the formation of complex and multiple phases. The differences in drug components in different phases induce gastrointestinal absorption and physiological response. Nux vomica (Strychnos nux-vomica L) is a typical toxic TCM used in China, with remarkable pharmacological activity. In order to reduce its toxicity, nux vomica (NV) is often decocted with Glycyrrhiza glabra (GG) in clinic, and the detoxification mechanism has always been the focus of research interest. Most studies investigated the compatibility of NV-GG, but the in vivo behavior of individual constituents based on phase state has yet to be elucidated. Aim of the studyTo investigate the pharmacokinetic behavior of typical toxic components in different phase states of “NV-GG decoction” in rat plasma. Materials and methodsThe sediment, suspension, colloid and true solution of “NV-GG decoction” was obtained via physical methods. The main components in different phase states were analyzed via reliable UFLC-Q-TOF-MS high-resolution mass spectrometry. A rapid and accurate HPLC-qqq-MS/MS method was established and validated for accurate determination of brucine and strychnine levels in plasma, followed by pharmacokinetic evaluation of different phase states of “NV-GG decoction” in rats. Kinetex F5 100A (50 mm × 3.0 mm, 2.6 μm) column was used for chromatographic separation. Aqueous solution containing acetonitrile and 0.1% formic acid was used as the mobile phase, followed by gradient elution at 0.4 mL/min. Mass spectra were detected by electrospray ionization (ESI) multiple reaction monitoring (MRM) in positive ion mode. ResultsFifteen different alkaloids were detected in different phase states of “NV-GG decoction”. Strychnine and brucine, which are toxic components with high content, were selected for quantitative analysis. The established UPLC-qqq-MS/MS method is accurate and reliable with a good linearity (R2 > 0.99) in the respective concentration range, satisfying the quantitative requirements. The pharmacokinetic parameters of different phase states of rats differed significantly after gavage. The deposition phase was the most prominent. The index components showed higher Cmax, AUC0 and Tmax, while the T1/2, MRT, V/F and CL/F were the smallest, with a relatively slow plasma clearance rate in rats. The true solution group showed the lowest Tmax and the fastest absorption. ConclusionThis method has been successfully utilized to study the pharmacokinetics of different phase states of “NV-GG decoction”. Among the four phases, the deposition phase contributed to a large proportion of the in vivo kinetic behavior similar to that of sustained-release preparations, with slow absorption of toxic components and prolonged peak time. The pharmacokinetic parameters and plasma concentration-time curves of each phase can be used to study toxicity reduction of NV-GG and increase its biocompatibility.

Targeting HER2-positive metastatic breast cancer with ARX788, a novel anti-HER2 antibody-drug conjugate in patients whose disease is resistant or refractory to T-DM1, and/or T-DXd, and/or tucatinib-containing regimens.

TPS1112 Background: The overexpression and/or amplification of human epidermal growth factor receptor 2 (HER2) occurs in approximately 20% of breast cancers (BC) and is a major driver of tumor development and progression. This HER2 subtype confers aggressive tumor behavior and the HER2 receptor remains a valuable target for antibodies, bi-specifics, and antibody drug conjugates (ADC). With advances in targeted therapy, patients with HER2-positive breast cancer (HER2+ BC) may experience an improved prognosis, including survival. Novel HER2-targeted therapies are being investigated to overcome drug resistance and to help mitigate adverse events (e.g., cardiotoxicity). ARX788 is a next-generation ADC using a technology platform whereby a HER2 specific monoclonal antibody is conjugated with Amberstatin269 (AS269), a potent cytotoxic tubulin inhibitor. Site-specificity, high homogeneity, and stable covalent conjugation of ARX788 leads to its slow release and prolonged peak of serum pAF-AS269, which may contribute to the lower systemic toxicity and increased targeted delivery of payload to tumor cells at a lower effective dose compared to other HER2 ADCs. Clinical activity has been seen in Phase I HER2 breast and pan-tumor studies. Methods: Trial Design: ACE-Breast-03 (NCT04829604) is a global, phase 2 study designed to assess anticancer activity and safety of ARX788 in patients with metastatic HER2 positive breast cancer. Patients whose disease is resistant or refractory to T-DM1, and/or T-DXd, and/or tucatinib-containing regimens are eligible. Patients must have adequate organ function. Any brain metastases must be radiographically stable without steroid dependence. Efficacy will be assessed using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 by imaging every 6 weeks on study. Endpoints include objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), best overall response (BOR), duration of response (DOR), and time to response (TTR). The safety and tolerability profile will be evaluated. Blood samples will be collected at specified time points to determine serum concentrations of ARX788, total antibody, and metabolite pAF-AS269. Potential predictive and/or prognostic biomarkers at baseline and on-treatment will be analyzed for exploratory purposes. Descriptive statistics will be used to evaluate anticancer activity, safety, and tolerability. The study is currently recruiting patients. Please contact breast03trialinquiry@ambrx.com for additional information. Clinical trial information: NCT04829604.