Citations

Abstract ONC201, a bitopic DRD2 antagonist and allosteric ClpP agonist, has shown encouraging efficacy in H3 K27M-mutant glioma. Given that the thalamus has the highest extra-striatal expression of DRD2, we performed an integrated preclinical and clinical analysis of ONC201 in thalamic H3 K27M-mutant glioma. ONC201 was effective in mouse intra-uterine electroporation (IUE)-generated H3 K27M-mutant gliomas, with an in vitro IC50 of 500 nM and 50% prolongation of median survival in vivo (p=0.02, n=14). We analyzed thalamic H3 K27M-mutant glioma patients treated with ONC201 on active clinical trials as of 5/22/19 enrollment (n=19 recurrent and 10 post-radiation, non-recurrent; 5–70 years old). As of 12/18/2019, PFS6 and OS12 are 26.3% and 36.8%, respectively, in the recurrent group. For non-recurrent patients, with median follow up of 21.9 months (8.6–26.6) from diagnosis, median PFS or OS have not been reached. This surpasses historical OS of 13.5 months. Best response by RANO includes 1 CR, 3 PR, 4 SD, 8 PD for recurrent patients and 2 PR, 4 SD, 1 PD for non-recurrent patients (4 on-trial patients experienced regressions that are yet unconfirmed responses). Median duration of response for recurrent patients is 14.0 months (2.0–33.1). Furthermore, H3 K27M cell-free tumor DNA in plasma and CSF correlated with MRI response. In summary, single agent ONC201 administered at recurrence, or adjuvantly following radiation, demonstrates promising clinical efficacy in thalamic H3 K27M-mutant glioma patients who currently have no effective treatments following radiation. Investigations are ongoing to assess whether micro-environmental DRD2 expression explains the early exceptional responses in thalamic H3 K27M-mutant glioma.

Abstract BACKGROUND Intravenous (IV) alteplase with mechanical thrombectomy has been found to be superior to alteplase alone in select patients with intracranial large vessel occlusion. Current guidelines discourage the use of antiplatelet agents or heparin for 24 h following alteplase. However, their use is often necessary in certain circumstances during thrombectomy procedures. OBJECTIVE To study the safety and outcomes in patients who received blood thinning medications for thrombectomy after IV Tissue-Type plasminogen activator (tPA). METHODS This is a multicenter retrospective review of the use of antiplatelet agents and/or heparin in patients within 24 h following tPA administration. Patient demographics, comorbidities, bleeding complications, and discharge outcomes were collected. RESULTS A series of 88 patients at 9 centers received antiplatelet medications and/or heparin anticoagulation following IV alteplase for revascularization procedures requiring stenting. The mean National Institutes of Health Stroke Scale (NIHSS) on admission was 14.6. Reasons for use of a stent included internal carotid artery occlusion in 74% of patients. Thrombolysis in cerebral infarction (TICI) 2b-3 revascularization was accomplished in 90% of patients. The rate of symptomatic intracranial hemorrhage (sICH) was 8%; this was not significantly different than the sICH rate for a matched group of patients not receiving antiplatelets or heparin during the same time frame. Functional independence at 90 d (modified Rankin Scale 0-2) was seen in 57.8% of patients. All-cause mortality was 12%. CONCLUSION The use of antiplatelet agents and heparin for stroke interventions following IV alteplase appears to be safe without significant increased risk of hemorrhagic complications in this group of patients when compared to control data and randomized controlled trials.

Introduction: While valve-sparing repair is ideal for Tetralogy of Fallot (TOF), it’s durability and which patients may benefit from a transannular patch remains unclear. To this end, we reviewed our experience with valve-sparing TOF repair. Methods: Retrospective review was performed of all primary TOF operations at our institution from 1/2008 to 12/2018. Standard demographic, operative, and echo data were collected, along with clinical outcomes. Transannular patch and valve-sparing repair groups were then compared. Results: Sixty-eight patients underwent TOF repair with a mean age of 4.1±2.2 months and weight of 5.7±1.8 kg. There was no difference in age or weight between patients who underwent a transannular patch repair and valve-sparing repair (Table). There was also no difference in the frequency of hypercyanotic spells or beta-blocker use. As expected the pre-operative pulmonary valve size and z-score were significantly different between groups. Bypass times were longer in the transannular patch group (176±40 vs. 144±40 minutes, p=0.005). There were no differences in post-operative complications. At last follow-up (median 41.5 months) there was a trend of a higher peak pulmonary valve gradient (p=0.07) in the valve-sparing group, but no difference in pulmonary valve annulus z-scores. Additionally, the pulmonary valve z-scores in the valve-sparing group decreased from -2.3±1.0 on pre-discharge echocardiogram to -1.2±1.6 on last follow-up, with the peak gradient on pre-discharge 20 (33) mmHg stable on last follow-up at 18 (29) mmHg and degree of pulmonary regurgitation stable. There was one reoperation in the cohort: a pulmonary valve replacement in a patient who had undergone a transannular patch repair 6 years prior. Conclusions: Valve-sparing TOF patients demonstrated stable repairs with pulmonary valve growth, acceptable gradients, minimal regurgitation, and high freedom from re-intervention during follow-up.

Abstract Purpose: Pediatric high-grade glioma (pHGG) diagnosis portends poor prognosis and therapeutic monitoring remains difficult. Tumors release cell-free tumor DNA (cf-tDNA) into cerebrospinal fluid (CSF), allowing for potential detection of tumor-associated mutations by CSF sampling. We hypothesized that direct, electronic analysis of cf-tDNA with a handheld platform (Oxford Nanopore MinION) could quantify patient-specific CSF cf-tDNA variant allele fraction (VAF) with improved speed and limit of detection compared with established methods. Experimental Design: We performed ultra-short fragment (100–200 bp) PCR amplification of cf-tDNA for clinically actionable alterations in CSF and tumor samples from patients with pHGG (n = 12) alongside nontumor CSF (n = 6). PCR products underwent rapid amplicon-based sequencing by Oxford Nanopore Technology (Nanopore) with quantification of VAF. Additional comparison to next-generation sequencing (NGS) and droplet digital PCR (ddPCR) was performed. Results: Nanopore demonstrated 85% sensitivity and 100% specificity in CSF samples (n = 127 replicates) with 0.1 femtomole DNA limit of detection and 12-hour results, all of which compared favorably with NGS. Multiplexed analysis provided concurrent analysis of H3.3A (H3F3A) and H3C2 (HIST1H3B) mutations in a nonbiopsied patient and results were confirmed by ddPCR. Serial CSF cf-tDNA sequencing by Nanopore demonstrated correlation of radiological response on a clinical trial, with one patient showing dramatic multi-gene molecular response that predicted long-term clinical response. Conclusions: Nanopore sequencing of ultra-short pHGG CSF cf-tDNA fragments is feasible, efficient, and sensitive with low-input samples thus overcoming many of the barriers restricting wider use of CSF cf-tDNA diagnosis and monitoring in this patient population.

Abstract The American Thoracic Society Core Curriculum updates clinicians annually in adult and pediatric pulmonary disease, medical critical care, and sleep medicine, in a 3- to 4-year recurring cycle of topics. These topics will be presented at the 2020 International Conference. Below is the adult critical care medicine core including complications of chemotherapy, acute-on-chronic liver failure, alcohol withdrawal syndrome, mechanical circulatory support, direct oral anticoagulants, upper gastrointestinal hemorrhage, and vasopressor selection.

AbstractBackgroundEligibility criteria and endpoints for cancer cachexia trials—and whether weight loss should be included—remain controversial. Although most cachexia trials enrol patients after initial cancer diagnosis, few studies have addressed whether weight loss well after a cancer diagnosis is prognostic.MethodsWe pooled data from non‐small cell lung cancer patients from prospectively conducted trials within the Alliance for Clinical Trials in Oncology (1998–2008), a nationally funded infrastructure. We examined (i) weight data availability and weight changes and (ii) survival.ResultsA total of 822 patients were examined. Of these, 659 (80%) were on treatment at the beginning of Cycle 2 of chemotherapy; weight was available for 656 (80%). By Cycles 3 and 4, weight was available for 448 (55%) and 384 (47%), respectively. From baseline to immediately prior to Cycle 2, 208 (32%) gained weight; 225 (34%) lost <2% of baseline weight; and 223 (34% of 656) lost 2% or more. Median survival from the beginning of Cycle 2 was 13.0, 10.9, and 6.9 months for patients with weight gain, weight loss of <2%, and weight loss of 2% or more, respectively. In multivariate analyses, adjusted for age, sex, performance score, type of treatment, and body mass index, weight loss of 2% or more was associated with poor overall survival compared with weight gain [hazard ratio (HR) = 1.66; 95% confidence interval (CI): 1.33–2.07; P < 0.001] and compared with weight loss of <2% (HR = 1.57; 95% CI: 1.27–1.95; P < 0.001). Although weight loss of <2% was not associated with poorer overall survival compared with weight gain, it was associated with poorer progression‐free survival (HR = 1.24; 95% CI: 1.01–1.51; P = 0.036). Similar findings were observed in a separate 255‐patient validation cohort.ConclusionsWeight should be integrated into cancer cachexia trials because of its ease of frequent measurement and sustained prognostic association.

Abstract Asparagine‐linked glycosylation 13 homolog ( ALG13 ) encodes a nonredundant, highly conserved, X‐linked uridine diphosphate (UDP)‐ N ‐acetylglucosaminyltransferase required for the synthesis of lipid linked oligosaccharide precursor and proper N‐linked glycosylation. De novo variants in ALG13 underlie a form of early infantile epileptic encephalopathy known as EIEE36, but given its essential role in glycosylation, it is also considered a congenital disorder of glycosylation (CDG), ALG13‐CDG. Twenty‐four previously reported ALG13‐CDG cases had de novo variants, but surprisingly, unlike most forms of CDG, ALG13‐CDG did not show the anticipated glycosylation defects, typically detected by altered transferrin glycosylation. Structural homology modeling of two recurrent de novo variants, p.A81T and p.N107S, suggests both are likely to impact the function of ALG13. Using a corresponding ALG13‐deficient yeast strain, we show that expressing yeast ALG13 with either of the highly conserved hotspot variants rescues the observed growth defect, but not its glycosylation abnormality. We present molecular and clinical data on 29 previously unreported individuals with de novo variants in ALG13 . This more than doubles the number of known cases. A key finding is that a vast majority of the individuals presents with West syndrome, a feature shared with other CDG types. Among these, the initial epileptic spasms best responded to adrenocorticotropic hormone or prednisolone, while clobazam and felbamate showed promise for continued epilepsy treatment. A ketogenic diet seems to play an important role in the treatment of these individuals.

e24086 Background: Nasal vestibulitis has been infrequently described as a side effect of cancer-directed therapy; however, a preliminary study reported that 71% of patients undergoing taxane chemotherapy experienced nasal vestibulitis symptoms. This natural history trial describes the incidence, characteristics, and severity of nasal vestibulitis symptoms among patients undergoing paclitaxel, docetaxel, and non-taxane chemotherapy. Methods: Eligible participants who reported baseline (prior to starting chemotherapy) nasal symptoms ≤ 2 on a 10-point scale were enrolled in this trial upon initiation of a new treatment regimen, involving paclitaxel or docetaxel, or non-taxane chemotherapy. Participants completed nasal symptom logs each time they received a dose of therapy until either the regimen was stopped or four months had passed. The proportion of patients reporting new nasal symptoms was estimated within each cohort with the 95% exact confidence interval (CI). A cumulative incidence model was utilized to quantify the incidence of treatment-emergent nasal symptoms within each cohort, while controlling for age, sex, smoking history, and history of asthma or allergies. Results: Thirty-five participants received paclitaxel, 21 received docetaxel, and 25 received other types of chemotherapy. 86.4% of participants were female, mean age was 60.2 ± 11.2 years; 93.8% of participants completed 2 or more surveys. A higher percentage of participants in the paclitaxel cohort experienced new nasal vestibulitis symptoms than participants in the other two cohorts. The percentage (95% CI) of participants with nasal symptoms, for patients receiving paclitaxel, docetaxel, and non-taxane chemotherapy were 74.3% (56.7%, 87.5%), 47.6% (25.7%, 70.2%), and 44.0% (24.4%, 65.1%), respectively. Epistaxis was reported by 60% of participants in the paclitaxel cohort. Paclitaxel-receiving participants also reported nasal dryness (48.6%), scabbing (40.0%), and pain (20.0%). Nearly half of participants reported moderate symptoms (4-7 out of a 10-point scale), with 8.6% reporting symptoms as severe (8-10 on a 10-point scale). Conclusions: Nasal vestibulitis is a common side effect of chemotherapy, especially paclitaxel chemotherapy.