Citations

AbstractObjectiveInfants with focal‐onset epilepsy are an understudied population, requiring additional evaluation for clinical assessment and prognostication. Our goal was to characterize the etiology and natural history of infantile‐onset focal epilepsy.MethodsWe retrospectively identified all infants (0–24 months) with onset of focal epilepsy while resident in Olmsted County, Minnesota, between 1980 and 2018, using the Rochester Epidemiology Project Database. We assessed the impact of etiology on both seizure and neurodevelopmental outcome, and mortality.ResultsOf 686 children with epilepsy onset <18 years, 125 (18.2%) presented with focal‐onset seizures in infancy. Median follow‐up for this group was 10.9 years (interquartile range [IQR] 6.2, 19.3). Etiology was identified in 65.6% (structural N = 62, genetic N = 13, both structural and genetic N = 3, metabolic N = 4). Of 107 patients followed >2 years, 38 (35.5%) developed drug‐resistant epilepsy (DRE). DRE was more likely with younger age at onset, known etiology, and presence of epileptic spasms. Sixty‐eight (63.0% of those with follow‐up) were developmentally delayed at last follow‐up, and known etiology, DRE, and presence of epileptic spasms were significantly associated with delay (p < .001 for all). Fifteen patients (12.0%) died at a median age of 7.1 years (IQR 1.7, 21.7), but only one death was seizure related (suspected sudden unexpected death in epilepsy [SUDEP]). Of 20 infants with normal development at onset and no known etiology with >2 years follow‐up, none developed DRE, all were seizure‐free at last follow‐up (95% off antiseizure medications [ASMs]), and all remained developmentally normal.SignificanceInfantile‐onset focal epilepsy accounts for 18% of all epilepsy in childhood, is frequently due to known etiologies, and has a high rate of DRE. However, developmentally normal infants without a known cause appear to have a very favorable course.

The NCCN Guidelines for Kidney Cancer focus on the screening, diagnosis, staging, treatment, and management of renal cell carcinoma (RCC). Patients with relapsed or stage IV RCC typically undergo surgery and/or receive systemic therapy. Tumor histology and risk stratification of patients is important in therapy selection. The NCCN Guidelines for Kidney Cancer stratify treatment recommendations by histology; recommendations for first-line treatment of ccRCC are also stratified by risk group. To further guide management of advanced RCC, the NCCN Kidney Cancer Panel has categorized all systemic kidney cancer therapy regimens as “Preferred,” “Other Recommended Regimens,” or “Useful in Certain Circumstances.” This categorization provides guidance on treatment selection by considering the efficacy, safety, evidence, and other factors that play a role in treatment selection. These factors include pre-existing comorbidities, nature of the disease, and in some cases consideration of access to agents. This article summarizes surgical and systemic therapy recommendations for patients with relapsed or stage IV RCC.

663 Background: GI malignancies continue to be a major cause of cancer related deaths, despite advances in therapy options. In pancreatic cancer, the presence of homologous recombination mutations (HRM) has been shown to confer increased sensitivity to platinum chemotherapy. However, the role of HRM mutations in other GI cancers remains to be determined. The focus of this study is to evaluate the prognostic nature of core and noncore HRM in nonpancreatic GI cancers. Additionally, we aim to understand the predictive nature of these mutations related to platinum exposure. Methods: This was a retrospective review of patients at Moffitt Cancer Center with a primary stage IV nonpancreatic GI cancer treated with platinum therapy. All patients had next generation sequencing and were in the Clinical Genomics Action Committee database between 1/1/2013 and 11/1/2020. All patients had either a core HRM (BRCA1, BRCA2, PALB2) or noncore HRM (such as ATM, ATR, BARD1, BRIP1, FANCA, NBN, and RAD51). Patients were grouped into core HRM vs. noncore HRM. Response was stratified between responders (complete response and partial response) vs. non responders (stable disease and progressive disease), based on RECIST criteria. Progression free survival and overall survival were estimated using Kaplan-Meier method, and the log-rank test was used to assess the difference in progression free survival (PFS) and overall survival (OS) by HRM status and type of platinum therapy used. Results: There were 72 patients included in the study: the majority of patients were male (65.3%) and Caucasian (87.5%). Twenty-one (29.2%) patients had a core HRM and 51 (70.8%) had a noncore HRM. There was no significant difference in response rate between patients with core HRM and patients with noncore HRM for evaluable patients (n = 66): 20.0% of patients with core HRM vs. 21.7% of patients with noncore HRM demonstrated a response to platinum therapy (p = 0.41). An improved OS was noted for patients with core HRM vs. those with noncore HRM at 68.9 vs. 24.3 months (p = 0.019). An improved PFS was also seen in patients with core HRM at 10.4 months vs. 6.3 months with noncore HRM (p = 0.027). There was no difference in PFS based on type of platinum therapy used (oxaliplatin vs. carboplatin vs. cisplatin), while an improved OS was noted for patients treated with oxaliplatin vs. carboplatin vs. cisplatin at 43.1 vs. 28.2 vs. 16.0 months (p = 0.011). Conclusions: Our study demonstrated that in stage IV nonpancreatic GI malignancies treated with platinum therapy, patients with core HRM had a greater OS and PFS compared to those with noncore HRM, suggesting a potential prognostic and predictive role of these mutations. Further studies are needed to confirm our findings.

260 Background: dysphagia (dys) palliation in non-operable esophageal cancer (EC) continues to be a challenge. While chemotherapy and radiation help with dys, many patients require endoscopic interventions during their illness. Self-expanding metal stents have been the mainstay of endoscopic interventions but have a significant risk of severe adverse events and prevent the patient from being able to lie flat without severe reflux. Cryotherapy (cryo) is an emerging technique that can be used while the patient is receiving systemic therapy (ST). Previous retrospective studies showed improvement in dys with a favorable adverse event profile but did not report on quality of life (QOL) or reflux symptoms in patients receiving ST. Prospective studies have shown modest improvement in dys and QOL in patients not receiving ST. This prospective study reports the outcomes of cryo including dys, QOL, reflux symptoms and adverse events (AE) in patients receiving ST. Methods: A prospective multicenter cohort study of 35 adult inoperable EC patients undergoing cryo from Sep 2017 to Aug 2021. QoL was assessed using a modified EORTC QLQ-OES18 questionnaire (score 18 to 72, higher scores indicating worse QoL) while dys was measured using a 4-point Likert scale (0, no Dys; 1, Dys to solids; 2, Dys to semi-solids; 3, Dys to liquids; 4, Dys to saliva) at the start of cyro and 1-2 weeks post cryo. Paired t-test was used to evaluate changes in QoL and Dys between pre- and post-cryo. Results: There were 29 males and 6 females (30 stage IV and 5 stage III at diagnosis). Among 35 patients, a total of 104 cryo procedures were performed, with a mean of 3 per patient. The median number of tumor sites treated per cryo was 2 while the median number of cryo cycles delivered per tumor site was 3. The median total freeze time per tumor site was 60 seconds. The mean QoL score improved significantly from 31.8 pre-cryo to 28.2 with one cryo session (improvement of 3.6 points; p < 0.001). The mean dysphagia score improved significantly from 1.42 to 1.05 per cryo session (improvement of 0.37 points; p = 0.002). The mean After a mean of 3 cryo sessions, QoL score improved significantly from 35.9 pre-cryo to 29.8 post-cryo (improvement of 6 points; p = 0.001) and the mean dysphagia score improved significantly from 1.97 pre-cryo to 1.25 post-cryo (improvement of 0.72 points; p = 0.004). 86.5% of patient were able to sleep lying flat without heartburn or regurgitation. 6 patients received another intervention (1 stenting, 3 radiation and 2 dilation) for Dys palliation. 8 patients underwent feeding tube placement. Cryotherapy related grade 3 or higher adverse events occurred after 3 cryo sessions. Conclusions: Cryotherapy for palliation in non operable esophageal cancer improved dysphagia and quality of life without causing reflux and had a favorable adverse event profile with most patients not needing another intervention for dysphagia palliation.

174 Background: Colorectal cancer (CRC), while one of the most common cancer diagnoses, can behave heterogeneously based on molecular characteristics. A subset of patients (pts) with CRC are characterized with mismatch repair deficiency (MMR-d), these pts exhibit encouraging responses to immunotherapy. The predictive nature of various factors, such as BRAF status, age, and MMR-D protein loss type, have been investigated in pts with MMR-d CRC. However, the prognostic role of these factors has not been well established. The purpose of this study was to identify characteristics that influence survival in MMR-d mCRC. Methods: This study evaluated pts with MMR-d mCRC in the Flatiron database. Overall survival (OS) was determined from date of diagnosis of stage IV disease to date of death and stratified based on age greater than or less than 50 years, BRAF mutation status, RAS mutation status, and type of MMR gene loss. For statistical analysis, the Chi-Square test was implemented to determine the prognostic significance of clinical and molecular features. Univariate and multivariate analyses were determined through the Cox regression model. Results: There were 1,101 pts in the study. The majority of pts were older than 50 (79.7%), Caucasian (75%), and had ECOG 0-1 (83.4%). Among the 803 pts with known BRAF status, 44.3% (n=356) had BRAF V600E mutation and 55.7% (n=447) were BRAF wildtype. Pts with BRAF V600E mutation had OS of 18.9 months vs. 33.2 months for pts with wild type BRAF (HR 1.52, 95% CI: 1.25-1.86, p<0.001). Pts older than 50 had a lower median OS vs. those who were ≤50 at 21.4 months vs. 38.7 months (HR 1.66, 95% CI: 1.33-2.07, p<0.001). When comparing MSH2/MSH6 mutations to MLH1/PMS2, a trend towards improved OS was seen with median survival of 35.2 months vs. 22.7 months, respectively (HR 0.79, 95% CI: 0.61-1.02, p=0.067). On multivariate analysis, BRAF mutation and older age continued to be associated with differences in survival, while KRAS mutation and specific MMR gene loss did not. Conclusions: BRAF V600E mutation and age greater than 50 are associated with decreased survival for pts with MMR-D mCRC. KRAS mutations and specific MMR alterations are not associated with differences in survival.

Abstract Patients with metastatic breast cancer (MBC) typically have short survival times and their successful treatment represents one of most challenging aspects of patient care. This poor prognostic behavior is in part due to molecular features including increased tumor cell clonal heterogeneity, multiple drug resistance mechanisms, and alterations of the tumor microenvironment. The AURORA US Metastasis Project was established with the goal to identify molecular features specifically associated with metastasis. We therefore collected and molecularly characterized specimens from 55 metastatic breast cancer (BC) patients representing 51 primary cancers and 102 metastases. The 153 unique tumors were assayed using RNAseq, tumor/germline DNA exomes and low pass whole genome sequencing, and global DNA methylation microarrays. We found intrinsic molecular subtype differences between primary tumors and their matched metastases to be rare in triple negative breast cancer (TNBC)/Basal-like subtype tumors. Conversely, tumor subtype changes were relatively frequent in estrogen receptor positive (ER+) cancers where ~30% of Luminal A cases switched to Luminal B or HER2-enriched (HER2E) subtypes. Clonal evolution studies identified changes in expression subtype coincident with DNA clonality shifts, especially involving HER2 amplification and/or the HER2E expression subtype. We further found evidence for ER-mediated downregulation of genes involved in cell-cell adhesion in metastases. Microenvironment differences varied according to tumor subtype where ER+/Luminal metastases had lower fibroblast and endothelial cell content, while TNBC/Basal-like metastases showed a dramatic decrease in B cells and T cells. In 17% of metastatic tumors, we identified DNA hypermethylation and/or focal DNA deletions near HLA-A that were associated with its’ significantly reduced expression, and with lower immune cell infiltrates. We also identified low immune cell features in brain and liver metastases when compared to other metastatic sites, even within the same patient. These findings have direct implications for the treatment of metastatic breast cancer patients with immune- and HER2-targeting therapies and suggest potential novel therapeutic avenues for the improvement of outcomes for some patients with MBC.

Introduction This study was designed to assess current recommendations from child neurologists and epileptologists on masking for school-age children with epilepsy. Methods A 7-item survey was created and sent out to members of the Child Neurology Society and Pediatric Epilepsy Research Consortium in August of 2021 to assess current practice and provider recommendations on masking. Results One hundred four individuals participated with representation from all regions of the United States. Masking was recommended by 95.1%, with 63.4% (n = 66) noting exception of those with severe intellectual disability, autism, and behavioral problems. Of those who write exemption letters, 54% write these <5% of the time. Only 3% reported potential adverse events associated with masking. Conclusion Nearly all respondents recommended masking for school-age children with epilepsy. Potential risks of masking and adverse events were low. Improved guidance on masking is needed to ensure academic success of our patients with epilepsy.

Background: The use of evidence-based therapies to treat cardiovascular comorbidities and risk factors in patients with AF in outpatient clinical practice has not been well characterized. Methods: Using a large, community-based registry of patients with AF in the United States, the prevalence of cardiovascular comorbidities and corresponding use of evidence-based therapies were determined. Results: Among 9,589 enrolled patients with AF, the median age was 75 years; 57.8% were male; 10.7% were non-white; 69.9% had Medicare or Medicaid; 31.8% had coronary heart disease, 32.2% had heart failure, 13.0% had peripheral vascular disease, and 29.5% had diabetes mellitus. Among eligible patients, 62.8% of 3,612 were prescribed an antiplatelet agent, 72.1% of 4,674 were prescribed a β-blocker, 59.7% of 5,121 were prescribed an angiotensin converting enzyme inhibitor or angiotensin receptor blocker, 15.7% of 624 were prescribed an aldosterone antagonist, 70.1% of 6,914 were prescribed a statin, 94.7% of 8,329 were prescribed an antihypertensive, 58.3% of 504 had an ICD, and 44.5% of 9,589 received all indicated evidence-based therapies ( Table ). Conclusion: Cardiovascular comorbidities and risk factors in patients with AF are often inadequately treated with evidence-based therapies in the outpatient practice setting, underscoring opportunities to improve care for patients with AF.