Citations

Abstract BACKGROUND TTFields are electric fields that exert physical forces to disrupt cellular processes critical for cancer cell viability and tumor progression. TTFields therapy is approved for adults with recurrent (r) and newly diagnosed (nd) glioblastoma (GBM), based on the phase 3 EF-11 (TTFields 200 kHz) and EF-14 studies (TTFields therapy 200 kHz + temozolomide), respectively, which showed clinical benefit without increase in systemic adverse events (AEs). Pediatric patients were not included in the EF-11 and EF-14 studies. Here, we present pediatric safety data from an updated global post-marketing surveillance (PMS) analysis of patients with brain tumors treated with TTFields therapy, over an 11-year timeframe. METHODS Unsolicited PMS data from patients with brain tumors who received TTFields therapy from October 2011-March 2022 in North America, Europe, Middle East, Africa, and Japan were included. AEs were categorized using MedDRA version 25.1. RESULTS Overall, 25,898 patients were included. Diagnoses were ndGBM (68%), rGBM (26%), anaplastic astrocytoma/oligodendroglioma (4%) and other (2%). Two-thirds of patients were male. The analysis included 93 (0.4%) pediatric/adolescent patients (<18 years). In pediatric patients, 62% experienced ≥1 AE, with 53% related to TTFields therapy; these values were comparable with the overall population (73% and 56%, respectively). The most common treatment-related AEs in pediatric patients were: skin reaction (39%), heat sensation (14%), and headache (12%); and in the overall population were: skin reaction (43%), electric sensation (14%), and heat sensation (12%). CONCLUSIONS This long-term, global, real-world data analysis, including pediatric patients with brain tumors, demonstrates a tolerable safety profile of TTFields therapy, consistent with pivotal clinical studies. There were no major differences in AEs between pediatric and adult patients and no new safety signals identified in the pediatric population. Consistent with the overall dataset, most AEs in pediatric patients were localized mild–moderate skin events, which are typically easily managed.

2049 Background: Glioblastoma (GBM) has a poor prognosis. Standard treatments are associated with systemic toxicity, further increasing the disease burden in this patient population. Tumor Treating Fields (TTFields) are electric fields that disrupt cancer cell processes which affect cancer cell viability, and are generated by a portable, wearable device which is locoregional and noninvasive. TTFields therapy was approved by the FDA for the treatment of newly diagnosed (nd) and recurrent (r) GBM based on the phase 3 EF-14 (TTFields therapy 200 kHz + temozolomide) and EF-11 (TTFields 200 kHz) studies, respectively. TTFields therapy is also approved for pleural mesothelioma. We report an updated global, post-marketing surveillance (PMS) safety analysis of patients with CNS malignancies treated with TTFields therapy over an 11-year timeframe. This analysis represents the largest dataset of TTFields therapy use to date. Methods: Unsolicited safety data were collected from routine post-marketing activities for patients (N = 25,898) in North America, Europe, Middle East and Africa and Japan, from October 2011 to March 2022. AEs were stratified by diagnosis, age, and sex and categorized using MedDRA version 25.1. Results: Diagnoses were ndGBM (68%), rGBM (26%), anaplastic astrocytoma/oligodendroglioma (4%) and other (2%). Baseline demographics were reflective of real-world practice: median (range) age was 59 (3–103) years; two-thirds of patients were male. Most (69%) patients were 18–65 years; 0.4% were < 18 years, and 30% were > 65 years. All-cause and TTFields-related AEs occurred in 18,798 (73%) and 14,599 (56%), patients, respectively. The most common device-related AE was skin reaction (43% patients overall). There were no major differences in occurrence of this AE between pediatric, adult, and elderly groups (39%, 42%, and 45%, respectively), or between males and females (41% and 46%, respectively). The incidence of device-related skin reactions was higher in ndGBM than rGBM (46% vs 34%, respectively), in line with previous reports. Only 405 (2%) of patients overall reported an AE of treatment-related ‘quality-of-life decreased’. In line with the phase 3 studies, there were no treatment-related systemic AEs. Conclusions: In this updated global PMS safety analysis, TTFields therapy demonstrated a tolerable safety profile in patients with CNS malignancies, with no new safety findings. In line with previous real-world and clinical data, most AEs were localized, non-serious skin events, which were consistent between age groups. Such events can typically be managed easily using prophylaxis and topical therapies, together with optimization of caregiver techniques. Importantly, no TTFields therapy-related systemic AEs were detected.

Abstract Patients with glioblastoma (GBM) face poor outcomes; the 5-year survival rate is 7% with standard of care treatments, which are frequently associated with systemic toxicity. Tumor Treating Fields (TTFields) are electric fields that disrupt critical cancer cell processes. The TTFields therapy device consists of a portable electric field generator and arrays placed on the patient’s scalp, thus delivery is locoregional and noninvasive. Currently, TTFields therapy is approved for recurrent and newly diagnosed GBM, based on the phase 3 EF-11 (TTFields 200 kHz) and EF-14 studies (TTFields therapy 200 kHz + temozolomide), respectively. These studies confirmed that TTFields therapy had a tolerable safety profile with mild-to-moderate localized skin adverse events (AEs) being the most common related AEs. Here, we present an updated analysis of the largest global real-world evidence dataset of patients with brain tumors receiving TTFields therapy over an 11-year time period. Unsolicited safety data were obtained from routine post-marketing activities, including published literature and interactions with patients, caregivers, and healthcare professionals. Safety data were grouped according to age, diagnosis, and sex. AEs were categorized using MedDRA version 25. Data from 25,898 patients were included in this analysis; median age was 59 years (range: 3-103) for patients with known age. Diagnoses were ndGBM (67.7%), rGBM (26.1%), anaplastic astrocytoma/oligodendroglioma (4.2%) and other (2.1%). Most (n=17,817, 68.8%) patients were 18-65 years of age; n=93 (0.4%) were pediatric/adolescent patients (&lt;18 years), and n=7,808 (30.2%) were elderly patients (&gt;65 years). For 130 patients (0.5%) age was not known. Two-thirds of patients were male, which reflects the preponderance of CNS tumors in males. Most patients were based in North America (72.1%), followed by Europe, the Middle East and Africa (23.3%), and Japan (4.6%). Overall, 72.4% of patients experienced at least one AE, with 55.9% being related to TTFields therapy. The most common AEs (overall and related to TTFields therapy) were skin reactions (42.0%), electric (tingling) sensations (13.5%), and heat (warmth) sensations (11.8%). The percentage of patients experiencing ≥1 AE in the pediatric/adolescent, 18-65, and elderly groups was 63.4%, 74.6%, and 68.4%, respectively. The percentage of females and males experiencing ≥1 AE was 75.2% and 70.9%, respectively. These long-term, real-world data from the largest global dataset of patients with brain tumors using TTFields therapy to date demonstrate a tolerable safety profile consistent with pivotal clinical studies. There were no new safety signals, and most AEs were manageable localized mild-moderate skin events that can be resolved. The distribution of AEs between age and sex was similar, with broad applicability among different patient groups. Citation Format: Maciej M. Mrugala, Wenyin Shi, Fabio Iwamoto, Rimas V. Lukas, Joshua D. Palmer, John H. Suh, Martin Glas. Patients with glioblastoma (GBM) treated with tumor treating fields (TTFields) therapy: post-marketing safety data over the last decade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3221.

Background: Open hand fractures are one of the most common injuries in the pediatric population. These injuries are at higher risk of infection, especially in cases of frank contamination. Several studies on adult hand fractures are available in the literature; however, pediatric open hand fractures have yet to be extensively studied. This study aimed to define pediatric open hand fracture’s demographics, clinical characteristics, and treatment patterns. Methods: Using the Protected Health Information database, pediatric patients (<18 y old) with the diagnosis of open hand fracture from June 2016 to June 2018 were extracted. Demographic, treatment, and follow-up data were collected. Clinical outcomes included readmission and postoperative infection rates. Results: There were a total of 4516 patients who met the inclusion criteria; the median age was 7 years (interquartile range: 3 to 11); 60% males; 60% white. Displaced fractures occurred in 74% of patients, with the right hand (52%) and middle finger (27%) predominance. The most common mechanism of injury was a crushing injury in-between objects (56%). Associated nerve injury occurred in 78 patients (4%) and vascular injury in 43 patients (2%). Open reduction and internal fixation were performed in 30% of patients. Cephalosporins were the most commonly prescribed antibiotics (73%), followed by aminopenicillins (7%). Nine patients had complications related to surgical intervention (0.2%), and postoperative infection occurred in 44 patients (1%). Conclusions: Pediatric open hand fractures most often occur during childhood and more frequently in males. These fractures tend to be more distal and displaced; reduction and fixation are required in one-third of the cases. Despite the absence of treatment guidelines and variability, this injury exhibits low complication rates. Level of Evidence: Level III, retrospective study.

Brain and spinal tumors affect 1 in 1000 people by 25 years of age, and have diverse histological, biological, anatomical and dissemination characteristics. A mortality of 30–40% means the majority are cured, although two-thirds have life-long disability, linked to accumulated brain injury that is acquired prior to diagnosis, and after surgery or chemo-radiotherapy. Only four drugs have been licensed globally for brain tumors in 40 years and only one for children. Most new cancer drugs in clinical trials do not cross the blood–brain barrier (BBB). Techniques to enhance brain tumor drug delivery are explored in this review, and cover those that augment penetration of the BBB, and those that bypass the BBB. Developing appropriate delivery techniques could improve patient outcomes by ensuring efficacious drug exposure to tumors (including those that are drug-resistant), reducing systemic toxicities and targeting leptomeningeal metastases. Together, this drug delivery strategy seeks to enhance the efficacy of new drugs and enable re-evaluation of existing drugs that might have previously failed because of inadequate delivery. A literature review of repurposed drugs is reported, and a range of preclinical brain tumor models available for translational development are explored.

Abstract Background Coronavirus disease 2019 (COVID-19) results from SARS-CoV-2-induced hyperinflammatory immune response, orchestrated by granulocyte-macrophage colony-stimulating factor (GM-CSF). GM-CSF increases interleukin-6 (IL-6) levels, ultimately leading to increased C-reactive protein (CRP). The LIVE-AIR trial demonstrated that lenzilumab, the GM-CSF neutralizing antibody, improved the likelihood of survival without invasive mechanical ventilation (IMV) in hospitalized COVID-19 patients requiring supplemental oxygen but not IMV. This sub-analysis correlated levels of cytokines before and after lenzilumab treatment. Methods LIVE-AIR was a phase 3, randomized, double-blind, placebo-controlled trial (NCT04351152). Patients hospitalized with COVID-19 pneumonia, requiring only supplemental oxygen, were randomized to receive lenzilumab (1800 mg in three equally divided doses of 600 mg, q8h) or placebo IV infusion, in addition to standard of care which included remdesivir and corticosteroids. Blood taken at baseline (BL) and subsequent to treatment through day 10 (D10) were obtained and analyzed by high sensitivity enzyme immunoassay for GM-CSF, IL-6, and CRP. Results Baseline IL-6 levels (Loge-transformed for all cytokines and biomarkers) were linearly correlated with higher baseline GM-CSF levels (slope=0.60, p&lt; 0.001). Baseline CRP levels were linearly correlated with higher baseline IL-6 levels (slope=0.29, p &lt; 0.001). GM-CSF levels decreased with lenzilumab treatment on day 1 (D1) which persisted through D10 (Table). In contrast, GM-CSF increased with placebo treatment. IL-6 levels decreased only with lenzilumab treatment. CRP following lenzilumab or placebo treatment decreased on D1 to similar levels and further decreased on D10 only with lenzilumab treatment. Cytokine Levels Associated with Lenzilumab Treatment Conclusion Lenzilumab decreased GM-CSF as well as downstream cytokines and systemic biomarkers of inflammation during the hyperinflammatory immune response of COVD-19. Disclosures Dale Chappell, MD, MBA, Humanigen, Inc: Employee|Humanigen, Inc: Ownership Interest Adrian Kilcoyne, MD, Humanigen, Inc: Employee Frank Cerasoli, PhD, Humanigen, Inc: Advisor/Consultant John Lukas, PhD, Humanigen, Inc: Advisor/Consultant Cameron Durrant, MD, Humanigen, Inc: Employee|Humanigen, Inc: Ownership Interest Zelalem Temesgen, MD, Gilead: unrestricted educational grant (to the institution)|Humanigen, Inc: Grant/Research Support|Merck: unrestricted educational grant (to the institution)|ViiV: Advisor/Consultant Christopher Polk, MD, Gilead: Advisor/Consultant Jason Baker, MD, Gilead: Grant/Research Support|Humanigen, Inc: Grant/Research Support Vincent Marconi, MD, Gilead: Grant/Research Support.

Abstract This study aimed to investigate the influence of stroke lesions in predefined highly interconnected (rich‐club) brain regions on functional outcome post‐stroke, determine their spatial specificity and explore the effects of biological sex on their relevance. We analyzed MRI data recorded at index stroke and ~3‐months modified Rankin Scale (mRS) data from patients with acute ischemic stroke enrolled in the multisite MRI‐GENIE study. Spatially normalized structural stroke lesions were parcellated into 108 atlas‐defined bilateral (sub)cortical brain regions. Unfavorable outcome (mRS > 2) was modeled in a Bayesian logistic regression framework. Effects of individual brain regions were captured as two compound effects for (i) six bilateral rich club and (ii) all further non‐rich club regions. In spatial specificity analyses, we randomized the split into “rich club” and “non‐rich club” regions and compared the effect of the actual rich club regions to the distribution of effects from 1000 combinations of six random regions. In sex‐specific analyses, we introduced an additional hierarchical level in our model structure to compare male and female‐specific rich club effects. A total of 822 patients (age: 64.7[15.0], 39% women) were analyzed. Rich club regions had substantial relevance in explaining unfavorable functional outcome (mean of posterior distribution: 0.08, area under the curve: 0.8). In particular, the rich club‐combination had a higher relevance than 98.4% of random constellations. Rich club regions were substantially more important in explaining long‐term outcome in women than in men. All in all, lesions in rich club regions were associated with increased odds of unfavorable outcome. These effects were spatially specific and more pronounced in women.

AbstractNeuro-oncology encompasses a broad field focusing on an array of neoplasms, many of which can mimic several diseases. Neurologists will often be involved in the initial diagnostic evaluation and management of these patients. Their insight is central to optimizing the diagnostic yield and providing high-level clinical care. Several neuro-oncologic cases are reviewed with a goal of increasing the understanding of these diseases in a clinically relevant manner and providing updates on the contemporary thinking in the subspecialty.

Abstract Tumor Treating Fields therapy (TTFields; 200 kHz) is a noninvasive, locoregional, antimitotic treatment approved for newly diagnosed glioblastoma (ndGBM), recurrent (r) GBM, malignant pleural mesothelioma, and is being investigated in additional solid tumors. Approval in GBM was based on results of the phase 3 EF-11 (TTFields monotherapy; rGBM) and EF-14 (TTFields therapy/maintenance temozolomide; ndGBM), which showed clinical benefit without an increase in adverse events (AEs). Here we review post-marketing surveillance (PMS) data from patients with brain tumors who received TTFields therapy over an 11-year period. Unsolicited PMS data from patients with brain tumors who received TTFields therapy between October 2011 and March 2022, were included. Overall 23,822 patients were included in this analysis. Most patients (72%) were from North America; 24% from Europe, Middle East and Africa, and 4% from Japan. Birth year was available for 23,784 patients; of these, the average age at treatment start was 57 years (range: 3–103). Diagnoses were ndGBM (67%), rGBM (27%), astrocytoma (WHO grade 3; 4%) and other (2%). Overall, 71% of patients reported ≥ 1 AE, with the most common being skin reaction (42%), electric (tingling) sensation (14%), heat (warmth) sensation (12%), and seizure (11%). Furthermore, 56% of patients reported AEs possibly related to TTFields therapy, with the most frequently reported being skin reaction (42%), electric sensation (14%) and heat sensation (12%), occurring underneath the arrays. Numbers and types of AEs were comparable between age and diagnosis groups. PMS data from &gt; 23,000 patients with brain tumors show that TTFields therapy (200 kHz) is well-tolerated, consistent with the known safety profile; no new safety signals were identified. TTFields therapy is not associated with systemic toxicity; most common possibly-related AEs are localized dermatologic events that can be managed with appropriate prophylaxis and treatment strategies.

Introduction: Radical nephroureterectomy with bladder cuff excision (BCE) is the standard of care all high-risk upper tract urothelial carcinomas. With continued advancements, robot-assisted segmental ureteral resection can be employed for ureteral tumors for ipsilateral renal preservation. Herein, we are presenting our experience of different techniques classified by the affected ureteral segment, along with perioperative and intermediate to long-term functional and oncologic outcomes. Methods: From January 2008 to June 2021, a total of 17 patients underwent robot-assisted renal preserving excisional procedures for ureteral tumors. We collected and analyzed baseline, perioperative and follow-up outcomes parameters from our prospectively maintained institutional database. Eleven patients underwent segmental ureterectomy (SU) with BCE and ureteroneocystostomy with psoas hitch, five patients underwent SU with ureteroureteral anastomosis with/without psoas hitch, and one patient underwent ileal patch interposition after segmental ureteral excision. Results: Although majority of the patients had inconclusive or low-grade pathology on initial ureteroscopic biopsies, 73.33% of the patients were found to have high-grade tumors on final pathology report. Median tumor size was 2.7 cm (1–5.5 cm), and the median operative duration was 193 minutes (142–400 minutes). None of the procedures required conversion to open. Overall, only one patient (5.9%) had Clavien–Dindo grade ≥ III complication (pelvic abscess). At median follow-up of 41 months (7–156 months), four patients (26.67%) developed urothelial recurrences out of which only one patient required nephroureterectomy. Overall survival and nephroureterectomy-free survival were 86.67% and 92.31%, respectively. Conclusions: Our study provides a comprehensive review of various surgical approaches of robot-assisted renal sparing management for ureteral tumors. These procedures are surgically safe, feasible, and effective with satisfactory oncologic outcomes at intermediate to long-term follow-up. These procedures may be safely employed in select patients with a localized ureteral tumor to salvage the ipsilateral kidney and estimated glomerular filtration rate.