Managing therapy-associated neurotoxicity in children with ALL

Several chemotherapeutic agents and novel immunotherapies provide excellent control of systemic and central nervous system (CNS) leukemia but can be highly neurotoxic. The manifestations of subacute methotrexate neurotoxicity are diverse and require vigilant management; nonetheless, symptoms are transient in almost all patients. As methotrexate is a crucial drug to prevent CNS relapse, it is important to aim to resume it after full neurologic recovery. Most children tolerate methotrexate rechallenge without significant delays or prophylactic medications. Neurotoxicity is more frequent with newer immunotherapies such as CD19– chimeric antigen receptor T (CAR T) cells and blinatumomab. A uniform grading system for immune effector cell–associated neurotoxicity syndrome (ICANS) and algorithms for management based on severity have been developed. Low-grade ICANS usually resolves within a few days with supportive measures, but severe ICANS requires multispecialty care in the intensive care unit for life-threatening seizures and cerebral edema. Pharmacologic interventions include anticonvulsants for seizure control and glucocorticoids to reduce neuroinflammation. Anticytokine therapies targeted to the pathophysiology of ICANS are in development. By using illustrative patient cases, we discuss the management of neurotoxicity from methotrexate, CAR T cells, and blinatumomab in this review.

Primary alveolar soft tissue sarcoma of the central nervous system. Case report

Background: Alveolar soft part sarcoma (ASPS) is a rare, slow-growing soft tissue tumor with uncertain etiology; it is considered among the least common sarcomas, representing 0.2-1% of these cases in large studies. These tumors usually appear during childhood or young patients, with predominance in females. Case description: We introduce the case of ASPS in a 62-year-old man, who presented with 7 months of progressive headache and diplopia. The brain MRI showed an infiltrative lesion in the anterior fossa that extended to the right orbital roof. The possibility of metastasis was ruled out. The patient underwent resection of the tumor with posteriorly good visual and neurologic recovery. Histologic characterization demonstrated homogeneous eosinophilic cells with a solid, vascularized pattern, cells with large and binucleated nucleoli, and vessels with endothelial and myoepithelial hyperplasia; numerous apoptotic bodies and mitosis figures were also present, but no necrosis. On immunohistochemistry, cells exhibited positive CD56, NSE in membrane form, and slight myogenin; vessels were strongly positive for myogenin, myoglobin, CD34, CD31, factor VIII, vimentin, and nestin as well as for HBM45, CD20, GFAP, and S-100; cytokeratin showed fine extracellular and intracellular filaments; GATA and TTF1 were negative. Some clear cells were observed to be positive for CD68. The piece was diagnosed as a non-meningeal alveolar sarcoma of the soft tissue with solid pattern. Discussion and Conclusion: This case corresponds to the second tumor of this kind presented at our institution, the first one reported, and perhaps, one of the oldest patients to develop it worldwide.

Abstract 13434: Chronic Total Occlusions in Refractory Cardiac Arrest Patients

Introduction: Coronary artery disease (CAD) is the most frequent cause of cardiac arrest (CA) in adults. Coronary chronic total occlusions (CTOs) are associated with an increased risk CA and predict future malignant arrhythmias in CA survivors. Nevertheless, the prevalence of CTOs in patients with CA and especially refractory CA is poorly characterized. We sought to evaluate the frequency and characteristics of CTOs in refractory CA patients included in the Prague-OHCA study. Methods: From 256 patients with refractory CA randomized in the Prague-OHCA study, coronary angiography (CAG) was performed in 181 subjects. Of the 128 patients with significant CAD (defined as more than 50% diameter stenosis in at least one major coronary vessel), 14 had a different primary cause of CA, leading to a study cohort of 114 patients with CAD as the primary cause of CA. 41 patients had at least one coronary CTO, whereas 73 patients had significant CAD without CTOs. Clinical, angiographic parameters, initial management and outcome was compared between the CTO and non-CTO groups. Results: Patients in the CTO cohort were older (59 ±12 versus 54 ±11 years, p = 0.015) and had shorter CA durations (45 ± 25 versus 55 ± 24 minutes, p = 0.03) as compared to patients in the non-CTO cohort. The CTO cohort presented less frequently with an acute coronary syndrome (ACS) (51 versus 89%, p < 0.0001) and had a higher prevalence of multi-vessel disease (89 versus 51%, p < 0.0001), as compared to the non-CTO cohort. Acute index PCI was performed less frequently in the CTO group (61 versus 86%, p = 0.002). Patients in the CTO group experienced more frequent neurologic recovery (51 versus 32%, p = 0.04), whereas cardiac recovery (63 versus 51%, p = 0.19) and six month mortality (51 versus 59%, p = 0.43) did not differ between the CTO and non-CTO group. Conclusions: CTOs represent a frequent cause of refractory CA. Patients with refractory CA due to CTOs were older with a high prevalence of multi-vessel disease and presented less frequently with an ACS, as compared to patients with significant CAD without CTOs. The observed more frequent neurologic recovery in the CTO cohort is presumably due to shorter CA durations in these patients. Mid- and long-term prognosis did not differ between the CTO and non-CTO cohort.

Blinatumomab Associated Seizure Risk in Patients with Down Syndrome and B-Lymphoblastic Leukemia: An Interim Report from Children's Oncology Group (COG) Study AALL1731

INTRODUCTION Children with Down Syndrome (DS) and B-lymphoblastic leukemia (B-ALL) are at an increased risk of both relapse and treatment-related mortality, compared to those without DS. On COG study AALL1731 for de novo B-ALL, patients with DS and higher risk features (DS-High) are non-randomly treated with a regimen replacing intensive elements of conventional chemotherapy with three 28-day cycles of blinatumomab, with the combined goals of reducing toxicity and enhancing anti-leukemic efficacy. The DS-High group includes all NCI high risk (HR) patients; NCI standard risk (SR) patients with end-induction minimal residual disease positivity (&gt;0.01%), unfavorable cytogenetics, CNS3 status, steroid pre-treatment, neutral cytogenetics with CNS2 status, or testicular disease. Neurotoxicity is a known risk of blinatumomab, with an incidence of 4% in block 1 and 1% in block 2 among pediatric patients with relapsed ALL (Brown et al, JAMA 2021). However, the specific risk in patients with DS has not been described to date. Here, we provide an early report of increased seizure incidence associated with blinatumomab in older DS-High patients enrolled on AALL1731 to date. METHODS We reviewed seizure incidence among patients with DS enrolled on AALL1731 from June 2019 to June 2021 who had proceeded to receive blinatumomab. Blinatumomab was administered at a dose of 15 mcg/m 2/day, using dexamethasone pre-medication in cycle 1. Infusions were interrupted for seizures, with resumption at 5 mcg/m 2/d permitted following full resolution for grade 1-3 seizures. RESULTS Among DS NCI HR patients, 8 of 47 (17%) had a seizure during blinatumomab infusion (Table 1). All 8 seizures occurred in patients over 10 years old. Six of the 8 seizures occurred in the first cycle of blinatumomab, most in the first 3 days of the infusion. Four had concomitant fever or cytokine release syndrome. Seizures were grade 2 (n=2) or grade 3 (n=6), and all resolved with full neurologic recovery. Of the 8 patients, 5 elected to resume blinatumomab; no further seizures occurred in these patients. There was no indication of increased seizure risk among NCI SR DS-High patients (1 seizure among 11 patients), or among DS or non-DS patients receiving blinatumomab on other study strata (0 of 7 DS SR-Avg; 1 of 146 non-DS SR-Avg; and 2 of 120 non-DS SR-High). CONCLUSIONS The incidence of seizures associated with blinatumomab in DS-ALL patients older than 10 years appears higher than previously reported in children without DS. The majority of seizures occurred within the first 3 days, all fully resolved with no sequelae, and no patient who resumed blinatumomab infusion at a lower rate experienced further seizures. Seizure prophylaxis may be advisable in DS patients while receiving blinatumomab, particularly those &gt;10 years of age. Further follow-up and a larger sample size are needed to confirm incidence and identify risk factors predisposing DS patients to neurologic toxicity. Figure 1 Figure 1. Disclosures Li: Novartis Canada: Membership on an entity's Board of Directors or advisory committees. Raetz: Pfizer: Research Funding; Celgene: Other: DSMB member. Loh: MediSix therapeutics: Membership on an entity's Board of Directors or advisory committees. Gupta: Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Rau: Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; AbbVie Pharmaceuticals: Other: Spouse is employee and stock holder; Servier Pharmaceuticals: Consultancy. OffLabel Disclosure: This trial includes the use of blinatumomab in combination with chemotherapy for treatment of de novo B-lymphoblastic leukemia.

Primary Central Nervous System Lymphoma

Primary central nervous system lymphoma (PCNSL) is a rare and aggressive non-Hodgkin lymphoma that affects the brain, eyes, cerebrospinal fluid (CSF), or spinal cord without systemic involvement. Here, we review the clinical presentation, diagnostic work-up, novel pathophysiologic insights, and treatment of immunocompetent PCNSL patients. Diagnosis of PCNSL requires a high level of suspicion as clinical signs and deficits can vary depending upon the involved CNS compartments. Rapid initiation of therapy is essential for good neurologic recovery and disease control. In general, the prognosis of PCNSL has improved significantly over the past few decades, largely due to the introduction and wide-spread use of high-dose methotrexate (MTX) chemotherapy, considered the backbone of first-line polychemotherapy treatment. Upon completion of MTX-based treatment, a consolidation strategy is often required and can consist of non-myeloablative or myeloablative chemotherapy followed by autologous stem cell transplant, radiation, maintenance therapy, or observation. Unfortunately, relapse is common and 5-year survival rates stand at only 30-40%. Novel insights into the pathophysiology of PCNSL have identified key mechanisms in tumor pathogenesis including activation of the B-cell receptor pathway, a suppressed tumor immune microenvironment, and immune evasion. These insights have led to the identification of novel small molecules and agents targeting these aberrant pathways. Agents such as the Bruton Tyrosine Kinase (BTK) inhibitor ibrutinib or immunomodulatory drugs (IMiDs) like lenalidomide or pomalidomide have shown promising response rates in the clinical trial setting for recurrent/refractory PCNSL and are increasingly being adopted in clinical use.

How to iGuide: flat panel detector, CT-assisted, minimally invasive evacuation of intracranial hematomas

Evidence is growing to support minimally invasive surgical evacuation of intraparenchymal hematomas, particularly those with minimal residual hematoma volumes following evacuation. To maximize the potential for neurologic recovery, it is imperative that the trajectory for access to the hematoma minimizes disruption of normal parenchyma. Flat panel detector CT-based navigation and needle guidance software provides a platform that uses flat panel detector CT imaging obtained on the angiography table to aid reliable and safe access to the hematoma. In addition to providing a high degree of accuracy, this method also allows convenient and rapid re-imaging to assess navigation accuracy and the degree of hematoma evacuation prior to procedural completion. We provide a practical review of the syngo iGuide needle guidance software and the methodology for incorporating its use, and the software of other vendors, in a variety of minimally invasive methods for evacuation of intraparenchymal hematomas.

Syndrome of the trephined: clinical spectrum, risk factors, and impact of cranioplasty on neurologic recovery in a prospective cohort

Syndrome of the trephined (SoT) is an underrecognized complication after decompressive craniectomy. We aimed to investigate SoT incidence, clinical spectrum, risk factors, and the impact of the cranioplasty on neurologic recovery. Patients undergoing a large craniectomy (> 80 cm2) and cranioplasty were prospectively evaluated using modified Rankin score (mRS), cognitive (attention/processing speed, executive function, language, visuospatial), motor (Motricity Index, Jamar dynamometer, postural score, gait assessment), and radiologic evaluation within four days before and after a cranioplasty. The primary outcome was SoT, diagnosed when a neurologic improvement was observed after the cranioplasty. The secondary outcome was a good neurologic outcome (mRS 0–3) 4 days and 90 days after the cranioplasty. Logistic regression models were used to evaluate the risk factors for SoT and the impact of cranioplasty timing on neurologic recovery. We enrolled 40 patients with a large craniectomy; 26 (65%) developed SoT and improved after the cranioplasty. Brain trauma, hemorrhagic lesions, and shifting of brain structures were associated with SoT. After cranioplasty, a shift towards a good outcome was observed within 4 days (p = 0.025) and persisted at 90 days (p = 0.005). Increasing delay to cranioplasty was associated with decreased odds of improvement when adjusting for age and baseline disability (odds ratio 0.96; 95% CI, 0.93–0.99, p = 0.012). In conclusion, SoT is frequent after craniectomy and interferes with neurologic recovery. High suspicion of SoT should be exercised in patients who fail to progress or have a previous trauma, hemorrhage, or shifting of brain structures. Performing the cranioplasty earlier was associated with improved and quantifiable neurologic recovery.

119 Communicating Sensitive Information - An Exploration of Parental Perspectives on Prognostication of High Risk Infants

Primary Subject area Neonatal-Perinatal Medicine Background Preterm infants are at high risk of experiencing a range of impairments that may contribute to long-term challenges such as neurocognitive deficits. Physicians are often expected to give an outlook on future developmental outcomes of high-risk infants, often before sufficient time has elapsed to observe whether that particular child will demonstrate neurologic recovery from the initial injury. Clinicians often struggle with communicating this information, especially a poor prognosis, because of the worry about how these conversations affect families and their future expectations of the child. Objectives Our aim was to capture parents' retrospective perceptions of how their infant’s prognosis was communicated to them during their NICU stay. Design/Methods Semi-structured interviews were conducted over the phone with parents of former preterm infants with a birthweight below 1500 grams or parents of term infants who have sustained HIE requiring cooling. Parents were invited to participate when their child was between 12-36 months old at the time of the interview, so that parents would be able to have a sense of their child’s development and possible impairments. The data was analyzed thematically, with particular focus around the discourse of communication and prognostication. Results Twenty-three interviews were conducted: 20 with the biological mother, two with both biological parents, and one with the biological father. The average length of the interviews was 30 minutes. The main themes that recurred in the interviews included parental loss of control, needing to prepare for the unexpected, the value of shared decision making between the health care practitioners and parents, recognition and conveyance of uncertainty by the physician, and the importance of celebrating the present. Above all, a recurring theme mentioned by the majority of interviewees was the power of hope. While wanting to receive transparent and honest updates, parents felt strongly that giving them realistic hope was of utmost importance. Conclusion Although clinicians often feel pressured to deliver answers, parents found it helpful when clinicians acknowledged and explained the uncertainty that surrounds prognostication. While healthcare providers may feel the need to prepare parents for the worst, the importance of balancing this information with hope and positivity is what families remember and value years after the prognosis was given.

Neuroprognostication after Cardiac Arrest: Who Recovers? Who Progresses to Brain Death?

Approximately 15% of deaths in developed nations are due to sudden cardiac arrest, making it the most common cause of death worldwide. Though high-quality cardiopulmonary resuscitation has improved overall survival rates, the majority of survivors remain comatose after return of spontaneous circulation secondary to hypoxic ischemic injury. Since the advent of targeted temperature management, neurologic recovery has improved substantially, but the majority of patients are left with neurologic deficits ranging from minor cognitive impairment to persistent coma. Of those who survive cardiac arrest, but die during their hospitalization, some progress to brain death and others die after withdrawal of life-sustaining treatment due to anticipated poor neurologic prognosis. Here, we discuss considerations neurologists must make when asked, “Given their recent cardiac arrest, how much neurologic improvement do we expect for this patient?”

The effect of video-instructed versus audio-instructed dispatcher-assisted cardiopulmonary resuscitation on patient outcomes following out of hospital cardiac arrest in Seoul

We aimed to investigate whether video-instructed dispatcher-assisted (DA)-cardiopulmonary resuscitation (CPR) improved neurologic recovery and survival to discharge compared to audio-instructed DA-CPR in adult out-of-hospital cardiac arrest (OHCA) patients in a metropolitan city with sufficient experience and facilities. A retrospective cohort study was conducted for adult bystander-witnessed OHCA patients administered DA-CPR due to presumed cardiac etiology between January 1, 2018 and October 31, 2019 in Seoul, Korea. The primary and secondary outcomes were the differences in favorable neurologic outcome and survival to discharge rates in adult OHCA patients in the two instruction groups. Binary logistic regression analysis was performed to identify the outcome predictors after DA-CPR. A total of 2109 adult OHCA patients with DA-CPR were enrolled. Numbers of elderly patients in audio instruction and video instruction were 1260 (73.2%) and 214 (55.3%), respectively. Elderly patients and those outside the home or medical facility were more likely to receive video instruction. Favorable neurologic outcome was observed more in patients who received video-instructed DA-CPR (n = 75, 19.4%) than in patients who received audio-instructed DA-CPR (n = 117, 6.8%). The survival to discharge rate was also higher in video-instructed DA-CPR (n = 105, 27.1%) than in audio-instructed DA-CPR (n = 211, 12.3%). Video-instructed DA-CPR was significantly associated with neurologic recovery (aOR = 2.11, 95% CI 1.48–3.01) and survival to discharge (aOR = 1.81, 95% CI 1.33–2.46) compared to audio-instructed DA-CPR in adult OHCA patients after adjusting for age, gender, underlying diseases and CPR location. Video-instructed DA-CPR was associated with favorable outcomes in adult patients with OHCA in a metropolitan city equipped with sufficient experience and facilities.