Multicenter Review Research Articles

Best Abstract: Right-sided VNS in epilepsy: an international multicentre review of 27 cases with special focus on safety/efficacy

Best Abstract: Right-sided VNS in epilepsy: an international multicentre review of 27 cases with special focus on safety/efficacy

The Enterprise stent…still useful after all these years.

The Enterprise stent (Codman Neuro, Massachusetts, USA) received Food and Drug Administration (FDA) approval in 2007 for stent-assisted coiling (SAC). Since its introduction, newer stents and devices for aneurysm treatment have been developed resulting in a shift in the utilization of this stent from SAC to other off-label indications. To describe our experience with the Enterprise stent being used for SAC and other off-label indications. This is a multi-center retrospective review of the use of the Enterprise stent between 2018 and 2023. All patients in which the Enterprise stent was successfully deployed were included in the study. Our study cohort comprised of 194 patients, mostly females (n = 112, 57.7%), with a mean age of 63.2 years ± 14.3. The Enterprise stent was used for SAC in only 24 (12.4%) patients and was used for rescue stenting in stroke in 101 patients (52.1%), treatment of intracranial stenosis in 53 patients (27.3%), treatment of in-stent stenosis in 1 patient (0.5%), and for treatment of dissections in 15 patients (7.7%). From 2018 to 2023, the use of Enterprise stents for SAC significantly decreased (p < 0.0001) while the use of Enterprise stents for non-SAC purposes was insignificantly variable (p = 0.05). Our study shows that the Enterprise stent remains a reliable tool in neuroendovascular procedures, even if its original intended use has been supplanted by other devices.

Influence of Surgical Approach and Fixation on Complications in Talus Fractures: A Multicenter Review

Fractures of the talus are infrequent injuries often associated with substantial morbidity and imperfect outcomes. We undertook a retrospective review of talus fractures at multiple level 1 trauma centers in order to identify common treatment patterns and potential predictors of complications. All cases of talar fractures meeting inclusion criteria at our institution were reviewed. 54 of 103 talus fractures met inclusion criteria. 33 (61.1%) involved the talar neck, 13 (24.1%) the talar body, and 6 (9.2%) involved the lateral process. The most common etiology was motor vehicle accidents, accounting for 27 (50.0%). Mean follow up was 13.6 months (range 8-52 months). 37 (68.5%) fractures were fixated with screws, and 17 (31.5%) were fixated with a plate construct. Single and dual incisions were used in 63.0% and 25.9% of cases, respectively. Complications were seen in 46.3% of cases, with post-traumatic osteoarthritis being the most common complication (35.1%). Avascular necrosis occurred in 4 (7.4%) patients. No independent variables met the statistical threshold to be associated with complications. The present data alludes to possibility of over-reporting complications due to historical literature and the need for further studies.

Notable Clinical Differences Between Neonatal and Post-Neonatal Intestinal Malrotation: A Multicenter Review in Southern Japan

BackgroundMost cases of intestinal malrotation appear in neonates with bilious vomiting due to midgut volvulus, whereas in cases that develop beyond infancy, the initial symptoms vary. This study investigated the clinical features of these two populations and identified issues that should be considered in daily practice. MethodsA retrospective chart review was conducted from January 1, 2010, to December 31, 2022. Data on patients with intestinal malrotation were collected in an anonymized fashion from five pediatric surgical hub facilities in the Southern Kyushu and Okinawa areas of Japan. ResultsOf the 80 subjects, 57 (71.3%) were neonates (Group N) and 23 (28.7%) were infants and schoolchildren (Group I). The frequencies of initial symptoms, such as abdominal distention (Group N: 19.3% vs. Group I: 13.0%), bilious vomiting (59.6% vs. 43.5%), and hematochezia (8.8% vs. 21.7%), were not skewed by the age of onset (p = 0.535, 0.087, and 0.141, respectively). Midgut volvulus was significantly more frequent in Group N (71.9% [41/57] vs. 34.8% [8/23]; p = 0.005), while the degree of torsion was greater in group I (median 360° [interquartile range: 180–360°] vs. 450° [360–540°]; p = 0.029). Although the bowel resection rate was equivalent (7.0% [4/57] vs. 4.3% [1/23]; p = 1.000), half of the patients in Group N presented with 180° torsion. The neonatal intestine has been highlighted as being more susceptible to ischemia than that in older children. ConclusionsThe incidence of midgut volvulus is higher in neonates than in older children. Even relatively mild torsion can cause ischemic bowel changes during the neonatal period. Level of EvidenceLEVEL III.

Comparative Analysis of Clinical Outcomes and Healthcare Resource Utilization (HRU) in Patients (Pts) with Newly Diagnosed (ND) Acute Myeloid Leukemia (AML) Unfit for High-Intensity Chemotherapy Treated with Venetoclax (VEN) Vs Other Therapies: Results from the AML Real World Evidence (ARC) Initiative

Introduction: The BCL-2 inhibitor VEN is approved in combination with hypomethylating agents or low-dose cytarabine for adults with ND AML. The ARC Initiative is a multicenter chart review study of adult pts with AML. This abstract presents real-world clinical outcomes and hospitalizations among ND AML VEN treated pts ineligible for intensive chemotherapy (IC) and their matched controls. Methods: This multicenter chart review study included adult pts (≥18 years) with ND AML who received VEN in combination with HMA on or after April 2016, or non-VEN regimens on or after May 2015, from 15 international academic sites (US: 11; Israel: 4). Pts ineligible for IC (i.e., ≥75 years or ≥1 comorbidity based on the Ferrara criteria) and treated with VEN (VEN cohort) were matched 1:1 to control pts who received non-VEN-based regimens (CON cohort). Pts were matched based on age (&amp;lt;60, 60-74, ≥75 years) and European LeukemiaNet (ELN 2017) risk. All analyses are based on the May 2023 data cutoff; data collection is ongoing. Clinical outcomes include composite complete remission (CRc; i.e., CR, CR with partial hematologic recovery [CRh], or CR with incomplete marrow recovery [CRi]) and overall survival (OS; assessed using Kaplan-Meier analysis). Hospitalizations were assessed overall and among pts who achieved CRc. Results were separately reported overall and among the respective subsets of VEN pts matched to CON pts treated with high-intensity regimens (CON-H) or low-intensity regimens (CON-L). Results: A total of 142 IC-ineligible VEN pts and 142 matched CON pts were included in the analysis, including 80 VEN pts matched to CON-H pts (56.3%) and 62 VEN pts matched to CON-L pts (43.7%) ( Table 1). Overall, VEN pts received VEN-azacitidine (75.4%) or VEN-decitabine (24.6%). A total of 68.3% of all pts were classified as ELN adverse risk, and 24.6% of VEN pts and 20.4% of CON pts were classified as Eastern Cooperative Oncology Group (ECOG) Grade ³2. Among pts with genetic mutations tested (96.5% of VEN pts and 94.4% of CON pts), 22.6% of VEN pts and 14.2% of CON pts had TP53 mutations and 21.9% and 19.4%, respectively, had IDH1/2 mutations. VEN pts had a mean of 11.6 months of follow-up, and CON pts had a mean of 15.0 months of follow-up. VEN pts were significantly more likely to achieve CRc than CON pts (64.7% vs 44.3%, p=0.001). This difference was more pronounced for VEN pts matched to CON-L pts (62.1% vs 18.0%, p&amp;lt;0.001). The 6-month OS rates were not statistically different between VEN pts and matched CON pts (74.7% vs 67.6%; p=0.20), despite the majority of CON pts receiving high-intensity regimens, but improved among VEN pts matched to CON-L pts (73.5% vs 55.3%; p&amp;lt;0.05). VEN pts had fewer days of hospitalization per pt per month (PPPM; mean 6.3 days vs 8.9 days, p=0.045) and shorter mean duration of hospitalization (13.7 days vs 18.2 days, p&amp;lt;0.001) compared with CON pts. A larger difference was seen in the amount of time (days) (6.5 vs 10.5 PPPM, p=0.006) and mean length of hospital stay (13.9 vs 22.4 days, p&amp;lt;0.001) for VEN pts matched to CON-H pts. Among pts with ≥1 all-cause hospitalization, 69.2% of VEN pts and 74.8% of CON pts were hospitalized for treatment administration (p=0.42). Among pts who achieved CRc, VEN pts had fewer days of hospitalization PPPM than CON pts (mean 4.3 days vs 6.8 days, p=0.002). This difference was more pronounced for VEN pts compared to CON-H pts (4.3 days vs 7.7 days, p=0.001). Mean duration of hospitalization was also shorter for VEN vs CON pts (13.6 days vs 20.4 days, p&amp;lt;0.001). Both VEN and CON pts experienced more hospitalizations before CRc was achieved, with statistically fewer hospitalizations for VEN pts compared with CON pts (days of hospitalization PPPM: 10.1 vs 17.4, p=0.001; duration of hospitalization: 16.4 vs 28.2, p&amp;lt;0.001). In the 60 days after CRc was achieved, VEN pts still had fewer days of hospitalization PPPM than CON pts (1.4 vs 5.2, p&amp;lt;0.001). Conclusions: Pts with ND AML who were ineligible for IC and received VEN had significantly higher rates of CRc than matched pts who received non-VEN-based regimens. Although pts treated with VEN-based regimens achieved similar rates of CRc compared to matched control pts treated with high-intensity therapy, pts treated with VEN-based regimens required a significantly lower burden of hospitalizations compared with matched pts on non-VEN-based regimens.

Impact of Pre-Transplant Molecular and Cytogenetic Remission on Outcomes of Allogeneic Stem Cell Transplant in Patients with Myelodysplastic Syndrome

Background: Allogeneic stem cell transplant (allo-SCT) carries a high relapse rate (~35% within 2 years) in patients (pts) with myelodysplastic syndrome (MDS). Pre-transplant measurable residual disease (MRD) increases the risk of relapse and death in acute myeloid leukemia (Thol et al, Blood 2018). However, the impact of pre-transplant MRD on post-transplant outcomes is less clear in MDS. Prior studies have compared outcomes between myeloablative (MAC) and reduced intensity conditioning (RIC) in pts with pre-transplant MRD persistence based on either cytogenetic remission alone or ultra-deep genomic sequencing with a limited 10-gene panel, suggesting reduced risk of relapse in pts receiving MAC (Festuccia et al, Biol Blood Marrow Transplant 2016; Dillon et al, JCO PO 2021). However, pre-transplant MRD assessment using a commercial next-generation sequencing (NGS) panel in addition to cytogenetic testing to assess post-transplant outcomes has not been evaluated in MDS. Methods: We conducted a multicenter retrospective review of MDS pts who underwent allo-SCT from 2015-2022. Pts with FISH/cytogenetic (FC) and/or molecular abnormalities at diagnosis and MRD assessment by commercial myeloid-panel NGS (with a variant-allele frequency detection limit up to 5%) and FC performed on peripheral blood (PB) or bone marrow (BM) aspirate within 3 months prior to transplant were included for analysis. The Kaplan-Meier method and log-rank tests were used to estimate overall survival (OS). Gray's test/cumulative incidence functions were used to estimate relapse-free survival (RFS) with non-relapse mortality (NRM) as competing risk. Results: Table 1 includes baseline pt characteristics. Of 81 pts, 69 pts (85.2%) had residual FC and/or molecular abnormalities (MRD+) at pre-transplant PB/BM assessment. Twelve (14.8%) pts were in both FC and molecular remission (MRD-) prior to transplant. With a median follow-up of 13.9 months [IQR 6.8 - 38.9], 43 (53%) died and 24 (30%) pts experienced a relapse. Twenty-three of 69 (33%) MRD+ pts had relapsed disease with a 38% cumulative incidence of relapse (CIR) at 2 years. In contrast, only 1/12 (8.3%) MRD- pts experienced a relapse after 7 years, with chromosomal loss of TP53 not present at initial diagnosis. CIR at 2 years was 33% and 41% (p=0.207) for MRD+ pts who received MAC vs RIC, respectively with NRM of 34.5% associated with MAC vs 28.2% for RIC (p=0.61). TP53 mutations were most frequently associated with relapse in 8/24 (33%) pts with a median OS of 9.8 months [8.2 - NR]. Besides the previously defined 10-gene panel (Dillon et al, JCO PO 2021), relapses were also driven by SRSF2, U2AF1, KRAS, SETBP1 and NF1 mutations present in the original clone. Six pts had DNMT3A, TET2 and/or ASXL1 (DTA) mutations only on pre-transplant NGS, with 2/6 pts relapsing without the re-emergence of DTA mutations. Median OS was not reached for MRD- pts and was 14.1 months [11.35-NR] for MRD+ pts, p = 0.061 [Fig.1]. OS probability at 2 years was 35% for MRD+ pts vs 75% for MRD- pts. Type of conditioning regimen, RIC vs MAC, did not impact OS (p= 0.6). An equal number of deaths, 35% each, were attributable to GvHD and relapse, respectively. Thirteen (30%) pts died from other causes, primarily infections and bleeding complications. NRM was 25% and 36% for MRD- and MRD+ cohorts, respectively. Pts received a median of 6 cycles [range, 2-36] of hypomethylating agent (HMA) +/- venetoclax prior to transplant with no association between the number of cycles and MRD status (p=0.80). The incidence of grade 3-4 acute GvHD and chronic GvHD requiring systemic therapy did not significantly differ, at 25% and 18.8% (p= 0.696) and 33.3% and 31.8% (p= 1.00) in MRD+ and MRD- pts, respectively. Conclusions: MRD assessment using commercially available NGS panels and cytogenetic testing that are routinely performed in MDS pts in real-world practice can predict risk of relapse. Pre-transplant MRD is associated with worse OS irrespective of the intensity of conditioning regimen. Although limited in statistical power due to a small sample size of MRD- pts in our cohort, further studies with a larger cohort are underway to better clarify the role of MRD on transplant outcomes in MDS. Our data also highlights that only a small minority of MDS pts (&amp;lt;15%) achieve complete molecular and cytogenetic remission at the time of transplant; strategies to eliminate the pre-transplant MDS clone are urgently needed.

Craniotomy versus craniectomy for traumatic acute subdural hematoma—coarsened exact matched analysis of outcomes

Background and objectivesAcute subdural hematoma (aSDH) after traumatic brain injury frequently requires emergent craniotomy (CO) or decompressive craniectomy (DC). We sought to determine the variables associated with either surgical approach and to compare outcomes between matched patients. MethodsA multi-center retrospective review was used to identify traumatic aSDH patients who underwent CO or DC. Patient variables independently associated with surgical approach were used for coarsened exact matching.Multivariate logistic regression and multivariate Cox proportional-hazards regression wereconducted on matched patients to determine independent predictors of mortality. ResultsSeventy-six patients underwent CO and sixty-two underwent DC for aSDH evacuation. DC patients were21.4 years younger (P < 0.001), more likely to be male (80.6 % vs 60.5 %,P = 0.011), and present with GCS ≤ 8 (64.5 % vs 36.8 %,P = 0.001). Age (P < 0.001), epidural hematoma (P = 0.01), skull fracture (P = 0.001), and cisternal effacement (P = 0.02) were independently associated with surgical approach. After coarsened exact matching, DC (P = 0.008), older age (P = 0.007), male sex (P = 0.04), and intraventricular hemorrhage (P = 0.02), were independently associated with inpatient mortality. Multivariate Cox proportional-hazards regression demonstrated that DC was independently associated with mortality at 90-days (P = 0.001) and 1-year post-operation (P = 0.003). ConclusionaSDH patients who receive surgical evacuation via DC as opposed to CO are younger, more likely to be male, and have worse clinical exam. After controlling for patient differences via coarsened exact matching, DC is independently associated with mortality.

Real world utilisation of doravirine among people living with human immunodeficiency virus in England (DRIVE-REAL).

Doravirine is a non-nucleoside reverse transcriptase inhibitor recommended for the treatment of virologically suppressed and treatment naïve people living with HIV. The DRIVE-REAL study aimed to describe the characteristics, treatment patterns, and virological outcomes of doravirine users in a real-world cohort in the UK. A retrospective, observational, multi-centre chart review was conducted for 300 adults living with HIV initiating doravirine-containing antiretroviral therapy. At baseline 83% of individuals were male, 45% aged ≥50years, 65% white ethnicity. Median time since HIV diagnosis was 12years. 96% were antiretroviral therapy-experienced, 87% had a HIV viral load <50 copies/ml, and 15% had resistance to at least one antiretroviral drug. 66% had comorbidities, most commonly depression (26%), and 70% were taking at least one co-medication. At six months, 94% (n = 283/300) were still receiving doravirine. Viral load data were available for n = 266/300 individuals and 95% (n = 253/266) had viral load <50copies/ml. Individuals initiating doravirine in this cohort are predominantly treatment-experienced white middle-aged males, with a high frequency of comorbidities and co-medication. The majority of individuals at 6 months remained on doravirine and maintained or achieved HIV viral suppression. This study provides epidemiologic characteristics that can inform clinical care and subsequent hypothesis-testing studies.

Abstract 17332: Length of Diagnosis, Diagnostic Tests, and Referral Patterns of Transthyretin Amyloid Cardiomyopathy Patients in the United States, United Kingdom, France, Germany, Italy, and Spain

Introduction: Transthyretin amyloid cardiomyopathy (ATTR-CM) is a rare disease that typically presents with symptoms like those commonly associated with heart failure and is frequently misdiagnosed. Timely diagnosis and treatment are key to a favorable prognosis. This study aims to investigate and compare the length between suspicion of ATTR-CM and confirmed diagnosis, examine the number of diagnostic tests, and explore the referral dynamics in the US versus EU4+UK (United Kingdom, France, Germany, Italy, and Spain) using real-world data among patients diagnosed in 2022. Methods: A multi-center online medical chart review of patients was fielded in Q4’2022. Cardiologists and cardiology-focused internists from the US and EU4+UK from hospitals and private practices were recruited and screened for ATTR-CM patient management. A total of 239 physicians (US: 109, EU5: 130) who reported on patients diagnosed in 2022 were included, providing data on 759 patients diagnosed during this period (US: 481, EU5: 278). Results: Reported patients in the US experienced a shorter length of time from first suspicion of ATTR-CM to confirmed diagnosis, on average, than those in the EU4+UK (p&lt;0.01); US: 6.3 weeks (n=392), EU4+UK: 9.6 weeks (n=205). The average number of tests ordered to diagnose patients was greater in the EU4+UK than in the US cohort (p&lt;0.01); EU4+UK: 6.8 tests (n=277), US: 5.8 tests. A greater proportion of reported patients in the US (p&lt;0.05) first presented their symptoms prior to diagnosis to the reporting physician (35.1%) than those in EU4+UK (27.3%). In the US, 88.4% of the patients were diagnosed by the reporting physician (n=481), whereas in EU4+UK (n=278) this rate was 78.1% (p&lt;0.01). Conclusions: This study demonstrated that it took significantly less time to diagnose patients in 2022 in the US than in the EU4+UK. Patients in the EU4+UK were more likely to present symptoms to and be diagnosed by a physician other than the reporting physician, with a greater number of diagnostic tests ordered compared to those in the US. Further investigation using comparator cohort and to discover if there is a difference in patient outcomes is warranted.

Abstract 16392: Arrhythmias in Acute Care Cardiology: Prevalence, Therapies, and Outcomes- An Analysis of the Pediatric Acute Care Cardiology Collaborative (PAC 3 ) Database

Introduction: Arrhythmias are common in pediatric cardiology patients, yet prevalence during hospitalizations and treatments are poorly defined. This descriptive study reports arrhythmia prevalence and medical management from Pediatric Acute Care Cardiology Collaborative (PAC 3 ) centers. Aims Our primary aim is to describe prevalence and outcomes of treated arrhythmias among acute care cardiology units (ACCU). Secondary aims include comparison of medical vs. post-operative admissions and selection of antiarrhythmics. Methods: We performed a multi-center retrospective review of the PAC 3 registry limited to hospitalized patients with an arrhythmia treated from 2/2019-2/2023 among 33 centers. Arrhythmias are classified in the registry as Atrial Tachycardia/Supraventricular Tachycardia (AT/SVT), Junctional Tachycardia (JT), or Ventricular Tachycardia (VT). Descriptive statistics, Wilcoxon-Mann-Whitney, and χ2 testing were used. Results: Prevalence of treated arrhythmia in the cohort (n=38,396) was 5.4% (n=2,090 patients) over 2291 hospitalizations. AT /SVT (68.3%) were more frequent than VT (21.5%) or JT (2.8%) (p&lt;0.01). Bradyarrhythmias (7.5%) were infrequent. Of 8,733 CICU transfers, 513 (5.9 %) transfers of 257 patients (2.0 transfers/patient) were due to arrhythmia. Medical and Surgical patients varied in demographics and outcomes (Table). For AT/SVT, propranolol was the most prescribed antiarrhythmic, followed by sotalol. (Figure). Conclusions: Treated arrhythmias are prevalent in ACCU patients and are a relatively frequent cause of ICU transfers. Arrhythmia treatment patterns warrant further investigation and could be the subject of QI.

Efficacy of Siltuximab for Chimeric Antigen Receptor T-Cell Therapy Toxicities - a Multicenter Retrospective Analysis

Background: Chimeric Antigen Receptor T-Cell therapies (CAR-T) are effective in a variety of hematologic (hem) malignancies; however, adverse events including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) can affect a significant number of patients (pts). Tocilizumab, a monoclonal antibody (mAb) binding the interleukin-6 (IL-6) receptor, is the standard of care for managing CRS, but is ineffective for ICANS. Corticosteroids remain the standard of care for managing ICANS. Pts who develop refractory CRS or ICANS have few treatment options. Siltuximab, a mAb binding circulating IL-6, has been proposed to have clinical activity in both CRS and ICANS (Patel, ASH, 2022; Narkhede, TCT, 2023). This study assesses the efficacy of siltuximab for managing CRS and ICANS in a real-world cohort from six academic medical centers. Methods: We conducted a multicenter retrospective review of adult pts with hem malignancies treated with CAR-T therapy who received siltuximab for treatment of CRS and/or ICANS. Siltuximab administration occurred between January 2020 and August 2022. Pts who died within 48 hours of siltuximab administration (n=2) were excluded from this analysis. The co-primary endpoints were the percentage of pts who had improvement in CRS or ICANS after receiving siltuximab. Secondary endpoints included time to improvement of CRS or ICANS and overall survival (OS) from the date of CAR-T infusion. Time to event endpoints were evaluated by Kaplan-Meier methodology. Results: Fifty-two pts were eligible and evaluated. The median age was 60 years (range 23-81). Diffuse large B-cell lymphoma was the most common hem malignancy (52%). Axicabtagene ciloleucel (42%) was the most common cellular therapy product. Table 1 describes disease subtypes and cell therapy products in detail. Fifty-one pts (98%) developed CRS with median time to onset of 2 days (range 0-9). Max CRS grade prior to siltuximab administration was grade 1-2 in 83% and grade 3-4 in 15%. ICANS occurred in 65% with median time to onset of 6 days (range 0-16). Max ICANS grade prior to siltuximab administration was grade 1-2 in 29% and grade 3-4 in 37%. Prior to siltuximab, 52% of pts received tocilizumab with the majority (59%) receiving more than 1 dose, 69% of pts received corticosteroids, and 10 pts received additional treatments: anakinra (7/10 pts), LP with intrathecal (IT) chemo (3/10 pts), LP with IT steroids (2/10 pts), ruxolitinib (1/10 pt). Reasons for siltuximab administration included steroid refractory ICANS in 17 pts (33%), tocilizumab refractory CRS in 8 pts (15%), tocilizumab shortage in 26 pts (50%), and non-steroid refractory grade 4 ICANS in 1 pt (2%). At the time of siltuximab administration, 42 pts (81%) had evidence of CRS (10% grade 3-4 CRS) and 28 pts (54%) had evidence of ICANS (31% grade 3-4 ICANS). 18 pts (35%) had concurrent CRS and ICANS. Thirty-six pts (86%) had improved CRS grade following siltuximab treatment. The median time to CRS resolution after siltuximab was 1.5 days (range 0-18). Twelve pts with CRS received more than 1 dose of siltuximab. 4/8 pts (50%) with tocilizumab refractory CRS had improved CRS grade after siltuximab. Nineteen pts (68%) had improved ICANS grade following siltuximab treatment. The median time to ICANS resolution after siltuximab was 5 days (range 1-40). Nine pts with ICANS received more than 1 dose of siltuximab. 13/17 pts (76%) with steroid refractory ICANS had improved ICANS grade after siltuximab. The median time to discharge after siltuximab administration was 14 days (range 7-90). CAR-T therapy objective response rate was 73% and complete response rate was 48%. Twenty-one pts had died at the time of data collection; 4 deaths were deemed secondary to CAR-T toxicity. The median OS was 13.8 months (95% CI 9.6-NR) and was not statistically different based on indication of CAR-T therapy, Figure 1. Conclusions: To our knowledge, this is the largest cohort of pts treated with siltuximab for CRS and/or ICANS following CAR-T therapy. Half of the pts had CRS or ICANS refractory to tocilizumab and/or steroids. Siltuximab appeared to be effective for both CRS and ICANS, including refractory toxicities. These data support the use of siltuximab for refractory CRS and ICANS and warrant further investigation of siltuximab in earlier lines of therapy for CRS and ICANS management.

Real World Outcomes of Patients with Secondary Acute Myeloid Leukemia Undergoing Allogeneic Hematopoietic Cell Transplantation after Induction with Liposomal Daunorubicin-Cytarabine (CPX-351)

Background: Liposomal Daunorubicin-Cytarabine (CPX-351 or Vyxeos), is approved for upfront treatment of adult and pediatric patients with secondary Acute Myeloid Leukemia (sAML) based on results of a randomized phase 3 trial comparing CPX-351 to conventional chemotherapy with 7+3 regimen. The study showed CPX-351 treated patients demonstrated superior complete remission (CR) rates and overall survival (OS) [Lancet et al JCO 2018]. In this study, a higher proportion of CPX-351 treated patients underwent allogeneic hematopoietic cell transplantation (alloHCT), and landmark OS analysis favored CPX-351 treated patients (HR=0.46; 95% CI: 0.24-0.89; p=0.009). Herein, we reviewed City of Hope (COH) and University of California Los Angeles Medical Center (UCLA) database for patients with sAML who underwent allogeneic HCT after CPX-351 induction to investigate OS and disease-free survival (DFS) outcomes of alloHCT in CPX-351 treated patients and to investigate if HCT outcomes are impacted by achievement of pre-HCT measurable residual disease (MRD) negative remission. Methods: We conducted a multi-center retrospective review of 38 consecutive patients who received CPX-351-based induction before allogeneic HCT to treat sAML, at COH (n=10) and UCLA (n=28), between 2017-2021. The primary endpoint was 2-year OS and DFS in all patients. Secondary outcomes included MRD-ve complete remission (CR) after CPX-351 induction. CR was defined as &amp;lt;5% blasts in bone marrow (BM) aspirates. CR with with hematologic recovery (CRh) was defined as absolute neutrophil counts &amp;gt;1000/µL and platelets ≥100,000/µL. Patients without CRh were categorized as CR with incomplete blood recovery (CRi). MRD assessment was done on day-28 BM aspirate using multiparametric flow cytometric (FC) assay with lower limit of sensitivity of 0.01%. OS was defined as the time from the start of therapy to death and patients were censored if alive at the last follow-up, DFS was defined as the time interval from the date of response to relapse or death, whichever occurred first, and patients were censored at the last follow-up if still leukemia free. Descriptive statistics were used to summarize patient demographics, and disease characteristics. Kaplan-Meier curves and log-rank test were used to evaluate OS and LFS. Results: Patients' demographic and disease features are summarized in Table 1. Briefly, the median age at diagnosis was 65 years (range: 14-77) and median blast percentage in BM at diagnosis was 34% (range: 20-69%). Based on ELN criteria, 25 patients (66%) had adverse risk, 12 (32%) had intermediate risk and one (2.6%) had favorable risk AML. sAML was due to antecedent hematologic disorder (AHD) in majority of patients (n=32; 84%), therapy related in four (10%) and MDS-related changes (MRC) in two patients (5.3%). Following Vyxeos treatment, the composite CR rate (CRh+CRi) was 76% (CRh in 25, CRi in 4 patients) and 9 patients (23%) were refractory to upfront therapy. Pre-HCT MRD status was available for majority of patients (n=34; 89%). MRD negative remission by FC was achieved in 58% (20/34) patients (Table 2). The 1- and 2-years OS was 65% (95% CI: 48-78%) and 54% (95% CI: 36-68%), respectively and the 1- and 2-years DFS was 58% (95% CI: 41-71) and 50% (95%CI: 33-64%), respectively (Figure 1). In the 34 patients with available pre-HCT MRD data, no significant difference in OS (50% vs 58%; p=0.4) or DFS (50% vs 48%; p=0.93) was observed based on pre-HCT MRD status. More patients with who were MRD-positive after induction (50%; 7/14) received myeloablative conditioning (MAC) regimen compared to only 15% (3/20) of patients with MRD negative remission. Conclusion: CPX-351 induction in patients with sAML is associated with high MRD negative remission and promising 2-year OS/DFS after allogeneic HCT. In patients with MRD positive remission status after CPX-351 induction, MAC conditioning regimens may be preferred to reduce relapse incidence after alloHCT.

Risk Factors for CD19-Targeting CAR T Manufacturing Failure and Patient Outcomes: A Report from the UK National CAR T Panel

CAR T manufacturing failure (MF) rates reported in literature range between 1-13%. In some cases the manufacturing process fails to yield a product and in others results in one which does not meet pre-specified criteria for release and labelled an out of specification (OOS) product. We conducted a multicentre retrospective review of factors contributing to MF and its impact on patient outcomes. Patients with relapsed or refractory large B cell lymphoma (LBCL), mantle cell lymphoma (MCL) or B acute lymphoblastic leukemia (B-ALL) approved for CAR T therapy with axicabtagene ciloleucel (axi-cel), brexucabtagene autoleucel (brexu-cel) or tisagenlecleucel (tisa-cel) by the UK national CAR T panel between January 2019 and January 2023 were eligible. Patients with MF were identified from databases of the 11 participating CAR T centres and from the national OOS CAR T panel. In total 1138 patients were approved for CAR T therapy (903 LBCL, 97 MCL and 138 B-ALL). We identified 58 patients who had at least 1 CAR T MF; 38 LBCL (LBCL-MF), 14 MCL and 6 B-ALL with inferred MF frequency of 4.20%, 14.43% and 4.34% respectively. Intended CAR T product was axi-cel in 28 and tisa-cel in 10 LBCL, brexu-cel for all MCL and tisa-cel for all B-ALL patients. Most frequent reasons for MF were poor growth in culture (n=12), low cell viability (n=12) and low T cell purity (n=6). Of the 58 patients with MF, OOS product was available and infused in 19 patients (OOS cohort: 14 LBCL, 2 MCL and 3 B-ALL). Repeat apheresis led to infusion of a product in-specification in 17 patients (MF-delayed-infusion cohort: 10 LBCL, 6 MCL and 1 B-ALL). Another 22 patients did not proceed to CAR T infusion (MF-no-infusion cohort: 14 LBCL, 6 MCL and 2 B-ALL), some despite attempts at remanufacture (n=9) or available OOS product (n=5). We included 25 randomly selected matched (for disease subtype and product) controls (all LBCL: 19 axi-cel and 6 tisa-cel) without MF, 18 of whom received infusion. Univariable analysis of potential baseline clinical factors contributing to risk of MF did not reveal any significant impact of the number of lines of prior therapy, history of prior stem cell transplant or a need for holding therapy prior to apheresis. Bendamustine therapy was significantly associated with risk of MF for all lymphoma patients and the LBCL subset; prior exposure in 4% controls vs 32.7% of all lymphoma MF (p=0.004) and 26.3% of LBCL-MF (p=0.039). This was largely due to therapy within 6 months; 0% of controls vs 19.2% of all lymphoma MF (p=0.026) and 23.7% of LBCL-MF (p=0.009). Factors at apheresis including white cell count, neutrophil count, platelet count, absolute lymphocyte count, CD3 count, CRP, LDH and volume of blood processed had no impact on the risk of MF. With a median follow up of 11.6 months, the 12-month overall survival (OS) from date of approval for CAR T therapy was 45.0% (31.4 - 57.7) for all MF patients (n=58), 49% (24.7 - 69.5) for the OOS cohort (n=19), 64.2% (33.6 - 83.5) for the MF-delayed-infusion cohort (n=17) and 27.3% (11.1 - 46.4) for the MF-no-infusion cohort (n=22). Corresponding 12-month OS was 43.0% (26.7 - 58.3) for all LBCL-MF (n=38), 49.0% (21.6 - 71.7) for LBCL-OOS (n=14), 53.3% (17.3 - 79.8) for the LBCL-delayed-infusion cohort (n=10) and 28.6% (8.8 - 52.4) for the no-infusion cohort (n=14). The 12-month OS for LBCL controls (n=25) was 51.2% (30.3-68.7) for all and 65.5% (38.6 - 82.8) for infused patients (n=18). There was no significant difference between OS for LBCL-MF and LBCL controls (HR 1.38, p=0.31). Though OS was numerically lower for LBCL-OOS compared to infused LBCL controls, it was not statistically different (HR 1.82, p=0.21). For infused patients, the 3 months complete response (CR) rates were similar for the LBCL-OOS (38.5%), LBCL controls (40%) and MF-delayed infusion (53.3%) cohorts. The 3 months overall response rate (OR) was non-significantly lower in the LBCL-OOS (38.5%) compared to LBCL controls (60%) and MF-delayed infusion (53.3%) cohorts. There was no difference between any grade or grade ≥3 CRS or ICANS between the LBCL-OOS, LBCL-control and MF-delayed-infusion cohorts. In summary, outcomes for patients infused with an in-specification or OOS CAR T product following MF are comparable to those of controls. Prior bendamustine therapy within 6 months of apheresis is the only risk factor associated with risk of MF in lymphoma patients. Further analysis will be presented at the meeting.

Evaluating Procedural Performance: A Composite Outcome for Aortic and Pulmonary Valvuloplasty in Congenital Cardiac Catheterization.

Safety events and technical success (TS) have been previously reported for aortic and pulmonary valvuloplasty, but a composite performance measure as a novel, patient-centered strategy has neither been developed nor been studied. This study aims to refine a procedural performance (PP) variable, a composite of TS and procedural safety, for isolated, standard-risk aortic and pulmonary valvuloplasty. A multicenter review was performed using data from the Congenital Cardiac Catheterization Project on Outcomes registry. Data were collected for all cases of isolated balloon aortic and pulmonary valvuloplasty from 2014 through 2017. Patients were excluded if they were aged <1 month, were inpatient at the time of the procedure, or had significant comorbidities, such as Williams or Noonan syndrome. Criteria for TS were developed and categorized (optimal, satisfactory, and unsatisfactory) by expert consensus based on previous outcome research. Adverse events (AE) were categorized by severity (level 1-5) using established criteria. Level 4 and 5 severity AE were considered high-severity AE. Using criteria of TS and AE severity, PP was divided into 3 composite outcome classes. Factors correlating with class III (suboptimal) PP were analyzed. There were 169 cases of aortic and 270 cases of pulmonary valvuloplasty in the cohorts. In the aortic valvuloplasty cohort, a suboptimal PP (class III) occurred in 14% of cases, mostly due to high-severity AE (7%). No significant correlation between patient or case characteristics and PP was demonstrated. In the pulmonary valvuloplasty cohort, class III PP occurred in 9% of cases, predominantly due to residual valve gradient, which correlated with lower weight (P = .02). We designed a composite variable of PP consisting of TS and safety as a comprehensive measure of outcome. Incorporating both TS and AE may better reflect patient outcome than each metric measured separately. PP indices may identify areas for further investigation and quality improvement.

Incidence and treatment of checkpoint inhibitor induced immune related adverse events in the emergency department.

438 Background: Immune checkpoint inhibitors (ICPis) are currently indicated for the treatment of various types of cancers. Through inhibition of the cancer cell’s checkpoint mediated T-cell evasion, ICPis allow for sustained T-cell activation and proliferation, resulting in increased cancer cell death. However, due to increased activation and proliferation of cytotoxic T-cells, ICPis have been associated with a wide spectrum of adverse effects, known as immune related adverse effects (irAEs). Although recently updated, the 2018 NCCN and ASCO guidelines state that treatment is based on the location and severity of irAEs. In general, grade 3 toxicities warrant suspension of ICPis and initiation of high-dose corticosteroids. Corticosteroids should then be tapered over the course of at least 4-6 weeks. The diagnosis of an irAE is challenging, toxicities may be misdiagnosed as there is a diverse familiarity with ICPis and their associated irAEs. Subsequently, care may be delayed, and patients may not receive appropriate guideline directed care. Methods: This multi-center chart review included 7 hospitals within a large health system. Our electronic health record was utilized to compile a report of patients who had received ICPIs within 12 months of presentation to an ED within the health system between 9/1/2019 and 9/1/2022. Assessed outcomes included incidence and type of irAE, time between last ICPi dose and presentation to the ED, steroid used for treatment, time to steroid, treatment driver, and the action that deviated from the 2018 ASCO/NCCN guideline directed treatment if applicable. Results: Of the 241 patients receiving an ICPi, 26 (10.8%) experienced an irAE that prompted a visit to an ED within our health system. Guideline directed treatment of irAE(s) was followed 76.9% of the time, with the steroid dose being too low (15.4%) and the steroid taper occurring too quickly (7.7%) being the two reasons for discordant treatment. Treatment started a median of 1.1 after presentation to an ED, with colitis as the most prevalent irAE in 11 patients (42%) presenting. For all patients, there was an average of 20 days between the last ICPi dose and presentation to ED. The main steroid used was methylprednisolone (42%). Conclusions: The 10.8% of patients who experienced an irAE that prompted a visit to an ED within our health system is a lower rate than what has been described in the literature previously, where rates of presentation to an ED due to an irAE ranged from 25-37%. This could be due to previous data coming from before or shortly after the publication of ASCO and NCCN guidelines in 2018, or because our outpatient medical staff has become more aware of irAEs and their appropriate treatment. Limitations include this review was retrospective, no patients had an irAE that was refractory to steroids, and the study period being soon after national guidelines were published.

Iron sucrose hypersensitivity reactions in patients within the cancer care setting.

397 Background: As a National Cancer Institute-designated comprehensive cancer center, we manage a wide variety of patient care, from treatment to supportive measures. In the first three months of 2023, our safety event reporting software recorded 30 iron sucrose reactions, more than the three reactions reported from July to November 2022. This increase triggered our medication safety team to focus on identifying the cause of these reactions to improve patient safety. Methods: A multicenter retrospective chart review was conducted of patients who received IV iron sucrose and experienced a hypersensitivity reaction between July 2021 and March 2023 at the University of Kansas Cancer Center. The goal of the review was to identify potential risk factors for these adverse events. The chart review first investigated reaction type and symptoms, then the manufacturer, and finally the dose. Results: We identified 40 patients who experienced 44 reactions to iron sucrose from July 2021 to March 2023. Delayed reactions were observed in 68% of patients (n = 30), and 52% of patients (n = 23) had received premedication before their infusion. 25% of patients (n = 11) required an emergency department visit, and three were admitted to inpatient care. 80% of reactions (n = 35) followed a dose of iron sucrose greater than 300 mg. 60% of patients (n = 24) had previously tolerated iron infusions, with 23% (n = 9) previously receiving iron sucrose at a lower dose and 45% (n = 18) previously receiving a different iron infusion. Conclusions: We found that higher doses of iron sucrose were associated with an increased risk of reaction. Based on this finding, we proposed to our Cancer Center Medication Safety Subcommittee that a maximum dose of 300 mg should be considered for patients who receive iron sucrose infusions to improve patient safety. A rapid iterative change in dosing was implemented and has resulted in a reduction in iron sucrose reactions to previously observed numbers. This reduction in reactions further supports our initial findings and has improved patient safety across our patient care sites.

Safety of the modified posteromedial approach in complex ankle fractures: Comparative analysis versus posterolateral access

IntroductionThe aim of the study was to evaluate the safety of the modified posteromedial approach (MfPM) in the surgical management of complex ankle fractures in terms of local complications. MethodsRetrospective multicenter review of a series of malleolar fractures surgically treated by posterior ankle approaches between 2016 and 2022. Two approaches were used. In the MfPM group patients were placed in a prone position and the incision was made 1 cm medially to the Achilles tendon. In the posterolateral access (PL) group patients were placed in a prone or lateral decubitus position and the incision was made between the lateral malleolus and the Achilles tendon. Complications evaluated were divided into wound complications, infections, neuritis, vascular alterations and others. Results81 ankle fractures with a posterior malleolar fragment treated by open reduction and internal fixation were identified. 20 cases were approached through the MfPM approach and 61 through the PL access. The mean follow up was 18.60 months (range 4–78 months). In the MfPM group the local complication rate was 10% (2/10 patients), both corresponding to minor wound problems which required no surgical intervention. No infection or other neural or vascular complications were found. In the PL group a complication rate of 8,19% (5/61 patients) was found, all of them corresponding to minor wound problems which required no surgical intervention. No infection or other neural or vascular complications were found. There were no significant differences between the two approaches regarding postoperative local complications (z score 0.249 - P: 0.803). ConclusionThe MfPM approach is safe and may become as readily used as the PL due to the low incidence of postoperative local complications, especially in fractures with a large fragment and posteromedial extension in which greater access to the posterior pilon can facilitate instrumentation for anatomic reduction and fixation.

A multicentre review of the direct-access mammography programme in Ireland for women with breast pain

To assess the current use of the direct access mammography pathway for breast pain and the rate of breast cancer detection in this patient cohort. A retrospective review of general practitioner (GP)-referred mammograms performed during a 12-month period from January to December 2022 across four tertiary referral centres. With the use of medical records and GP referrals, patient demographics, presenting symptoms, family history, and clinical outcomes were recorded. The present study comprised 2,046 patients of which 21.6% did not report breast pain at the time of referral. Thirty-five per cent had a positive family history with 40% of these patients having no breast pain. Twelve per cent were recalled with 30% of these patients requiring biopsy. An overall cancer detection rate (CDR) of 7 per 1000 was determined for women with mastalgia. A CDR of 0 per 1,000 was determined for women <50 years with mastalgia alone and no additional risk factors for malignancy. Fisher's exact test showed no statistically significant association between breast pain and breast cancer. There was no statistically significant relationship found between breast pain and breast cancer. This review suggests a low cancer detection rate in women <50 years. In women <50 years with mastalgia without additional symptoms or family history, breast imaging is not required.

Hypovitaminosis D in persons with Down syndrome and autism spectrum disorder

BackgroundPlasma levels of vitamin D have been reported to be low in persons with Down syndrome (DS) and existing data is limited to small and homogenous cohorts. This is of particular importance in persons with DS given the high rates of autoimmune disease in this population and the known relationship between vitamin D and immune function. This study sought to investigate vitamin D status in a multi-center cohort of individuals with DS and compare them to individuals with autism spectrum disorder (ASD) and neurotypical (NT) controls.MethodsA retrospective, multi-center review was performed. The three sites were located at latitudes of 42.361145, 37.44466, and 34.05349. Patients were identified by the International Classification of Diseases (ICD)-9 or ICD-10 codes for DS, ASD, or well-child check visits for NT individuals. The first vitamin D 25-OH level recorded in the electronic medical record (EMR) was used in this study as it was felt to be the most reflective of a natural and non-supplemented state. Vitamin D 25-OH levels below 30 ng/mL were considered deficient.ResultsIn total, 1624 individuals with DS, 5208 with ASD, and 30,775 NT controls were identified. Individuals with DS had the lowest mean level of vitamin D 25-OH at 20.67 ng/mL, compared to those with ASD (23.48 ng/mL) and NT controls (29.20 ng/mL) (p < 0.001, 95% CI: −8.97 to −6.44). A total of 399 (24.6%) individuals with DS were considered vitamin D deficient compared to 1472 (28.3%) with ASD and 12,397 (40.3%) NT controls (p < 0.001, 95% CI: −5.43 to −2.36). Individuals with DS with higher body mass index (BMI) were found to be more likely to have lower levels of vitamin D (p < 0.001, 95% CI: −0.3849 to −0.1509). Additionally, having both DS and a neurologic diagnosis increased the likelihood of having lower vitamin D levels (p < 0.001, 95% CI: −5.02 to −1.28). Individuals with DS and autoimmune disease were much more likely to have lower vitamin D levels (p < 0.001, 95% CI: −6.22 to −1.55). Similarly, a history of autoimmunity in a first-degree relative also increased the likelihood of having lower levels of vitamin D in persons with DS (p = 0.01, 95% CI: −2.45 to −0.63).ConclusionsIndividuals with DS were noted to have hypovitaminosis D in comparison to individuals with ASD and NT controls. Associations between vitamin D deficiency and high BMI, personal autoimmunity, and familial autoimmunity were present in individuals with DS.

Post-operative weight loss in venous sinus stenting patients: A multi-center review, systematic review, and meta-analysis.

Idiopathic intracranial hypertension (IIH) can result in headaches, pulsatile tinnitus, papilledema, and other neurological symptoms. Weight loss can alleviate some symptoms of IIH. This study aims to investigate the effect of venous sinus stenting on post-operative weight and body mass index (BMI) changes among IIH patients. The secondary objective is to investigate the relationship between post-operative weight changes and papilledema resolution. Patients with papilledema undergoing venous sinus stenting for IIH were retrospectively reviewed from two comprehensive North American cerebrovascular centers. Patient demographics, surgical course, post-operative outcomes, and weight were analyzed. A systematic review and meta-analysis of post-operative weight in stented IIH patients was conducted. Twenty-eight patients with a diagnosis of IIH and papilledema who underwent venous sinus stenting were identified across two institutions. Patients had a mean pre-operative weight of 103.2 kg, which decreased to 101.5 kg at 3-month follow up (p = 0.0757). Patients at 6-month follow-up saw a weight decrease to 97.4 kg (p = 0.0066). Patients who saw papilledema resolution saw a mean greater decrease in weight (-4.5%) at 6-month follow up than those whose papilledema did not resolve (-1.7%), although this was insignificant (p = 0.1091). A total of 41 patients were included in the meta-analysis. Patients had an average of 1.1 increase in BMI at 3-month follow up. This study shows that venous sinus stenting leads to modest weight reduction in IIH patients, and those with resolved papilledema experience slightly greater weight loss. Further research is necessary to determine the clinical significance of these findings.