Development of a Safety Surveillance Plan for the Academic Medicine Sponsor Performing First-in-Human Cellular Therapy Clinical Trials: A Report from the Consortium for Pediatric Cellular Immunotherapy.

Pharmacovigilance (PV), also known as drug safety, is the science of risk management involving the detection, assessment, understanding, and prevention of adverse effects related to a medication. This discipline has traditionally focused on the postmarketing period, with less attention to early-phase clinical trials. However, during the immunotherapy and cellular therapy investigational stage, regulatory agencies are increasingly emphasizing the need to identify and characterize safety signals earlier in clinical development as part of a comprehensive safety surveillance plan. Compliance with PV and safety regulations are further heightened as cell and gene therapy (CGT) trials grow in complexity and scope owing to ever-changing and increasingly rigorous regulatory mandates. Based on this changing landscape, a critical aspect of early-phase trials of cellular products where significant safety events are anticipated is to ensure that every effort is made to protect clinical trial participants by maximizing attention to the risk-versus-benefit profile. This includes the development of robust plans for safety surveillance that provide a continual assessment of safety signals to enable safety reporting to regulatory bodies and the Food and Drug Administration, a regular analysis of aggregate safety data, and a plan to communicate safety findings. This report focuses on PV in early-phase clinical trials of first-in-human investigational products sponsored by academic centers in which the availability of PV resources and subject matter experts is limited. To more fully understand the challenges of CGT PV oversight within pediatric academic medical centers conducting early-phase clinical trials, a working group from institutions participating in the Consortium for Pediatric Cellular Immunotherapy composed of faculty and regulatory professionals was convened to compare experiences, identify best practices, and review published literature to identify commonalities and opportunities for alignment. Here we present guidelines on PV planning in early-phase CGT clinical trials occurring in academic medical centers and offer strategies to mitigate risk to trial participants. Standards to address regulatory requirements and governance for safety signal identification and risk assessment are discussed.

Phase 1 study of high-dose DFMO, celecoxib, cyclophosphamide and topotecan for patients with relapsed neuroblastoma: a New Approaches to Neuroblastoma Therapy trial.

BACKGROUND: MYC genes regulate ornithine decarboxylase (Odc) to increase intratumoral polyamines. We conducted a Phase I trial [NCT02030964] to determine the maximum tolerated dose (MTD) of DFMO, an Odc inhibitor, with celecoxib, cyclophosphamide and topotecan. METHODS: Patients 2-30 years of age with relapsed/refractory high-risk neuroblastoma received oral DFMO at doses up to 9000 mg/m2/day, with celecoxib (500 mg/m2 daily), cyclophosphamide (250 mg/m2/day) and topotecan (0.75 mg/m2/day) IV for 5 days, for up to one year with G-CSF support. RESULTS: Twenty-four patients (median age, 6.8 years) received 136 courses. Slow platelet recovery with 21-day courses (dose-levels 1 and 2) led to subsequent dose-levels using 28-day courses (dose-levels 2a-4a). There were three course-1 dose-limiting toxicities (DLTs; hematologic; anorexia; transaminases), and 23 serious adverse events (78% fever-related). Five patients (21%) completed 1-year of therapy. Nine stopped for PD, 2 for DLT, 8 by choice. Best overall response included two PR and four MR. Median time-to-progression was 19.8 months, and 3 patients remained progression-free at >4 years without receiving additional therapy. The MTD of DFMO with this regimen was 6750 mg/m2/day. CONCLUSION: High-dose DFMO is tolerable when added to chemotherapy in heavily pre-treated patients. A randomized Phase 2 trial of DFMO added to chemoimmunotherapy is ongoing [NCT03794349].

Improvements in Glucose Regulation in Children and Young People with Cystic Fibrosis-Related Diabetes following Initiation of Elexacaftor/Tezacaftor/Ivacaftor.

INTRODUCTION: Cystic fibrosis transmembrane conductance regulator (CFTR) modulators are increasingly used in children and young people with cystic fibrosis (CF). Data in adults show there may be an impact on glycaemic control in those with CF-related diabetes (CFRD). Paediatric data are rare. Case Series/Presentation: Children aged >12 years with CFRD, who were eligible for elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) were commenced on treatment. Glucose monitoring via the FreeStyle Libre system was commenced prior to, immediately after, and several months after commencing ELX/TEZ/IVA. Glycaemic control, shown by time in range (3-10 mmol/L), percentage of time spent hypoglycaemic (<3 mmol/L), and percentage of time spent hyperglycaemic (>10 mmol/L) on Insulin doses were recorded. Following ELX/TEZ/IVA, four of seven children stopped insulin, two required substantially reduced doses of insulin, one showed no response. Glycaemic control remained similar on lower doses or no insulin. Hypoglycaemia was detected in those not requiring insulin. CONCLUSION: ELX/TEZ/IVA has a positive impact on glycaemic control and insulin requirements in children with CFRD. Close monitoring is required when commencing treatment. Children with CFRD need counselling regarding possible reductions in insulin requirement and re-education regarding symptoms, signs, and management of hypoglycaemia.

Indirect treatment comparison of brexucabtagene autoleucel (ZUMA-2) versus standard of care (SCHOLAR-2) in relapsed/refractory mantle cell lymphoma.

The SCHOLAR-2 retrospective study highlighted poor overall survival (OS) with standard of care (SOC) regimens among patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL) who failed a covalent Bruton tyrosine kinase inhibitor (BTKi). In the ZUMA-2 single-arm trial, brexucabtagene autoleucel (brexu-cel; autologous anti-CD19 CAR T-cell therapy) demonstrated high rates of durable responses in patients with R/R MCL who had previous BTKi exposure. Here, we compared OS in ZUMA-2 and SCHOLAR-2 using three different methods which adjusted for imbalances in prognostic factors between populations: inverse probability weighting (IPW), regression adjustment (RA), and doubly robust (DR). Brexu-cel was associated with improved OS compared to SOC across all unadjusted and adjusted comparisons. Hazard ratios (95% confidence intervals) were 0.38 (0.23, 0.61) for IPW, 0.45 (0.28, 0.74) for RA, and 0.37 (0.23, 0.59) for DR. These results suggest a substantial survival benefit with brexu-cel versus SOC in patients with R/R MCL after BTKi exposure.

Norepinephrine transporter and vesicular monoamine transporter 2 tumor expression as a predictor of response to 131 I-MIBG in patients with relapsed/refractory neuroblastoma.

BACKGROUND: Prior studies suggest that norepinephrine transporter (NET) and vesicular monoamine transporter 2 (VMAT2) mediate meta-iodobenzylguanidine (MIBG) uptake and retention in neuroblastoma tumors. We evaluated the relationship between NET and VMAT2 tumor expression and clinical response to 131 I-MIBG therapy in patients with neuroblastoma. METHODS: Immunohistochemistry (IHC) was used to evaluate NET and VMAT2 protein expression levels on archival tumor samples (obtained at diagnosis or relapse) from patients with relapsed or refractory neuroblastoma treated with 131 I-MIBG. A composite protein expression H-score was determined by multiplying a semi-quantitative intensity value (0-3+) by the percentage of tumor cells expressing the protein. RESULTS: Tumor samples and clinical data were available for 106 patients, of whom 28.3% had partial response (PR) or higher. NET H-score was not significantly associated with response (≥PR), though the percentage of tumor cells expressing NET was lower among responders (median 80% for ≥PR vs. 90% for

Factors influencing parents' choice of palliative treatment goals for children with relapsed or refractory neuroblastoma: A multi-site longitudinal survey study.

BACKGROUND: Many parents of children with advanced cancer report curative goals and continue intensive therapies that can compound symptoms and suffering. Factors that influence parents to choose palliation as the primary treatment goal are not well understood. The objective of this study was to examine experiences impacting parents' report of palliative goals adjusted for time. The authors hypothesized that awareness of poor prognosis, recall of oncologists' prognostic disclosure, intensive treatments, and burdensome symptoms and suffering would influence palliative goal-setting. METHODS: The authors collected prospective, longitudinal surveys from parents of children with relapsed/refractory neuroblastoma at nine pediatric cancer centers across the United States, beginning at relapse and continuing every 3 months for 18 months or until death. Hypothesized covariates were examined for possible associations with parental report of palliative goals. Generalized linear mixed models were used to evaluate factors associated with parents' report of palliative goals at different time points. RESULTS: A total of 96 parents completed surveys. Parents were more likely to report a primary goal of palliation when they recalled communication about prognosis by their child's oncologist (odds ratio [OR], 52.48; p = .010). Treatment intensity and previous ineffective therapeutic regimens were not associated with parents' report of palliative goals adjusted for time. A parent who reported new suffering for their child was less likely to report palliative goals (OR, 0.13; p = .008). CONCLUSIONS: Parents of children with poor prognosis cancer may not report palliative goals spontaneously in the setting of treatment-related suffering. Prognostic communication, however, does influence palliative goal-setting. Evidence-based interventions are needed to encourage timely, person-centered prognostic disclosure in the setting of advanced pediatric cancer. PLAIN LANGUAGE SUMMARY: Many parents of children with poor-prognosis cancer continue to pursue curative treatments that may worsen symptoms and suffering. Little is known about which factors influence parents to choose palliative care as their child's main treatment goal. To explore this question, we asked parents of children with advanced neuroblastoma across the United States to complete multiple surveys over time. We found that the intensity of treatment, number of treatments, and suffering from treatment did not influence parents to choose palliative goals. However, when parents remembered their child's oncologist talking about prognosis, they were more likely to choose palliative goals of care.

Unanchored Population-Adjusted Indirect Comparison Methods for Time-to-Event Outcomes Using Inverse Odds Weighting, Regression Adjustment, and Doubly Robust Methods With Either Individual Patient or Aggregate Data.

OBJECTIVES: Several methods for unanchored population-adjusted indirect comparisons (PAICs) are available. Exploring alternative adjustment methods, depending on the available individual patient data (IPD) and the aggregate data (AD) in the external study, may help minimize bias in unanchored indirect comparisons. However, methods for time-to-event outcomes are not well understood. This study provides an overview and comparison of methods using a case study to increase familiarity. A recent method is applied to marginalize conditional hazard ratios, which allows for the comparisons of methods, and a doubly robust method is proposed. METHODS: The following PAIC methods were compared through a case study in third-line small cell lung cancer, comparing nivolumab with standard of care based on a single-arm phase II trial (CheckMate 032) and real-world study (Flatiron) in terms of overall survival: IPD-IPD analyses using inverse odds weighting, regression adjustment, and a doubly robust method; IPD-AD analyses using matching-adjusted indirect comparison, simulated treatment comparison, and a doubly robust method. RESULTS: Nivolumab extended survival versus standard of care with hazard ratios ranging from 0.63 (95% CI 0.44-0.90) in naive comparisons (identical estimates for IPD-IPD and IPD-AD analyses) to 0.69 (95% CI 0.44-0.98) in the IPD-IPD analyses using regression adjustment. Regression-based and doubly robust estimates yielded slightly wider confidence intervals versus the propensity score-based analyses. CONCLUSIONS: The proposed doubly robust approach for time-to-event outcomes may help to minimize bias due to model misspecification. However, all methods for unanchored PAIC rely on the strong assumption that all prognostic covariates have been included.

Biologic use and treatment patterns in patients with chronic rhinosinusitis with nasal polyps: a US real-world study.

BACKGROUND: Several biologics are now approved in the US as add-on treatments for chronic rhinosinusitus with nasal polyps (CRSwNP). This cross-sectional, retrospective, real-world study aimed to characterize treatment patterns and identify predictors of biologic use among patients with CRSwNP. METHODS: Adults in the Merative MarketScan Commercial and Medicare Supplemental Databases with medical claims for CRSwNP were identified June 2018-June 2019 (identification period [IP]). Patient characteristics were collated in the IP and treatment pattern data during the IP plus the following year (July 2019-June 2020; observation period [OP]). Data were stratified by sinus surgery and biologic use. RESULTS: Of the 5997 eligible patients identified (58% male, mean age 48.1 years), 10.7% (n = 642) used biologics during the OP. More biologic users had common respiratory conditions than non-users, particularly asthma (89.1% vs 35.0%; P < 0.001). Biologic users had fewer diagnostic services but more drug-related services than non-users. Only 11.6% of patients who had sinus surgery used biologics, with most (56.1%) having their first biologic dose before sinus surgery and 12.5% ≤ 30 days after. Oral corticosteroid (OCS) use was higher in biologic users than non-users (all patients: 68.8% vs 42.5%; P < 0.001) and in those with/without sinus surgery. Comorbidities, prior OCS/doxycycline use, and age (< 65 years) increased the odds of biologic use, with asthma increasing the odds 5.46 times (P < 0.001). CONCLUSIONS: Biologic use was more common before first/next sinus surgery and in patients with high unmet need, elucidating predictors of biologic use that could be used in clinical practice.

Neurodevelopmental Outcome in Very Preterm Infants Randomised to Receive Two Different Standardised, Concentrated Parenteral Nutrition Regimens.

We have previously shown that increasing parenteral protein (target: 3.8 versus 2.8 g/kg/d) and energy (12% versus 10% glucose; 3.8 versus 2.8 g/kg/d) intake using a Standardised, Concentrated with Added Macronutrients Parenteral (SCAMP) nutrition regimen ameliorates early head growth failure in very-preterm infants (VPIs). We hypothesised that the SCAMP nutrition regimen would also improve neurodevelopmental outcome. The original double-blind randomised, controlled study (ISRCTN: 76597892) received ethical approval. VPIs were randomised to either start SCAMP or remain on the control regimen. The consent process included neurodevelopmental assessments (Bayley III), all of which were performed (blinded) at 2-3.5 years of corrected gestational age. Bayley III assessments were performed for 38/60 SCAMP survivors and 41/63 control survivors at means of (sd) 29.2 (3.7) and 20.0 (3.9) months, respectively. Motor, cognitive, language, and combined scores were all higher in the SCAMP intervention group, but none of the differences were statistically significant. Nutrient intake and biochemical monitoring data confirmed that protein/energy ratios were maintained in the SCAMP intervention group without increasing the incidence of hyperglycaemia, insulin treatment, or the derangement of plasma mineral/electrolyte levels. This study did not show a statistically significant improvement in neurodevelopmental outcome when administering higher parenteral protein/energy intakes despite optimal energy and mineral intakes.

Healthcare costs among hemophilia A patients in the United States treated with rurioctocog alfa pegol (FVIII-PEG) or antihemophilic factor (recombinant), FC fusion protein (rFVIIIFc) using real-world data.

AIMS: To compare healthcare costs in patients with non-inhibitor hemophilia A treated with Rurioctocog Alfa Pegol (FVIII-PEG) versus Antihemophilic Factor (Recombinant), FC Fusion Protein (rFVIIIFc). MATERIALS AND METHODS: Administrative claims data from the Merative MarketScan Commercial (Commerical) and Medicaid (Medicaid) databases were used for these analyses. Males with non-inhibitor hemophilia A treated with FVIII-PEG or rFVIIIFc from 1 January 2016 to 31 March 2021 were identified (earliest treatment = index). Patients were required to have continuous database enrollment for six months before and after the index date. Follow-up was variable in length until disenrollment or study end. All-cause and hemophilia-related healthcare costs were reported per-patient per month [PPPM] and the average weekly dose during follow-up was compared between treatment groups. Generalized linear regressions were used to estimate multivariable-adjusted differences in total costs and weekly dosage in the two treatment groups. RESULTS: A total of 131 FVIII-PEG (66 Commercial; 65 Medicaid) and 204 rFVIIIFc (111 Commercial; 93 Medicaid) patients were eligible. Mean age was 20.5 and 24.4 for FVIII-PEG and rFVIIIFc in Commercial and 14.9 and 17.5 for FVIII-PEG and rFVIIIFc in Medicaid. PPPM mean (standard deviations [SD]) total healthcare costs in Commercially insured patients were $35,868 [$21,717] for FVIII-PEG vs $40,424 [$25,882] for rFVIIIFc. Costs in Medicaid were $27,495 [$23,243] for FVIII-PEG vs $30,237 [$28,430] for rFVIIIFc. After adjusting for baseline characteristics, the costs for rFVIIIFc (vs FVIII-PEG) were higher by $5,215 in Commercial and $3,895 in Medicaid, but the differences were not statistically significant (p > 0.05). Similar findings were observed for hemophilia-specific healthcare costs. The adjusted mean weekly dose was 6,047 vs 4,892 IU, p = 0.21 for FVIII-PEG vs rFVIIIFc in Commercial and 5,549 vs 7,228 IU, p = 0.07 for FVIII-PEG vs rFVIIIFc in Medicaid. CONCLUSIONS: Healthcare costs and treatment dosing were similar (p > 0.05) for non-inhibitor hemophilia A patients treated with FVIII-PEG and rFVIIIFc.

Matching-Adjusted Indirect Comparisons of Brexucabtagene Autoleucel with Alternative Standard Therapies for Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia in Adult Patients.

INTRODUCTION: Brexucabtagene autoleucel (brexu-cel), a CD19-directed chimeric antigen receptor T-cell therapy, is approved for relapsed/refractory B-cell precursor acute lymphoblastic leukemia in adults aged 18+/26+ years in the US/European Union (EU), based on efficacy results from the single-arm ZUMA-3 trial. This study aimed to estimate the relative treatment effects of brexu-cel versus inotuzumab ozogamicin (InO), blinatumomab (blina), and chemotherapies using unanchored matching-adjusted indirect comparison (MAIC) methods. METHODS: Individual patient data from ZUMA-3 and published aggregate level data from two randomized controlled trials, INO-VATE (InO versus chemotherapy) and TOWER (blina versus chemotherapy), were used. Patient-level data from ZUMA-3 were weighted to match the mean of the following prognostic variables at baseline, which were pre-specified based on clinical input, for each comparator population: primary refractory disease, duration of first remission < 12 months, prior stem-cell transplantation, age, performance status, salvage status, bone marrow blast, complex karyotype, and Philadelphia chromosome status. The base case analysis was conducted using the modified intention-to-treat population (i.e., received brexu-cel) from ZUMA-3. Relative treatment effects for overall survival (OS) and event-free survival (EFS) were expressed as hazard ratios (HR) and differences in restricted mean survival time (RMST) with 95% confidence intervals (CI). RESULTS: The base case MAIC results suggested brexu-cel improved OS and EFS compared to blina (OS HR 0.46 [95% CI 0.28, 0.75]; EFS HR 0.37 [95% CI 0.25, 0.56]) and pooled INO-VATE/TOWER chemotherapy (OS HR 0.32 [95% CI 0.18, 0.56]; EFS HR 0.27 [0.18, 0.40]). Brexu-cel also improved OS compared to InO (HR 0.45 [95% CI 0.24, 0.85]). The point estimate for EFS favored brexu-cel over Ino but the difference was not statistically significant (HR 0.67 [95% CI 0.41, 1.10]). Findings were consistent between the HR and RMST analyses. CONCLUSION: Despite limitations, these MAIC results suggest that brexu-cel may improve OS and EFS versus currently used therapies in this population.

Characteristics and Complication Rates of Mandibular Fractures Caused by Violent Mechanisms Versus Nonviolent Mechanisms.

Background: Mandibular fractures due to intentionally violent mechanisms represent a unique subset of facial fractures. The objective of our research is to identify how violence affects patterns of mandibular fractures and their outcomes. Methods: In this institutional review board-approved, retrospective study, we examined our institution's records for adult patients >18 years of age who presented with ≥ 1 mandibular fractures from January 2011 to January 2022. Violence was defined as trauma intended to hurt another or self. Demographics, fractures, mechanism, concomitant injuries, treatment, and complications were analyzed with Excel and SPSS statistical software. Results: A total of 692 patients were diagnosed with mandibular fractures, with 323 of these due to violence (47%). These patients of violence (POVs) had an average fracture per patient of 1.6 ± 0.7. The majority (88%) were male and African American (33%), and the average age was 34.3 ± 13.2 years. The most common violent mechanism was a punch (68%). The POVs presented with fewer concomitant injuries, were less likely to be admitted to the intensive care unit, and were more often surgically managed with open reduction than were patients of nonviolence (PONVs) (P < .01). POVs were more likely to have healing complications; though not statistically significant, this population was observed to be frequently lost to follow-up (P = .12). POVs notably had a much higher proportion of hardware exposure among complications than was seen in PONVs (23% vs 9%). Conclusions: Patients with violent fracture mechanisms may tend to be predisposed to more complications compared with patients who have nonviolent fracture mechanisms despite lesser severities due to social determinants of health. Characteristics of this patient subset may tend to cause difficulties in postoperative care and follow-up. Effective discharge instruction communication, patient outreach programs, and homelessness and drug abuse screening in this subset may help reduce healing complications.

Topotecan clearance based on a single sample and a population pharmacokinetic model: Application to a pediatric high-risk neuroblastoma clinical trial.

BACKGROUND: Topotecan, an antitumor drug with systemic exposure (SE)-dependent activity against many pediatric tumors has wide interpatient pharmacokinetic variability, making it challenging to attain the desired topotecan SE. The study objectives were to update our topotecan population pharmacokinetic model, to evaluate the feasibility of determining individual topotecan clearance using a single blood sample, and to apply this approach to topotecan data from a neuroblastoma trial to explore exposure-response relationships. PROCEDURE: Our previous population pharmacokinetic and covariate model was updated using data from 13 clinical pediatric studies. A simulation-based Bayesian analysis was performed to determine if a single blood sample could be sufficient to estimate individual topotecan clearance. Following the Bayesian approach, single pharmacokinetic samples collected from a Children's Oncology Group Phase III clinical trial (ANBL0532; NCT0056767) were analyzed to estimate individual topotecan SE. Associations between topotecan SE and toxicity or early response were then evaluated. RESULTS: The updated population model included the impact of patient body surface area (BSA), age, and renal function on topotecan clearance. The Bayesian analysis with the updated model and single plasma samples showed that individual topotecan clearance values were estimated with good precision (mean absolute prediction error ≤16.2%) and low bias (mean prediction error ≤7.2%). Using the same approach, topotecan SE was derived in patients from ANBL0532. The exposure-response analysis showed an increased early response after concomitant cyclophosphamide and topotecan up to a topotecan SE of 45 h ng/mL. CONCLUSIONS: A simple single-sample approach during topotecan therapy could guide dosing for patients, resulting in more patients reaching target attainment.

Neoadjuvant immunotherapy and chemotherapy regimens for the treatment of high-risk, early-stage triple-negative breast cancer: a systematic review and network meta-analysis.

BACKGROUND: Patients with triple-negative breast cancer (TNBC) are generally younger and more likely to experience disease recurrence and have the shortest survival among all breast cancer patients. Recently, neoadjuvant delivery of the programmed cell death protein-1 inhibitor pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab was approved for patients with high-risk, early-stage TNBC, but this treatment regimen has not been evaluated in head-to-head trials with other neoadjuvant treatment regimens. Therefore, the objective of this study was to estimate the relative efficacy of neoadjuvant pembrolizumab + chemotherapy followed by adjuvant pembrolizumab versus other neoadjuvant treatments for early-stage TNBC through a systematic review and network meta-analysis (NMA). METHODS: EMBASE, MEDLINE, Cochrane Central Register of Controlled Trials, conference abstracts, and clinical trial registries were searched for randomized controlled trials evaluating neoadjuvant treatments for early-stage TNBC. NMA was performed to estimate relative treatment effects among evaluated interventions. RESULTS: Five trials met the inclusion criteria and were included in the NMA. The relative efficacy of neoadjuvant pembrolizumab + chemotherapy followed by adjuvant pembrolizumab was favorable to paclitaxel followed by anthracycline + cyclophosphamide in terms of pathologic complete response (pCR), event-free survival (EFS), and overall survival; paclitaxel + carboplatin followed by anthracycline + cyclophosphamide in terms of pCR and EFS; paclitaxel + bevacizumab followed by anthracycline + cyclophosphamide + bevacizumab in terms of pCR; and paclitaxel + carboplatin + veliparib followed by anthracycline + cyclophosphamide in terms of EFS. CONCLUSIONS: Neoadjuvant pembrolizumab + chemotherapy followed by adjuvant pembrolizumab confers benefits in response and survival outcomes versus alternative neoadjuvant treatments for early-stage TNBC.

The Plasma Membrane Monoamine Transporter is Highly Expressed in Neuroblastoma and Functions as an mIBG Transporter.

Neuroblastoma (NB) is a pediatric cancer with low survival rates in high-risk patients. 131I-mIBG has emerged as a promising therapy for high-risk NB and kills tumor cells by radiation. Consequently, 131I-mIBG tumor uptake and retention are major determinants for its therapeutic efficacy. mIBG enters NB cells through the norepinephrine transporter (NET), and accumulates in mitochondria through unknown mechanisms. Here we evaluated the expression of monoamine and organic cation transporters in high-risk NB tumors and explored their relationship with MYCN amplification and patient survival. We found that NB mainly expresses NET, the plasma membrane monoamine transporter (PMAT), and the vesicular membrane monoamine transporter 1/2 (VMAT1/2), and that the expression of these transporters is significantly reduced in MYCN-amplified tumor samples. PMAT expression is the highest and correlates with overall survival in high-risk NB patients without MYCN amplification. Immunostaining showed that PMAT resides intracellularly in NB cells and co-localizes with mitochondria. Using cells expressing PMAT, mIBG was identified as a PMAT substrate. In mitochondria isolated from NB cell lines, mIBG uptake was reduced by ∼50% by a PMAT inhibitor. Together, our data suggest that PMAT is a previously unrecognized transporter highly expressed in NB and could impact intracellular transport and therapeutic response to 131I-mIBG. SIGNIFICANCE STATEMENT: This study identified that plasma membrane monoamine transporter (PMAT) is a novel transporter highly expressed in neuroblastoma and its expression level is associated with overall survival rate in high-risk patients without MYCN amplification. PMAT is expressed intracellularly in neuroblastoma cells, transports meta-iodobenzylguanidine (mIBG) and thus could impact tumor retention and response to 131I-mIBG therapy. These findings have important clinical implications as PMAT could represent a novel molecular marker to help inform disease prognosis and predict response to 131I-mIBG therapy.

A 9-Year Review of Ethics Complaints to the American Society of Plastic Surgeons.

PURPOSE: The American Society of Plastic Surgeons (ASPS) provides an avenue for filing formal complaints regarding unethical behavior of Members. These complaints are investigated by the Ethics Committee and referred to the Judicial Council if a violation may have occurred. METHODS: A review of complaints filed with the ASPS from 2013-2021 was performed. Data surrounding both complaints and complainant type were reviewed, as well as region of complaint origin. Categories of violations resulting formal investigations and Judicial Council referrals were also reviewed. RESULTS: A total of 584 complaints were filed with the ASPS Ethics Committee from 2013-2021, which was nearly 100 fewer than from a prior review of 2004-2008. Twenty-one percent of complaints were formally investigated by the Ethics Committee, and 26% of these were referred to the Judicial Council. The most common complaint investigated was related to advertising/misleading communications, whereas the most common complaint referred to the Judicial Council was regarding expert testimony. Most complaints were filed by ASPS members. CONCLUSIONS: The total number of complaints filed decreased significantly, the reasons for which are unclear. Evolution of culture and thought likely impacted not only specific behaviors, but also the likelihood of reporting those behaviors. It remains incumbent on plastic surgeons to utilize the self-regulating mechanisms available in order to maintain the autonomy we enjoy as a profession.

Incremental cost burden among patients with severe uncontrolled asthma in the United States.

BACKGROUND: The economic burden of severe asthma and severe uncontrolled asthma (SUA) is significant. Updated assessments of health care resource utilization (HCRU) and cost are needed given the increase in treatment options and updates to guidelines in recent years. OBJECTIVE: To describe all-cause and asthma-related HCRU and costs among patients with SUA vs patients with nonsevere asthma in the United States using real-world data. METHODS: MarketScan administrative claims databases were used to select adults with persistent asthma for this retrospective analysis between January 1, 2013, and December 31, 2019. Asthma severity status was defined using the Global Initiative for Asthma step 4/5 criteria (index is the earliest date qualifying patients as severe or randomly assigned for nonsevere patients). Patients with SUA were a subset of the severe cohort meeting the following criteria: those who were hospitalized with asthma as the primary diagnosis or had at least 2 emergency department or outpatient visits with an asthma diagnosis and a steroid burst within 7 days. HCRU, costs (allcause and asthma-related defined as medical claims with an asthma diagnosis and pharmacy claims for asthma treatment), work loss, and indirect costs due to absenteeism and short-term disability (STD) were compared between patients with SUA, severe, and nonsevere asthma. Outcomes were reported during a fixed 12-month post-index period using chi-square and t-tests where appropriate. RESULTS: 533,172 patients with persistent asthma were identified (41.9% [223,610]) severe and 58.1% [309,562] nonsevere). Of the severe patients, 17.6% (39,380) had SUA. The mean (SD) all-cause total health care costs were significantly higher in patients with SUA ($23,353 [$40,817]) and severe asthma ($18,554 [$36,147]) compared with those with nonsevere asthma ($16,177 [$37,897], P < 0.001 vs nonsevere asthma). The results were consistent for asthma-related costs. In addition, although patients with severe asthma made up 41.9% of the total study population, they contributed disproportionately higher costs (60.5%) to the total asthma-related direct costs, with the effect more evident among patients with SUA (7.4% of study population contributed 17.7% of the total asthma-related costs). For the subset of patients with asthma with workplace absenteeism, patients with SUA lost more time from work (259.3 vs 236.2 hours lost, P = 0.002; 7.8 vs 5.3 STD days, P < 0.001), and had higher corresponding indirect costs ($5,944 vs $5,415, P = 0.002 for absenteeism related; $856 vs $582, P < 0.001 for STD related) compared with patients with nonsevere asthma. CONCLUSIONS: Patients with SUA have significantly higher asthma-related economic burden compared with patients with nonsevere asthma and contribute a disproportionally higher percentage of asthma-related costs. DISCLOSURES: This study was funded by Amgen and AstraZeneca. The design and analysis for this study was conducted primarily by Merative. Amgen and AstraZeneca provided funding to support protocol development, data analysis, and manuscript development activities associated with this study. Dr Burnette is on the advisory board and a consultant for GSK, a consultant and member of the advisory boards and speakers' bureaus of Sanofi, Genzyme, Regeneron, AstraZeneca, and Amgen Inc. Dr Wang, Dr Rane, Dr Lindsley, and Dr Llanos are employees and shareholders of Amgen Inc. Dr Chung and Dr Ambrose are employees and shareholders of AstraZeneca. Ms Princic and Ms Park are employees of Merative, which received funding from Amgen to conduct this study.

Children's Oncology Group's 2023 blueprint for research: Neuroblastoma.

Neuroblastoma is the most common extra-cranial solid tumor in children and is known for its clinical heterogeneity. A greater understanding of the biology of this disease has led to both improved risk stratification and new approaches to therapy. Outcomes for children with low and intermediate risk disease are excellent overall, and efforts to decrease therapy for such patients have been largely successful. Although survival has improved over time for patients with high-risk disease and treatments evaluated in the relapse setting are now being moved into earlier phases of treatment, much work remains to improve survival and decrease therapy-related toxicities. Studies of highly annotated biobanked samples continue to lead to important insights regarding neuroblastoma biology. Such studies, along with correlative biology studies incorporated into therapeutic trials, are expected to continue to provide insights that lead to new and more effective therapies. A focus on translational science is accompanied by an emphasis on new agent development, optimized risk stratification, and international collaboration to address questions relevant to molecularly defined subsets of patients. In addition, the COG Neuroblastoma Committee is committed to addressing the patient/family experience, mitigating late effects of therapy, and studying social determinants of health in patients with neuroblastoma.

20 years on - the measurement of blood pressure and detection of hypertension in children and adolescents: a national descriptive survey.

In 1997 a survey identified a general lack of standardisation of blood pressure (BP) measurement and little consensus on the criteria for diagnosing hypertension amongst paediatricians. We have conducted a new online survey in 2021, to compare clinical practice between the two time periods. A national quality improvement survey was approved by the GAPRUKI committee and then circulated to consultant-grade general paediatricians. 125 analysable replies from 34 different sites were received and compared with the 1997 data. 106 (84.8%) reported clinic nurse involvement in BP measurement, more than twice than reported previously (40.6%). Most paediatricians (53.6%) now rely on oscillometric devices, whereas the mercury sphygmomanometer was favoured previously (82.7%). If assessing BP manually (n = 89), most (79.8%) now use Korotkoff phase V as the auscultatory endpoint for diastolic BP (phase IV was previously used (52.1%)). Diagnostic criteria of hypertension, the criteria (≥95th centile for gender, age and height) were constant, and 100% of paediatricians diagnosed it using systolic BP, but only 43 (34.4%) used diastolic BP, a decrease from 79.4% previously. Ambulatory BP Monitoring was six times more available than in 1997 (81.6% vs 13.6%). Similar to previous findings, only 12 (9.6%) paediatricians would manage hypertensive patients themselves, however 82 (72.6%) would keep general paediatric input. There have been important changes in the assessment of BP in children, including increased nurse involvement and greater use of technology. However, fewer paediatricians are responding to high diastolic pressures than twenty years ago.