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The MEK inhibitor selumetinib induces objective responses and provides clinical benefit in children with neurofibromatosis type 1 (NF1) and inoperable plexiform neurofibromas (PNs). To evaluate whether similar outcomes were possible in adult patients, in whom PN growth is generally slower than in pediatric patients, we conducted an open-label phase 2 study of selumetinib in adults with NF1 PNs. The study was designed to evaluate objective response rate (primary objective), tumor volumetric responses, patient-reported outcomes and pharmacodynamic effects in PN biopsies. The objective response rate was 63.6% (21/33 participants). Median maximal PN volume decrease was 23.6% (range: −48.1% to 5.5%). No disease progression relative to baseline PN volumes occurred before data cutoff, with a median of 28 cycles completed (range: 1–78, 28 d per cycle). Participants experienced decreased tumor pain intensity and pain interference. Adverse events (AEs) were similar to those of the pediatric trial; acneiform rash was the most prevalent AE. Phosphorylation ratios of ERK1/2 decreased significantly (ERK1 median change: −64.6% (range: −99.5% to 90.7%), ERK2 median change: −57.3% (range: −99.9% to 84.4%)) in paired PN biopsies (P≤ 0.001 for both isoforms) without compensatory phosphorylation of AKT1/2/3. The sustained PN volume decreases, associated improvement in pain and manageable AE profile indicate that selumetinib provides benefit to adults with NF1 and inoperable PNs. ClinicalTrials.gov identifier: NCT02407405.

Acceptance and Commitment Therapy (ACT) is a well-evidenced therapeutic model for the treatment of chronic pain. While there is substantial data that indicates improvement in the cognitive and behavioral aspects of pain (e.g., pain acceptance, pain inflexibility, pain interference), significantly less research has explored changes in physiological variables following acceptance-based interventions. In particular, heart rate variability (HRV) is a physiological marker of pain and reflects the time elapsed between heart beats. The current study examined whether HRV changed following a randomized-controlled trial of ACT for individuals with neurofibromatosis type 1 and chronic pain (N = 62). Repeated measures analyses of covariance assessed change following ACT. In addition, hierarchical linear regression models examined pain-related predictors of HRV at follow-up. The results suggest that HRV improves following ACT, although given the small sample and limited analytical model, the findings should be considered preliminary. Further, improvements in HRV over the course of the intervention predicted improvements in pain intensity at follow-up suggesting a relationship between these two variables. Taken together, these data provide modest evidence of the relationships between ACT and HRV within a chronic pain population. Additional implications and future directions are discussed.

Remission durability following single-antigen targeted chimeric antigen receptor (CAR) T-cells is limited by antigen modulation, which may be overcome with combinatorial targeting. Building upon our experiences targeting CD19 and CD22 in B-cell acute lymphoblastic leukemia (B-ALL), we report on our phase 1 dose-escalation study of a novel murine stem cell virus (MSCV)-CD19/CD22-4-1BB bivalent CAR T-cell (CD19.22.BBζ) for children and young adults (CAYA) with B-cell malignancies. Primary objectives included toxicity and dose finding. Secondary objectives included response rates and relapse-free survival (RFS). Biologic correlatives included laboratory investigations, CAR T-cell expansion and cytokine profiling. Twenty patients, ages 5.4 to 34.6 years, with B-ALL received CD19.22.BBζ. The complete response (CR) rate was 60% (12 of 20) in the full cohort and 71.4% (10 of 14) in CAR-naïve patients. Ten (50%) developed cytokine release syndrome (CRS), with 3 (15%) having ≥ grade 3 CRS and only 1 experiencing neurotoxicity (grade 3). The 6- and 12-month RFS in those achieving CR was 80.8% (95% confidence interval [CI]: 42.4%-94.9%) and 57.7% (95% CI: 22.1%-81.9%), respectively. Limited CAR T-cell expansion and persistence of MSCV-CD19.22.BBζ compared with EF1α-CD22.BBζ prompted laboratory investigations comparing EF1α vs MSCV promoters, which did not reveal major differences. Limited CD22 targeting with CD19.22.BBζ, as evaluated by ex vivo cytokine secretion and leukemia eradication in humanized mice, led to development of a novel bicistronic CD19.28ζ/CD22.BBζ construct with enhanced cytokine production against CD22. With demonstrated safety and efficacy of CD19.22.BBζ in a heavily pretreated CAYA B-ALL cohort, further optimization of combinatorial antigen targeting serves to overcome identified limitations (www.clinicaltrials.gov #NCT03448393).

Objective: To investigate possible alterations in dopaminergic function in children with acquired immunodeficiency syndrome by evaluating spontaneous eye blink rate, a putative measure of central dopaminergic function. Design: Evaluation of previously videotaped test sessions of a consecutive case series of 50 children (mean age, 5.2 years; range, 2-12 years) with acquired immunodeficiency syndrome. Setting: Government medical research center. Results: Intrarater reliability was high, expected covariation of blink rate with age and concurrent mental activity were confirmed, and obtained rates were similar to published data. Higher blink rates, suggestive of increased dopaminergic function, were associated with more severe cortical atrophy (P[is less than].05) and white matter abnormality (P[is less than].05) on computed tomographic brain scans. The presence or severity of basal ganglia calcifications did not seem to influence blink rate. In addition, higher blink rates were associated with higher ratings of depressed affect (P[is less than].05) and lower ratings of hyperactive behaviors (P[is less than].05) during other test activities. Conclusions: The higher blink rates in human immunodeficiency virus-infected children with more severe cortical abnormalities suggest increased central dopamine activity compared with that in children without cortical computed tomographic brain scan abnormalities. Thus, as a result of structural brain abnormalities, neurotransmitter levels in children with acquired immunodeficiency syndrome may vary and this may be reflected in their socioemotional functioning. Arch Pediatr Adolesc Med. 1997;151:1025-1032, Children with HIV infection may have increased dopamine activity in their brains, as measured by spontaneous eye blinking. Progressive HIV infection has been reported to impair the neurotransmitter dopamine and its activities in the brain. Researchers studied 50 children with HIV infection by evaluating their eye blink rate, a probable measure of dopamine activity. Higher blink rates were related to shrinking of the brain cortex, white matter abnormalities, and depression. Higher blink rates were associated with more brain abnormalities, contrary to expectations.

As clinical advances with chimeric antigen receptor (CAR) T cells are increasingly described and the potential for extending their therapeutic benefit grows, optimizing the implementation of this therapeutic modality is imperative. The recognition and management of cytokine release syndrome (CRS) marked a milestone in this field; however, beyond the understanding gained in treating CRS, a host of additional toxicities and/or potential late effects of CAR T cell therapy warrant further investigation. A multicentre initiative involving experts in paediatric cell therapy, supportive care and/or study of late effects from cancer and haematopoietic stem cell transplantation was convened to facilitate the comprehensive study of extended CAR T cell-mediated toxicities and establish a framework for new systematic investigations of CAR T cell-related adverse events. Together, this group identified six key focus areas: extended monitoring of neurotoxicity and neurocognitive function, psychosocial considerations, infection and immune reconstitution, other end organ toxicities, evaluation of subsequent neoplasms, and strategies to optimize remission durability. Herein, we present the current understanding, gaps in knowledge and future directions of research addressing these CAR T cell-related outcomes. This systematic framework to study extended toxicities and optimization strategies will facilitate the translation of acquired experience and knowledge for optimal application of CAR T cell therapies.

Neurofibromatosis type 1 (NF1) plexiform neurofibromas (PNs) are progressive, multicellular neoplasms that cause morbidity and may transform to sarcoma. Treatment of Nf1fl/fl;Postn-Cre mice with cabozantinib, an inhibitor of multiple tyrosine kinases, caused a reduction in PN size and number and differential modulation of kinases in cell lineages that drive PN growth. Based on these findings, the Neurofibromatosis Clinical Trials Consortium conducted a phase II, open-label, nonrandomized Simon two-stage study to assess the safety, efficacy and biologic activity of cabozantinib in patients =16 years of age with NF1 and progressive or symptomatic, inoperable PN (NCT02101736). The trial met its primary outcome, defined as =25% of patients achieving a partial response (PR, defined as =20% reduction in target lesion volume as assessed by magnetic resonance imaging (MRI)) after 12 cycles of therapy. Secondary outcomes included adverse events (AEs), patient-reported outcomes (PROs) assessing pain and quality of life (QOL), pharmacokinetics (PK) and the levels of circulating endothelial cells and cytokines. Eight of 19 evaluable (42%) trial participants achieved a PR. The median change in tumor volume was 15.2% (range, +2.2% to -36.9%), and no patients had disease progression while on treatment. Nine patients required dose reduction or discontinuation of therapy due to AEs; common AEs included gastrointestinal toxicity, hypothyroidism, fatigue and palmar plantar erythrodysesthesia. A total of 11 grade 3 AEs occurred in eight patients. Patients with PR had a significant reduction in tumor pain intensity and pain interference in daily life but no change in global QOL scores. These data indicate that cabozantinib is active in NF1-associated PN, resulting in tumor volume reduction and pain improvement.

Neurotoxicity associated with CAR-T cell therapy can be life-threatening. With rapid development of CAR-T therapies, a systematic method is needed to identify and monitor symptoms of neurotoxicity, elucidate potential etiologies, and compare toxicity across trials. This paper presents a systematic evaluation developed and used to prospectively assess neurotoxicity in our phase I anti-CD22 CAR-T-cell trial and describes the symptoms of neurotoxicity identified using this methodology. Central nervous system (CNS) studies included routine lumbar punctures performed for disease evaluation pretherapy and posttherapy and a baseline brain MRI. Brief cognitive evaluations, assessing 4 domains (attention, working memory, cognitive flexibility, and processing speed), were administered preinfusion and postinfusion. A newly developed CAR-T-specific neurological symptom checklist (NSC) was completed by caregivers at 3 designated time-points. Serial serum cytokine levels were compared with neurotoxicity symptoms and severity. The majority of the first 22 consecutively treated subjects (ages, 7–30) demonstrated stable or improved cognitive test scores following therapy and no irreversible neurotoxicity, despite CAR-T-related antileukemic response, cytokine release syndrome, and trafficking of CAR-T cells to the CSF. The NSC allowed us to document the type and timing of symptoms and explore the etiology of neurotoxicity associated with CD22 CAR-T therapy. Cytokine profiling demonstrated that more concerning symptoms of neurotoxicity, such as hallucination and disorientation, were significantly associated with higher serum cytokine levels, supporting the hypothesis of inflammation-driven neurotoxicity. Systematic assessments of neurotoxicity were feasible in acutely ill children and young adults and served to characterize and monitor the symptoms associated with CAR-T therapy. We recommend these evaluations be incorporated into future immunotherapy protocols.

Chimeric antigen receptor (CAR) T cells targeting CD19 mediate potent effects in relapsed and/or refractory pre–B cell acute lymphoblastic leukemia (B-ALL), but antigen loss is a frequent cause of resistance to CD19-targeted immunotherapy. CD22 is also expressed in most cases of B-ALL and is usually retained following CD19 loss. We report results from a phase 1 trial testing a new CD22-targeted CAR (CD22-CAR) in 21 children and adults, including 17 who were previously treated with CD19-directed immunotherapy. Dose-dependent antileukemic activity was observed, with complete remission obtained in 73% (11/15) of patients receiving ≥1 × 106CD22-CAR T cells per kg body weight, including 5 of 5 patients with CD19dimor CD19−B-ALL. Median remission duration was 6 months. Relapses were associated with diminished CD22 site density that likely permitted CD22+cell escape from killing by CD22-CAR T cells. These results are the first to establish the clinical activity of a CD22-CAR in B-ALL, including leukemia resistant to anti-CD19 immunotherapy, demonstrating potency against B-ALL comparable to that of CD19-CAR at biologically active doses. Our results also highlight the critical role played by antigen density in regulating CAR function.

•Acute toxicities of chimeric antigen receptor T cell (CAR-T) therapy are well recognized with standardized definitions.•Preemptive strategies may mitigate CAR-T therapy-related inflammatory toxicities.•Monitoring pediatric-specific late toxicities of CAR-T therapy is a research priority.•A pediatric-focused review of emergent CAR-T therapy toxicities and their management is presented.

Context:Limited data suggest that interrupting sedentary behaviors with activity improves metabolic parameters in adults.Objective:We tested whether interrupting sitting with short, moderate-intensity walking bouts improved glucose tolerance in children.Design:Participants underwent two experimental conditions in random order on different days: continuous sitting for 3 hours or sitting interrupted by walking (3 min of moderate-intensity walking every 30 min). Insulin, C-peptide, glucose, and free fatty acids were measured every 30 minutes for 3 hours during an oral glucose tolerance test. Area under the curve (AUC) was calculated from hormone and substrate measurements. Children were given a buffet meal after each condition.Setting:The study was conducted at the National Institutes of Health Hatfield Clinical Research Center.Participants:Twenty-eight normal-weight 7–11 year olds participated.Main Outcomes:Patterns of substrate/hormone secretion and AUC, as well as energy intake, were examined by experimental condition.Results:Interrupting sitting resulted in a 32% lower insulin AUC (P< .001), 17% lower C-peptide AUC (P< .001), and 7% lower glucose AUC (P= .018) vs continuous sitting. Mixed model results indicated that insulin (P= .036) and free fatty acid concentrations (P= .009) were significantly lower in the interrupted vs the continuous sitting condition. Lunchtime buffet meal energy intake did not significantly differ between the conditions (975 ± 387 vs 963 ± 309 kcal; P= .85).Conclusions:Interrupting sedentary time with brief moderate-intensity walking improved short-term metabolic function in non-overweight children without increasing subsequent energy intake. These findings suggest that interrupting sedentary behavior may be a promising prevention strategy for reducing cardiometabolic risk in children.

Neurofibromatosis (NF) is a genetic disease with multiple clinical manifestations that can significantly impact quality of life (QOL). Clinical trials should include patient-reported outcomes (PROs) as endpoints to assess treatment effects on various aspects of QOL, but there is no consensus on the selection and use of such measures in NF. This article describes the PRO Working Group of the Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) Collaboration, its main goals, methods for identifying appropriate PRO measures for NF clinical trials, and recommendations for assessing pain intensity.

The neurofibromatoses (NF)—including neurofibromatosis 1 (NF1), neurofibromatosis 2 (NF2), and schwannomatosis—are related tumor-suppressor syndromes characterized by a predisposition to multiple tumor types and other disease manifestations, which often result in functional disability, reduced quality of life, pain, and, in some cases, malignancy. With increasing knowledge of the biology and pathogenesis of NF, clinical trials with targeted agents directed at NF tumors have become available. Most clinical trials for patients with NF have used designs and endpoints similar to oncology trials. However, differences in the disease manifestations and natural history of NF (compared to cancers) require the development of new designs and endpoints to perform meaningful NF clinical trials. The Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) International Collaboration was established in 2011 at the Children's Tumor Foundation meeting to achieve consensus within the NF community about the design of future clinical trials, with a specific emphasis on endpoints. The REiNS Collaboration includes 7 working groups that focus on imaging of tumor response; functional, visual, patient-reported, and neurocognitive outcomes; whole-body MRI; and disease biomarkers. This supplement includes the first series of recommendations by the REiNS Collaboration. The hope is that these recommendations will be used by members of the group and by researchers outside of the REiNS International Collaboration to standardize the measurement of outcomes and thus improve clinical trials for patients with NF. Ultimately, we plan to engage industry partners and national regulatory agencies in this process to facilitate the approval of drugs for patients with NF.

The Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) International Collaboration was established with the goal to develop consensus recommendations for the use of endpoints in neurofibromatosis (NF) clinical trials. This supplement includes the first series of REiNS recommendations for the use of patient-reported, functional, and visual outcomes, and for the evaluation of imaging response in NF clinical trials. Recommendations for neurocognitive outcome measures, the use of whole-body MRI in NF, the evaluation of potential biomarkers of disease, and the comprehensive evaluation of functional and patient-reported outcomes in NF are in development. The REiNS recommendations are made based on current knowledge. Experience with the use of the recommended endpoints in clinical trials, development of new tools and technologies, new knowledge of the natural history of NF, and advances in the methods used to analyze endpoints will likely lead to modifications of the currently proposed guidelines, which will be shared with the NF research community through the REiNS Web site www.reinscollaboration.org. Due to the clinical complexity of NF, there is a need to seek expertise from multiple medical disciplines, regulatory agencies, and industry to develop trial endpoints and designs, which will lead to the identification and approval of effective treatments for NF tumor and nontumor manifestations. The REiNS Collaboration welcomes anyone interested in providing his or her expertise toward this effort.

This study assesses the relationship between child and caregiver perceptions of medication responsibility, disease knowledge, regimen complexity and adherence to highly active antiretroviral therapy among HIV-positive children. We also examine the association of adherence to child and caregiver demographic characteristics and surrogate markers of HIV disease.

The effect of white matter abnormalities on neurobehavioral dysfunction was investigated in 58 children with symptomatic HIV-1 disease, 28 with CT white matter abnormalities and 30 matched (for age, gender, route of infection, and stage of disease) control patients with comparable levels of cortical atrophy, but no white matter abnormalities. Children with white matter abnormalities were more impaired on measures of general level of mental functioning (standard scores of 70.3 vs. 86.1; p < .05). They also scored lower than the group without white matter abnormalities on activities of daily living (76.9 vs. 87.4; p < .05), particularly those requiring self-help skills, and in socialization (79.5 vs. 89.3; p < .05). Furthermore, patients with white matter abnormalities exhibited higher levels of attention deficit/hyperactive behaviors (p < .05) and more severe autistic symptoms (p < .05). White matter abnormalities by themselves were, thus, associated with deficits in cognitive function and socio-emotional behavior. These findings are in partial agreement with the nonverbal learning disabilities (NLD) model. Although NLD profiles, in general, have been described in older children, the current results seem to suggest that antecedents for these behavior patterns can be found in much younger children with white matter abnormalities.

Although psychologists recognize the limitations of currently available tests for assessing the cognitive abilities of nonvocal, physically handicapped children, they continue to have responsibility for such assessment. Assessment is necessary to provide access to services, to determine the most appropriate learning environments and educational programs, and to develop effective augmentative communication systems. Providing a “fair” assessment is difficult. There are three approaches to such assessment: the use of currently available standardized instruments that accommodate the child's mode of response indication, the use of test modifications and the use of unique test instruments developed for this population. The problems and advantages of each of these approaches are discussed. Current best practice involves a careful consideration of the referral questions; working closely with occupational and physical therapists to assure that the child is optimally positioned and is using the most efficient mode of indication; selecting assessment instruments that will both address the specific referral questions and accommodate the child's mode of indication; remaining cautious in the interpretation of the test findings; and providing frequent re-evaluations.

Neurofibromatosis type 1 (NF1) is a genetic syndrome associated with multiple complications that cause chronic pain, including plexiform neurofibroma (PN) tumors. However, no randomized studies have examined non-pharmacological interventions for pain specifically targeting individuals with NF1 and PNs. In the current randomized controlled trial, an Acceptance and Commitment Therapy intervention was conducted with older adolescents and adults ages 16–59 years with NF1, PNs, and chronic pain. We hypothesized that pain interference would decrease from pre-to post-intervention compared to a wait-list control group. We also examined potential mediators, including pain acceptance and inflexibility. The intervention consisted of two 2-h in-person sessions followed by 8 weeks of online training including weekly email assignments and biweekly video chats. Outcome measures evaluating pain interference, pain intensity, pain anxiety, and depression and process measures evaluating pain acceptance and pain inflexibility were administered at baseline and after the 8-week intervention. Sixty-two participants (M age = 30.7 ± 11.5 years, 61.3% female) completed the intervention. Results indicated that the ACT intervention significantly reduced how much pain interfered with daily functioning. Improvements in pain acceptance and, separately, pain inflexibility, mediated the treatment benefit for individuals in the ACT group. No improvements in pain intensity, pain anxiety, or depression were noted following the intervention. Durable treatment benefits were seen at 6 months albeit only among those who improved more during the 8-week intervention. While the immediate post-intervention effects were seen after 4 h of in-person training and limited online sessions, more support is likely needed to maintain these effects long-term. Results indicate that remote ACT interventions have promise and could make this treatment accessible to more patients with NF1, PNs and chronic pain.

Lee: Juno: Honoraria. Mackall:NCI: Patents & Royalties: B7H3 CAR.