Abstract: Cranial computed tomography (CT) scans are frequently obtained in the evaluation of blunt head trauma in children. These scans may detect unexpected incidental findings. The objectives of this study were to determine the prevalence and significance of incidental findings on cranial CT scans in children evaluated for blunt head trauma. METHODS: This was a secondary analysis of a multicenter study of pediatric blunt head trauma. Patients & lt;18 years of age with blunt head trauma were eligible, with those undergoing cranial CT scan included in this substudy. Patients with coagulopathies, ventricular shunts, known previous brain surgery or abnormalities were excluded. We abstracted radiology reports for nontraumatic findings. We reviewed and categorized findings by their clinical urgency. RESULTS: Of the 43 904 head-injured children enrolled in the parent study, 15 831 underwent CT scans, and these latter patients serve as the study cohort. On 670 of these scans, nontraumatic findings were identified, with 16 excluded due to previously known abnormalities or surgeries. The remaining 654 represent a 4% prevalence of incidental findings. Of these, 195 (30%), representing 1% of the overall sample, warranted immediate intervention or outpatient follow-up. CONCLUSIONS: A small but important number of children evaluated with CT scans after blunt head trauma had incidental findings. Physicians who order cranial CTs must be prepared to interpret incidental findings, communicate with families, and ensure appropriate follow-up. There are ethical implications and potential health impacts of informing patients about incidental findings.

Abstract: Introduction: Preclinical data suggest that PD-1 and PD-L1/PD-L2 mediate immune evasion in CLL. However, clinical data (Ding, BLOOD 2017) demonstrate that pembrolizumab monotherapy (pembro) is ineffective in relapsed/refractory (r/r) CLL patients (pts) (ORR 0%, med PFS 2.4 months). Additional data with an anti-PD1 demonstrated a 90% failure rate in Richter's Transformation (RT) with a med 2-month OS (Rogers, BJH 2018). Combinations may represent the future of anti-PD-1 therapy in CLL/RT, especially in RT pts rel/ref to ibrutinib, where median OS is ~3.5 mos. We hypothesized synergistic activity with PD-1 + PI3K blockade. Umbralisib (UMB), is a highly-specific PI3K-δ inhibitor with additional effects on casein kinase-1 epsilon (CK-1ε), which may have an inhibitory effect on Treg function (Deng et al, 2016). We tested the safety and activity of UMB in combination with the anti-CD20 mAb ublituximab (UTX) and pembro in r/r CLL and RT - the first reported combination of a PD-1 inhibitor + PI3K-δ inhibitor in this population. Methods: Ph I (3+3 design), multicenter study to assess the safety/efficacy of UMB + UTX + pembro in pts with r/r CLL and RT. Treatment for CLL pts involved three stages: Induction: UMB (800mg daily) and UTX (900mg 3 out of 4 wks) for the first two 28-day cycles. Consolidation: Pembro (dose level 1=100mg, dose level 2=200mg) was then initiated every 3 wks in combination with UMB and UTX (900mg week 2 of cycle 4 and 6) for cycles 3-6. Maintenance: Cycle 〉 6, UMB 800 mg daily until progressive disease (PD) or unacceptable AE. For RT pts, all study drugs are started in cycle 1 with the following schedule: UMB 800 mg daily; UTX 900 mg cycle 1 (D1, 8, 15), D1 cycles 2-4, cycle 7 and q3 cycles thereafter; and pembro D3 of cycle 1 and D2 of cycles 2-4. The primary endpoint is safety of the triple combination with efficacy as a secondary endpoint. Response assessments for CLL, based on the iwCLL 2008 criteria, were performed after cycles 2, 6 and 12. RT response assessments (Cheson 2007) were completed at the end of cycles 2, 4 and every 3 cycles until month 12. Peripheral blood and/or bone marrow biopsy, enriched for mononuclear cells, were obtained for correlative analyses at screening, month 2 and 6. Results: Fourteen pts have been treated to date: 9 with CLL (3 at 100 mg pembro / 6 at 200 mg pembro) and 5 with RT (4 at 100 mg pembro / 1 at 200 mg). Baseline demographics were as follows: male/female (9/5), med age 71 yrs (range 60-81), med prior therapies 2 (1-8), 79% were refractory to immediate prior therapy. 10 pts had prior ibrutinib of which 9 were ibrutinib refractory. 64% of pts had at least 1 high risk genetic feature (del17p, del11q, TP53 mut, NOTCH1 mut or complex karyotype). AE's (all causality) were manageable. Grade 3/4 AE's occurring in ≥ 3 pts included neutropenia (n=6, 43%), ALT/AST increase (n=3, 21%) and hypophosphatemia (n=3, 21%). One DLT occurred in a CLL pt at 200 mg dose level (ALT/AST elevation) which trigged expansion to 6 pts. No additional DLTs were reported, and no MTD was achieved. No increase in expected grade ≥ 3 PI3Kδ-associated toxicities were noted (1 pneumonitis event, no colitis events). ORR was 89% for CLL pts with ORR of 75% in BTK refractory CLL pts (3/4). Notably 2/4 BTK refractory CLL pts achieved a response to UMB + UTX (U2) induction alone prior to the addition of pembro. 4/5 RT pts were eligible for efficacy evaluation with 50% ORR (2/4, CR). The 2 RT CRs were durable and are ongoing (15+ mos and 7+ mos); both pts were ibrutinib refractory and had 7 (including SCT) and 8 prior lines respectively, and one had failed CAR-T. With a med follow up of 15 mos, 10/14 (71%) remain progression free (range 3 - 44 mos, Fig 1), including one CLL pt who completed consolidation and has been off therapy for 27+ mos. Sequential sampling for correlative studies demonstrated modest changes in Tregs numbers (Fig 2). Conclusion: The triplet combination of umbralisib + ublituximab + pembro was well-tolerated. Responses were durable in BTK refractory, high risk pts, including two CR's in RT pts. In contrast to pembro monotherapy, data suggest that CLL/RT pts who achieve ≥ PR with this checkpoint inhibitor-containing regimen can achieve durable responses. Correlative studies suggest that maintenance of Tregs may limit autoimmune sequelae. Enrollment is ongoing in both the CLL (BTK refractory only) and RT cohorts. Disclosures Mato: AbbVie: Consultancy, Research Funding; Portola: Research Funding; Regeneron: Research Funding; AstraZeneca: Consultancy; Johnson & Johnson: Consultancy; Celgene: Consultancy; Medscape: Honoraria; TG Therapeutics: Consultancy, Research Funding; Pharmacyclics, an AbbVie Company: Consultancy, Research Funding; Acerta: Research Funding; Prime Oncology: Honoraria. Svoboda:Regeneron: Research Funding; KITE: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; TG Therapeutics: Research Funding; Pharmacyclics: Consultancy, Research Funding; Kyowa: Consultancy; Seattle Genetics: Consultancy, Research Funding; Merck: Research Funding. Schuster:Gilead: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Nordic Nanovector: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria, Research Funding; Dava Oncology: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Honoraria, Research Funding. Becker:GlycoMimetics: Research Funding. Brander:DTRM: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; BeiGene: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Novartis: Consultancy, Other: DSMB; Pharmacyclics, an AbbVie Company: Consultancy, Honoraria, Research Funding; Acerta: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; TG Therapeutics: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Teva: Consultancy, Honoraria; Genentech: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; AbbVie: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding. Dwivedy Nasta:Aileron: Research Funding; Pharmacyclics: Research Funding; Debiopharm: Research Funding; Incyte: Research Funding; Rafael/WF: Research Funding; Roche: Research Funding; Takeda/Millenium: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Merck: Other: DSMC. Landsburg:Takeda: Consultancy; Curis: Consultancy, Research Funding. Kennard:AbbVie, Gilead, Verastem: Consultancy. Zelenetz:Abbvie: Research Funding; Celgene: Consultancy; AstraZeneca: Consultancy; Novartis/Sandoz: Consultancy; Amgen: Consultancy; Gilead: Consultancy, Research Funding; Genentech/Roche: Consultancy, Research Funding. Purdom:TG Therapeutics: Employment, Equity Ownership. Paskalis:TG Therapeutics: Employment, Equity Ownership. Sportelli:TG Therapeutics: Employment, Equity Ownership. Miskin:TG Therapeutics: Employment, Equity Ownership. Weiss:TG Therapeutics: Employment, Equity Ownership. Shadman:Gilead Sciences: Research Funding; Celgene: Research Funding; AstraZeneca: Consultancy; Beigene: Research Funding; AbbVie: Consultancy; Genentech: Research Funding; Qilu Puget Sound Biotherapeutics: Consultancy; Genentech: Consultancy; Mustang Biopharma: Research Funding; Acerta Pharma: Research Funding; TG Therapeutics: Research Funding; Pharmacyclics: Research Funding; Verastem: Consultancy.

Abstract: Computed tomography ( CT ) is often used in the emergency department ( ED ) evaluation of children with posttraumatic seizures ( PTS ); however, the frequency of traumatic brain injuries ( TBI s) and short‐term seizure recurrence is lacking. Our main objective was to evaluate the frequency of TBI s on CT and short‐term seizure recurrence in children with PTS . We also aimed to determine the associations between the likelihood of TBI on CT with the timing of onset of PTS after the traumatic event and duration of PTS . Finally, we aimed to determine whether patients with normal CT scans and normal neurological examinations are safe for discharge from the ED . Methods This was a planned secondary analysis from a prospective observational cohort study to derive and validate a neuroimaging decision rule for children after blunt head trauma at 25 ED s in the Pediatric Emergency Care Applied Research Network. We evaluated children  〈  18 years with head trauma and PTS between June 2004 and September 2006. We assessed TBI on CT , neurosurgical interventions, and recurrent seizures within 1 week. Patients discharged from the ED were contacted by telephone 1 week to 3 months later. Results Of 42,424 children enrolled, 536 (1.3%, 95% confidence interval [ CI ] = 1.2%–1.4%) had PTS . A total of 466 of 536 (86.9%, 95% CI  = 83.8%–89.7%) underwent CT in the ED . TBI s on CT were identified in 72 (15.5%, 95% CI  = 12.3%–19.1%), of whom 20 (27.8%, 95% CI  = 17.9%–39.6%) underwent neurosurgical intervention and 15 (20.8%, 95% CI  = 12.2%–32.0%) had recurrent seizures. Of the 464 without TBI s on CT (or no CT s performed), 457 had recurrent seizure status known, and five (1.1%, 95 CI  = 0.4%–2.5%) had recurrent seizures; four of five presented with Glasgow Coma Scale scores  〈  15. None of the 464 underwent neurosurgical intervention. We found significant associations between likelihood of TBI on CT with longer time until the PTS after the traumatic event (p = 0.006) and longer duration of PTS (p  〈  0.001). Conclusions Children with PTS have a high likelihood of TBI on CT , and those with TBI on CT frequently require neurosurgical interventions and frequently have recurrent seizures. Those without TBI s on CT , however, are at low risk of short‐term recurrent seizures, and none required neurosurgical interventions. Therefore, if CT ‐negative and neurologically normal, patients with PTS may be safely considered for discharge from the ED .

Abstract: The objective was to compare the accuracy of the pediatric Glasgow Coma Scale ( GCS ) score in preverbal children to the standard GCS score in older children for identifying those with traumatic brain injuries ( TBI s) after blunt head trauma. Methods This was a planned secondary analysis of a large prospective observational multicenter cohort study of children with blunt head trauma. Clinical data were recorded onto case report forms before computed tomography ( CT ) results or clinical outcomes were known. The total and component GCS scores were assigned by the physician at initial emergency department evaluation. The pediatric GCS was used for children 〈 2 years old and the standard GCS for those ≥2 years old. Outcomes were TBI visible on CT and clinically important TBI (ci TBI ), defined as death from TBI , neurosurgery, intubation for more than 24 hours for the head injury, or hospitalization for 2 or more nights for the head injury in association with TBI on CT . We compared the areas under the receiver operating characteristic ( ROC ) curves between age cohorts for the association of GCS and the TBI outcomes. Results We enrolled 42,041 patients, of whom 10,499 (25.0%) were 〈 2 years old. Among patients 〈 2 years, 313/3,329 (9.4%, 95% confidence interval [ CI ] = 8.4% to 10.4%) of those imaged had TBI s on CT and 146/10,499 (1.4%, 95% CI = 1.2% to 1.6%) had ci TBI s. In patients ≥2 years, 773/11,977 (6.5%, 95% CI = 6.0% to 6.9%) of those imaged had TBI s on CT and 572/31,542 (1.8%, 95% CI = 1.7% to 2.0%) had ci TBI s. For the pediatric GCS in children 〈 2 years old, the area under the ROC curve was 0.61 (95% CI = 0.59 to 0.64) for TBI on CT and 0.77 (95% CI = 0.73 to 0.81) for ci TBI . For the standard GCS in older children, the area under the ROC curve was 0.71 (95% CI = 0.70 to 0.73) for TBI on CT scan and 0.81 (95% CI = 0.79 to 0.83) for ci TBI . Conclusions The pediatric GCS for preverbal children was somewhat less accurate than the standard GCS for older children in identifying those with TBI on CT . However, the pediatric GCS for preverbal children and the standard GCS for older children were equally accurate for identifying ci TBI .