PURPOSE The combination of irinotecan, temozolomide, dintuximab, and granulocyte-macrophage colony-stimulating factor (I/T/DIN/GM-CSF) demonstrated activity in patients with relapsed/refractory neuroblastoma in the randomized Children’s Oncology Group ANBL1221 trial. To more accurately assess response rate and toxicity, an expanded cohort was nonrandomly assigned to I/T/DIN/GM-CSF. PATIENTS AND METHODS Patients were eligible at first relapse or first designation of refractory disease. Oral T and intravenous (IV) irinotecan were administered on days 1 to 5 of 21-day cycles. DIN was administered IV (days 2-5), and GM-CSF was administered subcutaneously (days 6-12). The primary end point was objective response, analyzed on an intent-to-treat basis per the International Neuroblastoma Response Criteria. RESULTS Seventeen eligible patients were randomly assigned to I/T/DIN/GM-CSF (February 2013 to March 2015); 36 additional patients were nonrandomly assigned to I/T/DIN/GM-CSF (August 2016 to May 2017). Objective (complete or partial) responses were observed in nine (52.9%) of 17 randomly assigned patients (95% CI, 29.2% to 76.7%) and 13 (36.1%) of 36 expansion patients (95% CI, 20.4% to 51.8%). Objective responses were seen in 22 (41.5%) of 53 patients overall (95% CI, 28.2% to 54.8%); stable disease was also observed in 22 of 53. One-year progression-free and overall survival for all patients receiving I/T/DIN/GM-CSF were 67.9% ± 6.4% (95% CI, 55.4% to 80.5%) and 84.9% ± 4.9% (95% CI, 75.3% to 94.6%), respectively. Two patients did not receive protocol therapy and were evaluable for response but not toxicity. Common grade ≥ 3 toxicities were fever/infection (18 [35.3%] of 51), neutropenia (17 [33.3%] of 51), pain (15 [29.4%] of 51), and diarrhea (10 [19.6%] of 51). One patient met protocol-defined criteria for unacceptable toxicity (grade 4 hypoxia). Higher DIN trough levels were associated with response. CONCLUSION I/T/DIN/GM-CSF has significant antitumor activity in patients with relapsed/refractory neuroblastoma. Study of chemoimmunotherapy in the frontline setting is indicated, as is further evaluation of predictive biomarkers.

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Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background Complications in pediatric regional anesthesia are rare, so a large sample size is necessary to quantify risk. The Pediatric Regional Anesthesia Network contains data on more than 100,000 blocks administered at more than 20 children’s hospitals. This study analyzed the risk of major complications associated with regional anesthesia in children. Methods This is a prospective, observational study of routine clinical practice. Data were collected on every regional block placed by an anesthesiologist at participating institutions and were uploaded to a secure database. The data were audited at multiple points for accuracy. Results There were no permanent neurologic deficits reported (95% CI, 0 to 0.4:10,000). The risk of transient neurologic deficit was 2.4:10,000 (95% CI, 1.6 to 3.6:10,000) and was not different between peripheral and neuraxial blocks. The risk of severe local anesthetic systemic toxicity was 0.76:10,000 (95% CI, 0.3 to 1.6:10,000); the majority of cases occurred in infants. There was one epidural abscess reported (0.76:10,000, 95% CI, 0 to 4.8:10,000). The incidence of cutaneous infections was 0.5% (53:10,000, 95% CI, 43 to 64:10,000). There were no hematomas associated with neuraxial catheters (95% CI, 0 to 3.5:10,000), but one epidural hematoma occurred with a paravertebral catheter. No additional risk was observed with placing blocks under general anesthesia. The most common adverse events were benign catheter-related failures (4%). Conclusions The data from this study demonstrate a level of safety in pediatric regional anesthesia that is comparable to adult practice and confirms the safety of placing blocks under general anesthesia in children.

Objectives: The present study aimed to (1) evaluate the accuracy of envelope following responses (EFRs) in predicting speech audibility as a function of the statistical indicator used for objective response detection, stimulus phoneme, frequency, and level, and (2) quantify the minimum sensation level (SL; stimulus level above behavioral threshold) needed for detecting EFRs. Design: In 21 participants with normal hearing, EFRs were elicited by 8 band-limited phonemes in the male-spoken token /susa∫i/ (2.05 sec) presented between 20 and 65 dB SPL in 15 dB increments. Vowels in /susa∫i/ were modified to elicit two EFRs simultaneously by selectively lowering the fundamental frequency (f 0) in the first formant (F1) region. The modified vowels elicited one EFR from the low-frequency F1 and another from the mid-frequency second and higher formants (F2+). Fricatives were amplitude-modulated at the average f 0. EFRs were extracted from single-channel EEG recorded between the vertex (Cz) and the nape of the neck when /susa∫i/ was presented monaurally for 450 sweeps. The performance of the three statistical indicators, F-test, Hotelling’s T2, and phase coherence, was compared against behaviorally determined audibility (estimated SL, SL ≥0 dB = audible) using area under the receiver operating characteristics (AUROC) curve, sensitivity (the proportion of audible speech with a detectable EFR [true positive rate]), and specificity (the proportion of inaudible speech with an undetectable EFR [true negative rate]). The influence of stimulus phoneme, frequency, and level on the accuracy of EFRs in predicting speech audibility was assessed by comparing sensitivity, specificity, positive predictive value (PPV; the proportion of detected EFRs elicited by audible stimuli) and negative predictive value (NPV; the proportion of undetected EFRs elicited by inaudible stimuli). The minimum SL needed for detection was evaluated using a linear mixed-effects model with the predictor variables stimulus and EFR detection p value. Results: of the 3 statistical indicators were similar; however, at the type I error rate of 5%, the sensitivities of Hotelling’s T2 (68.4%) and phase coherence (68.8%) were significantly higher than the F-test (59.5%). In contrast, the specificity of the F-test (97.3%) was significantly higher than the Hotelling’s T2 (88.4%). When analyzed using Hotelling’s T2 as a function of stimulus, fricatives offered higher sensitivity (88.6 to 90.6%) and NPV (57.9 to 76.0%) compared with most vowel stimuli (51.9 to 71.4% and 11.6 to 51.3%, respectively). When analyzed as a function of frequency band (F1, F2+, and fricatives aggregated as low-, mid- and high-frequencies, respectively), high-frequency stimuli offered the highest sensitivity (96.9%) and NPV (88.9%). When analyzed as a function of test level, sensitivity improved with increases in stimulus level (99.4% at 65 dB SPL). The minimum SL for EFR detection ranged between 13.4 and 21.7 dB for F1 stimuli, 7.8 to 12.2 dB for F2+ stimuli, and 2.3 to 3.9 dB for fricative stimuli. Conclusions: EFR-based inference of speech audibility requires consideration of the statistical indicator used, phoneme, stimulus frequency, and stimulus level.

BACKGROUND Inadequately treated hypertension (HTN) leads to considerable morbidity and mortality. Despite many treatment options, blood pressure (BP) control is suboptimal. Missed opportunities due to the growing complexity of primary care office visits contribute. Electronic health records (EHRs) offer best practice alerts (BPA) tools to support clinicians in identifying poor BP control. BPAs have demonstrated effectiveness for other health outcomes. METHODS EHR data were collected for patients ≥18 years old seen for primary care office visits prior to, during, and after the BPA active period and used to identify patients for whom the BPA fired or would have fired during control periods. Logistic regression examined the association of BPA activation with follow-up BP check within 14–90 days and with BP control at follow-up, controlling for demographics and health conditions. RESULTS The BPA active period was associated with reduced patient follow-up; however, a number of covariates were predictive of increased follow-up: Black non-Hispanics, Hispanics, patients on the chronic kidney disease, HTN, or diabetes registries, as well as the morbidly obese, insurance status, and seasonal factors. For those who did follow-up, BPA activation was associated with improved BP control. CONCLUSIONS BPA activation was associated with worse patient follow-up but improved BP control. Some subgroups had significantly different rates of follow-up and BP control. This study did not have an experimental design as the BPA was a quality improvement initiative. These results highlight the critical importance of planning experimentally designed organizational initiatives to fully understand their impact.