Citations

Objectives: Noise pollution in pediatric intensive care units (PICU) contributes to poor sleep and may increase risk of developing delirium. The Environmental Protection Agency (EPA) recommends <45 decibels (dB) in hospital environments. The objectives are to assess the degree of PICU noise pollution, to develop a delirium bundle targeted at reducing noise, and to assess the effect of the bundle on nocturnal noise pollution. Methods: This is a QI initiative at an academic PICU. Thirty-five sound sensors were installed in patient bed spaces, hallways, and common areas. The pediatric delirium bundle was implemented in 8 pilot patients (40 patient ICU days) while 108 non-pilot patients received usual care over a 28-day period. Results: A total of 20,609 hourly dB readings were collected. Hourly minimum, average, and maximum dB of all occupied bed spaces demonstrated medians [interquartile range] of 48.0 [39.0-53.0], 52.8 [48.1-56.2] and 67.0 [63.5-70.5] dB, respectively. Bed spaces were louder during the day (10AM to 4PM) than at night (11PM to 5AM) (53.5 [49.0-56.8] vs. 51.3 [46.0-55.3] dB, P < 0.01). Pilot patient rooms were significantly quieter than non-pilot patient rooms at night (n=210, 45.3 [39.7-55.9]) vs. n=1841, 51.2 [46.9-54.8] dB, P < 0.01). The pilot rooms compliant with the bundle had the lowest hourly nighttime average dB (44.1 [38.5-55.5]). Conclusions: Substantial noise pollution exists in our PICU, and utilizing the pediatric delirium bundle led to a significant noise reduction that can be perceived as half the loudness with hourly nighttime average dB meeting the EPA standards when compliant with the bundle.

Purpose Endoxifen is a tamoxifen metabolite with potent antiestrogenic activity. Patients and Methods We performed a phase I study of oral Z-endoxifen to determine its toxicities, maximum tolerated dose (MTD), pharmacokinetics, and clinical activity. Eligibility included endocrine-refractory, estrogen receptor–positive metastatic breast cancer. An accelerated titration schedule was applied until moderate or dose-limiting toxicity occurred, followed by a 3+3 design and expansion at 40, 80, and 100 mg per day. Tumor DNA from serum (circulating cell free [cf); all patients] and biopsies [160 mg/day and expansion]) was sequenced. Results Of 41 enrolled patients, 38 were evaluable for MTD determination. Prior endocrine regimens during which progression occurred included aromatase inhibitor (n = 36), fulvestrant (n = 21), and tamoxifen (n = 15). Patients received endoxifen once daily at seven dose levels (20 to 160 mg). Dose escalation ceased at 160 mg per day given lack of MTD and endoxifen concentrations > 1,900 ng/mL. Endoxifen clearance was unaffected by CYP2D6 genotype. One patient (60 mg) had cycle 1 dose-limiting toxicity (pulmonary embolus). Overall clinical benefit rate (stable > 6 months [n = 7] or partial response by RECIST criteria [n = 3]) was 26.3% (95% CI, 13.4% to 43.1%) including prior tamoxifen progression (n = 3). cfDNA mutations were observed in 13 patients ( PIK3CA [n = 8], ESR1 [n = 5], TP53 [n = 4], and AKT [n = 1]) with shorter progression-free survival ( v those without cfDNA mutations; median, 61 v 132 days; log-rank P = .046). Clinical benefit was observed in those with ESR1 amplification (tumor; 80 mg/day) and ESR1 mutation (cfDNA; 160 mg/day). Comparing tumor biopsies and cfDNA, some mutations ( PIK3CA, TP53, and AKT) were undetected by cfDNA, whereas cfDNA mutations ( ESR1, TP53, and AKT) were undetected by biopsy. Conclusion In endocrine-refractory metastatic breast cancer, Z-endoxifen provides substantial drug exposure unaffected by CYP2D6 metabolism, acceptable toxicity, and promising antitumor activity.

PurposeLow contrast (LC) detectability is a common test criterion for diagnostic radiologic quality control (QC) programs. Automation of this test is desirable in order to reduce human variability and to speed up analysis. However, automation is challenging due to the complexity of the human visual perception system and the ability to create algorithms that mimic this response. This paper describes the development and testing of an automated LC detection algorithm for use in the analysis of magnetic resonance (MR) images of the American College of Radiology (ACR) QC phantom.MethodsThe detection algorithm includes fuzzy logic decision processes and various edge detection methods to quantify LC detectability. Algorithm performance was first evaluated using a single LC phantom MR image with the addition of incremental zero mean Gaussian noise resulting in a total of 200 images. A c‐statistic was calculated to determine the role of CNR to indicate when the algorithm would detect ten spokes. To evaluate inter‐rater agreement between experienced observers and the algorithm, a blinded observer study was performed on 196 LC phantom images acquired from nine clinical MR scanners. The nine scanners included two MR manufacturers and two field strengths (1.5 T, 3.0 T). Inter‐rater and algorithm‐rater agreement was quantified using Krippendorff's alpha.ResultsFor the Gaussian noise added data, CNR ranged from 0.519 to 11.7 with CNR being considered an excellent discriminator of algorithm performance (c‐statistic = 0.9777). Reviewer scoring of the clinical phantom data resulted in an inter‐rater agreement of 0.673 with the agreement between observers and algorithm equal to 0.652, both of which indicate significant agreement.ConclusionsThis study demonstrates that the detection of LC test patterns for MR imaging QC programs can be successfully developed and that their response can model the human visual detection system of expert MR QC readers.

Akt is a downstream target of B cell receptor signaling and is a central regulator of CLL cell survival. We aim to investigate the safety and efficacy of the Akt inhibitor MK‐2206 in combination with bendamustine and rituximab (BR) in relapsed and/or refractory CLL in a phase I/II study. A standard phase I design was used with cohorts of three plus three patients to determine the maximum tolerated dose (MTD) of MK‐2206 in combination with BR in relapsed CLL. Single‐agent MK‐2206 (weekly dosed) was administered one‐week in advance before BR on cycle 1 and subsequently was given with BR at the same time for cycle 2‐6. Phase II employed the MTD of MK‐2206 with BR to evaluate safety and efficacy of this study combination. Thirteen relapsed/refractory CLL were treated for maximal 6‐cycle of therapy. The maximum tolerated dose of MK‐2206 was 90 mg by mouth once weekly. The most common grade 3/4 adverse events were neutropenia (46%), febrile neutropenia (23%), rash (15%), diarrhea (15%), and thrombocytopenia (15%). Overall response rate was 92% with a median progression free survival and treatment free survival of 16 and 24 months, respectively. Five patients (38%) achieved complete remission or complete remission with incomplete count recovery, two of whom were MRD negative. The efficacy and tolerability of this combination indicates that Akt inhibition combined with chemoimmunotherapy is a promising novel treatment combination in CLL and deserves further prospective clinical trial.

ObjectiveTo compare the efficacy of abatacept to that of placebo for the treatment of giant cell arteritis (GCA).MethodsIn this multicenter trial, patients with newly diagnosed or relapsing GCA were treated with abatacept 10 mg/kg intravenously on days 1, 15, and 29 and week 8, together with prednisone administered daily. At week 12, patients in remission underwent a double‐blinded randomization to continue to receive abatacept monthly or switch to placebo. Patients in both study arms received a standardized prednisone taper, with discontinuation of prednisone at week 28. All patients remained on their randomized assignment until meeting criteria for early termination or until 12 months after enrollment of the last patient. The primary end point was duration of remission (relapse‐free survival rate).ResultsForty‐nine eligible patients with GCA were enrolled and treated with prednisone and abatacept; of these, 41 reached the week 12 randomization and underwent a blinded randomization to receive abatacept or placebo. Prednisone was tapered using a standardized schedule, reaching a daily dosage of 20 mg at week 12 with discontinuation in all patients at week 28. The relapse‐free survival rate at 12 months was 48% for those receiving abatacept and 31% for those receiving placebo (P = 0.049). A longer median duration of remission was seen in those receiving abatacept compared to those receiving placebo (median duration 9.9 months versus 3.9 months; P = 0.023). There was no difference in the frequency or severity of adverse events, including infection, between the treatment arms.ConclusionIn patients with GCA, the addition of abatacept to a treatment regimen with prednisone reduced the risk of relapse and was not associated with a higher rate of toxicity compared to prednisone alone.

Objective To compare the efficacy of abatacept to that of placebo for the treatment of Takayasu arteritis (TAK). Methods In this multicenter trial, patients with newly diagnosed or relapsing TAK were treated with abatacept 10 mg/kg intravenously on days 1, 15, and 29 and week 8, together with prednisone administered daily. At week 12, patients in remission underwent a double‐blinded randomization to continue to receive abatacept monthly or switch to placebo. Patients in both study arms received a standardized prednisone taper, reaching a dosage of 20 mg daily at week 12, with discontinuation of prednisone at week 28. All patients remained on their randomized assignment until meeting criteria for early termination or until 12 months after enrollment of the last patient. The primary end point was duration of remission (relapse‐free survival). Results Thirty‐four eligible patients with TAK were enrolled and treated with prednisone and abatacept; of these, 26 reached the week 12 randomization and underwent a blinded randomization to receive either abatacept or placebo. The relapse‐free survival rate at 12 months was 22% for those receiving abatacept and 40% for those receiving placebo ( P = 0.853). Treatment with abatacept in patients with TAK enrolled in this study was not associated with a longer median duration of remission (median duration 5.5 months for abatacept versus 5.7 months for placebo). There was no difference in the frequency or severity of adverse events, including infection, between the treatment arms. Conclusion In patients with TAK, the addition of abatacept to a treatment regimen with prednisone did not reduce the risk of relapse.

Summary Objective Infantile spasms ( IS ) represent a severe epileptic encephalopathy presenting in the first 2 years of life. Recommended first‐line therapies (hormonal therapy or vigabatrin) often fail. We evaluated response to second treatment for IS in children in whom the initial therapy failed to produce both clinical remission and electrographic resolution of hypsarhythmia and whether time to treatment was related to outcome. Methods The National Infantile Spasms Consortium established a multicenter, prospective database enrolling infants with new diagnosis of IS. Children were considered nonresponders to first treatment if there was no clinical remission or persistence of hypsarhythmia. Treatment was evaluated as hormonal therapy (adrenocorticotropic hormone [ ACTH ] or oral corticosteroids), vigabatrin, or “other.” Standard treatments (hormonal and vigabatrin) were compared to all other nonstandard treatments. We compared response rates using chi‐square tests and multivariable logistic regression models. Results One hundred eighteen infants were included from 19 centers. Overall response rate to a second treatment was 37% (n = 44). Children who received standard medications with differing mechanisms for first and second treatment had higher response rates than other sequences (27/49 [55%] vs. 17/69 [25%], p < 0.001). Children receiving first treatment within 4 weeks of IS onset had a higher response rate to second treatment than those initially treated later (36/82 [44%] vs. 8/34 [24%], p = 0.040). Significance Greater than one third of children with IS will respond to a second medication. Choosing a standard medication ( ACTH , oral corticosteroids, or vigabatrin) that has a different mechanism of action appears to be more effective. Rapid initial treatment increases the likelihood of response to the second treatment.