Immunosuppression and outcomes in adult patients with de novo acute myeloid leukemia with normal karyotypes.

Acute myeloid leukemia (AML) patients rarely have long first remissions (LFRs; >5 y) after standard-of-care chemotherapy, unless classified as favorable risk at presentation. Identification of the mechanisms responsible for long vs. more typical, standard remissions may help to define prognostic determinants for chemotherapy responses. Using exome sequencing, RNA-sequencing, and functional immunologic studies, we characterized 28 normal karyotype (NK)-AML patients with >5 y first remissions after chemotherapy (LFRs) and compared them to a well-matched group of 31 NK-AML patients who relapsed within 2 y (standard first remissions [SFRs]). Our combined analyses indicated that genetic-risk profiling at presentation (as defined by European LeukemiaNet [ELN] 2017 criteria) was not sufficient to explain the outcomes of many SFR cases. Single-cell RNA-sequencing studies of 15 AML samples showed that SFR AML cells differentially expressed many genes associated with immune suppression. The bone marrow of SFR cases had significantly fewer CD4+ Th1 cells; these T cells expressed an exhaustion signature and were resistant to activation by T cell receptor stimulation in the presence of autologous AML cells. T cell activation could be restored by removing the AML cells or blocking the inhibitory major histocompatibility complex class II receptor, LAG3. Most LFR cases did not display these features, suggesting that their AML cells were not as immunosuppressive. These findings were confirmed and extended in an independent set of 50 AML cases representing all ELN 2017 risk groups. AML cell-mediated suppression of CD4+ T cell activation at presentation is strongly associated with unfavorable outcomes in AML patients treated with standard chemotherapy.

Genome Sequencing as an Alternative to Cytogenetic Analysis in Myeloid Cancers.

BACKGROUND: Genomic analysis is essential for risk stratification in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS). Whole-genome sequencing is a potential replacement for conventional cytogenetic and sequencing approaches, but its accuracy, feasibility, and clinical utility have not been demonstrated. METHODS: We used a streamlined whole-genome sequencing approach to obtain genomic profiles for 263 patients with myeloid cancers, including 235 patients who had undergone successful cytogenetic analysis. We adapted sample preparation, sequencing, and analysis to detect mutations for risk stratification using existing European Leukemia Network (ELN) guidelines and to minimize turnaround time. We analyzed the performance of whole-genome sequencing by comparing our results with findings from cytogenetic analysis and targeted sequencing. RESULTS: Whole-genome sequencing detected all 40 recurrent translocations and 91 copy-number alterations that had been identified by cytogenetic analysis. In addition, we identified new clinically reportable genomic events in 40 of 235 patients (17.0%). Prospective sequencing of samples obtained from 117 consecutive patients was performed in a median of 5 days and provided new genetic information in 29 patients (24.8%), which changed the risk category for 19 patients (16.2%). Standard AML risk groups, as defined by sequencing results instead of cytogenetic analysis, correlated with clinical outcomes. Whole-genome sequencing was also used to stratify patients who had inconclusive results by cytogenetic analysis into risk groups in which clinical outcomes were measurably different. CONCLUSIONS: In our study, we found that whole-genome sequencing provided rapid and accurate genomic profiling in patients with AML or MDS. Such sequencing also provided a greater diagnostic yield than conventional cytogenetic analysis and more efficient risk stratification on the basis of standard risk categories. (Funded by the Siteman Cancer Research Fund and others.).

The Immunologic Effect of Early Intravenous Two and Four Gram Bolus Dosing of Tranexamic Acid Compared to Placebo in Patients With Severe Traumatic Bleeding (TAMPITI): A Randomized, Double-Blind, Placebo-Controlled, Single-Center Trial.

Background: The hemostatic properties of tranexamic acid (TXA) are well described, but the immunological effects of TXA administration after traumatic injury have not been thoroughly examined. We hypothesized TXA would reduce monocyte activation in bleeding trauma patients with severe injury. Methods: This was a single center, double-blinded, randomized controlled trial (RCT) comparing placebo to a 2 g or 4 g intravenous TXA bolus dose in trauma patients with severe injury. Fifty patients were randomized into each study group. The primary outcome was a reduction in monocyte activation as measured by human leukocyte antigen-DR isotype (HLA-DR) expression on monocytes 72 h after TXA administration. Secondary outcomes included kinetic assessment of immune and hemostatic phenotypes within the 72 h window post-TXA administration. Results: The trial occurred between March 2016 and September 2017, when data collection ended. 149 patients were analyzed (placebo, n = 50; 2 g TXA, n = 49; 4 g TXA, n = 50). The fold change in HLA-DR expression on monocytes [reported as median (Q1-Q3)] from pre-TXA to 72 h post-TXA was similar between placebo [0.61 (0.51-0.82)], 2 g TXA [0.57 (0.47-0.75)], and 4 g TXA [0.57 (0.44-0.89)] study groups (p = 0.82). Neutrophil CD62L expression was reduced in the 4 g TXA group [fold change: 0.73 (0.63-0.97)] compared to the placebo group [0.97 (0.78-1.10)] at 24 h post-TXA (p = 0.034). The fold decrease in plasma IL-6 was significantly less in the 4 g TXA group [1.36 (0.87-2.42)] compared to the placebo group [0.46 (0.19-1.69)] at 72 h post-TXA (p = 0.028). There were no differences in frequencies of myeloid or lymphoid populations or in classical complement activation at any of the study time points. Conclusion: In trauma patients with severe injury, 4 g intravenous bolus dosing of TXA has minimal immunomodulatory effects with respect to leukocyte phenotypes and circulating cytokine levels. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT02535949.

Oxytocin and Oxytocinase in the Obese and Nonobese Parturients during Induction and Augmentation of Labor.

Objective To investigate differences in oxytocin (OXT) biodistribution between nonobese and obese parturients during labor. Study Design Patients with body mass index (BMI) of either ≥ 18 ≤ 24.9 kg/m 2 ("nonobese") or ≥ 30 kg/m 2 ("obese") undergoing elective induction of labor were included ( N = 25 each). Blood samples were collected at baseline (T 0 ), and 20 minutes after maximal OXT augmentation or adequate uterine contractions (T 1 ) for OXT and oxytocinase assays. A mixed-model repeated-measures analysis of variance was used to test for group versus time interaction and analysis of covariance to detect a difference in OXT level at T 1 . Data presented as mean ± standard deviation or median (interquartile range), with p < 0.05 considered significant. Results The mean BMIs (kg/m 2 ) were 22.1 ± 1.6 and 35.9 ± 5.1 in the nonobese and obese groups, respectively. No differences were observed in either the duration of OXT infusion, total dose of OXT, or plasma OXT (pg/mL) either at T 0 or T 1 . However, plasma oxytocinase (ng/mL) was significantly lower at T 0 (1.41 [0.67, 3.51] vs. 0.40 [0.29, 1.12]; p = 0.03) in the obese group. Conclusion We provide preliminary evidence that the disposition of OXT may not be different between obese and nonobese women during labor.

A Pilot Study Evaluating the Effect of Cooler Dialysate Temperature on Hemodynamic Stability During Prolonged Intermittent Renal Replacement Therapy in Acute Kidney Injury.

OBJECTIVES: Acute kidney injury requiring renal replacement therapy is associated with high morbidity and mortality. Complications of renal replacement therapy include hemodynamic instability with ensuing shortened treatments, inadequate ultrafiltration, and delay in renal recovery. Studies have shown that lowering dialysate temperature in patients with end-stage renal disease is associated with a decrease in the frequency of intradialytic hypotension. However, data regarding mitigation of hypotension by lowering dialysate temperature in patients with acute kidney injury are scarce. We conducted a prospective, randomized, cross-over pilot study to evaluate the effect of lower dialysate temperature on hemodynamic status of critically ill patients with acute kidney injury during prolonged intermittent renal replacement therapy. DESIGN: Single-center prospective, randomized, cross-over study. SETTING: ICUs and a step down unit in a tertiary referral center. PATIENTS: Acute kidney injury patients undergoing prolonged intermittent renal replacement therapy. INTERVENTIONS: Participants were randomized to start prolonged intermittent renal replacement therapy with dialysate temperature of 35°C or dialysate temperature of 37°C. MEASUREMENTS AND MAIN RESULTS: The primary endpoint was the number of hypotensive events, as defined by any of the following: decrease in systolic blood pressure greater than or equal to 20 mm Hg, decrease in mean arterial pressure greater than or equal to 10 mm Hg, decrease in ultrafiltration, or increase in vasopressor requirements. The number of events was analyzed by Poisson regression and other outcomes with repeated-measures analysis of variance. Twenty-one patients underwent a total of 78 prolonged intermittent renal replacement therapy sessions, 39 in each arm. The number of hypotensive events was twice as high during treatments with dialysate temperature of 37°C, compared with treatments with the cooler dialysate (1.49 ± 1.12 vs 0.72 ± 0.69; incidence rate ratio, 2.06; p ≤ 0.0001). Treatment sessions with cooler dialysate were more likely to reach prescribed ultrafiltration targets. CONCLUSIONS: Patients with acute kidney injury undergoing prolonged intermittent renal replacement therapy with cooler dialysate experienced significantly less hypotension during treatment. Prevention of hemodynamic instability during renal replacement therapy helped to achieve ultrafiltration goals and may help to prevent volume overload in critically ill patients.

Muscle atrophy in mechanically-ventilated critically ill children.

IMPORTANCE: ICU-acquired muscle atrophy occurs commonly and worsens outcomes in adults. The incidence and severity of muscle atrophy in critically ill children are poorly characterized. OBJECTIVE: To determine incidence, severity and risk factors for muscle atrophy in critically ill children. DESIGN, SETTING AND PARTICIPANTS: A single-center, prospective cohort study of 34 children receiving invasive mechanical ventilation for ≥48 hours. Patients 1 week- 18 years old with respiratory failure and without preexisting neuromuscular disease or skeletal trauma were recruited from a tertiary Pediatric Intensive Care Unit (PICU) between June 2015 and May 2016. We used serial bedside ultrasound to assess thickness of the diaphragm, biceps brachii/brachialis, quadriceps femoris and tibialis anterior. Serial electrical impedance myography (EIM) was assessed in children >1 year old. Medical records were abstracted from an electronic database. EXPOSURES: Respiratory failure requiring endotracheal intubation for ≥48 hours. MAIN OUTCOME AND MEASURES: The primary outcome was percent change in muscle thickness. Secondary outcomes were changes in EIM-derived fat percentage and "quality". RESULTS: Of 34 enrolled patients, 30 completed ≥2 ultrasound assessments with a median interval of 6 (IQR 6-7) days. Mean age was 5.42 years, with 12 infants <1 year (40%) and 18 children >1 year old (60%). In the entire cohort, diaphragm thickness decreased 11.1% (95%CI, -19.7% to -2.52%) between the first two assessments or 2.2%/day. Quadriceps thickness decreased 8.62% (95%CI, -15.7% to -1.54%) or 1.5%/day. Biceps (-1.71%; 95%CI, -8.15% to 4.73%) and tibialis (0.52%; 95%CI, -5.81% to 3.40%) thicknesses did not change. Among the entire cohort, 47% (14/30) experienced diaphragm atrophy (defined a priori as ≥10% decrease in thickness). Eighty three percent of patients (25/30) experienced atrophy in ≥1 muscle group, and 47% (14/30)-in ≥2 muscle groups. On multivariate linear regression, increasing age and traumatic brain injury (TBI) were associated with greater muscle loss. EIM revealed increased fat percentage and decreased muscle "quality". CONCLUSIONS AND RELEVANCE: In children receiving invasive mechanical ventilation, diaphragm and other skeletal muscle atrophy is common and rapid. Increasing age and TBI may increase severity of limb muscle atrophy. Prospective studies are required to link muscle atrophy to functional outcomes in critically ill children.

Immune Escape of Relapsed AML Cells after Allogeneic Transplantation.

BACKGROUND: As consolidation therapy for acute myeloid leukemia (AML), allogeneic hematopoietic stem-cell transplantation provides a benefit in part by means of an immune-mediated graft-versus-leukemia effect. We hypothesized that the immune-mediated selective pressure imposed by allogeneic transplantation may cause distinct patterns of tumor evolution in relapsed disease. METHODS: We performed enhanced exome sequencing on paired samples obtained at initial presentation with AML and at relapse from 15 patients who had a relapse after hematopoietic stem-cell transplantation (with transplants from an HLA-matched sibling, HLA-matched unrelated donor, or HLA-mismatched unrelated donor) and from 20 patients who had a relapse after chemotherapy. We performed RNA sequencing and flow cytometry on a subgroup of these samples and on additional samples for validation. RESULTS: On exome sequencing, the spectrum of gained and lost mutations observed with relapse after transplantation was similar to the spectrum observed with relapse after chemotherapy. Specifically, relapse after transplantation was not associated with the acquisition of previously unknown AML-specific mutations or structural variations in immune-related genes. In contrast, RNA sequencing of samples obtained at relapse after transplantation revealed dysregulation of pathways involved in adaptive and innate immunity, including down-regulation of major histocompatibility complex (MHC) class II genes ( HLA-DPA1, HLA-DPB1, HLA-DQB1, and HLA-DRB1) to levels that were 3 to 12 times lower than the levels seen in paired samples obtained at presentation. Flow cytometry and immunohistochemical analysis confirmed decreased expression of MHC class II at relapse in 17 of 34 patients who had a relapse after transplantation. Evidence suggested that interferon-γ treatment could rapidly reverse this phenotype in AML blasts in vitro. CONCLUSIONS: AML relapse after transplantation was not associated with the acquisition of relapse-specific mutations in immune-related genes. However, it was associated with dysregulation of pathways that may influence immune function, including down-regulation of MHC class II genes, which are involved in antigen presentation. These epigenetic changes may be reversible with appropriate therapy. (Funded by the National Cancer Institute and others.).

An Epidemiologic Perspective on Scaphoid Fracture Treatment and Frequency of Nonunion Surgery in the USA.

BACKGROUND: Scaphoid fractures treated non-operatively and operatively may be complicated by nonunion. QUESTIONS/PURPOSES: We sought to test the primary hypothesis that the incidence density of scaphoid fracture treatment is higher than previously estimated, to determine the frequency and risk factors for nonunion treatment, and to determine whether the frequency of surgical treatment increased over time. METHODS: The MarketScan® database was queried for all records of treatment (casting and surgery) for closed scaphoid fractures over a 6-year period. We examined subsequent claims to determine frequency of additional procedures for nonunion treatment (revision fixation or vascularized grafting occurring 28 days or more after initial treatment). Trend analyses were used to determine whether changes in frequency of surgical treatment or revision procedure occurred. RESULTS: The estimated incidence density of scaphoid fracture is 10.6 per 100,000 person-years in a commercially insured population of less than 65 years of age. Of 8923 closed scaphoid fractures, 29 and 71% were treated with surgery and casting, respectively. The frequency of surgical treatment rose significantly, from 22.1% in 2006 to 34.1% in 2012. The frequency of nonunion treatment was 10.8% after surgery and 3% after casting; neither changed over time. Younger age, male sex, and surgical treatment are associated with a higher risk of nonunion treatment. CONCLUSIONS: Our estimated incidence of scaphoid fracture is higher than previously reported. The increased enthusiasm in the USA to surgically treat scaphoid fractures is reflected by our trend analysis. The frequency of surgical treatment for presumed nonunion after initial surgical management for closed scaphoid fractures exceeded 10%. Given the increased utilization of surgery, surgeons and patients should be aware of the frequency of nonunion treatment to inform treatment decisions.

MIR142 Loss-of-Function Mutations Derepress ASH1L to Increase HOXA Gene Expression and Promote Leukemogenesis.

Point mutations in the seed sequence of miR-142-3p are present in a subset of acute myelogenous leukemia (AML) and in several subtypes of B-cell lymphoma. Here, we show that mutations associated with AML result both in loss of miR-142-3p function and in decreased miR-142-5p expression. Mir142 loss altered the hematopoietic differentiation of multipotent hematopoietic progenitors, enhancing their myeloid potential while suppressing their lymphoid potential. During hematopoietic maturation, loss of Mir142 increased ASH1L protein expression and consequently resulted in the aberrant maintenance of Hoxa gene expression in myeloid-committed hematopoietic progenitors. Mir142 loss also enhanced the disease-initiating activity of IDH2-mutant hematopoietic cells in mice. Together these data suggest a novel model in which miR-142, through repression of ASH1L activity, plays a key role in suppressing HOXA9/A10 expression during normal myeloid differentiation. AML-associated loss-of-function mutations of MIR142 disrupt this negative signaling pathway, resulting in sustained HOXA9/A10 expression in myeloid progenitors/myeloblasts and ultimately contributing to leukemic transformation.Significance: These findings provide mechanistic insights into the role of miRNAs in leukemogenesis and hematopoietic stem cell function. Cancer Res; 78(13); 3510-21. ©2018 AACR.

Cellular stressors contribute to the expansion of hematopoietic clones of varying leukemic potential.

Hematopoietic clones harboring specific mutations may expand over time. However, it remains unclear how different cellular stressors influence this expansion. Here we characterize clonal hematopoiesis after two different cellular stressors: cytotoxic therapy and hematopoietic transplantation. Cytotoxic therapy results in the expansion of clones carrying mutations in DNA damage response genes, including TP53 and PPM1D. Analyses of sorted populations show that these clones are typically multilineage and myeloid-biased. Following autologous transplantation, most clones persist with stable chimerism. However, DNMT3A mutant clones often expand, while PPM1D mutant clones often decrease in size. To assess the leukemic potential of these expanded clones, we genotyped 134 t-AML/t-MDS samples. Mutations in non-TP53 DNA damage response genes are infrequent in t-AML/t-MDS despite several being commonly identified after cytotoxic therapy. These data suggest that different hematopoietic stressors promote the expansion of distinct long-lived clones, carrying specific mutations, whose leukemic potential depends partially on the mutations they harbor.

Effect of sleep on overnight cerebrospinal fluid amyloid ß kinetics.

Sleep disturbances are associated with future risk of Alzheimer disease. Disrupted sleep increases soluble amyloid ß, suggesting a mechanism for sleep disturbances to increase Alzheimer disease risk. We tested this response in humans using indwelling lumbar catheters to serially sample cerebrospinal fluid while participants were sleep-deprived, treated with sodium oxybate, or allowed to sleep normally. All participants were infused with 13 C6 -leucine to measure amyloid ß kinetics. We found that sleep deprivation increased overnight amyloid ß38, amyloid ß40, and amyloid ß42 levels by 25 to 30% via increased overnight amyloid ß production relative to sleeping controls. These findings suggest that disrupted sleep increases Alzheimer disease risk via increased amyloid ß production. Ann Neurol 2018;83:197-204.

Somatic mutations and clonal hematopoiesis in congenital neutropenia.

Severe congenital neutropenia (SCN) and Shwachman-Diamond syndrome (SDS) are congenital neutropenia syndromes with a high rate of leukemic transformation. Hematopoietic stressors may contribute to leukemic transformation by increasing the mutation rate in hematopoietic stem/progenitor cells (HSPCs) and/or by promoting clonal hematopoiesis. We sequenced the exome of individual hematopoietic colonies derived from 13 patients with congenital neutropenia to measure total mutation burden and performed error-corrected sequencing on a panel of 46 genes on 80 patients with congenital neutropenia to assess for clonal hematopoiesis. An average of 3.6 ± 1.2 somatic mutations per exome was identified in HSPCs from patients with SCN compared with 3.9 ± 0.4 for healthy controls (P = NS). Clonal hematopoiesis due to mutations in TP53 was present in 48% (13/27) of patients with SDS but was not seen in healthy controls (0/17, P < .001) or patients with SCN (0/40, P < .001). Our SDS cohort was young (median age 6.3 years), and many of the patients had multiple TP53 mutations. Conversely, clonal hematopoiesis due to mutations of CSF3R was present in patients with SCN but was not detected in healthy controls or patients with SDS. These data show that hematopoietic stress, including granulocyte colony-stimulating factor, do not increase the mutation burden in HSPCs in congenital neutropenia. Rather, distinct hematopoietic stressors result in the selective expansion of HSPCs carrying specific gene mutations. In particular, in SDS there is enormous selective pressure to expand TP53-mutated HSPCs, suggesting that acquisition of TP53 mutations is an early, likely initiating event, in the transformation to myelodysplastic syndrome/acute myeloid leukemia in patients with SDS.

Patient-Reported Outcomes of Periacetabular Osteotomy from the Prospective ANCHOR Cohort Study.

BACKGROUND: Current literature describing the periacetabular osteotomy (PAO) is mostly limited to retrospective case series. Larger, prospective cohort studies are needed to provide better clinical evidence regarding this procedure. The goals of the current study were to (1) report minimum 2-year patient-reported outcomes (pain, hip function, activity, overall health, and quality of life), (2) investigate preoperative clinical and disease characteristics as predictors of clinical outcomes, and (3) report the rate of early failures and reoperations in patients undergoing contemporary PAO surgery. METHODS: A large, prospective, multicenter cohort of PAO procedures was established, and outcomes at a minimum of 2 years were analyzed. A total of 391 hips were included for analysis (79% of the patients were female, and the average patient age was 25.4 years). Patient-reported outcomes, conversion to total hip replacement, reoperations, and major complications were documented. Variables with a p value of ≤0.10 in the univariate linear regressions were included in the multivariate linear regression. The backward stepwise selection method was used to determine the final risk factors of clinical outcomes. RESULTS: Clinical outcome analysis demonstrated major clinically important improvements in pain, function, quality of life, overall health, and activity level. Increasing age and a body mass index status of overweight or obese were predictive of improved results for certain outcome metrics. Male sex and mild acetabular dysplasia were predictive of lesser improvements in certain outcome measures. Three (0.8%) of the hips underwent early conversion to total hip arthroplasty, 12 (3%) required reoperation, and 26 (7%) experienced a major complication. CONCLUSIONS: This large, prospective cohort study demonstrated the clinical success of contemporary PAO surgery for the treatment of symptomatic acetabular dysplasia. Patient and disease characteristics demonstrated predictive value that should be considered in surgical decision-making. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

TP53 and Decitabine in Acute Myeloid Leukemia and Myelodysplastic Syndromes.

BACKGROUND: The molecular determinants of clinical responses to decitabine therapy in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) are unclear. METHODS: We enrolled 84 adult patients with AML or MDS in a single-institution trial of decitabine to identify somatic mutations and their relationships to clinical responses. Decitabine was administered at a dose of 20 mg per square meter of body-surface area per day for 10 consecutive days in monthly cycles. We performed enhanced exome or gene-panel sequencing in 67 of these patients and serial sequencing at multiple time points to evaluate patterns of mutation clearance in 54 patients. An extension cohort included 32 additional patients who received decitabine in different protocols. RESULTS: Of the 116 patients, 53 (46%) had bone marrow blast clearance (<5% blasts). Response rates were higher among patients with an unfavorable-risk cytogenetic profile than among patients with an intermediate-risk or favorable-risk cytogenetic profile (29 of 43 patients [67%] vs. 24 of 71 patients [34%], P<0.001) and among patients with TP53 mutations than among patients with wild-type TP53 (21 of 21 [100%] vs. 32 of 78 [41%], P<0.001). Previous studies have consistently shown that patients with an unfavorable-risk cytogenetic profile and TP53 mutations who receive conventional chemotherapy have poor outcomes. However, in this study of 10-day courses of decitabine, neither of these risk factors was associated with a lower rate of overall survival than the rate of survival among study patients with intermediate-risk cytogenetic profiles. CONCLUSIONS: Patients with AML and MDS who had cytogenetic abnormalities associated with unfavorable risk, TP53 mutations, or both had favorable clinical responses and robust (but incomplete) mutation clearance after receiving serial 10-day courses of decitabine. Although these responses were not durable, they resulted in rates of overall survival that were similar to those among patients with AML who had an intermediate-risk cytogenetic profile and who also received serial 10-day courses of decitabine. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT01687400 .).

A Population-Based Analysis of Time to Surgery and Travel Distances for Brachial Plexus Surgery.

PURPOSE: Despite the importance of timely evaluation for patients with brachial plexus injuries (BPIs), in clinical practice we have noted delays in referral. Because the published BPI experience is largely from individual centers, we used a population-based approach to evaluate the delivery of care for patients with BPI. METHODS: We used statewide administrative databases from Florida (2007-2013), New York (2008-2012), and North Carolina (2009-2010) to create a cohort of patients who underwent surgery for BPI (exploration, repair, neurolysis, grafting, or nerve transfer). Emergency department and inpatient records were used to determine the time interval between the injury and surgical treatment. Distances between treating hospitals and between the patient's home ZIP code and the surgical hospital were recorded. A multivariable logistic regression model was used to determine predictors for time from injury to surgery exceeding 365 days. RESULTS: Within the 222 patients in our cohort, median time from injury to surgery was 7.6 months and exceeded 365 days in 29% (64 of 222 patients) of cases. Treatment at a smaller hospital for the initial injury was significantly associated with surgery beyond 365 days after injury. Patient insurance type, travel distance for surgery, distance between the 2 treating hospitals, and changing hospitals between injury and surgery did not significantly influence time to surgery. CONCLUSIONS: Nearly one third of patients in Florida, New York, and North Carolina underwent BPI surgery more than 1 year after the injury. Patients initially treated at smaller hospitals are at risk for undergoing delayed BPI surgery. CLINICAL RELEVANCE: These findings can inform administrative and policy efforts to expedite timely referral of patients with BPI to experienced centers.

Localization of Peripheral Pulmonary Lesions Using a Method of Computed Tomography-Anatomic Correlation and Radial Probe Endobronchial Ultrasound Confirmation.

RATIONALE: Peripheral pulmonary lesions requiring a diagnosis continue to present challenges to clinicians. One significant barrier is the inability to reliably locate peripheral lesions by bronchoscopic approaches. Multiplanar computed tomographic (CT) scan reconstruction is available to most physicians and provides axial, coronal, and sagittal images that may be used to estimate target lesion location and guide bronchoscopists during procedures. OBJECTIVES: This study was performed to evaluate a systematic method of CT-anatomic correlation based on multiplanar reconstruction CT scanning with monoplanar fluoroscopy during bronchoscopy to locate peripheral pulmonary lesions and confirm lesion location, using radial probe endobronchial ultrasound. METHODS: A retrospective review of peripheral bronchoscopy cases in which radial probe endobronchial ultrasound for peripheral lesions was performed at a tertiary care, university hospital. All cases involved a systematic approach of reviewing axial, coronal, and sagittal CT reconstructions, coupled with monoplanar fluoroscopy during procedures to assist with locating peripheral lesions. MEASUREMENTS AND MAIN RESULTS: Using the method of CT-anatomic correlation, 332 of 348 (95.4%) of all lesions were successfully localized and confirmed, using radial probe endobronchial ultrasound. Lesions 1-2 cm in size accounted for 45% of all lesions, and the ability to locate lesions was not significantly different based on lesion size. Mean time to lesion localization was 6.8 minutes. Larger lesions and lesions demonstrating an air bronchus sign on CT scan were located in less time. The overall diagnostic yield was 58.9%. CONCLUSIONS: A systematic approach applying CT-anatomic correlation with multiplanar CT scan reconstruction and monoplanar fluoroscopy during procedures can result in an efficient, and successful process for locating peripheral pulmonary lesions.

Trends in the utilization of imaging for upper tract urothelial carcinoma.

OBJECTIVES: To evaluate the changes in use of the different imaging modalities for diagnosing upper tract urothelial carcinoma (UTUC) and assess how these changes have affected tumor stage at the time of surgery. MATERIALS AND METHODS: We assessed the Surveillance, Epidemiology, and End Results (SEER) cancer registry and linked Medicare claims data (1992-2009) for 5377 patients who underwent surgery for UTUC. We utilized International Classification of Disease-Oncology 3 codes to identify UTUC. International Classification of Disease, ninth Revision, Clinical Modification and Current Procedure Terminology codes identified surgical treatment and imaging modalities. We assessed for use of intravenous pyelography, retrograde pyelography (RGP), computed tomography urography (CTU), magnetic resonance urography (MRU), and endoscopy. For each modality, patients were categorized as having received the modality at least once or not at all. Patient characteristics were compared using chi-squared tests. Usage of imaging modalities and tumor stage was trended using Cochran-Armitage tests. We stratified our data into 2 multivariate logistic regression models to determine the effect of imaging modalities on tumor stage: 1992 to 1999 with all modalities except MRU, and 2000 to 2009 with all modalities. RESULTS: Our patient population was predominantly White males of more than 70 years old. Intravenous pyelography and RGP declined in use (62% and 72% in 1992 vs. 6% and 58% in 2009, respectively) while computed tomography urography, MRU, and endoscopy increased in use (2%, 0%, and 37% in 1992 vs. 44%, 6%, and 66% in 2009, respectively). In both regression analyses, endoscopy was associated with lower-stage tumors. In the 2000 to 2009 model, RGP was associated with lower-stage tumors, and MRU was associated with higher-stage tumors. Finally, our data showed an increasing number of modalities utilized for each patient (1% receiving 4 modalities in 1992 vs. 20% in 2009). CONCLUSIONS: We found trends toward the utilization of newer imaging modalities to diagnose UTUC and more modalities per patient. Endoscopy and RGP were associated with smaller tumors, whereas MRU was associated with larger tumors. Further studies are needed to evaluate the utility of the different modalities in diagnosing UTUC.

Clinical Characterization of Children Presenting to the Hospital with Enterovirus D68 Infection During the 2014 Outbreak in St. Louis.

BACKGROUND: The largest known outbreak of enterovirus D68 (EV-D68) infections occurred during 2014. The goal of our study is to characterize the illness severity and clinical presentation of children infected with EV-D68 in comparison to non-EV-D68-human rhinoviruses/enteroviruses (HRV/EV). METHOD: Our study is a retrospective analysis of severity level, charges and length of stay of children who presented to St. Louis Children's Hospital from August 8, 2014 to October 31, 2014 and tested positive for EV-D68 in comparison to non-EV-D68-HRV/EV-infected patients. Chart review was performed for all EV-D68-infected patients and age and severity matched non-EV-D68-HRV/EV-infected patients. RESULT: There was a striking increase in hospital census in August of 2014 in our hospital with simultaneous increase in the number of patients with EV-D68 infection. There was no significant difference in severity of illness, length of stay or total charges between EV-D68-infected and non-EV-D68-HRV/EV-infected children. EV-D68 infection was characterized by presenting complaints of difficulty breathing (80%) and wheezing (67%) and by findings of tachypnea (65%), wheezing (71%) and retractions (65%) on examination. The most common interventions were albuterol (79%) and corticosteroid (68%) treatments, and the most common discharge diagnosis was asthma exacerbation (55%). CONCLUSION: EV-D68 caused a significant outbreak in 2014 with increased hospital admissions and associated increased charges. There was no significant difference in severity of illness caused by EV-D68 compared with non-EV-D68-HRV/EV infections suggesting that the impact from EV-D68 was because of increased number of infected children presenting to the hospital and not necessarily due to increased severity of illness.