Aligning EHR Data for Pediatric Leukemia With Standard Protocol Therapy.

PURPOSE: Children with acute lymphoblastic leukemia (ALL) are treated according to risk-based protocols defined by the Children's Oncology Group (COG). Alignment between real-world clinical practice and protocol milestones is not widely understood. Aggregate deidentified electronic health record (EHR) data offer a useful resource to evaluate real-world clinical practice. METHODS: A cohort of children with ALL was identified in the Cerner Health Facts deidentified aggregate EHR data. Manual review identified candidate procedural milestones. Automated methods were developed to classify likely standard-risk precursor B-cell ALL patients. Milestone procedures were adjusted relative to initiation of therapy and then aligned to the COG protocols for standard induction therapy. RESULTS: We identified 7,728 patients with pediatric ALL with 188,187 encounters. Records for lumbar punctures (LP) and bone marrow biopsies were frequently present in the data and were appropriate targets to evaluate guideline performance. Alluvial graph analysis of 14 health systems indicated that none of the systems have data from all three COG-recommended lumbar procedures for all patients but alignment demonstrated that most systems test at the recommended times. CONCLUSION: Source-system variation introduces inconsistency and incompleteness into aggregate EHR data. Data visualization was helpful in characterizing and interpreting the data. Health systems with patients meeting the inclusion criteria demonstrated strong alignment with the recommended milestones for LP. Large-scale aggregate EHR data are useful to evaluate alignment of recommended versus actual clinical milestones in support of treating children with ALL. This work can inform other guideline and protocol driven care.

Big Data in Transplantation Practice-the Devil Is in the Detail-Fontan-associated Liver Disease.

BACKGROUND: As a result of the Fontan procedure, the prognosis of congenital single-ventricle heart disease has improved, with many affected children surviving into adulthood. However, the unanticipated consequences of chronic exposure to Fontan hemodynamics have revealed a new set of secondary noncardiac complications. Fontan-associated liver disease (FALD) is characterized by progressive hepatic fibrosis in nearly all patients post-Fontan, with the potential to develop cirrhosis, hepatocellular carcinoma, and the need for liver transplantation. A lack of data regarding FALD-related prognosis makes consideration of indications for and timing of heart alone versus combined heart-liver transplantation challenging. METHODS: A multidisciplinary group within the American Society for Transplantation analyzed several administrative datasets to study the epidemiology of FALD. RESULTS: This approach presented several obstacles, and efforts to characterize FALD were limited by a lack of Fontan- and FALD-specific diagnostic codes and an inability to follow individual patients through multiple health systems. Several ongoing Fontan registries were also reviewed but these do not adequately capture FALD-related variables. Such barriers highlight the need for large-scale data collection in patients post-Fontan to better understand and care for this complex population. CONCLUSIONS: This study emphasizes the challenges of studying emerging transplant-related diagnoses in existing datasets and the need for mechanisms to adapt registries to appropriately identify patients with rare or emerging conditions.

Small sleepers, big data: leveraging big data to explore sleep-disordered breathing in infants and young children.

STUDY OBJECTIVES: Infants represent an understudied minority in sleep-disordered breathing (SDB) research and yet the disease can have a significant impact on health over the formative years of neurocognitive development that follow. Herein we report data on SDB in this population using a big data approach. METHODS: Data were abstracted using the Cerner Health Facts database. Demographics, sleep diagnoses, comorbid medication conditions, healthcare utilization, and economic outcomes are reported. RESULTS: In a cohort of 68.7 million unique patients, over a 9-year period, there were 9,773 infants and young children with a diagnosis of SDB (obstructive sleep apnea [OSA], nonobstructive sleep apnea, and "other" sleep apnea) who met inclusion criteria, encompassing 17,574 encounters, and a total of 27,290 diagnoses across 62 U.S. health systems, 172 facilities, and 3 patient encounter types (inpatient, clinic, and outpatient). Thirty-nine percent were female. Thirty-nine percent were ≤1 year of age (6,429 infants), 50% were 1-2 years of age, and 11% were 2 years of age. The most common comorbid diagnoses were micrognathia, congenital airway abnormalities, gastroesophageal reflux, chronic tonsillitis/adenoiditis, and anomalies of the respiratory system. Payor mix was dominated by government-funded entities. CONCLUSIONS: We have used a novel resource, large-scale aggregate, de-identified EHR data, to examine SDB. In this population, SDB is multifactorial, closely linked to comorbid medical conditions and may contribute to a significant burden of healthcare costs. Further research focusing on infants at highest risk for SDB can help target resources and facilitate personalized management.

Combined pembrolizumab and pegylated liposomal doxorubicin in platinum resistant ovarian cancer: A phase 2 clinical trial.

OBJECTIVE: Pegylated liposomal doxorubicin (PLD) in vitro may have immunomodulatory abilities and preclinical evidence suggests it synergizes with immune checkpoint blockade. We hypothesized that combining PLD and pembrolizumab would be active in patients with platinum-resistant ovarian cancer (PROC). METHODS: This was a single-arm, multi-center phase II trial. Eligible patients had PROC with ≤2 prior lines of cytotoxic therapy for recurrent or persistent disease. Twenty-six patients were enrolled and given pembrolizumab 200 mg intravenously (IV) every 3 weeks and PLD 40 mg/m2 IV every 4 weeks. Patients were assessed radiographically every 8 weeks. The primary endpoint was clinical benefit rate (CBR), defined as complete response (CR) + partial response (PR) + stable disease (SD) ≥24 weeks. The study was powered to detect an improvement in CBR from 25% to 50%, with rejection of the null hypothesis if at least 10 patients achieved clinical benefit. T-cell inflamed gene expression profiles (GEP) and PD-L1 were assessed and correlated with clinical outcome. RESULTS: Twenty-three patients were evaluable for best overall response. The study satisfied its primary endpoint, with 12 patients achieving clinical benefit for a CBR of 52.2% (95% CI 30.6-73.2%). There were 5 PRs (21.7%) and 1 CR (4.3%), for an overall response rate (ORR) of 26.1%. Six patients had SD lasting at least 24 weeks. Combination therapy was well tolerated without unexpected toxicities. CONCLUSIONS: The combination of pembrolizumab and PLD was manageable, without unexpected toxicities, and showed preliminary evidence of clinical benefit in the treatment of platinum resistant ovarian cancer. ORR and median PFS of combination therapy in this study was higher than historical comparisons of PLD alone or anti-PD-1/PD-L1 agents alone. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT02865811.

Anterior cruciate ligament reconstructed females who pass or fail a functional test battery do not exhibit differences in knee joint landing biomechanics asymmetry before and after exercise.

PURPOSE: A functional test battery (FTB) has been proposed to evaluate the readiness of return to activity after ACLR. However, there is limited evidence documenting the usefulness of an FTB. Therefore, the purpose of the current investigation was to compare knee joint landing biomechanics asymmetry during double-leg jump landing (DLJL) and single-leg jump cutting (SLJC) between healthy females and ACLR females who pass (ACLR-pass) or fail (ACLR-fail) an FTB before and after the completion of a sustained exercise protocol. METHOD: Eighteen ACLR females (ten ACLR-pass and eight ACLR-fail) and twelve healthy females performed an FTB including The 2000 International Knee Documentation Committee Subjective Knee Evaluation Form, the Knee Outcome Survey Activities of Daily Living Scale, quadriceps strength, and single-leg hop tests. DLJL and SLJC knee joint biomechanics asymmetry were measured before and after exercise. RESULTS: During DLJL, there were significant main effects of group on peak anterior tibial shear force (ATSF) asymmetry [F(2,27) = 3.86, p < 0.05, [Formula: see text] = 0.214] and peak vertical ground reaction force (vGRF) asymmetry [F(2,27) = 3.34, p = 0.05, [Formula: see text] = 0.198]. During SLJC, there was a significant group main effect for peak ATSF asymmetry [F(2,27) = 3.494, p = 0.04, [Formula: see text] = 0.206]. CONCLUSION: ACLR-fail exhibited greater asymmetry in peak ATSF during DLJL and SLJC compared to healthy females. In addition, ACLR-pass exhibited greater asymmetry in peak ATSF and peak vGRF during DLJL and SLJC, respectively, compared to healthy females. However, ACLR-fail did not exhibit any significant differences in landing biomechanics asymmetry during either task compared with ACLR-pass. Furthermore, the completion of a sustained exercise protocol did not affect knee joint landing biomechanics asymmetry across groups. LEVEL OF EVIDENCE: II.

Heterogeneity introduced by EHR system implementation in a de-identified data resource from 100 non-affiliated organizations.

OBJECTIVES: Electronic health record (EHR) data aggregated from multiple, non-affiliated, sources provide an important resource for biomedical research, including digital phenotyping. Unlike work with EHR data from a single organization, aggregate EHR data introduces a number of analysis challenges. MATERIALS AND METHODS: We used the Cerner Health Facts data, a de-identified aggregate EHR data resource populated by data from 100 independent health systems, to investigate the impact of EHR implementation factors on the aggregate data. These included use of ancillary modules, data continuity, International Classification of Disease (ICD) version and prompts for clinical documentation. RESULTS AND DISCUSSION: Health Facts includes six categories of data from ancillary modules. We found of the 664 facilities in Health Facts, 49 use all six categories while 88 facilities were not using any. We evaluated data contribution over time and found considerable variation at the health system and facility levels. We analyzed the transition from ICD-9 to ICD-10 and found that some organizations completed the shift in 2014 while others remained on ICD-9 in 2017, well after the 2015 deadline. We investigated the utilization of "discharge disposition" to document death and found inconsistent use of this field. We evaluated clinical events used to document travel status implemented in response to Ebola, height and smoking history. Smoking history documentation increased dramatically after Meaningful Use, but dropped in some organizations. These observations highlight the need for any research involving aggregate EHR data to consider implementation factors that contribute to variability in the data before attributing gaps to "missing data."

Complete remission of ALK-negative plasma cell granuloma (inflammatory myofibroblastic tumor) of the lung induced by celecoxib: A case report and review of the literature.

We report a case in which a 52-year-old female developed a multifocal inflammatory myofibroblastic tumor (IMT) of the lung. The tumor did not overexpress the anaplastic lymphoma kinase (ALK) protein, indicating a lack of ALK rearrangement. The patient required two wedge resections in 15 months due to recurrent disease. Recurrence after the second surgery was treated with corticosteroids, which only led to a transient response (6 months). Introduction of celecoxib, a cyclooxygenase-2 inhibitor, induced a complete remission in the patient. Maintenance on celecoxib further led to a progression-free survival of 34 months. A literature review retrieved a total of eight case reports, comprising ten patients, of IMT of various anatomical sites successfully treated with non-steroidal anti-inflammatory agent (NSAID) therapy. Nine of the ten patients achieved durable complete remission. Remission occurred rapidly and persisted even after termination of NSAID therapy. Although such a successful outcome may only be achieved rarely, a trial of an NSAID should be considered in any patient in whom complete resection is not an option. Our case also demonstrates that NSAID therapy may be successful in a non-ALK rearranged tumor in which ALK inhibition is not an option.

Lack of neuromuscular origins of adaptation after a long-term stretching program.

CONTEXT: Static stretching is commonly used during the treatment and rehabilitation of orthopedic injuries to increase joint range of motion (ROM) and muscle flexibility. Understanding the physiological adaptations that occur in the neuromuscular system as a result of long-term stretching may provide insight into the mechanisms responsible for changes in flexibility. OBJECTIVE: To examine possible neurological origins and adaptations in the Ia-reflex pathway that allow for increases in flexibility in ankle ROM, by evaluating the reduction in the synaptic transmission of Ia afferents to the motoneuron pool. DESIGN: Repeated-measures, case-controlled study. SETTING: Sports medicine research laboratory. PARTICIPANTS: 40 healthy volunteers with no history of cognitive impairment, neurological impairment, or lower extremity surgery or injury within the previous 12 mo. INTERVENTION: Presynaptic and postsynaptic mechanisms were evaluated with a chronic stretching pro- tocol. Twenty subjects stretched 5 times a wk for 6 wk. All subjects were measured at baseline, 3 wk, and 6 wk. MAIN OUTCOME MEASURES: Ankle-dorsiflexion ROM, Hmax:Mmax, presynaptic inhibition, and disynaptic reciprocal inhibition. RESULTS: Only ROM had a significant interaction between group and time, whereas the other dependent variables did not show significant differences. The experimental group had significantly improved ROM from baseline to 3 wk (mean 6.2 ± 0.9, P < .001), 3 wk to 6 wk (mean 5.0 ± 0.8, P < .001), and baseline to 6 wk (mean 11.2 ±0.9, P < .001). CONCLUSIONS: Ankle dorsiflexion increased by 42.25% after 6 wk of static stretching, but no significant neurological changes resulted at any point of the study, contrasting current literature. Significant neuromuscular origins of adaptation do not exist in the Ia-reflex-pathway components after a long-term stretching program as currently understood. Thus, any increases in flexibility are the result of other factors, potentially mechanical changes or stretch tolerance.

Interferon-alpha is a very effective salvage therapy for patients with hairy cell leukemia relapsing after cladribine: a report of three cases.

Therapy with a purine analogue (cladribine or pentostatin, most often cladribine) has revolutionized the care of patients with hairy cell leukemia, resulting in very long-lasting remissions in the majority of cases. For patients who relapse, re-induction with cladribine again induces durable remissions. For patients with short remission durations, rituximab can be effective, and for a small proportion of patients with more resistant disease, BL22 has been used successfully. I report three cases in which alpha interferon induction and maintenance has produced ongoing remissions in patients with short remission durations after cladribine. One patient had also not responded to rituximab. Alpha interferon may be a very effective treatment option for selected patients with relapsed hairy cell leukemia.

Shoulder joint position sense after thermal, open, and arthroscopic capsulorrhaphy for recurrent anterior instability.

Identifying the optimal surgical treatment for recurrent, anterior glenohumeral instability remains a challenge. Our purpose was to compare shoulder joint position sense among open, arthroscopic, and thermal capsulorrhaphy patients after repair of recurrent anterior instability and to compare these patients to healthy, control subjects. Sixty-seven adults (45 post-surgical patients, 22 controls) volunteered to participate in the study. We evaluated both the surgically repaired and contralateral shoulders of 45 capsulorrhaphy patients (28 men, 17 women) and compared their results with the normal bilateral shoulders of 22 age-matched controls (11 men, 11 women). Accuracy of joint position sense was quantified via passive reproduction of target positions set at 60% and 90% of each subject's maximum passive external rotation (ER(max)). We observed no significant differences in joint position sense between the repaired shoulders and the contralateral normal shoulders of all groups of capsulorrhaphy patients. Open and thermal capsulorrhaphy patients demonstrated significantly better (P

Bovine immune response to shiga-toxigenic Escherichia coli O157:H7.

Although cattle develop humoral immune responses to Shiga-toxigenic (Stx+) Escherichia coli O157:H7, infections often result in long-term shedding of these human pathogenic bacteria. The objective of this study was to compare humoral and cellular immune responses to Stx+ and Stx- E. coli O157:H7. Three groups of calves were inoculated intrarumenally, twice in a 3-week interval, with different strains of E. coli: a Stx2-producing E. coli O157:H7 strain (Stx2+ O157), a Shiga toxin-negative E. coli O157:H7 strain (Stx- O157), or a nonpathogenic E. coli strain (control). Fecal shedding of Stx2+ O157 was significantly higher than that of Stx- O157 or the control. Three weeks after the second inoculation, all calves were challenged with Stx2+ O157. Following the challenge, levels of fecal shedding of Stx2+ O157 were similar in all three groups. Both groups inoculated with an O157 strain developed antibodies to O157 LPS. Calves initially inoculated with Stx- O157, but not those inoculated with Stx2+ O157, developed statistically significant lymphoproliferative responses to heat-killed Stx2+ O157. These results provide evidence that infections with STEC can suppress the development of specific cellular immune responses in cattle, a finding that will need to be addressed in designing vaccines against E. coli O157:H7 infections in cattle.

Clinical presentations and complications of hairy cell leukemia.

HCL typically presents in middle-aged men, and is characterized by splenomegaly and cytopenias. Hepatomegaly may be present, but it usually is not a salient feature. Peripheral adenopathy is uncommon. Other organ manifestations occur, but are unusual. patients are now presenting with a less tumor burden, as a result of earlier diagnosis. Leukocytosis/lymphocytosis should suggest HCl variant. Infectious complications, which were common in the past and the major cause of death, have become rare in the era of purine analog therapy. Whether there is a true increased risk for second malignancies remains controversial.

A phase II trial of dolastatin-10 in recurrent platinum-sensitive ovarian carcinoma: a Gynecologic Oncology Group study.

OBJECTIVE: To estimate the antitumor efficacy of dolastatin-10 in patients with measurable recurrences of platinum-sensitive ovarian carcinoma and to determine the nature and degree of toxicity of dolastatin-10 in these patients. METHODS: Patients received dolastatin-10 400 microg/m(2) intravenously every 3 weeks and tumor measurements were performed every one to two cycles. RESULTS: Of 28 patients evaluable for response, there were no complete or partial responses. Seven patients had stable disease and 21 patients had increasing disease. CONCLUSION: Dolastatin-10 has minimal activity in recurrent platinum-sensitive ovarian carcinoma at the dose and schedule tested.

F-18 FDG versus Ga-67 for detecting splenic involvement in Hodgkin's disease.

PURPOSE: The objectives of this investigation were to characterize splenic uptake patterns of F-18 fluorodeoxyglucose (FDG) and Ga-67 in newly diagnosed Hodgkin's disease, to correlate these uptake patterns with the presence or absence of splenic disease, and to compare the accuracy of these two studies for detecting splenic disease. METHODS: FDG positron emission tomography and Ga-67 whole-body and SPECT imaging were performed in 32 patients with previously untreated Hodgkin's disease. Two readers, blinded to clinical information and final diagnoses, independently reviewed the study results. For both FDG and Ga-67, the intensity of splenic uptake was compared with the intensity of hepatic uptake and graded as follows: 0, less than liver uptake; 1, equal to liver uptake; and 2, greater than liver uptake. Differences in interpretation were resolved by consensus. RESULTS: Twelve (38%) of 32 patients had splenic disease. Using splenic uptake greater than hepatic uptake as the criterion for a positive study, the sensitivity, specificity, and accuracy of FDG were 92%, 100%, and 97%, respectively. Using splenic uptake at least as intense as hepatic uptake as the criterion for a positive study, the sensitivity specificity, and accuracy of Ga-67 were 50%, 95%, and 78%, respectively. The differences in sensitivity and accuracy of FDG and Ga-67 were significant (P = 0.04, and 0.03, respectively). CONCLUSION: In newly diagnosed Hodgkin's disease, FDG accurately diagnoses splenic involvement and is significantly more sensitive and accurate than Ga-67 for this purpose.