An atlas of causal and mechanistic drivers of interpatient heterogeneity in glioma.

Grade IV glioma, formerly known as glioblastoma multiforme (GBM) is the most aggressive and lethal type of brain tumor, and its treatment remains challenging in part due to extensive interpatient heterogeneity in disease driving mechanisms and lack of prognostic and predictive biomarkers. Using mechanistic inference of node-edge relationship (MINER), we have analyzed multiomics profiles from 516 patients and constructed an atlas of causal and mechanistic drivers of interpatient heterogeneity in GBM (gbmMINER). The atlas has delineated how 30 driver mutations act in a combinatorial scheme to causally influence a network of regulators (306 transcription factors and 73 miRNAs) of 179 transcriptional "programs", influencing disease progression in patients across 23 disease states. Through extensive testing on independent patient cohorts, we share evidence that a machine learning model trained on activity profiles of programs within gbmMINER significantly augments risk stratification, identifying patients who are super-responders to standard of care and those that would benefit from 2 nd line treatments. In addition to providing mechanistic hypotheses regarding disease prognosis, the activity of programs containing targets of 2 nd line treatments accurately predicted efficacy of 28 drugs in killing glioma stem-like cells from 43 patients. Our findings demonstrate that interpatient heterogeneity manifests from differential activities of transcriptional programs, providing actionable strategies for mechanistically characterizing GBM from a systems perspective and developing better prognostic and predictive biomarkers for personalized medicine.

Prospective, multicenter study of antimicrobial-coated, noncrosslinked, acellular porcine dermal matrix (XenMatrix™ AB Surgical Graft) for hernia repair in all centers for disease control and prevention wound classes: 24-month follow-up cohort.

Prospective, multicenter, single-arm study of antimicrobial-coated, noncrosslinked, acellular porcine dermal matrix (AC-PDM) in a cohort involving all centers for disease control and prevention wound classes in ventral/incisional midline hernia repair (VIHR). Materials and methods: Seventy-five patients (mean age 58.6±12.7 years; BMI 31.3±4.9 kg/m2) underwent ventral/incisional midline hernia repair with AC-PDM. Surgical site occurrence (SSO) was assessed in the first 45 days post-implantation. Length of stay, return to work, hernia recurrence, reoperation, quality of life, and SSO were assessed at 1, 3, 6, 12, 18, and 24 months. Results: 14.7% of patients experienced SSO requiring intervention within 45 days post-implantation, and 20.0% thereafter (>45 d post-implantation). Recurrence (5.8%), definitely device-related adverse events (4.0%), and reoperation (10.7%) were low at 24 months; all quality-of-life indicators were significantly improved compared to baseline. Conclusion: AC-PDM exhibited favourable results, including infrequent hernia recurrence and definitely device-related adverse events, with reoperation and SSO comparable to other studies, and significantly improved quality of life.

Virtual Trials: Causally-validated treatment effects efficiently learned from an observational cancer registry.

Randomized controlled trials (RCTs) offer a clear causal interpretation of treatment effects, but are inefficient in terms of information gain per patient. Moreover, because they are intended to test cohort-level effects, RCTs rarely provide information to support precision medicine, which strives to choose the best treatment for an individual patient. If causal information could be efficiently extracted from widely available real-world data, the rapidity of treatment validation could be increased, and its costs reduced. Moreover, inferences could be made across larger, more diverse patient populations. We created a "virtual trial" by fitting a multilevel Bayesian survival model to treatment and outcome records self-reported by 451 brain cancer patients. The model recovers group-level treatment effects comparable to RCTs representing over 3200 patients. The model additionally discovers the feature-treatment interactions needed to make individual-level predictions for precision medicine. By learning from heterogeneous real-world data, virtual trials can generate more causal estimates with fewer patients than RCTs, and they can do so without artificially limiting the patient population. This demonstrates the value of virtual trials as a complement to large randomized controlled trials, especially in highly heterogeneous or rare diseases.

Case report: response to the ERK1/2 inhibitor ulixertinib in BRAF D594G cutaneous melanoma.

Melanoma is characterized by oncogenic mutations in pathways regulating cell growth, proliferation, and metabolism. Greater than 80% of primary melanoma cases harbor aberrant activation of the mitogen-activated protein kinase kinase/extracellular-signal-regulated kinase (MEK/ERK) pathway, with oncogenic mutations in BRAF, most notably BRAF V600E, being the most common. Significant progress has been made in BRAF-mutant melanoma using BRAF and MEK inhibitors; however, non-V600 BRAF mutations remain a challenge with limited treatment options. We report the case of an individual diagnosed with stage III BRAF D594G-mutant melanoma who experienced an extraordinary response to the ERK1/2 inhibitor ulixertinib as fourth-line therapy. Ulixertinib was obtained via an intermediate expanded access protocol with unique flexibility to permit both single-agent and combination treatments, dose adjustments, breaks in treatment to undergo surgery, and long-term preventive treatment following surgical resection offering this patient the potential for curative treatment.

Gaining or wasting time? Influence of time to operating room on mortality after temporary hemostasis using resuscitative endovascular balloon occlusion of the aorta.

BACKGROUND: The optimal candidates for resuscitative endovascular balloon occlusion of the aorta (REBOA) remains unclear. We hypothesized patients with delayed transfer to operating room (OR) would benefit from REBOA. METHODS: Using the 2016-2017 ACS-TQIP database, patients were divided based on the transfer time to OR: ≤1 h (early) and >1 h (delayed). In each group, patients who underwent REBOA in emergency department (ED-REBOA) were matched with those without REBOA (non-REBOA) using propensity scores, and survival to discharge was compared. RESULTS: Among 163,453 patients, 114 and 138 patients (38 and 46 ED-REBOA) were included in the early and delayed groups, respectively. Survival to discharge was comparable between ED-REBOA and non-REBOA patients in the early group (39.5% vs. 48.7%, p = 0.35), whereas it was higher in ED-REBOA patients in the delayed group (39.1% vs. 12.0%, p < 0.01). CONCLUSIONS: Patients with delayed transfer to OR >1 h benefited from REBOA.

Neuroprotective Roles of the Adenosine A3 Receptor Agonist AST-004 in Mouse Model of Traumatic Brain Injury.

Traumatic brain injury (TBI) remains one of the greatest public health concerns with increasing morbidity and mortality rates worldwide. Our group reported that stimulation of astrocyte mitochondrial metabolism by P2Y1 receptor agonists significantly reduced cerebral edema and reactive gliosis in a TBI model. Subsequent data on the pharmacokinetics (PK) and rapid metabolism of these compounds suggested that neuroprotection was likely mediated by a metabolite, AST-004, which binding data indicated was an adenosine A3 receptor (A3R) agonist. The neuroprotective efficacy of AST-004 was tested in a control closed cortical injury (CCCI) model of TBI in mice. Twenty-four (24) hours post-injury, mice subjected to CCCI and treated with AST-004 (0.22 mg/kg, injected 30 min post-trauma) exhibited significantly less secondary brain injury. These effects were quantified with less cell death (PSVue794 fluorescence) and loss of blood brain barrier breakdown (Evans blue extravasation assay), compared to vehicle-treated TBI mice. TBI-treated mice also exhibited significantly reduced neuroinflammatory markers, glial-fibrillary acidic protein (GFAP, astrogliosis) and ionized Ca2+-binding adaptor molecule 1 (Iba1, microgliosis), both at the mRNA (qRT-PCR) and protein (Western blot and immunofluorescence) levels, respectively. Four (4) weeks post-injury, both male and female TBI mice presented a significant reduction in freezing behavior during contextual fear conditioning (after foot shock). AST-004 treatment prevented this TBI-induced impairment in male mice, but did not significantly affect impairment in female mice. Impairment of spatial memory, assessed 24 and 48 h after the initial fear conditioning, was also reduced in AST-004-treated TBI-male mice. Female TBI mice did not exhibit memory impairment 24 and 48 h after contextual fear conditioning and similarly, AST-004-treated female TBI mice were comparable to sham mice. Finally, AST-004 treatments were found to increase in vivo ATP production in astrocytes (GFAP-targeted luciferase activity), consistent with the proposed mechanism of action. These data reveal AST-004 as a novel A3R agonist that increases astrocyte energy production and enhances their neuroprotective efficacy after brain injury.

Is Cancer Solvable? Towards Efficient and Ethical Biomedical Science.

Global Cumulative Treatment Analysis (GCTA) is a novel clinical research model combining expert knowledge, and treatment coordination based upon global information-gain, to treat every patient optimally while efficiently searching the vast space that is the realm of cancer research.

Evaluation of high-risk pulmonary nodules and pathologic correlation in patients enrolled in a low-dose computed tomography (LDCT) program.

BACKGROUND: The American Cancer Society estimates that lung cancer is responsible for 155,870 deaths: 84,590 in men and 71,280 in women. In an effort to reduce lung cancer mortality, many major medical societies have recommended annual low-dose CT screenings for high-risk individuals. The Centers for Disease Control and Prevention (CDC) has recommended yearly lung cancer screening with LDCT for people who are classified as high-risk individuals. METHODS: In February 2014, our institution implemented a low-dose program. We analyzed patients seen between the dates of February 21, 2014 and June 1, 2017. Our studied population consisted of 639 total patients. We established a prospective database examining multiple parameters such as evolution of change in lung-RADS classification, histology of tumors, follow up rates, and overall success of the program. The eligibility criteria used at our institution mirrored the patient eligibility criteria posted on the American College of Radiology's Lung Cancer Screening website. In order for an individual to be evaluated within our low-dose CT screening program, the individual must be between the ages of fifty-five and eighty, be asymptomatic, have a thirty-pack years or greater history of smoking, and be a current smoker or have quit within the last 15 years. The patients were then assessed in a standardized fashion for radiographic risk of nodules according to the ACR Guidelines. RESULTS: Six hundred and thirty-nine total patients were evaluated over the course of the study and there were 759 total scans conducted. As a major goal was to identify frequency of pulmonary nodules, we noted that 43.9% (333/759) of scans showed the presence of pulmonary nodules. These nodules were found in 207 out of 639 patients (32.4%). Using the guidelines given by the American College of Radiology, we classified 36 out of 639 patients as high-risk individuals [4A, B, X (5.63%)]. We also studied the evolution of nodules over the time period of the study with respect to Lung-RADS and found that the most common change seen was migrating from lung-RADS 1 to lung-RADS 2. Within the study period, we found malignancies in eight patients (1.25%). These malignancies included one squamous cell carcinoma, five adenocarcinomas, one non-small cell carcinomas, and one lymphoma. We found five of the eight malignancies to be stage III (62.5%) and the remaining to be either stage I or stage II. CONCLUSIONS: This is one of the few studies that examined the correlation of lung-RADS risk stratification and histopathologic nature of nodules. In addition to demonstrating the merits of the low-dose CT screening program, our study has demonstrated, amongst the large number of patients, very low rates of migration from low lung-RADS classification to a higher risk category, the finding of more advanced stages of malignancies, and a preponderance of adenocarcinoma within the eight malignancies found.

The Use of Standardized Measures to Predict and Assess Quality of Life after Laparoscopic Hiatal Hernia Repair.

The literature regarding laparoscopic hiatal hernia repair is difficult to interpret because of inconsistencies in describing hernia characteristics and outcome measures. This study was performed to evaluate risk factors for an unsatisfactory outcome after repair using objective definitions of hernia size and a clinically relevant outcome instrument. A retrospective review of a prospectively maintained database was conducted over a seven-year period. Data collected included patient demographics and hernia-related variables. Outcomes were defined using a validated quality of life (QOL) instrument. Postoperatively, the mean total QOL score decreased from 22.9 to 5.8 (P < 0.001). In all, 13.8 per cent of patients had unsatisfactory QOL scores postoperatively. Multivariate analysis showed that high gastroesophageal (GE) junction position (P = 0.03) and female gender (P = 0.02) were the only significant factors associated with an unsatisfactory postoperative QOL. Laparoscopic hiatal hernia repair significantly improves QOL. With respect to predicting clinically relevant outcomes, hernias are best characterized by the position of the GE junction. Females with high GE junction position are at the highest risk for an unsatisfactory outcome.

Safety and efficacy of second-line bosutinib for chronic phase chronic myeloid leukemia over a five-year period: final results of a phase I/II study.

Bosutinib is a Src/Abl tyrosine kinase inhibitor indicated for adults with newly-diagnosed Philadelphia positive chronic myeloid leukemia or with resistant/intolerant disease. We report the final results of a phase I/II study of second-line bosutinib in chronic phase chronic myeloid leukemia patients after imatinib failure (n=284). Median follow up and treatment durations were 54.8 (range 0.6-96.3) and 25.6 (0.2-96.3) months, respectively. At years 2 and 5, 54% and 40% of patients, respectively, remained on bosutinib. Cumulative major cytogenetic response and complete cytogenetic response rates (newly-attained or maintained from baseline) were 58% and 46%, respectively, by year 2 and 60% and 50% by year 5. Kaplan-Meier probability of maintaining major and complete cytogenetic response was 76% and 78%, respectively, at year 2 and 71% and 69% at year 5. Cumulative incidence of on-treatment disease progression/death was similar at years 5 (19%) and 2 (15%); Kaplan-Meier overall survival was 91% at year 2 and 84% at year 5. Of 169 patients who had discontinued bosutinib by year 5, 38 did so after year 2, most commonly for disease progression (n=11). Most adverse events initially occurred within two years. Overall, gastrointestinal events were the most common (diarrhea 86%, nausea 46%, vomiting 37%); the most common grade 3/4 toxicity was thrombocytopenia (25%). None of the 4 on-treatment deaths in years 3-5 were related to bosutinib. Bosutinib demonstrated durable efficacy and manageable toxicity through year 5 confirming its importance in the treatment of chronic phase chronic myeloid leukemia patients resistant/intolerant to prior imatinib. This trial was registered at clinicaltrials.gov identifier: 00261846.

Long-term patient-reported outcomes from an open-label safety and efficacy study of bosutinib in Philadelphia chromosome-positive chronic myeloid leukemia patients resistant or intolerant to prior therapy.

BACKGROUND: Health-related quality of life (HRQOL) in patients with chronic-phase chronic myeloid leukemia (CML) is important because of the requirement for long-term treatment. This study assessed HRQOL in bosutinib-treated patients with Philadelphia chromosome-positive CML and resistance or intolerance to 1 (chronic-phase second-line [CP2L]) or more (chronic-phase third-line [CP3L]) tyrosine kinase inhibitors who had 264 weeks or more of follow-up (ClinicalTrials.gov identifier NCT00261846). METHODS: Patient-reported HRQOL was assessed with the EuroQol 5-Dimensions Questionnaire (EQ-5D) and the Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu). RESULTS: In total, 284 and 119 patients composed the CP2L and CP3L cohorts, respectively. At treatment completion, more than 50% of the patients in the CP2L and CP3L cohorts completed the EQ-5D and FACT-Leu assessments. The EQ-5D and EQ-5D visual analog scale scores were stable in both cohorts throughout treatment. The mean FACT-Leu scores were generally stable over time but were lower in magnitude in the CP3L cohort versus the CP2L cohort. The FACT-Leu scale scores of a subset of patients with chronic diarrhea (CP2L, n = 101; CP3L, n = 30) were similar to the scores of the larger cohorts. Minimally important differences (MIDs) from baseline for the FACT-Leu scale scores were observed for the following: emotional well-being (EWB), Functional Assessment of Cancer Therapy-General (FACT-G) Total, FACT-Leu Total, and Functional Assessment of Cancer Therapy Trial Outcome Index (FACT-TOI) in the CP2L cohort and FACT-Leu Total in the CP3L cohort. Among patients with chronic diarrhea, MIDs were observed for EWB, FACT-G Total, FACT-Leu Total, and FACT-TOI in the CP2L cohort and for EWB, FACT-G Total, and FACT-Leu Total in the CP3L cohort. CONCLUSIONS: HRQOL was maintained with long-term bosutinib treatment for patients with CP2L and CP3L CML. Cancer 2018;124:587-95. © 2017 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

The evolution of care improves outcome in blunt thoracic aortic injury: A Western Trauma Association multicenter study.

BACKGROUND: The management of blunt thoracic aortic injury (BTAI) has evolved radically in the last decade with changes in the processes of care and the introduction of thoracic endovascular aortic repair (TEVAR). These changes have wrought improved outcome, but the direct effect of TEVAR on outcome remains in question as previous studies have lacked vigorous risk adjustment and long-term follow-up. To address these knowledge gaps, we compared the outcomes of TEVAR, open surgical repair, and nonoperative management for BTAI. METHODS: Eight verified trauma centers recruited from the Western Trauma Association Multicenter Study Group retrospectively studied all patients with BTAI admitted between January 1, 2006, and June 30, 2016. Data included demographics, comorbidities, admitting physiology, injury severity, in-hospital care, and outcome. RESULTS: We studied 316 patients with BTAI; 57 (18.0%) were in extremis and died before treatment. Of the 259 treated surgically, TEVAR was performed in 176 (68.0%), open in 28 (10.8%), hybrid in 4 (1.5%), and nonoperative in 51 (19.7%). Thoracic endovascular aortic repair and open repair groups had similar Injury Severity Scale score, chest Abbreviated Injury Scale score, Trauma and Injury Severity Score, and probability of survival, but differed in median age (open: 28 [interquartile range {IQR}, 19-51]; TEVAR: 46 [IQR, 28-60]; p < 0.007), zone of aortic injury (p < 0.001), and grade of aortic injury (open: 6 [IQR, 4-6]; TEVAR: 2 [IQR, 2-4]; p < 0.001). The overall in-hospital mortality was 6.6% (TEVAR: 5.7%, open: 10.7%, nonoperative: 3.9%; p = 0.535). Of the 240 patients who survived to discharge, two died (one at 9 months and one at 8 years); both were managed with TEVAR, but the deaths were unrelated to the aortic procedure. Stent graft surveillance computed tomography scans were not obtained in 37.6%. CONCLUSIONS: The mortality of BTAI continues to decrease. Thoracic endovascular aortic repair, when anatomically suitable, should be the treatment of choice. Open repair remains necessary for more proximal injuries. Process improvement in computed tomography imaging in follow-up of TEVAR is warranted. LEVEL OF EVIDENCE: Therapeutic/care management, level III.

Current use and outcomes of helicopter transport in pediatric trauma: a review of 18,291 transports.

PURPOSE: The role of helicopter emergency medical services (HEMS) in pediatric trauma remains controversial. We examined its use in pediatric trauma and its effectiveness in children with moderate/severe injuries. METHODS: All blunt/penetrating trauma patients ≤18years old in the National Trauma Data Bank were evaluated for use of HEMS and in-hospital mortality. In a comparative effectiveness study, only patients treated at level I/II pediatric centers with injury severity score (ISS)≥9 were included. RESULTS: Of 127,489 included patients, 18,291 (14%) arrived via HEMS, compared to 56% by ground ambulance and 29% by private vehicle/walk-in. HEMS patients had more severe injuries (ISS≥25; 28% vs. 14%) and altered mental status (GCS≤8; 29% vs. 11%), but also contained many patients with only minor injuries or no major physiologic derangements. In unadjusted analysis, HEMS was associated with increased mortality (OR: 1.6; 95% CI: 1.4-1.7). However, it had decreased mortality by regression (0.5; 0.4-0.6) and propensity analysis (0.7; 0.6-0.8) to adjust for confounders. CONCLUSION: We found multiple indicators for overuse of HEMS, with nearly 40% of children having only minor injuries. In moderate/severe injuries, HEMS is associated with decreased mortality, potentially saving one life for every 47 flights. Research is needed to determine appropriate criteria for helicopter triage. COMPARATIVE STUDY/LEVEL OF EVIDENCE: III.

Acute myeloid leukemia: a retrospective claims analysis of resource utilization and expenditures for newly diagnosed patients from first-line induction to remission and relapse.

OBJECTIVE: The objective of this study was to estimate resource utilization and expenditures for patients with acute myeloid leukemia (AML) in a real-world claims database. RESEARCH DESIGN AND METHODS: AML patients were identified in MarketScan claims databases between 1 January 2009 and 31 January 2015. Patients had a minimum of two AML diagnosis codes, hospitalization within 14 days after initial diagnosis, and ≥6 months of enrollment before initial diagnosis. Patients were monitored from first-line induction to a record of remission. A subset had a record of a second treatment period, defined as time from relapse to remission. Patient demographics, AML risk factors, and comorbidities were recorded. Descriptive analysis of utilization and expenditures (in 2014 $US) were reported for each cohort. RESULTS: The inclusion criteria were met in 1597 patients (mean age, 58.4 years; 51.0% male). Ninety percent of patients had ≥1 risk factor for AML. Mean (SD) healthcare expenditures for patients from first-line induction to remission (n = 681) were $208,857 ($152,090). Of the 157 who had a record of relapse, 70 had a record of a second remission. Expenditures for these patients (n = 70) from relapse to remission were $142,569 ($208,307); 60% were admitted to a hospital for a mean of 18.5 hospital days, and 20% had ≥1 emergency room visit. CONCLUSIONS: Although this claims-based analysis is limited by a lack of generalizability to noninsured populations and potential underreporting of certain events and diagnoses, we found that treating AML patients poses a significant healthcare burden, during both first-line induction and relapse. With people living longer, the number of cases of AML is expected to increase in the future.

Extracorporeal life support use in pediatric trauma: a review of the National Trauma Data Bank.

PURPOSE: As the role of extracorporeal life support (ECLS) continues to evolve in the adult and pediatric populations, smaller studies and case reports have described successful use of ECLS in specific groups of pediatric trauma patients. To further define the role of ECLS in pediatric trauma, we examined indications and outcomes for use of ECLS in injured children using a large national database. METHODS: All trauma patients ≤18years old were identified from the 2007 to 2011 National Trauma Data Bank. We collected patient demographics, mechanism of injury, injury severity, use of ECLS, and survival to discharge. Children undergoing ECLS were compared to those who did not undergo ECLS, using a 3:1 propensity matched analysis to compare outcomes between ECLS and non-ECLS patients with similar injury patterns. RESULTS: Of 589,895 pediatric trauma patients identified, 36 patients underwent ECLS. Within the ECLS cohort, 21/36 (58%) survived, and 10/36 (28%) were discharged directly home. Most ECLS patients were between 15 and 18years 20/36 (56%). Mechanisms of injury (MOI) resulting in ECLS use included: motor vehicle collision (MVC) 16/36 (44%), gunshot wound (GSW) 6/36 (17%), burns 6/36 (17%), and drowning/suffocation (D/S) 5/36 (14%). Among the ECLS cohort, survival varied by MOI from 75% in D/S to 56% in MVC and 33% in GSW and was 55% in patients with significant head injuries. Using propensity analysis for matched injury patterns, survival for ECLS and non-ECLS patients was similar (58% vs. 65%, p=0.61). CONCLUSIONS: In the largest study to date of ECLS support in pediatric trauma patients, we found encouraging survival rates to discharge, comparable to patients not undergoing ECLS with similar injuries. These results support further use and focused research of ECLS in pediatric trauma, including drowning, burn, and MVC victims and those with significant head injuries. LEVEL OF EVIDENCE: Level III; treatment study.

Health-related quality of life during bosutinib (SKI-606) therapy in patients with advanced chronic myeloid leukemia after imatinib failure.

OBJECTIVES: The tyrosine kinase inhibitor (TKI) bosutinib has demonstrated activity in patients with advanced phase chronic myeloid leukemia (CML), but effects on health-related quality of life (HRQoL) remain unexplored. This study evaluated HRQoL in advanced CML patients receiving bosutinib in an ongoing phase 2 study following resistance or intolerance to prior imatinib therapy. METHODS: This analysis included data from 76 accelerated-phase (AP) and 64 blast-phase (BP) patients resistant/intolerant to prior imatinib with or without prior exposure to other TKIs. Patient-reported HRQoL assessments completed at baseline; weeks 4, 8, and 12; every 12 weeks thereafter; and at treatment completion included the Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu); general health status was assessed using the 5-item EuroQol (EQ-5D) instrument and a visual analog scale (VAS). RESULTS: HRQoL at baseline was somewhat worse in BP versus AP CML patients. There was a significant improvement in the mean FACT-Leu Total scale at weeks 24, 36, and 48 in AP CML patients and at weeks 4, 8, 12, 24, 36, 48, and 96 in BP CML patients compared with baseline. EQ-5D Utility scores were stable throughout treatment in AP CML patients but significantly improved versus baseline in BP CML patients at weeks 4, 8, 12, and 36. Mean VAS scores were significantly improved at weeks 8, 36, and 48 in AP CML patients and at weeks 4, 8, 12, 24, 36, and 96 in BP CML patients. The lack of a comparison group limits attribution of improvements in HRQoL specifically to bosutinib treatment; potential bias due to non-ignorable dropout may limit the ability to generalize these findings to situations where durations of therapy exceed the 96-week follow-up duration of the present study. CONCLUSION: These findings suggest that bosutinib therapy is associated with improved HRQoL in advanced phase CML patients. CLINICAL TRIAL REGISTRATION: NCT00261846.

Long-term evaluation of cardiac and vascular toxicity in patients with Philadelphia chromosome-positive leukemias treated with bosutinib.

Vascular and cardiac safety during tyrosine kinase inhibitor (TKI) therapy is an emerging issue. We evaluated vascular/cardiac toxicities associated with long-term bosutinib treatment for Philadelphia chromosome-positive (Ph+) leukemia based on treatment-emergent adverse events (TEAEs) and changes in QTc intervals and ejection fraction in two studies: a phase 1/2 study of second-/third-/fourth-line bosutinib for Ph+ leukemia resistant/intolerant to prior TKIs (N = 570) and a phase 3 study of first-line bosutinib (n = 248) versus imatinib (n = 251) in chronic phase chronic myeloid leukemia. Follow-up time was ≥48 months (both studies). Incidences of vascular/cardiac TEAEs in bosutinib-treated patients were 7%/10% overall with similar incidences observed with first-line bosutinib (5%/8%) and imatinib (4%/6%). Few patients had grade ≥3 vascular/cardiac events (4%/4%) and no individual TEAE occurred in >2% of bosutinib patients. Exposure-adjusted vascular/cardiac TEAE rates (patients with events/patient-year) were low for second-line or later bosutinib (0.037/0.050) and not significantly different between first-line bosutinib (0.015/0.024) and imatinib (0.011/0.017; P ≥ 0.267). Vascular/cardiac events were managed mainly with concomitant medications (39%/44%), bosutinib treatment interruptions (18%/21%), or dose reductions (4%/8%); discontinuations due to these events were rare (0.7%/1.0%). Based on logistic regression modelling, performance status >0 and history of vascular or cardiac disorders were prognostic of vascular/cardiac events in relapsed/refractory patients; hyperlipidemia/hypercholesterolemia and older age were prognostic of cardiac events. In newly diagnosed patients, older age was prognostic of vascular/cardiac events; history of diabetes was prognostic of vascular events. Incidences of vascular and cardiac events were low with bosutinib in the first-line and relapsed/refractory settings following long-term treatment in patients with Ph+ leukemia. Am. J. Hematol. 91:606-616, 2016. © 2016 Wiley Periodicals, Inc.

Factors influencing long-term efficacy and tolerability of bosutinib in chronic phase chronic myeloid leukaemia resistant or intolerant to imatinib.

The dual SRC/ABL1 tyrosine kinase inhibitor bosutinib is indicated for adults with Ph+ chronic myeloid leukaemia (CML) resistant/intolerant to prior therapy. This analysis of an ongoing phase 1/2 study (NCT00261846) assessed effects of baseline patient characteristics on long-term efficacy and safety of bosutinib 500 mg/day in adults with imatinib (IM)-resistant (IM-R; n = 196)/IM-intolerant (IM-I; n = 90) chronic phase (CP) CML. Median treatment duration was 24·8 months (median follow-up, 43·6 months). Cumulative major cytogenetic response (MCyR) rate [95% confidence interval (CI)], was 59% (53-65%); Kaplan-Meier (KM) probability of maintaining MCyR at 4 years was 75% (66-81%). Cumulative incidence of on-treatment progression/death at 4 years was 19% (95% CI, 15-24%); KM 2-year overall survival was 91% (87-94%). Significant baseline predictors of both MCyR and complete cytogenetic response (newly attained/maintained from baseline) at 3 and 6 months included prior IM cytogenetic response, baseline MCyR, prior interferon therapy and <6 months duration from diagnosis to IM treatment initiation and no interferon treatment before IM. The most common adverse event (AE) was diarrhoea (86%). Baseline bosutinib-sensitive BCR-ABL1 mutation was the only significant predictor of grade 3/4 diarrhoea; no significant predictors were identified for liver-related AEs. Bosutinib demonstrates durable efficacy and manageable toxicity in IM-R/IM-I CP-CML patients.

Comparative effectiveness of treatment strategies for severe splenic trauma in the pediatric population.

BACKGROUND: Splenic angioembolization (SAE) is increasingly used in the management of splenic injuries in adults, although its value in pediatric trauma is unclear. We sought to assess outcomes related to splenectomy vs SAE. METHODS: The National Trauma Data Bank was queried for patients 0 to 15 years of age from 2007 to 2011. Subgroup analysis of splenectomy vs SAE was performed for high-grade injuries using propensity analysis and inverse probability weighting. RESULTS: Of 11,694 children presenting with splenic trauma, over 90% were treated nonoperatively. Adjusted analysis of high-grade injuries included 265 children who underwent splenectomy and 199 who underwent SAE. The Injury Severity Score, number of transfusions, and complications rates were not significantly different between the 2 groups. Overall adjusted mortality for children with high-grade injuries was 13.4% following splenectomy and 10.0% following SAE (P = .31) CONCLUSION: Patients undergoing SAE for high-grade splenic trauma have comparable morbidity and mortality with splenectomy.

Leukopenia is associated with worse but not prohibitive outcomes following emergent abdominal surgery.

BACKGROUND: There are little data currently available to guide surgical decision making regarding emergent surgical interventions in leukopenic patients. The purpose of this study was to investigate the impact of leukopenia among patients undergoing emergency abdominal operations to better guide preoperative decision making. METHODS: The 2005 to 2012 American College of Surgeons' National Surgical Quality Improvement Program database was queried to identify patients who underwent emergent laparotomy. Patients were stratified by preoperative white blood cell (WBC) count (<4.0 × 10(9)/L vs. 4.0-12.0 × 10(9)/L). Baseline demographics, comorbidities, and outcomes were compared. Multivariable logistic regression was performed to estimate the adjusted association between leukopenia and mortality, taking into account the robust array of patient-related factors. RESULTS: Of the 20,443 patients who met study criteria, 2,057 (8.2%) were leukopenic (WBC < 4.0) before surgery. Unadjusted comparison demonstrated significantly increased major morbidity (45.4% vs. 26.9%, p < 0.001) as well as mortality (24.4% vs. 10.8%, p < 0.001) for patients with leukopenia compared with patients with a normal preoperative WBC count. Only 46.0% (n = 947) of patients with leukopenia before surgery were able to avoid major morbidity or mortality compared with 69.4% (n = 15,974) of patients with a normal preoperative WBC count (p < 0.001). After multivariable adjustment for patient-related factors, leukopenia was maintained as a significant predictor of mortality. CONCLUSION: Although leukopenia remains associated with mortality in patients undergoing emergent laparotomy despite adjustment for other patient-related factors, it is not necessarily prohibitive. Understanding the risk of complications and mortality associated with these procedures is pertinent for preoperative clinical decision making. LEVEL OF EVIDENCE: Prognostic and epidemiologic study, level III.