We report the results of a multicenter phase 1 dose-escalation study of the selective Bruton tyrosine kinase (BTK) inhibitor ONO/GS-4059 in 90 patients with relapsed/refractory B-cell malignancies. ...There were 9 dose-escalation cohorts ranging from 20 mg to 600 mg once daily with twice-daily regimens of 240 mg and 300 mg. Twenty-four of 25 evaluable chronic lymphocytic leukemia (CLL) patients (96%) responded to ONO/GS-4059, with a median treatment duration of 80 weeks; 21 CLL patients remain on treatment. Lymph node responses were rapid and associated with a concurrent lymphocytosis. Eleven of 12 evaluable patients with mantle cell lymphoma (92%) responded (median treatment duration, 40 weeks). Eleven of 31 non–germinal center B-cell diffuse large B-cell lymphoma patients (35%) responded but median treatment duration was 12 weeks due to development of progressive disease. ONO/GS-4059 was very well tolerated with 75% of adverse events (AEs) being Common Toxicity Criteria for Adverse Events version 4.0 grade 1 or grade 2. Grade 3/4 AEs were mainly hematologic and recovered spontaneously during therapy. One CLL patient experienced a grade 3 treatment-related bleeding event (spontaneous muscle hematoma) but no clinically significant diarrhea, cardiac dysrhythmias, or arthralgia were observed. No maximal tolerated dose (MTD) was reached in the CLL cohort. In the non-Hodgkin lymphoma cohort, 4 patients developed a dose-limiting toxicity, yielding an MTD of 480 mg once daily. ONO/GS-4059 has significant activity in relapsed/refractory B-cell malignancies without major drug-related toxicity. The selectivity of ONO/GS-4059 should confer advantages in combination therapies. This trial was registered at www.clinicaltrials.gov as #NCT01659255.
•We report a first-in-human dose-escalation study in relapsed/refractory B-cell malignancies with the potent BTK inhibitor ONO/GS-4059.•ONO/GS-4059 induced clinically durable responses in relapsed/refractory B-cell malignancies without significant toxicities.
In 2015, the American College of Surgeons Committee on Trauma introduced the Needs-Based Assessment of Trauma Systems (NBATS) tool to quantify the optimal number of trauma centers for a region. While ...useful, more focus was required on injury population, distribution, and transportation systems. Therefore, NBATS-2 was developed utilizing advanced geographical modeling. The purpose of this study was to evaluate NBATS-2 in a large regional trauma system.
Data from all injured patients from 2016 to 2017 with an Injury Severity Score greater than 15 was collected from the trauma registry of the existing (legacy) center. Injury location and demographics were analyzed by zip code. A regional map was built using US census data to include hospital and population demographic data by zip code. Spatial modeling was conducted using ArcGIS to estimate an area within a 45-minute drive to a trauma center.
A total of 1,795 severely injured patients were identified across 54 counties in the tri-state region. Forty-eight percent of the population and 58% of the injuries were within a 45-minute drive of the legacy trauma center. With the addition of another urban center, injured and total population coverage increased by only 1% while decreasing the volume to the existing center by 40%. However, the addition of two rural trauma centers increased coverage significantly to 62% of the population and 71% of the injured (p < 0.001). The volume of the legacy center was decreased by 25%, but the self-pay rate increased by 16%.
The geospatial modeling of NBATS-2 adds a new dimension to trauma system planning. This study demonstrates how geospatial modeling applied in a practical tool can be incorporated into trauma system planning at the local level and used to assess changes in population and injury coverage within a region, as well as potential volume and financial implications to a current system.
Care management/economic, level V.
A gold nanohole array is functionalized with a cortisol thiol derivative, and binding to a monoclonal antibody is conveniently detected using the sensitive shift in the 1060 nm transmission peak of ...the array. Detection is also enhanced 3-fold by the application of a secondary antibody−gold nanoparticle conjugate. This regenerable response represents a more sensitive shift than that obtained previously for higher affinity binding and opens the way to application of nanohole arrays in immunobiosensing of important biomolecules.
Exsanguination associated with acute traumatic coagulopathy is a leading cause of death following injury. While platelets occupy a pivotal role in clot formation, clinical research has been scant ...because of complexities resulting from the need for rapid handling and complex testing of platelet functions. While the thrombin pathway has been proposed as a mediator of platelet dysfunction in trauma, it has not been systematically investigated. The purpose of this study was to evaluate the thrombin pathway in platelet dysfunction.
Forty trauma patients and 20 noninjured controls were enrolled in the study at a Level I trauma center. Platelet aggregation was tested by light transmission aggregometry with two agonists, adenosine diphosphate (ADP) and thrombin receptor agonist peptide (TRAP). Mean fluorescence intensity and percent positivity of CD62 on ADP-activated platelets were evaluated using flow cytometry. Enzyme-linked immunosorbent assays were performed to evaluate the concentrations of D-dimer, thrombin-antithrombin complex (TAT), and prothrombin fragment 1 + 2 (PF 1 + 2) in each sample.
Compared with healthy controls, trauma patients had significantly decreased ADP- and TRAP-mediated platelet aggregation and ADP-mediated CD62 expression. In trauma patients, TRAP-mediated aggregation was inversely proportional to head Abbreviated Injury Scale (AIS) score. Glasgow Coma Scale (GCS) score was directly proportional to TRAP- and ADP-mediated aggregation. When compared with controls, significant differences of D-dimer, TAT, and PF 1 + 2 were found. Measures of shock, including admission blood pressure, pulse, base deficit, and lactate level, did not correlate with platelet dysfunction.
Trauma patients have significantly lower levels of platelet activation and aggregation compared with healthy controls. Severity of head injury was significantly correlated with platelet dysfunction in a stepwise fashion. Trauma patients also have significantly increased levels of D-dimer, TAT, and PF 1 + 2 when compared with healthy controls. Our data suggest that the thrombin receptor pathway plays an important role in platelet dysfunction in trauma.
Prognostic and epidemiologic study, level III.
Various management strategies exist for the abdomen that will not close. At our institution, these patients are managed with polyglactin 910 mesh followed 14 days later (LATE) by split-thickness skin ...graft (STSG) or, in some cases, earlier (EARLY, <14 days), if the wound is judged to be adequately granulated. The purpose of this study was to evaluate the impact of STSG timing for wounds felt ready for grafting on STSG failure.
Consecutive patients over a 3-year period managed with polyglactin 910 mesh followed by STSG were identified. Patient characteristics, severity of injury and shock, time to STSG, and outcomes, including STSG failure, were recorded and compared. Multivariable logistic regression analysis was performed to identify predictors of graft failure.
Sixty-one patients were identified: 31 EARLY and 30 LATE. There was no difference in severity of injury or shock between the groups. Split-thickness skin graft failure occurred in 11 patients (9 EARLY vs. 2 LATE, p < 0.0001). Time to STSG was significantly less in patients with graft failure (11 days vs. 15 days, p = 0.012). In fact, after adjusting for age, injury severity, severity of shock, and time to STSG, multivariable logistic regression identified EARLY STSG (odds ratio, 1.4; 95% confidence interval, 1.1-1.8, p = 0.020) as the only independent predictor of graft failure.
Appearance of the open abdomen can be misleading during the first 2 weeks following polyglactin 910 mesh placement. EARLY STSG was the only modifiable risk factor associated with graft failure. Thus, for optimal results, STSG should be delayed at least 14 days after polyglactin 910 mesh placement.
Prognostic study, level IV.
Abstract Background Outcome measures after cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) for peritoneal carcinomatosis in established centers are well defined. ...However, results from newly emerging US centers have not been reported. Methods This is a retrospective review of a prospectively maintained database of patients with peritoneal malignancies undergoing CRS/HIPEC. Results Fifty-six patients underwent exploratory laparotomy with 36 receiving CRS/HIPEC over 36 months. The median peritoneal cancer index score was 18, and the cytoreduction 0/1 rate was 92%. Postoperative major morbidity was 16.7% with one perioperative death. The median length of hospital stay and intensive care unit days were 9 and 3 days, respectively. Disease-free survival in high-grade vs low-grade tumors was 12.6 and 31.0 months ( P , .03), respectively. Average direct cost for patients undergoing CRS/HIPEC was $25,917. Conclusions Our emerging center's short-term results are comparable with established programs with a trend toward more selective intraoperative judgment on who undergoes CRS/HIPEC.
ONO-9054 is being developed for the reduction of intraocular pressure (IOP) in patients with ocular hypertension (OHT) and open-angle glaucoma (OAG). This study compared the novel dual EP3/FP agonist ...ONO-9054 with the FP agonist Xalatan.
Adults (n=123) with bilateral mild/moderate OAG or OHT, with unmedicated IOP of ≥24 mm Hg at 8:00 hours, ≥21 mm Hg at 10:00 hours and ≤36 mm Hg, were randomised 1:1 to receive ONO-9054 (0.003%, 30 μg/mL) or Xalatan (0.005%, 50 μg/mL) once daily for 28 days.
Day 29 mean diurnal IOP was -7.2 mm Hg for ONO-9054 vs -6.6 mm Hg for Xalatan. At 08:00 hours, the IOPs were comparable, and at all later time points the decrease in IOP was greater for ONO-9054. On day 29, the odds of a mean IOP reduction of ≤-25%, ≤-30% and ≤-35% for ONO-9054 were 2.39, 2.37 and 4.85 times more, respectively, than the odds for Xalatan (p<0.05,
analyses). The percentage of subjects achieving target IOPs on day 29 (≤17, ≤16 and ≤15 mm Hg) was greater for ONO-9054 than for Xalatan; the odds of achieving an IOP ≤15 mm Hg for ONO-9054 were 2.4 times more than the odds for Xalatan (p<0.01,
analysis).
Subjects randomised to receive ONO-9054 were more likely to achieve a greater per cent reduction in IOP and were more likely to achieve target IOPs than those receiving Xalatan. The effects of ONO-9054 in reducing IOP appear to persist longer than those of Xalatan.
NCT02083289, Results.
Gun violence is a substantial public health problem accounting for significant physical, psychological, and financial costs. Although aggregate data sources demonstrate decreasing rates of firearm ...violence, analyses from individual trauma centers have shown that mortality and injury severity from gunshot wounds (GSWs) are increasing. To evaluate the evolving characteristics of gun violence in our region, we studied all GSWs admitted to our trauma center over a 20-year period.
A retrospective analysis of all newly admitted patients with GSWs was performed from 1996 to 2016. Our trauma registry was used to collect data on demographics, mortality, injury severity, body regions injured, and geographic location of injury. Homicide data were obtained from local law enforcement.
A total of 11,294 patients with GSWs were reviewed. The number of GSWs treated per biennium increased from 1,349 in 1996-1997 to 1,484 in 2014-2015, with a 59% increase occurring from 2010-2011 to 2014-2015. Overall mortality was 14.6% and decreased from 15.8% in 1996-1997 to 10.2% in 2014-2015 (p < 0.0001). Mean Injury Severity Score was 12.6 and the percentage of patients who suffered GSWs to ≥3 Abbreviated Injury Scale body regions increased from 2.5% in 1996-1997 to 7.7% in 2014-2015 (p < 0.0001). Local firearm homicide data show a 118% increase from 2010 to 2016.
In contrast to other recent studies, we found that mortality decreased whereas the number of patients treated for GSWs and those with multicompartmental injuries increased. The decrease in mortality suggests improved trauma systems as well as an increase in nonfatal GSWs that dilutes overall mortality. Wounding in multiple body regions suggests more effective weaponry, including increased magazine size. The recent increase in local homicides parallels trends in registry data and illustrates worsening gun violence in our region. Further research is needed to understand local and regional determinants of increased gun violence to better guide prevention strategies.
Epidemiological study, level III.
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