Effects of dissolved organic carbon on potentially toxic element desorption in stormwater bioretention systems.

Stormwater runoff contains dissolved organic carbon (DOC) and potentially toxic elements (PTEs). Interactions between DOC and PTEs can impact PTE speciation and mobility, but are not fully understood. Soil samples were collected from a vegetated bioretention bed to investigate the effects of DOC (0, 15, and 50 mg-C/L) on the desorption of 10 PTEs captured by the soil media: Mn, Fe, Co, Cu, Zn, As, Cd, Sn, Sb, and Pb. In the absence of DOC, the desorbed PTE concentration from bioretention media into the aqueous phase ranking was as follows: Fe > Mn âˆ¼ Zn > Cu > Pb > Sb > As > Co > Sn âˆ¼ Cd. Increased DOC concentrations resulted in a reduction of the soil-water distribution coefficient (Kd) values. The greatest shift in Kd was observed for Cu and lowest for Sb. The PTE sorption capacities were lower for surficial soil samples (lower Kd) compared to the deep soil samples. Overall, the desorbed PTE (average midchannel 55.7 µg/g) fraction accounted for <1.1 % of the total extracted PTEs (5364 µg/g), and while this is a small percentage of the total, this is the fraction that is mobile. The extracted PTE fractions revealed that DOC reduced the organic matter-bound and carbonate-bound fractions. The PTE desorption trends suggest that reducing DOC in stormwater runoff could be an effective measure to mitigate the release of PTEs into the environment.

Quality-adjusted Time Without Symptoms of disease or Toxicity (Q-TWiST) analysis of CPX-351 versus 7 + 3 in older adults with newly diagnosed high-risk/secondary AML.

BACKGROUND: CPX-351 (United States: Vyxeos®; Europe: Vyxeos® Liposomal), a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar ratio, is approved by the US FDA and the EMA for the treatment of adults with newly diagnosed therapy-related acute myeloid leukemia or acute myeloid leukemia with myelodysplasia-related changes. In a pivotal phase 3 study that evaluated 309 patients aged 60 to 75 years with newly diagnosed high-risk/secondary acute myeloid leukemia, CPX-351 significantly improved median overall survival versus conventional 7 + 3 chemotherapy (cytarabine continuous infusion for 7 days plus daunorubicin for 3 days), with a comparable safety profile. A Quality-adjusted Time Without Symptoms of disease or Toxicity (Q-TWiST) analysis of the phase 3 study was performed to compare survival quality between patients receiving CPX-351 versus conventional 7 + 3 after 5 years of follow-up. METHODS: Patients were randomized 1:1 between December 20, 2012 and November 11, 2014 to receive induction with CPX-351 or 7 + 3. Survival time for each patient was partitioned into 3 health states: TOX (time with any grade 3 or 4 toxicity or prior to remission), TWiST (time in remission without relapse or grade 3 or 4 toxicity), and REL (time after relapse). Within each treatment arm, Q-TWiST was calculated by adding the mean time spent in each health state weighted by its respective quality-of-life, represented by health utility. The relative Q-TWiST gain, calculated as the difference in Q-TWiST between treatment arms divided by the mean survival of the 7 + 3 control arm, was determined in order to evaluate results in the context of other Q-TWiST analyses. RESULTS: The relative Q-TWiST gain with CPX-351 versus 7 + 3 was 53.6% in the base case scenario and 39.8% among responding patients. Across various sensitivity analyses, the relative Q-TWiST gains for CPX-351 ranged from 48.0 to 57.6%, remaining well above the standard clinically important difference threshold of 15% for oncology. CONCLUSIONS: This post hoc analysis demonstrates that CPX-351 improved quality-adjusted survival, further supporting the clinical benefit in patients with newly diagnosed high-risk/secondary acute myeloid leukemia. Trial registration This trial was registered on September 28, 2012 at www.clinicaltrials.gov as NCT01696084 ( https://clinicaltrials.gov/ct2/show/NCT01696084 ) and is complete.

A multicentre, multinational, prospective, observational registry study of defibrotide in patients diagnosed with veno-occlusive disease/sinusoidal obstruction syndrome after haematopoietic cell transplantation: an EBMT study.

Severe hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of haematopoietic cell transplantation (HCT). This multinational, prospective, observational study (NCT03032016), performed by the EBMT, enrolled patients treated with defibrotide from April 2015 to July 2018. This analysis focused on defibrotide-treated patients with VOD/SOS post-HCT. The primary endpoint was incidence of serious adverse events (SAEs) of interest up to 12 months post-HCT in patients with severe VOD/SOS. Overall, 104 defibrotide-treated patients with VOD/SOS post-HCT were enrolled: 62 had severe VOD/SOS and comprised the primary study population, including 36 with multi-organ dysfunction/failure (MOD/MOF). SAEs of interest occurred in 20 of 62 (32%) severe VOD/SOS patients; the most common by category were infection (24%) and bleeding (13%). In patients with severe VOD/SOS, the Kaplan-Meier-estimated Day 100 survival rate was 73% (95% CI: 60%, 82%) with VOD/SOS resolution by Day 100 in 45 of 62 (73%) patients. MOD/MOF resolved in 19 of 36 (53%) patients with MOD/MOF at VOD/SOS diagnosis. Results from this multicentre registry study build on prior defibrotide studies supporting the utility of defibrotide for the treatment of VOD/SOS post-HCT. These results provide additional real-world evidence of the effectiveness and safety of defibrotide in patients with VOD/SOS post-HCT.

Older adults with newly diagnosed high-risk/secondary AML who achieved remission with CPX-351: phase 3 post hoc analyses.

CPX-351, a dual-drug liposomal encapsulation of daunorubicin/cytarabine in a synergistic 1:5 molar ratio, is approved for the treatment of adults with newly diagnosed, therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC). In a pivotal phase 3 study, patients aged 60 to 75 years with newly diagnosed, high-risk/secondary AML were randomized to receive CPX-351 or conventional 7+3 chemotherapy. In the primary endpoint analysis, CPX-351 demonstrated significantly prolonged median overall survival (OS) vs 7+3. These exploratory post hoc subgroup analyses evaluated the impact of achieving complete remission (CR) or CR with incomplete neutrophil or platelet recovery (CRi) with CPX-351 (73/153 [48%]) vs conventional 7+3 (52/56 [33%]) on outcomes. CPX-351 improved median OS vs 7+3 in patients who achieved CR or CRi (25.43 vs 10.41 months; hazard ratio = 0.49; 95% confidence interval, 0.31, 0.77). Improved median OS was seen across AML subtypes (t-AML, AML-MRC), age subgroups (60 to 69 vs 70 to 75 years), patients with prior hypomethylating agent exposure, and patients who did not undergo transplantation. Patients who achieved CR or CRi with CPX-351 also had a higher rate of transplantation, a longer median OS landmarked from the date of transplantation (not reached vs 11.65 months; hazard ratio = 0.43; 95% confidence interval, 0.21, 0.89), and a safety profile that was consistent with the known safety profile of 7+3. These results suggest deeper remissions may be achieved with CPX-351, leading to improved OS. This study was registered at www.clinicaltrials.gov as #NCT01696084.

Analysis of Time to Complete Response after Defibrotide Initiation in Patients with Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome after Hematopoietic Cell Transplantation.

Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication that occurs after hematopoietic cell transplantation (HCT). The mortality associated with untreated VOD/SOS with multiorgan dysfunction (MOD) has been reported to be >80%. The recommended dose of defibrotide is 6.25 mg/kg every 6 hours, administered as a 2-hour i.v. infusion, for a minimum of 21 days or until resolution of VOD/SOS signs and symptoms. The objective of this analysis was to evaluate the time to complete response (CR) in patients with post-HCT VOD/SOS treated with defibrotide. The time to defibrotide discontinuation due to a CR served as a surrogate for time to CR in an expanded access study (T-IND; ClinicalTrials.gov NCT00628498; n = 1000), and was analyzed separately from the time to CR data pooled from a phase 2 randomized dose-finding study (NCT00003966; n = 74 patients who received 25 mg/kg/day) and a phase 3 historically controlled study (NCT00358501; n = 102). For all studies, a CR was defined as total serum bilirubin <2 mg/dL with resolution of VOD/SOS-related MOD (renal and/or pulmonary dysfunction); the phase 2 study also required resolution of central nervous system dysfunction. In the T-IND, 390 patients discontinued treatment due to a CR and had sufficient data for analysis. The median time to discontinuation was 22 days (range, 2 to 64 days). Discontinuation due to CR occurred beyond 21 days in 235 patients (60%) and beyond 28 days in 57 patients (15%). The pooled phase 2 and 3 studies included 60 patients who achieved a CR, with a median time to CR of 24.5 days (range, 7 to 123 days). A CR was achieved beyond 21 days in 32 patients (53%) and beyond 28 days in 24 patients (40%). The Kaplan-Meier estimate of day +100 survival rate was substantially higher in patients who discontinued due to a CR compared with those who did not (92.5% versus 37.3%). Treatment-emergent adverse events occurred in 185 of 390 patients (47%) who discontinued due to a CR in the T-IND and in 55 of 60 patients (92%) who achieved a CR in the pooled phase 2 and 3 studies, and rates did not differ according to duration of treatment (≤21 days versus >21 days). Taken together, these results highlight the importance of continued defibrotide therapy until resolution of VOD/SOS signs and symptoms, as currently indicated in the approved product labels, which may occur beyond the recommended minimum of 21 days.

Long-term simulation of potentially toxic elements (PTEs) accumulation and breakthrough in infiltration-based stormwater management practices (SMPs).

Stormwater management practices (SMPs) rely on infiltration and adsorption capabilities of soil and vegetative cover to mitigate the harmful impacts of contaminants in stormwater runoff, including potentially toxic elements (PTEs). Under chemical equilibrium conditions, the soil-water distribution coefficient (Kd) quantifies the relationship between the solid and aqueous phase PTE concentrations, and thus the PTE removal efficiency and mobility through the SMP soil layers during the infiltration process. The SMP loading ratio (LR), the ratio of the drainage area to the SMP infiltration area, combined with runoff concentration determines SMP mass loading and is also expected to impact PTE transport. In this study, a simulation model was developed to investigate PTE breakthrough and build-up in SMP media, considering the impacts of Kd and LR. Eight PTEs were simulated (Cl-, Cr, Fe, Zn, Cu, As, Cd, and Pb), and Cl- was the only PTE that showed high mobility and reached the groundwater table (e.g., ~ 1 year for breakthrough). Conversely, other PTEs were effectively immobilized in the top ~60 cm of soil for a simulated lifespan of 20 years. Soil and porewater contaminant indices, as indicators of SMP lifespan, were estimated based on the ratio of PTE porewater and soil concentrations after 20 years to published standards, suggesting the following order of environmental significance (most concern to least): Cl- > Cr > As > Pb > Fe > Cu > Cd > Zn. After 20 years of simulated use, only Cl- pore water concentrations at the groundwater table exceeded regulatory values, with porewater contamination index values of 4 to 7.5. Chloride also exceeded the surficial media soil contamination index, as did As and Cr, though these exceedences were largely associated with media background concentrations. Generally, higher LR and Kd contributed to higher accumulation of PTEs in top layers; however, simulations showed that the combination of low LR and high Kd may result in lower PTE accumulation in the media, such that the PTE concentration in soil may decrease in deeper layers. In these scenarios, a notable fraction of PTE load was adsorbed on top layers and considerably lower PTE concentrations reached the lower layers. Sensitivity analysis revealed that dispersion, infiltration rate, and kinetically-limited sorption did not impact the PTE accumulation and mobility to a practical extent. The results from this simulation may be adapted to various environmental conditions to enhance the design and maintenance of SMPs.

Pooled analysis of Day 100 survival for defibrotide-treated patients with hepatic veno-occlusive disease/sinusoidal obstruction syndrome and ventilator or dialysis dependence following haematopoietic cell transplantation.

For patients with untreated hepatic veno-occlusive disease (VOD)/sinusoidal obstruction syndrome (SOS) with multi-organ dysfunction (MOD), mortality is >80%. We conducted a pooled analysis of three studies that assessed Day 100 survival in relationship to MOD severity, with dialysis and/or ventilator dependence representing the most severe organ dysfunction. All patients in the analysis were diagnosed using Baltimore criteria/biopsy. This analysis of patients with VOD/SOS and MOD after haematopoietic cell transplantation (HCT; n = 651) demonstrated higher Day 100 survival rates amongst defibrotide-treated patients with VOD/SOS with less versus more severe forms of MOD. Even patients with severe forms of MOD post-HCT benefitted from defibrotide.

Incidence of Anicteric Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome and Outcomes with Defibrotide following Hematopoietic Cell Transplantation in Adult and Pediatric Patients.

Veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of hematopoietic cell transplantation (HCT) that is traditionally diagnosed using Baltimore or modified Seattle criteria. Whereas the Baltimore criteria require the presence of hyperbilirubinemia (bilirubin ≥2 mg/dL) for a diagnosis of VOD/SOS, the modified Seattle criteria do not. Before approval by the US Food and Drug Administration, defibrotide was available in the United States through an expanded-access study (T-IND). The T-IND protocol initially required post-HCT diagnosis of VOD/SOS by the Baltimore criteria or biopsy but was later amended to include patients diagnosed using the modified Seattle criteria. This post hoc analysis examined the incidence of VOD/SOS with a bilirubin level <2 mg/dL before and after Day 21 post-HCT in T-IND patients enrolled following the amendment allowing for diagnosis by the modified Seattle criteria. Survival of adult and pediatric patients with or without hyperbilirubinemia and with or without multiorgan dysfunction (MOD) was also evaluated. Of 803 post-HCT patients with VOD/SOS enrolled following the protocol amendment, 181 (23%) had a bilirubin level <2 mg/dL and would not have been diagnosed if hyperbilirubinemia was required. The bilirubin level at diagnosis was <2 mg/dL in 165 of 331 patients (50%) diagnosed by the modified Seattle criteria and in 16 of 23 patients (70%) diagnosed by biopsy. VOD/SOS with a bilirubin level <2 mg/dL was more common in pediatric patients (29%), although it also occurred in adult patients (15%). Patients with hyperbilirubinemia had lower Day 100 survival (54% versus 87% in patients with bilirubin <2 mg/dL) and a higher incidence of MOD (41% versus 26% in patients with bilirubin <2 mg/dL). The incidence of treatment-emergent adverse events and serious adverse events was lower in patients with a bilirubin level <2 mg/dL. These results indicate that anicteric VOD/SOS occurs in both adult and pediatric patients post-HCT and can be diagnosed before and after Day 21 in both groups. The worse survival in patients with bilirubin ≥2 mg/dL suggests that requiring hyperbilirubinemia may result in a progressed disease stage associated with worse outcomes. Taken together, these results highlight the importance of awareness and the possibility of VOD/SOS in the absence of elevated bilirubin level.

Healthcare resource utilization in a phase 3 study of CPX-351 in patients with newly diagnosed high-risk/secondary acute myeloid leukemia.

Aims: Treatment of acute myeloid leukemia (AML) requires significant healthcare resource utilization (HRU), including lengthy hospitalizations. In a phase 3 study (NCT01696084), CPX-351 (Vyxeos) showed significant benefits to overall survival and complete remission versus conventional 7 + 3 cytarabine/daunorubicin. This analysis evaluated HRU in patients aged 60-75 years with newly diagnosed high-risk/secondary AML treated with CPX-351 versus 7 + 3 in the phase 3 study.Materials and methods: Patients were randomized to receive up to two induction cycles with CPX-351 or 7 + 3. Responders could receive up to two cycles of consolidation. To normalize HRU to length of treatment, patients were assessed on a per patient-year (PPY) basis. HRU analyses included hospital and intensive care unit (ICU) stays, anti-infective use, transfusions, and white blood cell colony-stimulating factor (CSF).Results: The median (range) total duration of hospitalization was 39 (3-110) days with CPX-351 (n = 153) and 32 (2-83) days with 7 + 3 (n = 151); the estimated durations of hospitalization PPY were 198.4 and 240.5 days, respectively. The median (range) total duration of ICU stays was 0 (0-45) days with CPX-351 and 0 (0-17) days with 7 + 3; the estimated durations of ICU stays PPY were 6.7 and 10.5 days, respectively. When comparing supportive care use during CPX-351 and 7 + 3 treatment, the estimated number PPY of bags of platelets used (24.6 vs 26.9, respectively), bags of packed red blood cells used (13.0 vs 13.9), days of anti-infectives (162.0 vs 159.2), and days of CSF (4.0 vs 2.4) were not notably different.Limitations: This clinical study analysis may not represent real-world HRU patterns or be generalizable to a broader AML population.Conclusions: These PPY data, showing shorter durations of hospitalization and similar use of supportive care with CPX-351 versus 7 + 3, suggest CPX-351 is not associated with increased HRU in older patients with newly diagnosed high-risk/secondary AML.

Consolidation outcomes in CPX-351 versus cytarabine/daunorubicin-treated older patients with high-risk/secondary acute myeloid leukemia.

CPX-351 is a dual-drug liposomal encapsulation of cytarabine/daunorubicin. In a phase 3 study (ClinicalTrials.gov Identifier: NCT01696084), patients aged 60-75 years with newly diagnosed, high-risk/secondary AML received 1-2 induction cycles with CPX-351 or 7 + 3 chemotherapy; those achieving complete remission (including with incomplete platelet or neutrophil recovery) could receive up to 2 consolidation cycles with CPX-351 or 5 + 2 chemotherapy, respectively. In this exploratory analysis of the subgroup of patients who received consolidation, median overall survival was prolonged among patients receiving CPX-351 induction/consolidation versus 7 + 3/5 + 2 (25.43 vs. 8.53 months; HR = 0.44 [95% CI: 0.25-0.77]). The safety profile of CPX-351 consolidation was consistent with that of the overall study. Outpatient administration of CPX-351 consolidation occurred in 51%-61% of patients and did not diminish overall survival. These findings suggest consolidation with CPX-351 in this patient population contributed to the prolonged overall survival versus 7 + 3/5 + 2, building upon findings from the overall study population, and provide evidence that, with careful monitoring, some patients can successfully receive CPX-351 as outpatients.

Lateral and longitudinal variation of hyporheic exchange in a piedmont stream pool.

A conservative solute tracer experiment was conducted in Indian Creek, a small urban stream in Philadelphia, PA, to investigate the role of subsurface properties on the exchange between streamwater and the hyporheic zone (subsurface surrounding the stream). Sodium bromide (NaBr) was used as a conservative tracer, and it was monitored in the surface water and in the bed sediments of a 15 m long pool. Subsurface sampling occurred at 12 locations in the upper layer sediments (extending from 7.5 to 10 cm below the streambed) and 13 locations in the lower layer sediments (extending from 10 to 12.5 cm below the streambed). The hydraulic conductivity (K) of the upper bed sediments and the lower bed sediments was measured in situ. Several locations within the streambed exhibited an increase in tracer concentration with depth, suggesting the presence of horizontal flow paths within this small pool. Over the entire pool, the influence of K heterogeneity on hyporheic exchange was masked by the groundwater head gradient and the morphology of the stream. Together, the groundwater head gradient and stream morphology induced a generally high tracer concentration and fast hyporheic exchange on the left side and center of the channel and low concentrations and slower exchange on the right side. Although the reach-scale effects on the surface water concentration were small, groundwater greatly influenced the local-scale hyporheic exchange in the pool. Understanding how physical stream characteristics control the location and extent of hyporheic exchange pathways will lead to a better understanding of biogeochemical cycling of nutrients and contaminants.

Incomplete mixing in a small, urban stream.

Conservative solute tracer experiments were conducted in Indian Creek, a small urban stream located in Philadelphia, Pennsylvania, USA. Estimated flow rates were between 46 Ls(-1) and 81 Ls(-1), average stream width was 5.5m and average stream depth was 0.2m. Given these dimensions, most researchers would think it reasonable to assume that the stream is completely mixed vertically and horizontally. However, we found that the stream was not vertically completely mixed in a 1.0m deep, 30 m long pool. The limited mixing was demonstrated by the vertical stratification of a tracer cloud which was completely mixed both laterally and vertically across the stream prior to entering the pool. We suggest that the cause of limited mixing is due to a balance between groundwater inflow and transverse dispersion at the cross-section. We show that the unsupported assumption of complete mixing may result in a wide range, and thus increased uncertainty, of the values of stream flow and longitudinal dispersion coefficient estimated from these data. We conclude that the assumption of complete mixing and one-dimensional modeling must be checked against actual field conditions, even in small streams.