Depth-varying rupture properties of subduction zone megathrust faults

Subduction zone plate boundary megathrust faults accommodate relative plate motions with spatially varying sliding behavior. The 2004 Sumatra-Andaman (M_w 9.2), 2010 Chile (Mw 8.8), and 2011 Tohoku (M_w 9.0) great earthquakes had similar depth variations in seismic wave radiation across their wide rupture zones – coherent teleseismic short-period radiation preferentially emanated from the deeper portion of the megathrusts whereas the largest fault displacements occurred at shallower depths but produced relatively little coherent short-period radiation. We represent these and other depth-varying seismic characteristics with four distinct failure domains extending along the megathrust from the trench to the downdip edge of the seismogenic zone. We designate the portion of the megathrust less than 15 km below the ocean surface as domain A, the region of tsunami earthquakes. From 15 to ∼35 km deep, large earthquake displacements occur over large-scale regions with only modest coherent short-period radiation, in what we designate as domain B. Rupture of smaller isolated megathrust patches dominate in domain C, which extends from ∼35 to 55 km deep. These isolated patches produce bursts of coherent short-period energy both in great ruptures and in smaller, sometimes repeating, moderate-size events. For the 2011 Tohoku earthquake, the sites of coherent teleseismic short-period radiation are close to areas where local strong ground motions originated. Domain D, found at depths of 30–45 km in subduction zones where relatively young oceanic lithosphere is being underthrust with shallow plate dip, is represented by the occurrence of low-frequency earthquakes, seismic tremor, and slow slip events in a transition zone to stable sliding or ductile flow below the seismogenic zone

Results from the Phase 1 Portion of a Trial of Oral Ixazomib Combined with Chemotherapy in Relapsed/Refractory Acute Lymphoblastic Leukemia or Lymphoma in Children, Adolescents and Young Adults: A Report from the Therapeutic Advances in Childhood Leukemia and Lymphoma (TACL) Consortium

ACKNOWLEDGEMENT Proteasome inhibitors potentiate anti-tumor effects of standard cytotoxic chemotherapy in childhood leukemia. Ixazomib is an oral proteasome inhibitor that has a shorter proteasome dissociation half-life than bortezomib, which leads to a higher tumor-to-blood ratio inhibition. We performed a phase 1 trial to determine the dose limiting toxicities (DLT), Recommended Phase 2 Dose (RP2D) of ixazomib in pediatric patients with relapsed/refractory acute lymphoblastic leukemia (ALL) or lymphoma (LL). Patients ≤ 21 years of age with relapsed or refractory ALL (with ≥ 5% detectable disease in the marrow) or LL were eligible. Ixazomib was combined with 28-day blocks of well-established, relapsed ALL backbone chemotherapy. Block 1 contained vincristine (1.5 mg/m 2/dose IV Days 1, 8, 15, 22), dexamethasone (5 mg/m 2/dose IV or oral twice daily Days 1-14), PEG-asparaginase (2500 IU/m 2/dose IV Days 2, 15) and daunorubicin (60 mg/m 2/dose IV Day 1) (VXLD). An optional Block 2 contained vincristine (1.5 mg/m 2/dose IV Day 1), dexamethasone (3 mg/m 2/dose oral twice daily Days 1-5), methotrexate (1000 mg/m 2/dose IV over 36 hours Day 8), PEG-asparaginase (2500 IU/m 2/dose IV Day 9), cyclophosphamide (440 mg/m 2/dose IV Days 15-19) and etoposide (100 mg/m 2/dose IV Days 15-19). An additional optional Maintenance Block contained vincristine (1.5 mg/m 2/dose IV Day 1), prednisone (20 mg/m 2/dose oral twice daily Days 1-5), mercaptopurine (75 mg/m 2/dose oral daily) and methotrexate (20 mg/m 2/dose oral weekly). Intrathecal therapy was given throughout with agents and dosing based on the patient's CNS disease status upon study entry. Ixazomib was given orally and tested at two dose levels (DL) (DL1: 1.6 mg/m 2/dose; DL2: 2 mg/m 2/dose) using a 3+3 design and was given during Block 1 on Days 1, 4, 8 and 11; during Block 2 on Days 1, 4, 8, 15 and 18 and during Maintenance on Days 1, 8 and 15. DLTs during Block 1 only were utilized to make DL escalation decisions and determine the RP2D. Patients without Down Syndrome (DS) entered Cohort A, used to determine the P2RD. Patients with DS were eligible for a 1 DL lagging descriptive-only Cohort B. Ten patients were treated; nine in Cohort A (n = 3 at DL1 and n = 6 at DL2) and one in Cohort B (DL1). Median age (range) at study entry was 10.5 years (5 - 20 years). Nine patients had B-ALL and one had T-ALL. Most were heavily pretreated with a median (range) of 3.4 (1 - 7) previous remission attempts with six having had prior immunotherapy and three patients having had at least one prior hematopoietic stem cell transplant. After Block 1, two patients received Block 2 and one received Maintenance. In Block 1 of Cohort A, non-hematological Grade 3/4 adverse events (AE) possibly, probably or definitely related to ixazomib or the backbone chemotherapy were limited and included neutropenic fever (n = 7), increased AST (n = 3), increased ALT (n = 2) and hypokalemia (n = 2). Two septic events occurred (n = 1 in Cohort A (Grade 3) and n = 1 in Cohort B (Grade 4)). Block 2 and Maintenance AEs were not significantly different than those seen in Block 1. No deaths or DLTs occurred. Response assessment showed that at DL1 two of three patients had a Complete Remission (CR) both of whom were Minimal Residual Disease (MRD) negative (-) and at DL2 three of six patients had a CR, two of whom were MRD- and two patients had a CR with incomplete count recovery (CRi). The overall response rate (CR + CRi) was 78% (7 of 9 patients). With a minimum of 20 months of follow-up six of nine patients in Cohort A and the single patient in Cohort B are still alive. All three deceased patients died of disease progression. Ixazomib can be combined with standard chemotherapy with an acceptable safety profile and an encouraging early efficacy signal in pediatric relapsed ALL including those with DS. The RP2D of Ixazomib combined with chemotherapy is 2 mg/m 2/dose, which is being used in the ongoing phase 2/expansion cohort of the study. We acknowledge the TACL Consortium's scientific contribution to and participation in this study, including participating member institutions, investigators, research teams, and the TACL Operations Center. Takeda Pharmaceuticals Company provided the investigative drug and funding in support of this trial

Maximal concentration of intravenous busulfan as a determinant of veno-occlusive disease: a pharmacokinetic-pharmacodynamic analysis in 293 hematopoietic stem cell transplanted children

International audienceVeno-occlusive disease (VOD) is a severe adverse reaction to busulfan-containing regimens used in the preparation of children for hematopoietic stem cell transplantation (HSCT). We conducted a retrospective analysis of data to examine determinants of VOD in children who received IV busulfan for HSCT conditioning. Busulfan PK parameters as well as various indices (maximal concentration-Cmax, area under the concentration-time curve-AUC) were estimated using a validated Bayesian approach. The influence of available PK, demographic, and clinical variables on the incidence of VOD was evaluated by using logistic regression and classification and regression tree (CART) analyses. Among the 293 patients included, the mean age was 6.5 years and the mean actual body weight was 26.3 kg. The incidence of VOD was 25.6%. Busulfan Cmax as well as weight <9 kg or age <3 years were identified as independent predictors of VOD in logistic regression analysis. CART analysis identified busulfan Cmax over the entire regimen as the strongest predictor of VOD. This study suggests that busulfan-associated VOD is in part a concentration-dependent reaction. In addition, the youngest children showed the highest risk of VOD. These findings may have important implications for busulfan dosing and therapeutic drug monitoring practice in HSCT children

Interventions to improve system-level coproduction in the Cystic Fibrosis Learning Network

Background Coproduction is defined as patients and clinicians collaborating equally and reciprocally in healthcare and is a crucial concept for quality improvement (QI) of health services. Learning Health Networks (LHNs) provide insights to integrate coproduction with QI efforts from programmes from various health systems.Objective We describe interventions to develop and maintain patient and family partner (PFP) coproduction, measured by PFP-reported and programme-reported scales. We aim to increase percentage of programmes with PFPs reporting active QI work within their programme, while maintaining satisfaction in PFP-clinician relationships.Methods Conducted in the Cystic Fibrosis Learning Network (CFLN), an LHN comprising over 30 cystic fibrosis (CF) programmes, people with CF, caregivers and clinicians cocreated interventions in readiness awareness, inclusive PFP recruitment, onboarding process, partnership development and leadership opportunities. Interventions were adapted by CFLN programmes and summarised in a change package for existing programmes and the orientation of new ones. We collected monthly assessments for PFP and programme perceptions of coproduction and PFP self-rated competency of QI skills and satisfaction with programme QI efforts. We used control charts to analyse coproduction scales and run charts for PFP self-ratings.Results Between 2018 and 2022, the CFLN expanded to 34 programmes with 52% having ≥1 PFP reporting active QI participation. Clinicians from 76% of programmes reported PFPs were actively participating or leading QI efforts. PFPs reported increased QI skills competency (17%–32%) and consistently high satisfaction and feeling valued in their work.Conclusions Implementing system-level programmatic strategies to engage and sustain partnerships between clinicians and patients and families with CF improved perceptions of coproduction to conduct QI work. Key adaptable strategies for programmes included onboarding and QI training, supporting multiple PFPs simultaneously and developing financial recognition processes. Interventions may be applicable in other health conditions beyond CF seeking to foster the practice of coproduction