Blinatumomab for First-Line Treatment of Children and Young Persons With B-ALL.

PURPOSE: We tested whether blinatumomab (Blina) is effective as a toxicity-sparing alternative to first-line intensive chemotherapy in children and young persons (CYP) with B-ALL who were chemotherapy-intolerant or chemotherapy-resistant. METHODS: Data were collected for consecutive CYP (age 1-24 years) with Philadelphia chromosome-positive or Philadelphia chromosome-negative B-ALL who received Blina as first-line therapy. Blina was given as replacement for postremission intensive chemotherapy to patients with chemotherapy intolerance or resistance. Blina responders received further chemotherapy (Blin-CT) or first remission hematopoietic stem-cell transplant (Blin-HSCT) if indicated. Event-free survival (EFS) and overall survival (OS) of the Blin-CT group were compared with those of matched controls treated with standard chemotherapy in the UKALL 2003 trial. Events were defined as death, relapse, or secondary cancer. RESULTS: From February 2018 to February 2023, 105 patients were treated, of whom 85 were in the Blin-CT group and 20 were in the Blin-HSCT group. A majority of Blin-CT patients received Blina for chemotherapy intolerance (70 of 85, 82%), and the group had a higher-risk profile than unselected patients with B-ALL. Blina was well tolerated with only one patient having a grade 3/4-related toxicity event, and of the 60 patients who were minimal residual disease-positive pre-Blina, 58 of 60 (97%) responded. At a median follow-up of 22 months, the 2-year outcomes of the 80 matched Blin-CT group patients were similar to those of 192 controls (EFS, 95% [95% CI, 85 to 98] v 90% [95% CI, 65 to 93] and OS, 97% [95% CI, 86 to 99] v 94% [95% CI, 89 to 96]). Of the 20 in the HSCT group, three died because of transplant complications and two relapsed. CONCLUSION: Blina is safe and effective in first-line treatment of chemotherapy-intolerant CYP with ALL.

EBV-driven lymphoid neoplasms associated with pediatric ALL maintenance therapy.

The development of a second malignancy after the diagnosis of childhood acute lymphoblastic leukemia (ALL) is a rare event. Certain second malignancies have been linked with specific elements of leukemia therapy, yet the etiology of most second neoplasms remains obscure and their optimal management strategies are unclear. This is a first comprehensive report of non-Hodgkin lymphomas (NHLs) following pediatric ALL therapy, excluding stem-cell transplantation. We analyzed data of patients who developed NHL following ALL diagnosis and were enrolled in 12 collaborative pediatric ALL trials between 1980-2018. Eighty-five patients developed NHL, with mature B-cell lymphoproliferations as the dominant subtype (56 of 85 cases). Forty-six of these 56 cases (82%) occurred during or within 6 months of maintenance therapy. The majority exhibited histopathological characteristics associated with immunodeficiency (65%), predominantly evidence of Epstein-Barr virus-driven lymphoproliferation. We investigated 66 cases of post-ALL immunodeficiency-associated lymphoid neoplasms, 52 from our study and 14 additional cases from a literature search. With a median follow-up of 4.9 years, the 5-year overall survival for the 66 patients with immunodeficiency-associated lymphoid neoplasms was 67.4% (95% confidence interval [CI], 56-81). Five-year cumulative risks of lymphoid neoplasm- and leukemia-related mortality were 20% (95% CI, 10.2-30) and 12.4% (95% CI, 2.7-22), respectively. Concurrent hemophagocytic lymphohistiocytosis was associated with increased mortality (hazard ratio, 7.32; 95% CI, 1.62-32.98; P = .01). A large proportion of post-ALL lymphoid neoplasms are associated with an immunodeficient state, likely precipitated by ALL maintenance therapy. Awareness of this underrecognized entity and pertinent diagnostic tests are crucial for early diagnosis and optimal therapy.

Safety and efficacy of rivaroxaban in pediatric cerebral venous thrombosis (EINSTEIN-Jr CVT).

Anticoagulant treatment of pediatric cerebral venous thrombosis has not been evaluated in randomized trials. We evaluated the safety and efficacy of rivaroxaban and standard anticoagulants in the predefined subgroup of children with cerebral venous thrombosis (CVT) who participated in the EINSTEIN-Jr trial. Children with CVT were randomized (2:1), after initial heparinization, to treatment with rivaroxaban or standard anticoagulants (continued on heparin or switched to vitamin K antagonist). The main treatment period was 3 months. The primary efficacy outcome, symptomatic recurrent venous thromboembolism (VTE), and principal safety outcome, major or clinically relevant nonmajor bleeding,were centrally evaluated by blinded investigators. Sinus recanalization on repeat brain imaging was a secondary outcome. Statistical analyses were exploratory. In total, 114 children with confirmed CVT were randomized. All children completed the follow-up. None of the 73 rivaroxaban recipients and 1 (2.4%; CVT) of the 41 standard anticoagulant recipients had symptomatic, recurrent VTE after 3 months (absolute difference, 2.4%; 95% confidence interval [CI], -2.6% to 13.5%). Clinically relevant bleeding occurred in 5 (6.8%; all nonmajor and noncerebral) rivaroxaban recipients and in 1 (2.5%; major [subdural] bleeding) standard anticoagulant recipient (absolute difference, 4.4%; 95% CI, -6.7% to 13.4%). Complete or partial sinus recanalization occurred in 18 (25%) and 39 (53%) rivaroxaban recipients and in 6 (15%) and 24 (59%) standard anticoagulant recipients, respectively. In summary, in this substudy of a randomized trial with a limited sample size, children with CVT treated with rivaroxaban or standard anticoagulation had a low risk of recurrent VTE and clinically relevant bleeding. This trial was registered at clinicaltrials.gov as #NCT02234843.

Bottom trawl fishing footprints on the world's continental shelves.

Bottom trawlers land around 19 million tons of fish and invertebrates annually, almost one-quarter of wild marine landings. The extent of bottom trawling footprint (seabed area trawled at least once in a specified region and time period) is often contested but poorly described. We quantify footprints using high-resolution satellite vessel monitoring system (VMS) and logbook data on 24 continental shelves and slopes to 1,000-m depth over at least 2 years. Trawling footprint varied markedly among regions: from <10% of seabed area in Australian and New Zealand waters, the Aleutian Islands, East Bering Sea, South Chile, and Gulf of Alaska to >50% in some European seas. Overall, 14% of the 7.8 million-km2 study area was trawled, and 86% was not trawled. Trawling activity was aggregated; the most intensively trawled areas accounting for 90% of activity comprised 77% of footprint on average. Regional swept area ratio (SAR; ratio of total swept area trawled annually to total area of region, a metric of trawling intensity) and footprint area were related, providing an approach to estimate regional trawling footprints when high-resolution spatial data are unavailable. If SAR was ≤0.1, as in 8 of 24 regions, there was >95% probability that >90% of seabed was not trawled. If SAR was 7.9, equal to the highest SAR recorded, there was >95% probability that >70% of seabed was trawled. Footprints were smaller and SAR was ≤0.25 in regions where fishing rates consistently met international sustainability benchmarks for fish stocks, implying collateral environmental benefits from sustainable fishing.

Physical activity and activity space in patients with pulmonary fibrosis not prescribed supplemental oxygen.

BACKGROUND: Patients with pulmonary fibrosis (PF) have impaired quality of life, and research suggests that dyspnea and physical activity are primary drivers. As PF progresses, some patients notice the disease "shrinks their worlds". The objective of this study is to describe movement (both physical activity and activity space) in a cohort of patients with PF of various etiologies who have not been prescribed supplemental oxygen (O2). METHODS: Subjects with PF not on supplemental O2 during the day were enrolled from across the U.S. from August 2013 to October 2015. At enrollment, each subject completed questionnaires and, for seven consecutive days, wore an accelerometer and GPS tracker. RESULTS: One hundred ninety-four subjects had a confirmed diagnosis of PF and complete, analyzable GPS data. The cohort was predominantly male (56%), Caucasian (95%) and had idiopathic pulmonary fibrosis (30%) or connective tissue disease related-PF (31%). Subjects walked a median 7497 (interquartile range [IQR] 5766-9261) steps per day. Steps per day were correlated with symptoms and several quality of life domains. In a model controlling for age, body mass index, wrist- (vs. waist) worn accelerometer and percent predicted diffusing capacity (DLCO%), fatigue (beta coefficient = -51.5 ± 11.7, p < 0.0001) was an independent predictor of steps per day (model R2=0.34). CONCLUSIONS: Patients with PF, who have not been prescribed O2 for use during the day, have wide variability in their mobility. Day-to-day physical activity is related to several domains that impact quality of life, but GPS-derived activity space is not. Wearable data collection devices may be used to determine whether and how therapeutic interventions impact movement in PF patients. TRIAL REGISTRATION: NCT01961362 . Registered 9 October, 2013.

Tracking dyspnea up to supplemental oxygen prescription among patients with pulmonary fibrosis.

BACKGROUND: Dyspnea is the hallmark symptom of pulmonary fibrosis. Supplemental oxygen (O2) is prescribed to many patients with pulmonary fibrosis in hopes of alleviating dyspnea and improving physical functioning. We used response data from the University of California San Diego Shortness of Breath Questionnaire (UCSD) which was administered monthly in the context of a longitudinal, observational study to plot a rich trajectory for dyspnea over time in patients with pulmonary fibrosis. We used other data from that study to identify clinical predictors of being prescribed O2 and to provide additional information for how UCSD scores could be used for clinical purposes. METHODS: We used linear mixed-effects models and multivariate Cox proportional hazards to model change in dyspnea scores over time and to identify significant predictors of time-to-O2-prescription among a pool of clinically-meaningful candidate variables. In the longitudinal study, all decisions, including whether or not to prescribe O2, were made by subjects' treating physicians, not members of the research team. RESULTS: One-hundred ninety-four subjects with pulmonary fibrosis completed more than one UCSD or were prescribed O2 at some point during the follow-up period (N = 43). Twenty-eight of the 43 had analyzable, longitudinal data and contribute data to the longitudinal UCSD analyses. All 43 were included in the time-to-O2-prescription analyses. Subjects prescribed O2 had more severe dyspnea at enrollment (38.4 ± 19.6 vs. 22.6 ± 18.7, p < 0.0001) and a steeper increase in UCSD scores over time (slope = 1.18 ± 0.53 vs. 0.24 ± 0.09 points per month, p = 0.02) than subjects not prescribed O2. Controlling for baseline UCSD score and FVC%, subjects with a clinical summary diagnosis of idiopathic pulmonary fibrosis (IPF) were far more likely to be prescribed O2 than subjects with other forms of pulmonary fibrosis (hazard ratio = 4.85, (2.19, 10.74), p < 0.0001). CONCLUSIONS: Baseline dyspnea and rise in dyspnea over time predict timing of O2 prescription. Accounting for disease severity, patients with IPF are more likely than patients with other forms of pulmonary fibrosis to be prescribed O2. UCSD scores provide clinically useful information; frequent administration could yield timely data on changes in disease status in patients with pulmonary fibrosis. TRIAL REGISTRATION: The longitudinal study is registered on ClinicalTrials.gov ( NCT01961362 ). Registered October 9, 2013.

Looking ahead and behind at supplemental oxygen: A qualitative study of patients with pulmonary fibrosis.

RATIONALE: Supplemental oxygen is prescribed to patients with pulmonary fibrosis to normalize oxygen saturations, decrease symptoms and improve quality of life. Along with potential benefits, patients face challenges as they incorporate oxygen into their lives. OBJECTIVE: Our aim was to better understand the perceptions and experiences of patients with pulmonary fibrosis as they confronted the possibility and realities of using supplemental oxygen. METHODS: We performed a mixed-methods study in which we conducted a series of four structured telephone interviews with five patients with pulmonary fibrosis enrolled in a longitudinal observational study. Questionnaires were administered at the time of the interviews, which were conducted at enrollment in the longitudinal study, immediately prior to starting supplemental oxygen, one month and then 9-12 months after starting oxygen. We used conventional content analysis to analyze interview data for themes within and across the four time points. RESULTS: Prior to starting supplemental oxygen, participants uniformly expected it would improve their physical function and quality of life. They also expected practical and psychological limitations, which after starting oxygen, they found to be more pronounced than anticipated. Despite the challenges, participants attributed benefits in symptoms, confidence and mobility to oxygen and came to a reluctant acceptance of it. Their expectations for guidance and support were inadequately met. CONCLUSIONS: For patients with pulmonary fibrosis, starting and using supplemental oxygen on an everyday basis confers benefits while also presenting a significant number of challenges. The process could be improved by providing them with clearer expectations and trustworthy educational resources. Oxygen case managers could help patients incorporate supplemental oxygen more seamlessly into their lives.

Informal caregivers experience of supplemental oxygen in pulmonary fibrosis.

BACKGROUND: Patients prescribed supplemental oxygen (O2) therapy face challenges as they adjust to being constantly "tethered" to an oxygen delivery device. Informal caregivers (ICs) of patients with pulmonary fibrosis (PF) face their own, often overlooked hardships when O2 is brought into their home and added to their lives. Our aim was to understand the multiple effects of supplemental oxygen therapy on ICs of patients with PF. METHODS: We conducted single, semi-structured telephone interviews with twenty ICs of patients with PF who were using O2 for at least 8 months. We performed a qualitative, content analysis based in grounded theory to examine data across subjects. RESULTS: ICs initially reacted to O2 with trepidation and sadness as they came to recognize the changes it would cause in the lives of their patient-loved one (PLO). ICs recognized both beneficial and negative effects of O2 on their PLOs. ICs also realized that O2 created significant changes in their own lives, including introducing new roles and responsibilities for them, altering their home environments and significantly impacting their relationships with their PLOs. Although O2 was a tangible and constant reminder of disease progression, over time ICs were able to adapt and accept their new lives with O2. CONCLUSION: ICs of patients with PF experience many life changes when their PLO is prescribed O2. Having O2 prescribers anticipate and recognize these challenges provides an opportunity to give support and guidance to ICs of PF patients who require O2 in the hopes of limiting the negative impact of O2 on their lives. TRIAL REGISTRATION: Clinicaltrials.gov , registration number NCT01961362 . Registered 9 October 2013.

Drug interactions may be important risk factors for methotrexate neurotoxicity, particularly in pediatric leukemia patients.

PURPOSE: Methotrexate administration is associated with frequent adverse neurological events during treatment for childhood acute lymphoblastic leukemia. Here, we present evidence to support the role of common drug interactions and low vitamin B12 levels in potentiating methotrexate neurotoxicity. METHODS: We review the published evidence and highlight key potential drug interactions as well as present clinical evidence of severe methotrexate neurotoxicity in conjunction with nitrous oxide anesthesia and measurements of vitamin B12 levels among pediatric leukemia patients during therapy. RESULTS: We describe a very plausible mechanism for methotrexate neurotoxicity in pediatric leukemia patients involving reduction in methionine and consequential disruption of myelin production. We provide evidence that a number of commonly prescribed drugs in pediatric leukemia management interact with the same folate biosynthetic pathways and/or reduce functional vitamin B12 levels and hence are likely to increase the toxicity of methotrexate in these patients. We also present a brief case study supporting out hypothesis that nitrous oxide contributes to methotrexate neurotoxicity and a nutritional study, showing that vitamin B12 deficiency is common in pediatric leukemia patients. CONCLUSIONS: Use of nitrous oxide in pediatric leukemia patients at the same time as methotrexate use should be avoided especially as many suitable alternative anesthetic agents exist. Clinicians should consider monitoring levels of vitamin B12 in patients suspected of having methotrexate-induced neurotoxic effects.

Seeking and sharing: why the pulmonary fibrosis community engages the web 2.0 environment.

BACKGROUND: Pulmonary fibrosis (PF) is a rare, progressive disease that affects patients and their loved ones on many levels. We sought to better understand the needs and interests of PF patients and their loved ones (collectively "reader-participants") by systematically analyzing their engagement with the World Wide Web (the current version referred to as Web 2.0). METHODS: Data were collected from three PF-focused, interactive websites hosted by physician-investigators with expertise in PF. All data generated by reader-participants for approximately 10 months were downloaded and then analyzed using qualitative content analysis methods. RESULTS: PF experts posted 38 blog entries and reader-participants posted 40 forum entries. Blogs received 363 responses, and forum entries received 108 responses from reader-participants. Reader-participants primarily used the three websites to seek information from or offer a contribution to the PF community. Information was sought about PF symptoms, diagnosis, prognosis, treatments, research, pathophysiology, and disease origin; reader-participants also made requests for new posts and pleas for research and sought clarification on existing content. Contributions included personal narratives about experiences with PF, descriptions of activities or behaviors found to be helpful with PF symptoms, resources or information about PF, and supportive comments to other PF sufferers. CONCLUSIONS: PF patients and their loved ones engage the Web 2.0 environment at these PF-focused sites to satisfy their needs to better understand PF and its impacts and to support others facing similar challenges. Clinicians may find it beneficial to encourage PF patients' involvement in internet forums that foster dynamic, bi-directional information sharing.

Protocol for a mixed-methods study of supplemental oxygen in pulmonary fibrosis.

BACKGROUND: Little is known about whether or how supplemental oxygen affects patients with pulmonary fibrosis. METHODS/DESIGN: A mixed-methods study is described. Patients with pulmonary fibrosis, informal caregivers of pulmonary fibrosis patients and practitioners who prescribe supplemental oxygen will be interviewed to gather data on perceptions of how supplemental oxygen impacts patients. In addition, three hundred pulmonary fibrosis patients who do not use daytime supplemental oxygen will be recruited to participate in a longitudinal, pre-/post- study in which patient-reported outcome (PRO) and activity data will be collected at baseline, immediately before daytime supplemental oxygen is initiated, and then once and again 9-12 months later. Activity data will be collected using accelerometers and portable GPS data recorders. The primary outcome is change in dyspnea from before to one month after supplemental oxygen is initiated. Secondary outcomes include scores from PROs to assess cough, fatigue and quality of life as well as the activity data. In exploratory analyses, we will use longitudinal data analytic techniques to assess the trajectories of outcomes over time while controlling for potentially influential variables. DISCUSSION: Throughout the study and at its completion, results will be posted on the website for our research program (the Participation Program for Pulmonary Fibrosis or P3F) at http://www.pulmonaryfibrosisresearch.org.

Family outbreaks of invasive community-associated methicillin-resistant Staphylococcus aureus infection.

Outbreaks of invasive methicillin-resistant Staphylococcus aureus infection within families are unusual. We investigated 2 family clusters of invasive methicillin-resistant Staphylococcus aureus infection, including 1 in which a young mother died of fulminant pneumonia. Although surveillance via culture of family contacts of patients with invasive methicillin-resistant Staphylococcus aureus infection is not currently recommended, such clusters should stimulate reevaluation of preventive measures.