Multicenter study of pediatric Epstein-Barr virus-negative monomorphic post solid organ transplant lymphoproliferative disorders.

BACKGROUND: Pediatric Epstein-Barr virus-negative monomorphic post solid organ transplant lymphoproliferative disorder [EBV(-)M-PTLD] comprises approximately 10% of M-PTLD. No large multi-institutional pediatric-specific reports on treatment and outcome are available. METHODS: A multi-institutional retrospective review of solid organ recipients diagnosed with EBV(-)M-PTLD aged ≤21 years between 2001 and 2020 in 12 centers in the United States and United Kingdom was performed, including demographics, staging, treatment, and outcomes data. RESULTS: Thirty-six patients were identified with EBV(-)M-PTLD. Twenty-three (63.9%) were male. Median age (range) at transplantation, diagnosis of EBV(-)M-PTLD, and interval from transplant to PTLD were 2.2 years (0.1-17), 14 years (3.0-20), and 8.5 years (0.6-18.3), respectively. Kidney (n = 17 [47.2%]) and heart (n = 13 [36.1%]) were the most commonly transplanted organs. Most were Murphy stage III (n = 25 [69.4%]). Lactate dehydrogenase was elevated in 22/34 (64.7%) and ≥2 times upper limit of normal in 11/34 (32.4%). Pathological diagnoses included diffuse large B-cell lymphoma (n = 31 [86.1%]) and B-non-Hodgkin lymphoma (B-NHL) not otherwise specified (NOS) (n = 5 [13.9%]). Of nine different regimens used, the most common were: pediatric mature B-NHL-specific regimen (n = 13 [36.1%]) and low-dose cyclophosphamide, prednisone, and rituximab (n = 9 [25%]). Median follow-up from diagnosis was 3.0 years (0.3-11.0 years). Three-year event-free survival (EFS) and overall survival (OS) were 64.8% and 79.9%, respectively. Of the seven deaths, six were from progressive disease. CONCLUSIONS: EFS and OS were comparable to pediatric EBV(+) PTLD, but inferior to mature B-NHL in immunocompetent pediatric patients. The wide range of therapeutic regimens used directs our work toward developing an active multi-institutional registry to design prospective studies. PLAIN LANGUAGE SUMMARY: Pediatric Epstein-Barr virus-negative monomorphic post solid organ transplant lymphoproliferative disorders (EBV(-)M-PTLD) have comparable outcomes to EBV(+) PTLD, but are inferior to diffuse large B-cell lymphoma in immunocompetent pediatric patients. The variety of treatment regimens used highlights the need to develop a pediatric PTLD registry to prospectively evaluate outcomes. The impact of treatment regimen on relapse risk could not be assessed because of small numbers. In the intensive pediatric B-non-Hodgkin lymphoma chemoimmunotherapy group, 11 of 13 patients remain alive in complete remission after 0.6 to 11 years.

Burkitt lymphoma after solid-organ transplant: Treatment and outcomes in the paediatric PTLD collaborative.

Burkitt lymphoma arising in paediatric post-solid-organ transplantation-Burkitt lymphoma (PSOT-BL) is a clinically aggressive malignancy and a rare form of post-transplant lymphoproliferative disorder (PTLD). We evaluated 35 patients diagnosed with PSOT-BL at 14 paediatric medical centres in the United States. Median age at organ transplantation was 2.0 years (range: 0.1-14) and age at PSOT-BL diagnosis was 8.0 years (range: 1-17). All but one patient had late onset of PSOT-BL (≥2 years post-transplant), with a median interval from transplant to PSOT-BL diagnosis of 4.0 years (range: 0.4-12). Heart (n = 18 [51.4%]) and liver (n = 13 [37.1%]) were the most frequently transplanted organs. No patients had loss of graft or treatment-related mortality. A variety of treatment regimens were used, led by intensive Burkitt lymphoma-specific French-American-British/Lymphomes Malins B (FAB/LMB), n = 13 (37.1%), and a low-intensity regimen consisting of cyclophosphamide, prednisone and rituximab (CPR) n = 12 (34.3%). Median follow-up was 6.7 years (range: 0.5-17). Three-year event-free and overall survival were 66.2% and 88.0%, respectively. Outcomes of PSOT-BL patients receiving BL-specific intensive regimens are comparable to reported BL outcomes in immunocompetent children. Multi-institutional collaboration is feasible and provides the basis of prospective data collection to determine the optimal treatment regimen for PSOT-BL.

Preemptive mitigation of CD19 CAR T-cell cytokine release syndrome without attenuation of antileukemic efficacy.

Immunotherapy with the adoptive transfer of T cells redirected with CD19-specific chimeric antigen receptors (CARs) for B-lineage acute lymphoblastic leukemia (ALL) can salvage >80% of patients having relapsed/refractory disease. The therapeutic index of this emerging modality is attenuated by the occurrence of immunologic toxicity syndromes that occur upon CAR T-cell engraftment. Here, we report on the low incidence of severe cytokine release syndrome (CRS) in a subject treated with a CAR T-cell product composed of a defined ratio CD4:CD8 T-cell composition with a 4-1BB:zeta CAR targeting CD19 who also recieved early intervention treatment. We report that early intervention with tocilizumab and/or corticosteroids may reduce the frequency at which subjects transition from mild CRS to severe CRS. Although early intervention doubled the numbers of subjects dosed with tocilizumab and/or corticosteroids, there was no apparent detrimental effect on minimal residual disease-negative complete remission rates or subsequent persistence of functional CAR T cells compared with subjects who did not receive intervention. Moreover, early intervention therapy did not increase the proportion of subjects who experience neurotoxicity or place subjects at risk for infectious sequelae. These data support the contention that early intervention with tocilizumab and/or corticosteroids in subjects with early signs of CRS is without negative impact on the antitumor potency of CD19 CAR T cells. This intervention serves to enhance the therapeutic index in relapsed/refractory patients and provides the rationale to apply CAR T-cell therapy more broadly in ALL therapy. This trial was registered at www.clinicaltrials.gov as #NCT020284.

Lymphocyte apheresis for chimeric antigen receptor T-cell manufacturing in children and young adults with leukemia and neuroblastoma.

BACKGROUND: The first step in the production of chimeric antigen receptor T cells is the collection of autologous T cells using apheresis technology. The procedure is technically challenging, because patients often have low leukocyte counts and are heavily pretreated with multiple lines of chemotherapy, marrow transplantation, and/or radiotherapy. Here, we report our experience of collecting T lymphocytes for chimeric antigen receptor T-cell manufacturing in pediatric and young adult patients with leukemia, non-Hodgkin lymphoma, or neuroblastoma. STUDY DESIGN AND METHODS: Apheresis procedures were performed on a COBE Spectra machine using the mononuclear cell program, with a collection target of 1 × 109 total mononuclear cells per kilogram. Data were collected regarding preapheresis and postapheresis blood counts, apheresis parameters, products, and adverse events. RESULTS: Ninety-nine patients (ages 1.3-25.7 years) and 102 apheresis events were available for analysis. Patients underwent apheresis at a variety of absolute lymphocyte cell counts, with a median absolute lymphocyte count of 944 cells/µL (range, 142-6944 cells/µL). Twenty-two patients (21.6%) had absolute lymphocyte counts less than 500 cells/µL. The mononuclear cell target was obtained in 100% of all apheresis harvests, and chimeric antigen receptor T-cell production was possible from the majority of collections (94%). Mononuclear cell collection efficiency was 65.4%, and T-lymphocyte collection efficiency was 83.4%. Ten patients (9.8%) presented with minor adverse events during the 102 apheresis procedures, with one exception of a severe allergy. CONCLUSIONS: Mononuclear cell apheresis for chimeric antigen receptor T-cell therapy is well tolerated and safe, and it is possible to obtain an adequate quantity of CD3+ lymphocytes for chimeric antigen receptor T-cell manufacturing in heavily pretreated patients who have low lymphocyte counts.

Feasibility and Favorable Responses Following Investigational CAR T-Cell Therapy for Relapsed and Refractory Infant ALL.

Infants with B-cell acute lymphoblastic leukemia (B-ALL) continue to have significantly worse outcomes compared to older children with B-ALL, and those with relapsed or refractory (R/R) infant ALL have especially dismal outcomes with conventional treatment. CD19-targeting chimeric antigen receptor (CAR) T-cell therapy has demonstrated remarkable success in the treatment of R/R childhood B-ALL, though the majority of reports have been in non-infant patients. Barriers to the successful implementation of CAR T-cell therapy in infant B-ALL include challenges related to apheresis, product manufacturing and disease-specific considerations such as lineage switch. We describe our experience utilizing two experimental CD19-CAR T-cell products, SCRI-CAR19 or SCRI-CAR19x22, for 19 patients with R/R infant B-ALL enrolled on three clinical trials. CAR T-cell products were successfully manufactured in 18/19 (94.7%) patients, with a median age of 22.5 months at enrollment (range, 14.5-40.1 months). Sixteen of 17 (94.1%) treated patients achieved a complete remission without detectable minimal residual disease. The 1-year leukemia free survival was 75% and 1-year overall survival was 76.5%, with a median follow up time of 35.8 months (range, 1.7-83.6 months). Cytokine release syndrome (CRS) occurred in 14/17 (82.4%) patients, with only 1 patient experiencing Grade 3 CRS. Neurotoxicity occurred in 2/17 (11.8%) patients with all events ≤ Grade 2. With the successful early clinical experience of CAR T-cell therapy in this population, more systematic evaluation specific to infant ALL is warranted.

Student and educator experiences of maternal-child simulation-based learning: a systematic review of qualitative evidence.

BACKGROUND: Although maternal-child care is a pillar of primary health care, there is a global shortage of maternal-child health care providers. Nurse educators experience difficulties providing undergraduate students with maternal-child learning experiences for a number of reasons. Simulation has the potential to complement learning in clinical and classroom settings. Although systematic reviews of simulation are available, no systematic reviews of qualitative evidence related to maternal-child simulation-based learning (SBL) for undergraduate nursing students and/or educators have been located. OBJECTIVES: The aim of this systematic review was to identify the appropriateness and meaningfulness of maternal-child simulation-based learning for undergraduate nursing students and nursing educators in educational settings to inform curriculum decision-making. The review questions are: INCLUSION CRITERIA TYPES OF PARTICIPANTS: Pre-registration or pre-licensure or undergraduate nursing or health professional students and educators. PHENOMENA OF INTEREST: Experiences of simulation in an educational setting with a focus relevant to maternal child nursing. TYPES OF STUDIES: Qualitative research and educational evaluation using qualitative methods. CONTEXT: North America, Europe, Australia and New Zealand. SEARCH STRATEGY: A three-step search strategy identified published studies in the English language from 2000 until April 2016. METHODOLOGICAL QUALITY: Identified studies that met the inclusion criteria were retrieved and critically appraised using the Joanna Briggs Institute Qualitative Assessment and Review Instrument (JBI-QARI) by at least two independent reviewers. Overall the methodological quality of the included studies was low. DATA EXTRACTION: Qualitative findings were extracted by two independent reviewers using JBI-QARI data extraction tools. DATA SYNTHESIS: Findings were aggregated and categorized on the basis of similarity in meaning. Categories were subjected to a meta-synthesis to produce a single comprehensive set of synthesized findings. RESULTS: Twenty-two articles from 19 studies were included in the review. A total of 112 findings were extracted from the included articles. Findings were grouped into 15 categories created on the basis of similarity of meaning. Meta-synthesis of these categories generated three synthesized findings.Synthesized finding 1 Students experienced simulated learning experiences (SLE) as preparation that enhanced their confidence in practice. When simulation was being used for evaluation purposes many students experienced anxiety about the SLE.Synthesized finding 2 Pedagogical practices thought to be appropriate and meaningful included: realistic, relevant and engaging scenarios, a safe non-threatening learning environment, supportive guidance throughout the process, and integration with curriculum.Synthesized finding 3 Barriers and enablers to incorporating SLEs into maternal child education were identified including adequate resources, technological support and faculty development. Students and educators recognized that some things, such as relationship building, could not be simulated. CONCLUSIONS: Students felt that simulation prepared them for practice through building their self-confidence related to frequently and infrequently seen maternal-child scenarios. Specific pedagogical elements support the meaningfulness of the simulation for student learning. The presence or absence of resources impacts the capacity of educators to integrate simulation activities throughout curricula.

Student and educator experiences of maternal-child simulation-based learning: a systematic review of qualitative evidence protocol.

REVIEW QUESTION/OBJECTIVE: The overall aim of this systematic review is to identify the appropriateness and meaningfulness of maternal-child simulation-based learning for undergraduate or pre-registration nursing students in educational settings to inform curriculum decision-making.1. What are the experiences of nursing or health professional students participating in undergraduate or pre-licensure maternal-child simulation-based learning in educational settings?2. What are the experiences of educators participating in undergraduate or pre-licensure maternal-child simulation-based learning in educational settings?3. What teaching and learning practices in maternal-child simulation-based learning are considered appropriate and meaningful by students and educators? BACKGROUND: Maternal-child care is one of the pillars of primary health care. Health promotion and illness/ injury prevention begin in the preconception period and continue through pregnancy, birth, the postpartum period and the childrearing years. Thus, lifelong wellness is promoted across the continuum of perinatal and pediatric care which influences family health and early child development. Registered nurses (RNs) are expected to have the knowledge and skills needed to provide evidence-based nursing with childbearing and child-rearing families to promote health and address health inequities in many settings, including inner city, rural, northern, indigenous and global communities. The Canadian Maternity Experiences survey and the Report by the Advisor on Healthy Children and Youth provide information on current shortages of perinatal and child health care providers and stress the importance of the role of nurses as providers of rural and remote care. From a global health perspective, continued concern with both perinatal and child health morbidities and mortalities highlight the importance of maintaining and strengthening the presence of maternal and child health learning opportunities within undergraduate nursing curriculum.Despite this importance, educators in many countries have acknowledged difficulties providing nursing students with maternal-child hospital learning experiencesdue to declining birth rates, women's changing expectations about childbirth (i.e. birth as an intimate experience), increased outpatient and community management of early childhood health conditions, and increased competition for clinical placements. Canadian nurse educators and practice leaders have also identified gaps in recent RN graduates' readiness to provide safe, competent and evidence-based care for childbearing and child-rearing families. Newly graduated RNs working in acute care hospitals and in rural/remote community practice settings report feeling unprepared for providing maternity, neonatal and early childhood care.Recent concerns about the clinical reasoning skills of new graduates and the link to poor patient outcomes (e.g. not recognizing deteriorating patients) have led to calls to reform nursing education. In the Carnegie report, Benner, Sutphen, Leonard and Day identified four essential themes needed in the thinking and approach to nursing education, including: (1) a shift in focus from covering decontextualized knowledge to "teaching for a sense of salience, situated cognition, and identifying action in particular clinical situations"; (2) better integration of classroom and clinical teaching; (3) more emphasis on clinical reasoning; and, (4) an emphasis on identity formation rather than socialization. Brown and Hartrick Doane propose that nurses need to draw on a range of knowledge that enhances the nurse's "sensitivity and ability to be responsive in particular moments of practice". Theoretical or decontextualized knowledge becomes a "pragmatic tool" used to improve nursing practice. Simulation has been identified as a promising pragmatic educational tool for practice learning that can be integrated with theoretical knowledge from nursing and other disciplines.Bland, Topping and Wood conducted a concept analysis and defined simulation in nursing education as:They also proposed that "simulated learning is a dynamic concept that deserves empirical evaluation not merely to determine its effects but to uncover its full potential as a learning strategy".Simulation usually involves student(s) providing nursing care to a simulated patient who might be a manikin or actor based on a standardized scenario. Following the experiential learning opportunity the scenario is debriefed and the clinical situation analyzed with opportunities for reflection on performance. In nursing education, simulation is usually used in a way that complements learning in practice settings. However simulation has also been used: to make up some clinical practice hours, to provide opportunities to practice and assess particular clinical skills, and for remedial learning when students encounter difficulties in practice settings. In addition simulation provides the opportunity to focus on quality and safety competencies (QSEN) that have been identified for nurses. New forms of simulation are being developed with multiple patients so that nursing students can learn to prioritize care needs and delegate care to other team members.Nurse educators have identified several advantages for learners using simulation, including: providing a safe environment to improve nursing competence, allowing learners to become more comfortable with receiving feedback about their clinical performance, providing consistent and comparable experiences for all students, and learning a mix of technical and non-technical skills including communication, teamwork and delegation. Within the Canadian context, students and instructors have reported positive learning experiences with simulation, particularly in understanding complex patient care scenarios, multidisciplinary team scenarios, team-based learning, and reflective debriefing. Furthermore, simulation technology has been proposed as a strategy for developing clinical reasoning skills, enhancing nurses' abilities to build upon previous knowledge and past experiences, and manage new or unfamiliar situations.Simulation has previously been integrated into nursing curricula in a "piecemeal" fashion that lacks an integrative pedagogy or theoretical approach. More recently a number of theoretical and pedagogical frameworks and best practice standards have been published. In April 2014 a preliminary search of literature (in CINAHL, Medline, Academic Search Complete and Web of Science) was conducted with guidance from our library specialist to test the search strategy and ensure that there would be enough qualitative findings to include in the systematic review. A preliminary scan of the abstracts from these searches demonstrated that many experiential case reports with qualitative findings were missed with the use of research limiters (including our search strategy specifically constructed to retrieve qualitative research) so the decision was made to err on the side of caution by searching more broadly and review a larger number of abstracts for inclusion in the study. However, a number of reports with qualitative findings were identified. For example, from a review of the abstracts from a CINAHL search dated April 17, qualitative research papers (including two dissertations), 12 evaluation study reports, six mixed methods studies and nine case reports with qualitative findings were identified. It is timely then to review qualitative studies to better understand the meaningfulness and appropriateness of integrating maternal-child simulation-based learning activities in undergraduate nursing education programs.A search of both the Cochrane Library of Systematic Reviews and the Joanna Briggs Institute Database of Systematic Reviews and Implementation Reports has been conducted. No systematic reviews of qualitative studies of maternal-child simulation-based learning for undergraduate or pre-registration nursing students in educational settings are evident in the literature. Although a systematic review of the meaningfulness and appropriateness of using human patient simulation manikins as a teaching and learning strategy in undergraduate nursing education had been planned and a protocol registered in October 2009, we learned from contacting the lead author that this systematic review was not completed. Currently little is known about how nursing students and/or educators have experienced maternal-child simulation or their understandings of the appropriateness and meaningfulness of particular simulation-based learning practices. Our proposed systematic review therefore fulfills all requirements for the PROSPERO database. DEFINITIONS: For this review we will use the definition of "simulation-based learning experience" adopted by the International Nursing Association for Clinical Simulation and Learning (INACSL):We will include any use of simulation in an educational setting (with pre-registration or pre-licensure or undergraduate nursing or health professional students) with a focus relevant for maternal-child nursing.Maternal-child nursing has been variously defined in literature to include maternity care and pediatric nursing. For the purposes of this review, we will include perinatal, neonatal and pediatric contexts of care that focus on families with children under the age of five. We will exclude studies that focus on school age children, adolescents and/or youth.We have adapted an earlier definition of "appropriateness" as the "best conditions under which simulation can be integrated into undergraduate nursing education". In this review "meaningfulness" refers to the experiences and reflections of undergraduate nursing or health professional students and educators as presented in the studies reviewed.

Campus Clinical: simulation-based curriculum designed to meet clinical course learning outcomes.

Campus Clinical is a simulation-based curriculum designed to meet the challenge of decreasing clinical spaces in maternal-child units. The curriculum framework is situated in a constructivist, experiential learning context, integrating Chickering and Gamson's principles for good practice in education. This innovative approach to meeting clinical course learning outcomes is transferable to a variety of settings.