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* Abbreviations: IRB — : institutional review board PPC — : pediatric palliative care Patient- and family-centered care “is an innovative approach to the planning, delivery, and evaluation of health care that is grounded in a mutually beneficial partnership among patients, families, and providers that recognizes the importance of the family in the patient’s life.”1 Similarly, family partnerships in pediatric palliative care (PPC) research represent an innovative approach to the planning, delivery, and evaluation of research that is grounded in mutually beneficial relationships that recognize the importance of the family caregiver perspective. The goal of partnered research or study teams is to synthesize the unique perspectives of family caregivers, clinicians, regulatory representatives, and researchers to strengthen research design and implementation. This is accomplished by each unique stakeholder speaking from their own perspective, contributing what they know, and working together to integrate perspectives. The process of moving from just inviting family caregivers to be research subjects to actually engaging with family caregivers as … Address correspondence to Meaghann S. Weaver, MD, MPH, FAAP, Hand in Hand/Division of Pediatric Palliative Care, Children’s Hospital and Medical Center, 8200 Dodge St, Omaha, NE 68198. E-mail: meweaver{at}childrensomaha.org

Background: The concept of vulnerability is a cornerstone of the theoretical basis and practical application of ethics in human subjects research. Risks to humans participating in research must be minimized; that is, subjects must be offered protection from risks. Vulnerable subjects require additional protections. Methods: This paper reviews the ethical and conceptual basis of vulnerability within the context of human subjects research and suggests a basic approach that institutional review boards (IRBs) can use when considering if the research includes adequate safeguards to protect the rights and welfare of subjects who are likely to be vulnerable. Results: Two distinct approaches to describing the features that make a person vulnerable are the categorical approach and the contextual approach. The categorical approach considers certain groups or populations as vulnerable. This approach is not optimal because it does not address persons with multiple vulnerabilities, does not account for variation in the degree of vulnerability within the group based on individual characteristics, and classifies certain persons as vulnerable rather than identifying situations in which individuals might be considered vulnerable. The alternate contextual approach allows for a more nuanced understanding of the nature of the vulnerability than the categorical approach and therefore a more focused approach to safeguards. The IRB is charged with ensuring that additional safeguards to protect the rights and welfare of subjects who are likely to be vulnerable are included in the study under review. To make this determination, the IRB might be advised to consider two questions: (1) is inclusion necessary? and (2) if so, are safeguards adequate? Conclusion: Although vulnerability is often presented as a yes/no consequence related to some characteristic of a group, a more accurate approach is to consider vulnerability as occurring along a spectrum of seriousness and as a consequence of situations and context. With this idea in mind, investigators and IRBs are advised to take a stepwise approach to determining if the study meets the regulatory and ethical admonition to ensure that safeguards protect the rights and welfare of vulnerable subjects.

The 2013-2016 epidemic of Ebola virus disease (EVD) that originated in West Africa underscored many of the challenges to conducting clinical research during an ongoing infectious disease epidemic, both in the most affected countries of Guinea, Liberia, and Sierra Leone, as well as in the United States and Europe, where a total of 27 patients with EVD received care in biocontainment units. The Special Pathogens Research Network (SPRN) was established in the United States in November 2016 to provide an organizational structure to leverage the expertise of the 10 Regional Ebola and Other Special Pathogen Treatment Centers (RESPTCs); it was intended to develop and support infrastructure to improve readiness to conduct clinical research in the United States. The network enables the rapid activation and coordination of clinical research in the event of an epidemic and facilitates opportunities for multicenter research when the RESPTCs are actively caring for patients requiring a biocontainment unit. Here we provide an overview of opportunities identified in the clinical research infrastructure during the West Africa EVD epidemic and the SPRN activities to meet the ongoing challenges in the context of Ebola virus and other special pathogens.

Juvenile myelomonocytic leukemia (JMML) is a rare mixed myelodysplastic and myeloproliferative clonal disorder of early childhood representing about 1% to 2% of all pediatric leukemias.1–3 Most cases present before 6 years of age, with a median age of 2 years. Clinical presentation includes pallor, rash, hepatomegaly, splenomegaly, lymphadenopathy, and recurrent infections.2–5 JMML has an increased incidence in patients with neurofibromatosis and Noonan syndrome as well as genetic mutations in the RAS signaling pathway, PTPN11, CBL, and NF1 gene.6–10 Although most children demonstrate a normal karyotype, monosomy 7 and other chromosome 7 abnormalities are reported in 25% of cases.4 Diagnostic criteria as defined by the International JMML Working Group include peripheral blood monocytosis >1000/mm3, absence of the Philadelphia chromosome t(9:22) and the BCR-ABL1 fusion gene rearrangement, and bone marrow blasts

AIM To evaluate personnel involved in scarce drug prioritization and distribution and the criteria used to inform drug distribution during times of shortage among pediatric hematologists/oncologists. METHODS Using the American Society of Pediatric Hematology/Oncology (ASPHO) membership list, a 20 question survey of pediatric hematologists/oncologists was conducted via email to evaluate personnel involved in scarce drug prioritization and distribution and criteria used to inform scarce drug distribution. RESULTS Nearly 65% of the 191 study respondents had patients directly affected by drug shortages. Most physicians find out about shortages from the pharmacist (n = 179, 98%) or other doctors (n = 75, 41%). One third of respondents do not know if there is a program or policy for handling drug shortages at their institution. The pharmacist was the most commonly cited decision maker for shortage drug distribution (n = 128, 70%), followed by physicians (n = 109, 60%). One fourth of respondents did not know who makes decisions about shortage drug distribution at their institution. The highest priority criterion among respondents was use of the shortage drug for curative, rather than palliative intent and lowest priority criterion was order of arrival or first-come first-served. CONCLUSION Despite pediatric hematology/oncology physicians and patients being heavily impacted by drug shortages, institutional processes for handling shortages are lacking. There is significant disparity between how decisions for distribution of shortage drugs are currently made and how study respondents felt those decisions should be made. An institution-based, and more importantly, a societal approach to drug shortages is necessary to reconcile these disparities.

A discussion of the impact of escalating regulatory requirements is provided, from the point of view of the administration of the institutional review board of an academic institution, and from clinical investigators who conduct studies at that same institution. Current and anticipated future issues are discussed.

Development of CNS dysfunction in the setting of hematopoietic stem cell transplant (HSCT) has been previously shown to predict for subsequent second organ dysfunction and death. In this paper, we describe the characteristics of this isolated CNS dysfunction, and its relationship to multiple organ dysfunction syndrome (MODS) after HSCT. Twenty-one of 186 patients undergoing HSCT developed CNS dysfunction as their first organ dysfunction a mean of 22.8 +/- 0.9 days after the start of the preparative regimen. Compared with 137 patients who developed no organ dysfunction, patients presenting with CNS dysfunction were more likely to have undergone allogeneic HSCT (P = 0.001) and to have received a total body irradiation-based regimen (P = 0.001), and were less likely to have been transplanted for lymphoma (P = 0.008). Patients who developed CNS dysfunction were more likely to die than those with no organ dysfunction (P0. 001). Of the 21 patients who developed CNS dysfunction, 48% resolved their dysfunction by a mean of 4.6 days later without progression to second organ dysfunction, and 90% of these patients survived to day 100. Fifty-two percent of patients with CNS dysfunction progressed to second organ dysfunction (pulmonary or hepatic) a mean of 5.5 days later, and only 36% survived to day 100 (P = 0.02). The patients who progressed to second organ dysfunction and those who did not were not different in terms of type of HSCT (allogeneic vs autologous), stem cell source (blood vs bone marrow), age, diagnosis or preparative regimen. Development of CNS dysfunction in the setting of HSCT, as with other organ dysfunctions (such as hepatic veno-occlusive disease), probably represents an early manifestation of a systemic disorder predisposing for MODS, increasing the risk of transplant-related mortality. Early systemic therapies directed at modulating this systemic disorder are probably indicated. Bone Marrow Transplantation (2000) 25, 79-83.

High-dose therapy and allogeneic matched sibling bone marrow transplantation (BMT) is considered to be the treatment of choice for children with relapsed acute lymphoblastic leukemia (ALL), or for children with acute myeloid leukemia (AML) in first remission. However, the rate of bone marrow relapse after transplant for either of these diseases remains high. In this study, we assessed the efficacy and toxicity of high-dose cytosine arabinoside and total body irradiation (TBI) followed by allogeneic BMT, for children with acute leukemia or myelodysplastic syndrome (MDS). Sixty-five pediatric patients underwent allogeneic related (n = 57) or unrelated (n = 8) BMT. Twenty-seven were transplanted for ALL in second remission (CR2), and 16 for AML in first remission (CR1). The other 22 were high risk patients: six were transplanted for ALL in third remission (CR3), two for AML in CR2, two for myelodysplastic syndrome (MDS) and 12 for acute leukemia in relapse. Patients were prepared with cytosine arabinoside 3000 mg/m2 per dose twice daily for 6 days followed by 12000 cGy TBI as 200 cGy fractions twice daily for 3 days. Minimum follow-up is 21 months. Five-year event-free survival (EFS) and the actuarial relapse rate is 59 and 14% for patients with ALL in second remission, and 38 and 14+% for patients with AML in first remission. Twelve patients have relapsed (three are alive in remission after testicular or marrow relapse) and 28 have died of other causes. Acute GVHD with or without infection was the cause of death in 11 patients. Ten of the 11 patients who died of acute GVHD were considered at 'high risk' for GVHD (inadequate GVHD prophylaxis, or mismatched family donor or a matched unrelated donor). Toxicities in the immediate post-BMT period included diarrhea, oropharyngeal mucositis and conjunctivitis. Significant late toxicities included short stature, avascular necrosis of bone, and poor school performance (most often in patients who had received prior cranial irradiation). Our conclusions are that high-dose Ara-C and TBI followed by allogeneic bone marrow transplantation is effective therapy for children in second complete remission of their acute leukemia. However, significant late toxicities occur, and it is clear that more effective, less toxic therapies are necessary for these patients.

Primary CD30(Ki-1)-positive anaplastic large-cell lymphoma (ALCL) is considered by some to be a distinct clinicopathologic entity associated with the t(2;5) (p23;q35). However, the specificity of t(2;5) for ALCL has not been carefully studied. Therefore, we performed a detailed analysis of all cases of ALCL with abnormal cytogenetics results in the Nebraska Lymphoma Study Group registry, as well as all other cases of non-Hodgkin's lymphoma with t(2;5) in the registry. We found the t(2;5) in only five of 10 cases of ALCL, four of whom were young patients. However, we also found the t(2;5) in 11 other cases of nonanaplastic lymphoma, including eight children with typical peripheral T-cell lymphomas of various types. The t(2;5) was also found in three older adults with B-cell lymphomas of various types. Thus, the t(2;5) was not specific for CD30+ ALCL. However, t(2;5) may define a clinicopathologic entity in children and young adults characterized by variable morphologies with a T-cell or indeterminate phenotype, CD30-positivity, nodal disease with frequent extranodal involvement, advanced stage, and an excellent response to therapy, including bone marrow transplantation for relapsed disease. The clinical relevance of the t(2;5) in older patients requires further study.

Bone marrow transplantation (BMT) for severe combined immunodeficiency (SCID) with human leukocyte antigen (HLA)-identical sibling donors but no pretransplantation cytoreduction results in T-lymphocyte engraftment and correction of immune dysfunction but not in full hematopoietic engraftment. A case of a 17-month-old girl with adenosine deaminase (ADA) deficiency SCID in whom full hematopoietic engraftment developed after BMT from her HLA-identical sister is reported. No myeloablative or immunosuppressive therapy or graft-versus-host disease (GVHD) prophylaxis was given. Mild acute and chronic GVHD developed, her B- and T-cell functions became reconstituted, and she is well almost 11 years after BMT. After BMT, repeated studies demonstrated: (1) Loss of a recipient-specific chromosomal marker in peripheral blood leukocytes (PBLs) and bone marrow, (2) conversion of recipient red blood cell antigens to donor type, (3) conversion of recipient T-cell, B-cell, and granulocyte lineages to donor origin by DNA analysis, and (4) increased ADA activity and metabolic correction in red blood cells and PBLs.

We report nine children with relapsed (n = 8) or high-risk (n = 1) peripheral T-cell lymphoma (PTCL) who underwent autologous (n = 6) or allogeneic (n = 3) bone marrow transplantation (BMT). These children received transplants as part of a prospective phase I/II study of thioTEPA (TT) and total body irradiation (TBI) with escalating doses of VP-16. The median age of these patients at time of BMT was 6.5 years (range 2.5 years to 14 years). Three were transplanted with active disease after failing salvage chemotherapy. Of the other six, one was transplanted in first complete remission (CR) and five in second or subsequent CR. Of these nine patients, eight are free of disease a median of 25 months after BMT (range, 6 to 48 months), with an estimated 2-year relapse-free survival (RFS) of 89%. Six of these eight patients have been followed for 12 or more months after BMT, and in each their current remission exceeds their longest previous remission duration. The toxicity of the TT/TBI +/- VP-16 regimens was significant but manageable, predominantly consisting of severe mucositis. For a comparison, we reviewed retrospective data on the six additional children and adolescents with PTCL who underwent BMT during the 3-year period preceding this phase I/II study. The median age at BMT of these six patients was 19 years (range 15.5 years to 20 years). These patients were prepared for BMT with a variety of other regimens. One had no response to BMT and the other five relapsed at 1.5 to 5 months after BMT (median, 3 months) with an RFS of 0%. Our data suggest that thioTEPA plus TBI, with or without VP-16, is an effective preparative regimen for BMT for young patients with relapsed or high-stage PTCL and leads to prolonged RFS.

Organ dysfunction following hematopoietic stem cell transplantation (HSCT) may be a manifestation of a systemic inflammatory response. We speculate that part of the platelet transfusion requirement in HSCT patients results from this systemic inflammatory response, and increased transfusion requirement would be associated with, or precede, organ dysfunction. We studied 199 adults undergoing autologous (n=173) or allogeneic (n=26) HSCT. Patients with CNS (P=0.008) or pulmonary (P=0.002) dysfunction, or with VOD (P=0.05) received a higher mean number of platelet transfusions per week than patients who did not have these dysfunctions. Furthermore, a higher number of platelet transfusions during any 1 week period was significantly associated with development of pulmonary (P=0.0002) or renal (P < 0.0001) dysfunction in the following week. This predictive value was strongest early in the HSCT course, but remained significant over all 4 weeks. In multivariate analysis the number of platelet transfusions during the previous week was independently predictive for development of pulmonary dysfunction in week 2 (P=0.01) and week 3 (P=0.055). We believe that occurrence of increased platelet transfusion requirement prior to onset of dysfunction is consistent with the concept that an antecedent inflammatory response results in both platelet consumption and various organ dysfunctions. Increased platelet transfusion requirement may act as an early marker of subsequent organ dysfunction. Additionally, there may be a direct role of platelets in the development and progression of organ dysfunction in HSCT patients.

Circulating anticoagulants protein C (PC) and antithrombin III (AT) are markers of, and possibly involved in the pathogenesis of, significant organ dysfunction, in patients undergoing autologous peripheral blood stem cell (PSBC) or autologous bone marrow (BM) transplantation. The effect of the stem cell source, the use of hematopoietic growth factors (GFs), and the specific preparative regimen on the incidence of organ system dysfunction or on post-transplant levels of circulating anticoagulants has not been well studied. We analyzed 205 patients in an attempt to correlate organ dysfunction and AT and PC deficiencies with these transplant-specific factors (78 BMT with GM-CSF after transplant, 95 PBSCT without GM-CSF after transplant, and 32 PBSCT with GM-CSF after transplant). Patients transplanted with PBSC had a lower incidence of pulmonary dysfunction (20 vs 40%, P = 0.006) and liver dysfunction (4 vs 13%, P = 0.05) than patients receiving BM. The use of GF after transplant did not influence the development of subsequent organ dysfunction. In multivariate analysis, the stem cell source was again predictive of pulmonary dysfunction. In contrast, although patients transplanted with PBSC also had a lower incidence of PC deficiency (50 vs 81%, P

Transient myeloproliferative disorder (TMD) and subsequent acute myeloid leukemia (AML) occur with increased frequency in infants and children with Down syndrome. TMD can also occur in phenotypically normal newborns. We describe the second case of a non-Down syndrome child with TMD who subsequently developed AML. Trisomy 21 karyotype was restricted to hematopoietic cells in the blood and bone marrow. No other karyotypic abnormalities were found. Leukemic blasts showed megakaryoblastic features with immunophenotyping. This case shows that TMD in a child without Down syndrome may not be entirely benign. Close follow-up is warranted. © 1994 Wiley-Liss, Inc.

The University of Nebraska Medical Center (UNMC) Institutional Review Board (IRB) reviewed a protocol for the treatment of short bowel syndrome (SBS) in children. The SBS protocol proved to be quite problematic in terms of whether was approvable under 45 CFR 46 subpart D, which specifies additional protections for children who are subjects of research. The protocol was designed as a multicenter study, but was not federally funded. The IRB's review required extensive interaction with the institutional