Velociraptor: Cross-Platform Quantitative Search Using Hallmark Cell Features.

A key challenge for single cell discovery analysis is to identify new cell types, describe them quantitatively, and seek these novel cells in new studies often using a different platform. Over the last decade, tools were developed to address identification and quantitative description of cells in human tissues and tumors. However, automated validation of populations at the single cell level has struggled due to the cytometry field's reliance on hierarchical, ordered use of features and on platform-specific rules for data processing and analysis. Here we present Velociraptor, a workflow that implements Marker Enrichment Modeling in three cross-platform modules: 1) identification of cells specific to disease states, 2) description of hallmark features for each cell and population, and 3) searching for cells matching one or more hallmark feature sets in a new dataset. A key advance is that Velociraptor registers cells between datasets, including between flow cytometry and quantitative imaging using different, overlapping feature sets. Four datasets were used to challenge Velociraptor and reveal new biological insights. Working at the individual sample level, Velociraptor tracked the abundance of clinically significant glioblastoma brain tumor cell subsets and characterized the cells that predominate in recurrent tumors as a close match for rare, negative prognostic cells originally observed in matched pre-treatment tumors. In patients with inborn errors of immunity, Velociraptor identified genotype-specific cells associated with GATA2 haploinsufficiency. Finally, in cross-platform analysis of immune cells in multiplex imaging of breast cancer, Velociraptor sought and correctly identified memory T cell subsets in tumors. Different phenotypic descriptions generated by algorithms or humans were shown to be effective as search inputs, indicating that cell identity need not be described in terms of per-feature cutoffs or strict hierarchical analyses. Velociraptor thus identifies cells based on hallmark feature sets, such as protein expression signatures, and works effectively with data from multiple sources, including suspension flow cytometry, imaging, and search text based on known or theoretical cell features.

Alemtuzumab and CXCL9 levels predict likelihood of sustained engraftment after reduced-intensity conditioning HCT.

Overall survival after reduced-intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (HCT) using alemtuzumab, fludarabine, and melphalan is associated with high rates of mixed chimerism (MC) and secondary graft failure (GF). We hypothesized that peritransplantation alemtuzumab levels or specific patterns of inflammation would predict these risks. We assessed samples from the Bone Marrow Transplant Clinical Trials Network 1204 (NCT01998633) to study the impact of alemtuzumab levels and cytokine patterns on MC and impending or established secondary GF (defined as donor chimerism <5% after initial engraftment and/or requirement of cellular intervention). Thirty-three patients with hemophagocytic lymphohistiocytosis (n = 25) and other IEIs (n = 8) who underwent HCTs with T-cell-replete grafts were included. Patients with day 0 alemtuzumab levels ≤0.32 µg/mL had a markedly lower incidence of MC, 14.3%, vs 90.9% in patients with levels >0.32 µg/mL (P = .008). Impending or established secondary GF was only observed in patients with day 0 alemtuzumab levels >0.32 µg/mL (P = .08). Unexpectedly, patients with impending or established secondary GF had lower CXCL9 levels. The cumulative incidence of impending or established secondary GF in patients with a day 14+ CXCL9 level ≤2394 pg/mL (day 14+ median) was 73.6% vs 0% in patients with a level >2394 pg/mL (P = .002). CXCL9 levels inversely correlated with alemtuzumab levels. These data suggest a model in which higher levels of alemtuzumab at day 0 deplete donor T cells, inhibit the graft-versus-marrow reaction (thereby suppressing CXCL9 levels), and adversely affect sustained engraftment in the nonmyeloablative HCT setting. This trial was registered at www.clinicaltrials.gov as #NCT01998633.

Applying a risk prediction model for bloodstream infection in a febrile, nonseverely neutropenic cohort of pediatric stem cell transplant patients.

BACKGROUND: The optimal management of febrile stem cell transplant (SCT) patients presenting without severe neutropenia (absolute neutrophil count [ANC] ≥ 500/µL) is unclear. The authors have developed iterative risk prediction models (Esbenshade Vanderbilt [EsVan] models) that reliably predict bloodstream infections (BSIs) in the febrile general pediatric oncology population without severe neutropenia, but SCT-specific data are limited. METHODS: All SCTs occurring from May 2005 to November 2019 at a single institution were identified. Episodes of fever with a central venous catheter and ANC values ≥ 500/µL were abstracted. All previous versions of the EsVan model were applied to the SCT data, and c-statistics were generated. The models were additionally applied to each type of transplant (autologous/allogeneic), and a new allogeneic model that further adjusted for metrics of immunosuppression, Esbenshade Vanderbilt Allogeneic SCT Model (EsVanAlloSCT), was developed and internally validated. RESULTS: For 429 SCT episodes (221 autologous and 208 allogeneic), the BSI incidence was 19.6% (84 of 429), and it was higher in allogeneic transplant patients (25.5%) than autologous transplant patients (14.0%; p < .01). All versions of the EsVan model performed well for the overall SCT cohort (c-statistics, 0.759-0.795). The EsVan models performed better for the autologous episodes (c-statistics, 0.869-0.881) than the allogeneic SCT episodes (c-statistics, 0.678-0.717). The new allogeneic transplant-specific model, EsVanAlloSCT, which added an adjustment for the extent of immunosuppression, yielded a c-statistic of 0.792 (bootstrap-corrected, 0.750). CONCLUSIONS: The EsVan models work exceptionally well when they are applied to autologous SCT, but they work less well for allogeneic SCT. EsVanAlloSCT appears to improve the predictive ability in allogeneic SCT, but it will need additional external validation.

Irradiation-free, T-cell replete haploidentical transplant for Fanconi anaemia, weighing the benefits.

The optimal haploidentical haematopoietic cell transplant approach for Fanconi anaemia (FA) patients is not well established, given the rarity of the disease, the increased sensitivity to DNA-damaging agents and the high risk of severe graft-versus-host disease (GVHD). The report by Xu et al. suggests that excellent engraftment and short-term survival can be achieved in FA patients without irradiation, but their retrospective cohort was plagued by a high rate of severe GVHD. Our commentary explores the outcomes in T-cell replete haploidentical haematopoietic cell transplant and ponders whether elimination of total body irradiation in FA patients is the best method if it limits the ability to safely administer post-transplant cyclophosphamide. Commentary on: Xu et al. Unmanipulated haploidentical haematopoietic cell transplantation with radiation-free conditioning in Fanconi anaemia: A retrospective analysis from the Chinese Blood and Marrow Transplantation Registry Group. Br J Haematol. 2022;199:401-410.

Disease Progression of WHIM Syndrome in an International Cohort of 66 Pediatric and Adult Patients.

Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome (WS) is a combined immunodeficiency caused by gain-of-function mutations in the C-X-C chemokine receptor type 4 (CXCR4) gene. We characterize a unique international cohort of 66 patients, including 57 (86%) cases previously unreported, with variable clinical phenotypes. Of 17 distinct CXCR4 genetic variants within our cohort, 11 were novel pathogenic variants affecting 15 individuals (23%). All variants affect the same CXCR4 region and impair CXCR4 internalization resulting in hyperactive signaling. The median age of diagnosis in our cohort (5.5 years) indicates WHIM syndrome can commonly present in childhood, although some patients are not diagnosed until adulthood. The prevalence and mean age of recognition and/or onset of clinical manifestations within our cohort were infections 88%/1.6 years, neutropenia 98%/3.8 years, lymphopenia 88%/5.0 years, and warts 40%/12.1 years. However, we report greater prevalence and variety of autoimmune complications of WHIM syndrome (21.2%) than reported previously. Patients with versus without family history of WHIM syndrome were diagnosed earlier (22%, average age 1.3 years versus 78%, average age 5 years, respectively). Patients with a family history of WHIM syndrome also received earlier treatment, experienced less hospitalization, and had less end-organ damage. This observation reinforces previous reports that early treatment for WHIM syndrome improves outcomes. Only one patient died; death was attributed to complications of hematopoietic stem cell transplantation. The variable expressivity of WHIM syndrome in pediatric patients delays their diagnosis and therapy. Early-onset bacterial infections with severe neutropenia and/or lymphopenia should prompt genetic testing for WHIM syndrome, even in the absence of warts.

Systems Immunology Analyses of STAT1 Gain-of-Function Immune Phenotypes Reveal Heterogeneous Response to IL-6 and Broad Immunometabolic Roles for STAT1.

Patients with STAT1 gain-of-function (GOF) pathogenic variants have enhanced or prolonged STAT1 phosphorylation following cytokine stimulation and exhibit increased yet heterogeneous susceptibility to infections, autoimmunity, and cancer. Although disease phenotypes are diverse and other genetic factors contribute, how STAT1 GOF affects cytokine sensitivity and cell biology remains poorly defined. In this study, we analyzed the immune and immunometabolic profiles of two patients with known pathogenic heterozygous STAT1 GOF mutation variants. A systems immunology approach of peripheral blood cells from these patients revealed major changes in multiple immune cell compartments relative to healthy adult and pediatric donors. Although many phenotypes of STAT1 GOF donors were shared, including increased Th1 cells but decreased class-switched B cells and plasmacytoid dendritic cell populations, others were heterogeneous. Mechanistically, hypersensitivity for cytokine-induced STAT1 phosphorylation in memory T cell populations was particularly evident in response to IL-6 in one STAT1 GOF patient. Immune cell metabolism directly influences cell function, and the STAT1 GOF patients shared an immunometabolic phenotype of heightened glucose transporter 1 (GLUT1) and carnitine palmitoyl transferase 1A (CPT1a) expression across multiple immune cell lineages. Interestingly, the metabolic phenotypes of the pediatric STAT1 GOF donors more closely resembled or exceeded those of healthy adult than healthy age-similar pediatric donors, which had low expression of these metabolic markers. These results define new features of STAT1 GOF patients, including a differential hypersensitivity for IL-6 and a shared increase in markers of metabolism in many immune cell types that suggests a role for STAT1 in metabolic regulation of immunity.

Outcomes for patients with severe chronic neutropenia treated with granulocyte colony-stimulating factor.

Severe chronic neutropenia (SCN), defined as blood neutrophils <0.5 × 109/L for >3 months, is an uncommon hematological condition associated with recurrent and severe bacterial infections. After short-term clinical trials showed the benefits of granulocyte colony-stimulating factor (G-CSF) treatment for SCN, SCNIR (Severe Chronic Neutropenia International Registry) opened to determine the long-term benefits and safety of this treatment. This report summarizes findings from more than 16 000 patient-years of prospective observations for patients with congenital and acquired SCN. We observed that adverse outcomes depend on the underlying etiology. Myelodysplasia (MDS) and acute myeloid leukemia (AML) occur infrequently and largely in patients with congenital neutropenias. Having cyclic or chronic autoimmune/ idiopathic neutropenia portends a favorable prognosis. A few patients with idiopathic neutropenia evolve to develop lymphoid malignancies, but they do not appear to be at increased risk of myeloid malignancies, even with very long-term G-CSF therapy. Progression to systemic autoimmune diseases, bone marrow (BM) failure, aplastic anemia, or nonmyeloid malignancies are not expected consequences of SCN or treatment with G-CSF.

Immunogenicity and safety of the human papillomavirus vaccine in young survivors of cancer in the USA: a single-arm, open-label, phase 2, non-inferiority trial.

BACKGROUND: Young survivors of cancer are at increased risk for cancers that are related to human papillomavirus (HPV), primarily caused by oncogenic HPV types 16 and 18. We aimed to examine the immunogenicity and safety of the three-dose series of HPV vaccine in young survivors of cancer. METHODS: We conducted an investigator-initiated, phase 2, single-arm, open-label, non-inferiority trial at five National Cancer Institute-designated comprehensive cancer centres in the USA. Eligible participants were survivors of cancer who were HPV vaccine-naive, were aged 9-26 years, in remission, and had completed cancer therapy between 1 and 5 years previously. Participants received three intramuscular doses of either quadrivalent HPV vaccine (HPV4; enrolments on or before March 1, 2016) or nonavalent HPV vaccine (HPV9; enrolments after March 1, 2016) over 6 months (on day 1, at month 2, and at month 6). We also obtained data from published clinical trials assessing safety and immunogenicity of HPV4 and HPV9 in 9-26-year-olds from the general population, as a comparator group. The primary endpoint was antibody response against HPV types 16 and 18 at month 7 in the per-protocol population. A response was deemed non-inferior if the lower bound of the multiplicity-adjusted 95% CI was greater than 0·5 for the ratio of anti-HPV-16 and anti-HPV-18 geometric mean titres (GMTs) in survivors of cancer versus the general population. Responses were examined separately in male and female participants by age group (ie, 9-15 years and 16-26 years). Safety was assessed in all participants who received at least one vaccine dose and for whom safety data were available. This study is registered with ClinicalTrials.gov, NCT01492582. This trial is now completed. FINDINGS: Between Feb 18, 2013, and June 22, 2018, we enrolled 453 survivors of cancer, of whom 436 received one or more vaccine doses: 203 (47%) participants had survived leukaemia, 185 (42%) were female, and 280 (64%) were non-Hispanic white. Mean age at first dose was 15·6 years (SD 4·6). 378 (83%) of 453 participants had evaluable immunogenicity data; main reasons for exclusion from per-protocol analysis were to loss to follow-up, patient reasons, and medical reasons. Data were also obtained from 26 486 general population controls. The ratio of mean GMT for anti-HPV types 16 and 18 in survivors of cancer versus the general population was more than 1 for all subgroups (ie, aged 9-15 years, aged 16-26 years, male, and female groups) in both vaccine cohorts (ranging from 1·64 [95% CI 1·12-2·18] for anti-HPV type 16 in female participants aged 9-15 years who received HPV9, to 4·77 [2·48-7·18] for anti-HPV type 18 in male participants aged 16-26 years who received HPV4). Non-inferiority criteria were met within each age and sex subgroup, except against HPV type 18 in female participants aged 16-26 years receiving HPV9 (4·30 [0·00-9·05]). Adverse events were reported by 237 (54%) of 435 participants; injection site pain was most common (174 [40%] participants). One serious adverse event (ie, erythema nodosum) was possibly related to vaccine (HPV9; 16-26 year female cohort). INTERPRETATION: Immunogenicity and safety of HPV vaccine three-dose series in survivors of cancer is similar to that in the general population, providing evidence for use in this clinically vulnerable population. FUNDING: US National Cancer Institute, Merck, Sharp & Dohme, and American Lebanese Syrian Associated Charities.

Understanding neutropenia secondary to intrinsic or iatrogenic immune dysregulation.

As a key member of the innate and adaptive immune response, neutrophils provide insights into the hematopoietic and inflammatory manifestations of inborn errors of immunity (IEI) and the consequences of immunotherapy. The facile recognition of IEI presenting with neutropenia provides an avenue for hematologists to facilitate early diagnosis and expedite biologically rationale care. Moreover, enhancing the understanding of the molecular mechanisms driving neutropenia in IEI-decreased bone marrow reserves, diminished egress from the bone marrow, and decreased survival-offers an opportunity to further dissect the pathophysiology driving neutropenia secondary to iatrogenic immune dysregulation, eg, immune checkpoint inhibitors and chimeric antigen receptor T-cell therapy.

Diagnosis and therapeutic decision-making for the neutropenic patient.

Determining the cause of a low neutrophil count in a pediatric or adult patient is essential for the hematologist's clinical decision-making. Fundamental to this diagnostic process is establishing the presence or lack of a mature neutrophil storage pool, as absence places the patient at higher risk for infection and the need for supportive care measures. Many diagnostic tests, eg, a peripheral blood smear and bone marrow biopsy, remain important tools, but greater understanding of the diversity of neutropenic disorders has added new emphasis on evaluating for immune disorders and genetic testing. In this article, a structure is provided to assess patients based on the mechanism of neutropenia and to prioritize testing based on patient age and hypothesized pathophysiology. Common medical quandaries including fever management, need for growth factor support, risk of malignant transformation, and curative options in congenital neutropenia are reviewed to guide medical decision-making in neutropenic patients.

Impact of COVID-19 on Pediatric Immunocompromised Patients.

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Sexual behaviors and human papillomavirus vaccine non-initiation among young adult cancer survivors.

BACKGROUND: Young adult cancer survivors are at risk for subsequent human papillomavirus (HPV)-related malignancies. High-risk sexual behavior increases risk for HPV acquisition; HPV vaccination protects against infection. We aimed to determine the prevalence of sexual behaviors, factors related to high-risk sexual behaviors, and the relationship between sexual behaviors and HPV vaccine non-initiation among survivors. METHODS: Survivors at comprehensive cancer centers, aged 18-26 years and 1-5 years post-treatment, reported sexual behaviors and HPV vaccine initiation (i.e., ≥ 1 dose). Multivariable logistic regression was performed to calculate odds ratios (OR) and 95% confidence intervals (95%CI) for factors associated with high-risk sexual behaviors (age at first intercourse < 16 years, ≥ 3 lifetime sexual partners, or condom use ≤ 50% of the time) and to explore the relationship between sexual behaviors and vaccine non-initiation. RESULTS: Of the 312 participants (48.1% female, median age at cancer diagnosis 17.2 years and at survey 20.9 years), sexual intercourse was reported by 63.1%. Of those reporting intercourse, 74.6% reported high-risk sexual behavior. Factors related to high-risk sexual behavior included currently dating/partnered (OR = 4.39, 95%CI 2.5-7.7, P < 0.001) and perceived susceptibility to HPV (OR = 1.76, 95%CI 1.3-2.5, P < 0.001). Most survivors (75.3%) reported HPV vaccine non-initiation; sexual behaviors were not associated with vaccine non-initiation (P = 0.4). CONCLUSIONS: Many survivors participate in high-risk sexual behaviors, yet HPV vaccine initiation rates are low. Factors related to high-risk sexual behaviors can inform interventions to reduce risk for HPV acquisition among survivors. IMPLICATIONS FOR CANCER SURVIVORS: Cancer survivors participate in sexual behaviors that increase risk for HPV acquisition and would benefit from vaccination.

Immunodeficiency and bone marrow failure with mosaic and germline TLR8 gain of function.

Inborn errors of immunity (IEI) are a genetically heterogeneous group of disorders with a broad clinical spectrum. Identification of molecular and functional bases of these disorders is important for diagnosis, treatment, and an understanding of the human immune response. We identified 6 unrelated males with neutropenia, infections, lymphoproliferation, humoral immune defects, and in some cases bone marrow failure associated with 3 different variants in the X-linked gene TLR8, encoding the endosomal Toll-like receptor 8 (TLR8). Interestingly, 5 patients had somatic variants in TLR8 with <30% mosaicism, suggesting a dominant mechanism responsible for the clinical phenotype. Mosaicism was also detected in skin-derived fibroblasts in 3 patients, demonstrating that mutations were not limited to the hematopoietic compartment. All patients had refractory chronic neutropenia, and 3 patients underwent allogeneic hematopoietic cell transplantation. All variants conferred gain of function to TLR8 protein, and immune phenotyping demonstrated a proinflammatory phenotype with activated T cells and elevated serum cytokines associated with impaired B-cell maturation. Differentiation of myeloid cells from patient-derived induced pluripotent stem cells demonstrated increased responsiveness to TLR8. Together, these findings demonstrate that gain-of-function variants in TLR8 lead to a novel childhood-onset IEI with lymphoproliferation, neutropenia, infectious susceptibility, B- and T-cell defects, and in some cases, bone marrow failure. Somatic mosaicism is a prominent molecular mechanism of this new disease.

Multidisciplinary Guidance Regarding the Use of Immunomodulatory Therapies for Acute Coronavirus Disease 2019 in Pediatric Patients.

BACKGROUND: Immune-mediated lung injury and systemic hyperinflammation are characteristic of severe and critical coronavirus disease 2019 (COVID-19) in adults. Although the majority of severe acute respiratory syndrome coronavirus 2 infections in pediatric populations result in minimal or mild COVID-19 in the acute phase of infection, a small subset of children develop severe and even critical disease in this phase with concomitant inflammation that may benefit from immunomodulation. Therefore, guidance is needed regarding immunomodulatory therapies in the setting of acute pediatric COVID-19. This document does not provide guidance regarding the recently emergent multisystem inflammatory syndrome in children (MIS-C). METHODS: A multidisciplinary panel of pediatric subspecialty physicians and pharmacists with expertise in infectious diseases, rheumatology, hematology/oncology, and critical care medicine was convened. Guidance statements were developed based on best available evidence and expert opinion. RESULTS: The panel devised a framework for considering the use of immunomodulatory therapy based on an assessment of clinical disease severity and degree of multiorgan involvement combined with evidence of hyperinflammation. Additionally, the known rationale for consideration of each immunomodulatory approach and the associated risks and benefits was summarized. CONCLUSIONS: Immunomodulatory therapy is not recommended for the majority of pediatric patients, who typically develop mild or moderate COVID-19. For children with severe or critical illness, the use of immunomodulatory agents may be beneficial. The risks and benefits of such therapies are variable and should be evaluated on a case-by-case basis with input from appropriate specialty services. When available, the panel strongly favors immunomodulatory agent use within the context of clinical trials. The framework presented herein offers an approach to decision-making regarding immunomodulatory therapy for severe or critical pediatric COVID-19 and is informed by currently available data, while awaiting results of placebo-controlled randomized clinical trials.

Pericardial effusion following hematopoietic stem cell transplantation in children: Incidence, risk factors, and outcomes.

PCE is a complication of HSCT that has previously been described in small single-center studies. This study aimed to assess the frequency of, risk factors for, and outcomes of children with a PCE following HSCT across a large multi-center cohort. All patients ≤21 years undergoing first HSCT (1/2005-9/2015) were identified from the Pediatric Health Information System. ICD-9 codes were used to identify patients with a PCE during or following the transplant encounter. Multivariable modeling assessed risk factors for developing a PCE and assessed the impact of PCE on patient outcome. Of 10 455 included patients, 739 (7.1%) developed a PCE (median 69 days post-HSCT, interquartile range 33-165 days). PCE developed more commonly in allogeneic vs autologous HSCT recipients (9.1% vs 2.9%, P < .001). Among allogeneic HSCT recipients, independent risk factors for PCE included thrombotic microangiopathy (AHR 2.94, 95% CI 2.16-4.00), heart failure (AHR 2.07, 95% CI 1.61-2.66), PCE pre-HSCT (AHR 1.92, 95% CI 1.19-3.09), arrhythmia (AHR 1.76, 95% CI 1.44-2.16), graft-versus-host disease (AHR 1.31, 95% CI 1.05-1.62), female sex (AHR 1.28, 95% CI 1.07-1.52), and malignancy (AHR 1.28, 95% CI 1.02-1.60). Allogeneic HSCT patients with PCE demonstrated worse survival than those without PCE (5-year survival 50.8% vs 76.9%, P < .001). PCE was independently associated with mortality (AHR 1.96, 95% CI 1.62-2.37) following allogeneic HSCT and was not impacted by pericardial intervention. PCE occurs more commonly in patients following allogeneic (vs autologous) HSCT and is associated with inferior outcomes.

Patient-Level Factors Associated With Lack of Health Care Provider Recommendation for the Human Papillomavirus Vaccine Among Young Cancer Survivors.

PURPOSE: Young cancer survivors are at increased risk for morbidities related to infection with the human papillomavirus (HPV), yet their HPV vaccine initiation rates remain low. Patient-/parent-reported lack of health care provider recommendation for HPV vaccination is strongly associated with vaccine noninitiation. We aimed to identify patient-level factors associated with survivor-/parent-reported lack of provider recommendation for HPV vaccination among young cancer survivors. METHODS: Cancer survivors ages 9-26 years and 1-5 years off therapy completed a cross-sectional survey (parent-completed for survivors 9-17 years of age). Lack of health care provider HPV vaccine recommendation was the outcome of interest in a multivariable logistic regression model that included relevant patient-level sociodemographic, clinical, and vaccine-related variables. RESULTS: Of 955 survivors, 54% were male, 66% were non-Hispanic White, and 36% had leukemia. At survey participation, survivors were an average age (± standard deviation) of 16.3 ± 4.7 years and 32.8 ± 14.7 months off therapy. Lack of provider HPV vaccine recommendation was reported by 73% (95% CI, 70% to 75%) of survivors. For the entire cohort, patient-level factors associated with lack of reported provider recommendation included perceived lack of insurance coverage for the HPV vaccine (odds ratio [OR], 4.0; 95% CI, 2.7 to 5.9; P < .001), male sex (OR, 2.8; 95% CI, 1.9 to 4.0; P < .001), and decreased parent-survivor communication regarding HPV vaccination (OR, 1.7 per unit decrease in score; 95% CI, 1.3 to 2.2; P < .001). In the sex- and age-stratified models, perceived lack of insurance coverage (all models) and male sex (age-stratified models) were also significantly associated with lack of reported provider recommendation. CONCLUSION: We identified factors characterizing survivors at risk for not reporting receipt of a health care provider HPV vaccine recommendation. Future research is needed to develop interventions that facilitate effective provider recommendations for HPV vaccination among all young cancer survivors.

Neutropenia Is an Underrecognized Finding in Pediatric Primary Immunodeficiency Diseases: An Analysis of the United States Immunodeficiency Network Registry.

BACKGROUND: The frequency of neutropenia in pediatric primary immunodeficiency disorders (PIDDs) is unknown and potentially underappreciated. Our study aimed to determine the overall frequency and severity of neutropenia in children diagnosed with a PIDD entered in the United States Immunodeficiency Network (USIDNET) patient registry. PROCEDURE: Neutropenia data and demographic/clinical information from 1145 patients younger than 21 years of age was obtained from the USIDNET registry. RESULTS: Neutropenia is more common in PIDD patients entered within the USIDNET registry than previously appreciated. There was a >10% occurrence rate of neutropenia in all broad primary immunodeficiency categories as well as in nearly all individual PIDDs. Neutropenia frequency was greater in African American pediatric PIDD patients than in white or Asian patients. The degree of neutropenia did not associate with mortality in pediatric patients with a PIDD. CONCLUSION: Although our study did not assess the frequency of PIDD in patients presenting with neutropenia, the possibility of a primary immune disorder should be considered in patients with idiopathic neutropenia.

Hematopoietic Stem Cell Transplantation to Treat Leukodystrophies: Clinical Practice Guidelines from the Hunter's Hope Leukodystrophy Care Network.

The leukodystrophies are a heterogeneous group of inherited diseases characterized by progressive demyelination of the central nervous system leading to devastating neurologic symptoms and premature death. Hematopoietic stem cell transplantation (HSCT) has been successfully used to treat certain leukodystrophies, including adrenoleukodystrophy, globoid leukodystrophy (Krabbe disease), and metachromatic leukodystrophy, over the past 30 years. To date, these complex patients have primarily been transplanted at a limited number of pediatric centers. As the number of cases identified through pregnancy and newborn screening is increasing, additional centers will be required to treat these children. Hunter's Hope created the Leukodystrophy Care Network in part to create and standardize high-quality clinical practice guidelines to guide the care of affected patients. In this report the clinical guidelines for the care of pediatric patients with leukodystrophies undergoing treatment with HSCT are presented. The initial transplant evaluation, determination of patient eligibility, donor selection, conditioning, supportive care, and post-transplant follow-up are discussed. Throughout these guidelines the need for early detection and treatment and the role of the partnership between families and multidisciplinary providers are emphasized.