Search

Background. Glucocorticoids used to treat childhood leukemia and lymphoma can result in osteonecrosis, leading to physical dysfunction and pain. Improving survival rates warrants research into long-term outcomes among this population. Objective. The objective of this study was to compare the physical function and quality of life (QOL) of survivors of childhood cancer who had an osteonecrosis history with that of survivors who had no osteonecrosis history and with that of people who were healthy (controls). Design. This was a cross-sectional study. Methods. This study included St Jude Lifetime Cohort Study participants who were [greater than or equal to] 10 years from the diagnosis of childhood leukemia or lymphoma and [greater than or equal to] 18 years old; 135 had osteonecrosis (52.5% men; mean age = 27.7 [SD = 6.08] years) and 1560 had no osteonecrosis history (52.4% men; mean age = 33.3 [SD = 8.54] years). This study also included 272 people who were from the community and who were healthy (community controls) (47.7% men; mean age = 35.1 [SD = 10.46] years). The participants completed functional assessments and questionnaires about QOL. Results. Survivors with osteonecrosis scored lower than other survivors and controls for dorsiflexion strength (mean score = 16.50 [SD = 7.91] vs 24.17 [SD = 8.61] N*m/kg) and scored lower than controls for flexibility with the sit-and-reach test (20.61 [SD = 9.70] vs 23.96 [SD = 10.73] cm), function on the Physical Performance Test (mean score = 22.73 [SD = 2.05] vs 23.58 [SD = 0.88]), and mobility on the Timed 'Up & Go' Test (5.66 [SD = 2.25] vs 5.12 [SD = 1.28] seconds). Survivors with hip osteonecrosis requiring surgery scored lower than survivors without osteonecrosis for dorsiflexion strength (13.75 [SD = 8.82] vs 18.48 [SD = 9.04] Nm/kg), flexibility (15.79 [SD = 8.93] vs 20.37 [SD = 10.14] cm), and endurance on the 6-minute walk test (523.50 [SD = 103.00] vs 572.10 [SD = 102.40] m). Limitations. Because some eligible survivors declined to participate, possible selection bias was a limitation of this study. Conclusions. survivors of childhood leukemia and lymphoma with and without osteonecrosis demonstrated impaired physical performance and reported reduced QOL compared with controls, with those requiring surgery for osteonecrosis most at risk for impairments. It may be beneficial to provide strengthening, flexibility, and endurance interventions for patients who have pediatric cancer and osteonecrosis for long-term function., Survival rates continue to improve among children treated for leukemia and lymphoma such that the vast majority of these children will survive their disease. (1) Five-year relative survival rates for [...]

ABSTRACTSocial epigenomics is an emerging field in which social scientist collaborate with computational biologists, especially epigeneticists, to address the underlying pathway for biological embedding of life experiences. This social epigenomics study included long-term childhood cancer survivors enrolled in the St. Jude Lifetime Cohort. DNA methylation (DNAm) data were generated using the Illumina EPIC BeadChip, and three social determinants of health (SDOH) factors were assessed: self-reported educational attainment, personal income, and an area deprivation index based on census track data. An epigenome-wide association study (EWAS) was performed to evaluate the relation between DNAm at each 5’-cytosine-phosphate-guanine-3’ (CpG) site and each SDOH factor based on multivariable linear regression models stratified by ancestry (European ancestry, n = 1,618; African ancestry, n = 258). EWAS among survivors of European ancestry identified 130 epigenome-wide significant SDOH–CpG associations (P< 9 × 10−8), 25 of which were validated in survivors of African ancestry (P< 0.05). Thirteen CpGs were associated with all three SDOH factors and resided at pleiotropic loci in cigarette smoking–related genes (e.g., CLDND1and CPOX). After accounting for smoking and body mass index, these associations remained significant with attenuated effect sizes. Seven of 13 CpGs were associated with gene expression level based on 57 subsamples with blood RNA sequencing data available. In conclusion, DNAm signatures, many resembling the effect of tobacco use, were associated with SDOH factors among survivors of childhood cancer, thereby suggesting that biologically distal SDOH factors influence health behaviours or related factors, the epigenome, and subsequently survivors’ health.

IMPORTANCE: Exercise intolerance is associated with increased risk for morbidity and mortality in childhood cancer survivors. However, an association between exercise intolerance and psychosocial outcomes has not been fully explored. OBJECTIVE: To examine the associations between exercise intolerance and emotional distress, attainment of social roles, and health-related quality of life in childhood cancer survivors. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional study including 1041 adult survivors of childhood cancer and 286 community controls in the St Jude Lifetime Cohort was conducted at St Jude Children’s Research Hospital. The study was performed from April 1, 2012, to March 15, 2020. EXPOSURES: Exercise intolerance was defined as relative peak oxygen uptake less than 85% of age- and sex-estimated levels from maximal cardiopulmonary exercise testing. MAIN OUTCOMES AND MEASURES: Emotional distress was measured with the 18-item Brief Symptom Inventory-18, which includes overall Global Severity Index and depression, anxiety, and somatization subscales. Participants with T scores greater than or equal to 63 were classified as having elevated levels of distress. Social attainment was evaluated using patient-reported educational, employment, and marital status. Health-related quality of life was examined with the Medical Outcomes Survey Short Form-36. Participants with T scores less than or equal to 40 were classified as reporting poor health-related quality of life. RESULTS: Of the 1041 participants, 528 were women (50.7%). The prevalence of exercise intolerance among survivors (mean [SD] age, 35.5 [9.2] years) was higher than that among controls (age, 34.5 [10.0] years) (survivors: 634 [60.9%] vs controls: 75 [26.2%], P &lt; .001). After adjusting for age at diagnosis and cardiopulmonary exercise testing, sex, race/ethnicity, smoking, physical activity, and exercise intolerance were associated with an increased risk for anxiety (prevalence rate ratio [PRR], 1.95; 95% CI, 1.20-3.16), somatization (PRR, 1.86; 95% CI, 1.23-2.80), and unemployment (PRR, 1.76; 95% CI, 1.23-2.52); an inverse association was noted with having a college degree (PRR, 0.67; 95% CI, 0.50-0.88). Exercise intolerance was associated with an increased the risk for scoring less than or equal to 40 on the physical component summary of the Medical Outcomes Survey Short Form-36 (PRR, 3.69; 95% CI, 2.34-5.84). These associations persisted when either cancer treatment exposures or chronic health conditions were added to the model. CONCLUSIONS AND RELEVANCE: The findings of this study suggest that exercise intolerance is independently associated with emotional distress, attainment of social roles, and health-related quality of life of long-term survivors of childhood cancer. The results also suggest that improving physiologic capacity may benefit general health and wellness, as well as emotional health, ability to participate in social roles, and health-related quality of life.

Data on hypothalamic-pituitary (HP) disorders in systematically evaluated childhood cancer survivors are limited.

We report on the prevalence, risk factors, and consequences on general health of premature ovarian insufficiency in a cohort of 921 long-term survivors of childhood cancers.

IMPORTANCE: This study provides the first objective data documenting neurocognitive impairment in long-term survivors of childhood osteosarcoma. OBJECTIVE: To examine neurocognitive, neurobehavioral, emotional, and quality-of-life outcomes in long-term survivors of childhood osteosarcoma. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional cohort study at an academic research hospital, with prospective treatment and chronic health predictors. Outcome data were collected from June 2008 to August 2014. Data analysis was completed in April 2015. Survivors of osteosarcoma recruited from the St Jude Lifetime Cohort Study were compared with community controls. MAIN OUTCOMES AND MEASURES: Neurocognitive function, neurobehavioral symptoms, emotional distress, and quality of life. Outcomes were examined in relation to pharmacokinetic indices of methotrexate exposure and current chronic health conditions, which were assessed through medical examination and coded according to Common Terminology Criteria for Adverse Events, Version 4.03. RESULTS: Eighty survivors of osteosarcoma (mean [SD] age, 38.9 [7.6] years; time since diagnosis, 24.7 [6.6] years; 42% female) were compared with 39 community controls (age, 39.0 [11.7] years; 56% female). Survivors demonstrated lower mean scores in reading skills (−0.21 [95% CI, −0.32 to −0.10] vs 0.05 [95% CI, −0.13 to 0.23]; P = .01), attention (−0.78 [95% CI, −1.32 to −0.24] vs 0.24 [95% CI, −0.07 to 0.55]; P = .002), memory (−0.24 [95% CI, −0.48 to 0] vs 0.27 [95% CI, −0.08 to 0.62]; P = .01), and processing speed (−0.15 [95% CI, −0.35 to 0.05] vs 0.74 [95% CI, 0.44 to 1.03]; P &lt; .001). Results of pharmacokinetic analysis showed that high-dose methotrexate maximum plasma concentration (estimate = 0; P = .48), median clearance (estimate = −0.11; P = .76), and median/cumulative exposure (estimate = 0; P = .45) were not associated with neurocognitive outcomes. Any grade 3 or 4 Common Terminology Criteria for Adverse Events cardiac, pulmonary, or endocrine condition was associated with poorer memory (t = 2.93; P = .006) and slower processing speed (t = 3.03; P = .002). Survivor-reported poor general health was associated with decreased sustained attention (estimate = 0.24; P = .05) and processing speed (estimate = 0.34; P = .005). CONCLUSIONS AND RELEVANCE: Long-term survivors of osteosarcoma are at risk for neurocognitive impairment, which is related to current chronic health conditions and not to original treatment with high-dose methotrexate. Prospective longitudinal studies are needed to identify onset and progression of impairment to inform optimal interventions.

Genome-wide association studies (GWAS) have successfully identified many common genetic variants associated with complex diseases over the past decade. The ‘gold standard’ method for validating the top single nucleotide polymorphisms (SNPs) identified in GWAS is to independently replicate the findings in similar or diverse large-scale external cohorts. However, for rare diseases, it can be difficult to find an external validation cohort within a reasonable timeframe. In such situations, resampling methods, such as the two-step iterative resampling (TSIR) approach have been used to identify SNPs associated with the outcome of interest. However, the TSIR approach involves choosing several parameters in each step, which can influence the performance of the approach. In this paper, we undertook extensive simulation studies to assess the effect of choice of different parameters on the type I error and power for both binary and continuous phenotypes and also compared the TSIR approach with the traditional one-stage (OS) and two-stage (TS) GWAS analysis. We illustrate the usefulness of the TSIR approach by applying it to a GWAS of childhood cancer survivors. Our results indicate that the TSIR approach with an at least 70:30 split and a cutoff of discovering and replicating SNPs at least 20 times in 100 replications provides conservative type I error control and has near ‘optimal’ power for internally validated SNPs. Its performance is comparable with the TS GWAS for which an external validation cohort is available with only slight reduction in power in some situations. It has almost the same power as OS GWAS with conservative type I error which leads to fewer false positive findings. TSIR is a powerful and efficient method for identifying and internally validating SNPs for GWAS when independent cohorts for external validation may not be available.

There is limited information on body composition, energy balance, and fitness among survivors of childhood acute lymphoblastic leukemia (ALL), especially those treated without cranial radiation therapy (CRT). This analysis compares these metrics among 365 ALL survivors with a mean age of 28.6 ± 5.9 years (149 treated with and 216 without CRT) and 365 age-, sex-, and race-matched peers. We also report risk factors for outcomes among survivors treated without CRT. Male survivors not exposed to CRT had abnormal body composition when compared with peers (% body fat, 26.2 ± 8.2 vs 22.7 ± 7.1). Survivors without CRT had similar energy balance but had significantly impaired quadriceps strength (−21.9 ± 6.0 Newton-meters [Nm]/kg, 60°/s) and endurance (−11.4 ± 4.6 Nm/kg, 300°/s), exercise capacity (−2.0 ± 2.1 ml/kg per minute), low-back and hamstring flexibility (−4.7 ± 1.6 cm), and dorsiflexion range of motion (−3.1 ± 0.9°) and higher modified total neuropathy scores (+1.6 ± 1.1) than peers. Cumulative asparaginase dose ≥120 000 IU/m2 was associated with impaired flexibility, vincristine dose ≥39 mg/m2 with peripheral neuropathy, glucocorticoid (prednisone equivalent) dose ≥8000 mg/m2 with hand weakness, and intrathecal methotrexate dose ≥225 mg with dorsiflexion weakness. Physical inactivity was associated with hand weakness and decreased exercise capacity. Smoking was associated with peripheral neuropathy. Elimination of CRT from ALL therapy has improved, but not eliminated, body-composition outcomes. Survivors remain at risk for impaired fitness.

Survivors of childhood acute lymphoblastic leukemia (ALL) treated with cranial radiation therapy (CRT) are at risk for cognitive impairment, although whether impairment progresses with age into adulthood is unknown. We report change in intelligence for 102 adult survivors of childhood ALL (age range, 26.6-54.7 years) during a median interval of 28.5 years. Survivors demonstrated lower Performance intelligence (mean, 95.3; standard deviation, 16.5; P= .005) but not Verbal IQ (mean, 97.4; standard deviation, 15.44; P= .09) at initial testing. Verbal intelligence declined an average of 10.3 points (P< .0001) during the follow-up interval with no decline in Performance intelligence. Decline was associated with current attention problems (P= .002) but not gender, CRT dose, age at CRT exposure, or years between testing. Results suggest long-term survivors of childhood ALL treated with CRT are at risk for progressive decline in verbal intellect, which may be driven by attention deficits. This trial was registered at clinicaltrials.govas no. NCT00760656.

To identify predictors for 2 risk measures—“proven invasive bacterial infection or culture-negative sepsis (IBD)” and “clinical complications (CC)”—in pediatric cancer patients with fever and neutropenia (FN).

The etiology, clinical course, and outcome of fever and neutropenia (FN) in children with cancer using the current FN guidelines and diagnostic resources in the United States have not been well described.

Fatigue, rated by adolescents as the most distressing symptom experienced during cancer treatment, is essential to the successful clinical care of patients of every culture and nationality. Efforts to provide relief from such symptom, in any area of the world, have been hampered by the lack of reliable and valid instruments used to measure fatigue. Our aims were to examine the semantic, conceptual, and normative equivalence of the Chinese version of the Fatigue Scale-Adolescent (FS-A-C) to the original Fatigue Scale-Adolescent (FS-A) and to estimate the reliability and validity of the FS-A-C. We recruited 51 Taiwanese adolescents in various stages of different types of cancer in this cross-sectional study. Results indicated that the initial panel estimates of semantic, conceptual, and normative equivalence of the FS-A-C with the original instrument (FS-A) were positive. The FS-A-C had acceptable internal consistency (Cronbach =.89) and moderate-to-high content validity (content validity index ranges from 87% to 100%). In addition, the FS-A-C achieved known-groups validity (anemic adolescents reporting higher fatigue than nonanemic adolescents do) and initial construct validity (a significant association between the FS-A-C and the Anxious/Depressed subscale). Its use in measuring the intensity of fatigue in adolescents is likely to yield accurate assessments of their fatigue that could prompt clinical efforts to relieve their fatigue-related distress.

Adenovirus (ADV) infections are associated with significant morbidity and mortality after hematopoietic stem cell transplantation (HSCT). The virus is endemic in the general pediatric population and frequently causes severe disease in immunocompromised patients, especially children. We report our experience with cidofovir (CDV) for treatment of ADV infection in 57 HSCT patients, median age 8 years (range 0.5–26).

To determine the incidence, etiology and outcome of graft failure in pediatric allogeneic bone marrow transplant (BMT) recipients.

The Wiskott-Aldrich syndrome (WAS) is an X-linked disorder characterized by immune dysfunction, thrombocytopenia, and eczema. We used a murine model created by knockout of the WAS protein gene (WASP) to evaluate the potential of gene therapy for WAS. Lethally irradiated, male WASP— animals that received transplants of mixtures of wild type (WT) and WASP— bone marrow cells demonstrated enrichment of WT cells in the lymphoid and myeloid lineages with a progressive increase in the proportion of WT T-lymphoid and B-lymphoid cells. WASP— mice had a defective secondary T-cell response to influenza virus which was normalized in animals that received transplants of 35% or more WT cells. The WASP gene was inserted into WASP— bone marrow cells with a bicistronic oncoretroviral vector also encoding green fluorescent protein (GFP), followed by transplantation into irradiated male WASP— recipients. There was a selective advantage for gene-corrected cells in multiple lineages. Animals with higher proportions of GFP+ T cells showed normalization of their lymphocyte counts. Gene-corrected, blood T cells exhibited full and partial correction, respectively, of their defective proliferative and cytokine secretory responses to in vitro T-cell–receptor stimulation. The defective secondary T-cell response to influenza virus was also improved in gene-corrected animals.

In a series of five studies, the research team tested components of the stress-response sequence (SRS) model to determine the relationships between role-related stress, coping, and work consequences in pediatric oncology nurses. The combined outcomes indicated that the model required revision to include role-related meaning; this study tested the revised model. Eighty-nine pediatric oncology nurses from one setting completed seven study questionnaires. The new scale, the Role-Related Meaning Scale, created for this study achieved a Cronbach's alpha of .83 and significant positive correlations with other study variables. Descriptive findings indicate that the nurses are moderately to highly stressed; use coping strategies frequently and effectively; have high levels of job satisfaction, organizational commitment, and group cohesion; and exhibit low intent to leave the organization. Importantly, the stress and coping components of the model did not predict role consequences. These outcomes suggest that the revised SRS model does not adequately predict role consequences in pediatric oncology nurses. A new model is proposed.

Treatment of acute myeloid leukemia (AML) is associated with substantial adverse effects, including neutropenia and infection. Viridansstreptococci (VS) are a primary cause of infection and pneumonia in patients with neutropenia. The authors determined the incidence, clinical features, and complications of VS sepsis in children receiving chemotherapy for AML.

It is well known that the Hotelling's T2 test for the significance of a mean vector is variously optimal under the assumption of multivariate normality; but is inappropriate otherwise. The assumption of mulitvariate normality is rarely satisfied since it involves joint normality in addition to marginal normality of the components. This suggests a need for robust procedures in the multivariate setting but such development is still in rudimentary stages. Mudholkar and Srivastava(1999, b) proposed the T2 test based on the vector of coordinatewise trimmed means as a robust alternative to one sample Hotelling's T2. In this paper we consider two two-sample extensions[image omitted]  and [image omitted] , of the T2 test for comparing two mean vectors. The asymptotic null distributions of the two statistics and their finite sample refinements are obtained. An extensive Monte Carlo study suggests that the two statistics provide satisfactory type I error control and have comparable power. A substantial gain in power over Hotelling's T2 when the underlying populations are heavy tailed is seen and there is very little loss in power when the populations are multivariate normal.

Survivors of childhood cancer are a growing and vulnerable population. Cure rates for pediatric cancers now exceed 60% and, by the year 2000, an estimated 1 of every 1,000 young adults will be a cancer survivor. Because this population is at increased risk for late medical and neoplastic complications that impact adversely on health-related quality of life, it is important to investigate methods to promote risk reduction by motivating survivors to practice health-promoting behaviors. With this background, we initiated a prospective, randomized, controlled feasibility study in which survivors attending a long-term follow-up clinic were randomized to receive standard care or standard care plus an educational intervention. Our objectives were to determine if the intervention would improve the survivors' knowledge about their cancer treatment and risks of late effects and increase their practice of health-protective behaviors. Since July 1995, 272 of 318 families (86%) approached about the study agreed to participate. Of these, 266 are evaluable for assessment of baseline knowledge and health behaviors. Demographic features, baseline knowledge, health perceptions and health behaviors did not differ among randomized groups. Assessment of the intervention's efficacy at changing health behaviors of survivors randomized to the intervention group will be available when the 1-year follow-up evaluations are completed for the study cohort. Our preliminary experience with this pilot study supports the feasibility of educational intervention research in a specialty clinic dedicated to monitoring long-term childhood cancer survivors. Int. J. Cancer Suppl. 12:138–142, 1999. ©1999 Wiley-Liss, Inc.

The non-Hodgkin's lymphoma (NHL) subset commonly referred to as large cell lymphoma (LCL) has historically been characterized by its marked cytological, immunological, and clinical heterogeneity. One potential defining feature of these lymphomas, the t(2; 5)(p23; q35), occurs in 25% to 30% of anaplastic LCLs and is also found in cases with diffuse large cell or immunoblastic morphology. We recently identified nucleophosmin (NPM ) and anaplastic lymphoma kinase (ALK ) as the genes on chromosomes 5 and 2, respectively, that are juxtaposed by this translocation. To provide a complementary approach to the use of classical cytogenetics or polymerase chain reaction-based methods for the detection of this abnormality, we have developed a two-color fluorescent in situ hybridization (FISH) assay for the t(2; 5) that may be used for the analysis of both interphase nuclei and metaphase chromosomes. Three overlapping chromosome 5 cosmid clones located immediately centromeric to the NPM gene locus and an ALK P1 clone located telomeric to the chromosome 2 breakpoint were labeled with digoxigenin or biotin, respectively, and used to visualize the derivative chromosome 5 produced by the t(2; 5), evident as juxtaposed or overlapping red and green fluorescent signals. This NPM-ALK FISH assay was initially validated by analysis of a series of cytogenetically characterized cell lines, with the presence of the der(5) chromosome showed specifically only in those lines known to contain the t(2; 5). The assay was then applied in a blinded fashion to a series of eight cytogenetically t(2; 5)-positive clinical specimens and seven known t(2; 5)-negative cases, including three NHL and four Hodgkin's disease biopsy samples. Whereas the t(2; 5)-negative cases were negative by FISH, all eight t(2; 5)-positive cases were positive. One additional case, initially thought to be positive for the translocation by cytogenetics, was proven to not be a classic t(2; 5) by interphase and metaphase FISH. These data indicate that the FISH assay described is a highly specific and rapid test that should prove to be a useful adjunct to the currently available methods for detection of the t(2; 5).

Epstein-Barr virus (EBV) causes potentially lethal immunoblastic lymphoma in up to 25% of children receiving bone marrow transplants from unrelated or HLA-mismatched donors. Because this complication appears to stem from a deficiency of EBV-specific cytotoxic T cells, we assessed the safety and efficacy of donor-derived polyclonal (CD4+ and CD8+) T-cell lines as immunoprophylaxis and treatment for EBV-related lymphoma. Thirty-nine patients considered to be at high risk for EBV-induced lymphoma each received 2 to 4 intravenous infusions of donor-derived EBV-specific T lymphocytes, after they had received T-cell–depleted bone marrow from HLA-matched unrelated donors (n = 33) or mismatched family members (n = 6). The immunologic effects of this therapy were monitored during and after the infusions. Infused cells were identified by detection of the neo marker gene. EBV-specific T cells bearing theneo marker were identified in all but 1 of the patients. Serial analysis of DNA detected the marker gene for as long as 18 weeks in unmanipulated peripheral blood mononuclear cells and for as long as 38 months in regenerated lines of EBV-specific cytotoxic T cells. Six patients (15.5%) had greatly increased amounts of EBV-DNA on study entry (>2,000 genome copies/106 mononuclear cells), indicating uncontrolled EBV replication, a complication that has had a high correlation with subsequent development of overt lymphoma. All of these patients showed 2 to 4 log decreases in viral DNA levels within 2 to 3 weeks after infusion and none developed lymphoma, confirming the antiviral activity of the donor-derived cells. There were no toxic effects that could be attributed to prophylactic T-cell therapy. Two additional patients who did not receive prophylaxis and developed overt immunoblastic lymphoma responded fully to T-cell infusion. Polyclonal donor-derived T-cell lines specific for EBV proteins can thus be used safely to prevent EBV-related immunoblastic lymphoma after allogeneic marrow transplantation and may also be effective in the treatment of established disease. © 1998 by The American Society of Hematology.

OBJECTIVE: To determine the frequency and nature of sexual dysfunction, as well as its response to medications, in a sample of patients with multiple sclerosis (MS). DESIGN: Retrospective and prospective survey of 65 female and 36 male patients with MS. RESULTS: Sixty-three percent of patients reported that they had less sexual activity, and 35% said that they had less interest in lovemaking than before their diagnosis of MS. Fifty-seven patients reported that they had problems with sexual dysfunction. Sexual dysfunction preceded the diagnosis of MS in only 10 of these patients. A higher percentage of men (78%) than women (45%) reported that they experienced sexual dysfunction (P=.002). Men had prominent erectile dysfunction, women had problems with vaginal lubrication, and both sexes had problems with decreased sensation and achieving orgasm. The presence of sexual dysfunction was associated with the presence of urinary problems (P=.02) and with a history of treatment of (P=.04) or a current report of (P=.02) depression. No association could be found between sexual dysfunction and duration of disease, type of disease, disability score, or presence of fatigue. Twenty of 57 patients with sexual dysfunction reported that they had associated marital problems. Forty-three of 60 patients who discussed sexual problems with their spouses and four of six who tried formal counseling found it helpful. Surprisingly, corticosteroid treatments that were started for problems other than sexual dysfunction resulted in improved sexual functioning in many patients. CONCLUSIONS: Sexual dysfunction is common in patients with MS. Determining the frequency and nature of problems allows issues of sexual dysfunction to be addressed as part of comprehensive care of patients with MS and suggests treatments that could improve their quality of life.

Descriptive statistics such as means, standard deviations and quantiles are often the only records retained for long-term use from an exploratory, or otherwise, analyses of data. The problem of comparing locations of two populations with comparable dispersions on the basis of such records alone is addressed in this note. We construct analogues of the pooled t statistics by studentizing difference between two quick estimators such as trimeans, and Gastwirth estimators, using ranges of quantiles constituting the statistics. The null distributions of these statistics are then approximated by scaled Student's t distributions, and examined for validity robustness and compared with competitors. It is seen that the operating characteristics of tests based on studentized differences of quick estimators are superior to those of pooled t tests, which can also be performed on the basis of summaries, and are comparable to those of Wilcoxon-Mann-Whitney rank sum tests which require the complete data rather than the summaries.

Despite numerous studies investigating the action of c-mpl ligand, no reports have defined the in vivo changes in megakaryocytopoiesis in response to a single injection of this cytokine. Here we compare the kinetics of the megakaryocytopoietic response in C57Bl/6J mice administered 25 μg/kg or 250 μg/kg of pegylated (PEG) murine megakaryocyte growth and development factor (MGDF ) as a single intravenous injection. Megakaryocytes of mice treated with MGDF had normal ultrastructure, showing a typical distribution of the demarcation membrane system, α-granules, and other cytoplasmic organelles. Megakaryocyte ploidy, size, and frequency were markedly increased with both MGDF doses. Megakaryocyte ploidy was maximally increased from a modal value of 16N to 64N on day 3, with both doses of MGDF. Similarly, a comparable increase in megakaryocyte size occurred in the two MGDF groups. Increased megakaryocyte size was coupled to the increase in megakaryocyte ploidy, and no evidence for independent regulation of megakaryocyte size within individual ploidy classes was apparent. In contrast to megakaryocyte ploidy and size, the increase in megakaryocyte frequency was markedly different with the two doses of MGDF. The proportion of 2N and 4N cells was increased from a baseline of 0.035% to 0.430% by day 4 in mice treated with the higher dose of MGDF, but only to 0.175% in mice administered 25 μg/kg of MGDF. The marked increase in the pool of these immature megakaryocytes translated to a sustained elevation in the frequency of polyploid megakaryocytes (8N cells and greater). In contrast to the sustained increase in the frequency of polyploid cells, the level of polyploidization was downregulated on days 6 to 10, but normalized by day 14. We conclude that a single injection of MGDF is able to expand the megakaryocytic pool in a dose-dependent manner, which, with subsequent maturation, should lead to an increased rate of platelet production.

The assumption of multivariate normality is a common prac-tice in the analyses of multivariate data. But it is rarely verified, in part, because of the lack of simple and easy to use test proce-dures to detect such violations. In this paper we decompose the problem of testing the hypothesis of multivariate normality into component problems of testing univariate normality. These prob-lems are then solved using the well known W-test due to Shapiro and Wilk (1965). The operating characteristics of the new test procedures are evaluated and compared with Zp test due to Mud-holkar, McDermott, and Srivastava (1992) and [image omitted]  test due to Mardia and Foster (1983). An extensive simulation study demon strates that the new test procedures have excellent type I error control for samples of size as small as 20 and have superior power properties as compared to their competitors.

Yuen and Dixon (1973) proposed a two sample homoscedastic extension of the trimmed-t statistic given by Tukey and McLaughlin (1963). In this paper, their problem is reconsidered and an alternative statistic together with an approximation to its distribution is proposed. By developing a scheme for pooling the estimated variances of the trimmed means, a pooled two sample t statistic is constructed, and the asymptotic theory and empirical evidence from a Monte Carlo experiment are used to obtain and approximation to its null distribution. The power properties of the resulting test are studied.

Relapse in acute myeloid leukemia (AML) following intensive chemotherapy bears a bad prognosis. We treated 18 children with relapsed AML on two separate protocols that included continuous infusion (CI) of cytosine arabinoside (ara-C) (total dose 4gr-6gr/m2) over 96120 hours. In an attempt to increase the fraction of blasts in S-phase and render them more sensitive to cell-cycle specific agents such as ara-C, 10 patients received Smcg/kg rhG-CSF twice daily beginning 48 hours before and continuing through the duration of the CI ara-C (POG #9192 study). The percentage of cells is S phase before and after G-CSF administration was determined. In a second group of patients (n = 8) who received ara-C alone, endogenous concentrations of G-CSF and serial blood counts were measured (St Jude's R4 study). The rationale of the St Jude's R4 was to optimize the schedule of the second course of ara-C at a time when the patient's endogenous G-CSF concentration was increased and thus maximize the percent of cells captured in S phase.Four out of 8 patients receiving CI ara-C alone and 4 out of 10 patients receiving CI ara-C with rhG-CSF achieved a complete remission (CR) after 1 cycle of therapy. Four patients in CR underwent marrow transplantation (2 allogeneic and 2 autologous). Cell cycle analysis of blast cells cultured in vitro with or without G-CSF showed a two fold increase in the percentage of cells in S phase (P = 0.03) whereas cells obtained from patients before and after G-CSF administration showed no difference in cell cycling. Correlation between G-CSF concentrations and ANC showed a negative association indicating that the regulatory mechanisms for G-CSF production remained intact. In our relatively small series, CI ara-C achieved a CR rate of 44% with rhG-CSF having no effect on the remission rate. Although in vitro rhG-CSF increased the percentage of blasts in S phase significantly, in vivo effects were not observed. Larger studies with combinations of different hematopoietic growth factors and cell-cycle active drugs are needed to evaluate the role of these cytokines in the therapy of recurrent AML.

(Abstracted from J Clin Endocrinol Metab2017;102:2242–2250)Survivors of childhood cancer are at an increased risk of premature ovarian insufficiency (POI) because of the vulnerability of the ovaries to pelvic radiotherapy, alkylating agent chemotherapy, and other gonadotoxic treatment modalities. Although POI can occur early, during, or immediately following cancer treatment completion, it more commonly develops in the years following completion of cancer treatment but prior to age 40 years.

No relevant conflicts of interest to declare.

Staphylococcus aureus is an important cause of blood stream infections in children and adults. In recent years, new strains of methicillin-resistant S. aureus (MRSA), also known as community-acquired (CA)-MRSA have been isolated from otherwise healthy individuals. These strains frequently carry the Panton-Valentine Leukocidin (PVL) leukotoxin and belong to spa type 8; USA300 genotype, which is the most common strain causing CA-MRSA infections in the U.S. The clinical course of infections with PVL-positive S.aureus strains appears to be more severe than infection from PVL-negative strains. Bacteremia due to these strains has been reported in children, adolescents and adults. It is not known if methcillin-resistance or infection with CA-MRSA strains adversely affects outcome in children with cancer. Colonization of MRSA in healthy children has increased significantly since 2001 and has shown to be a risk factor for subsequent infection. However the prevalence of nasal and rectal colonization with MRSA; in particular with PVL-positive strains and the relationship between colonization and infection is not known in children or adults with cancer.The epidemiology of MRSA and methicillin-sensitive S.aureus (MSSA) bacteremia and prevalence of MRSA nasal and rectal colonization in children with cancer was retrospectively studied from 2000 to 2007. Medical record review included patient demographics, underlying disease and antimicrobial susceptibility patterns of the MRSA and MSSA bacteremia isolates. Molecular typing was performed by polymerase chain reaction (PCR) on all isolates for detection of the PVL genes. Staphylococcus cassette chromosome (SCC) mec and spa typing was performed on all PVL-positive MRSA and MSSA bacteremia isolates and MRSA isolates causing colonization and infection. Demographic and treatment variables were compared between patients with MRSA and MSSA bacteremia and patients with PVL-positive and PVL-negative MRSA and MSSA bacteremia using exact two-sample Wilcoxon rank sum test or robust rank sum test for unequal variances and Fisher's exact chi-square test. The trend of MRSA/MSSA bacteremia and MRSA colonization was evaluated by logistic regression models.Ten (19%) MRSA and 42 (81%) MSSA isolates from clinically distinct infectious bacteremic episodes were collected from 52 patients with cancer during the eight year study period. The proportion of cancer patients with MRSA, or MSSA bacteremia did not change significantly over the duration of the study. A third of the patients, 17 (33%), had complications. Thirty-eight (73%) of the bacteremic episodes were catheter-related. Catheters were removed significantly more often for MRSA infections than for MSSA infections for persistently positive blood cultures or complications (p=0.003). Subcutaneous ports was removed significantly more often than Hickman catheters (p= 0.005). The number of patients with persistently positive MRSA bacteremia were higher as compared to MSSA bacteremia (p= 0.004). Methicillin resistance was associated with decreased susceptibility to erythromycin (p=0.0003) and gentamicin (p=0.03). The difference in PVL positivity between MRSA and MSSA was statistically significant (P=0.01). None of the other variables studied including complications were significantly different between patients with MRSA or MSSA bacteremia or between patients with PVL-positive and PVL-negative S.aureus bacteremia. The number of patients colonized with MRSA compared to the total number of samples tested increased significantly between 2000-2001 and 2006-2007 (p=0.0007). PVL-positivity was associated both with increased colonization (p=0.004) and with an increased risk of infection (p=0.0005). There was a discordance in the spa types between the colonization and infection isolates.This report represents the first description of the epidemiology of S.aureus bacteremia and colonization including analysis of PVL-positive strains in children with cancer. Methicillin-resistance or PVL-positivity did not appear to be associated with a worse outcome in our patient population. The number of patients colonized with MRSA increased significantly during this time period. PVL-positivity was associated with an increased risk of colonization and infection. Further studies are needed to confirm these observations in patients with cancer.No relevant conflicts of interest to declare.

Abstract 3666

Allogeneic hematopoietic stem cell transplantation (HSCT) is used to treat children with non-malignant disorders. As the number of survivors of non-malignant disorders after allogeneic HCST rises, monitoring late sequelae becomes increasingly important. However, no studies have solely targeted this population especially on pulmonary function. We therefore performed a long-term prospective study of pulmonary function in 38 pediatric survivors of non-malignant disorders after allogeneic HCST, including aplastic anemia (n = 15), sickle cell anemia (n = 13), immunodeficiency syndromes (n = 8), Hurler syndrome (n = 1), and osteopetrosis (n = 1). A total of 260 pulmonary function tests were conducted on the patients. Older age of recipients was associated with poorer pulmonary function; lower ratio of forced expiratory volume in 1 second and forced vital capacity (FEV1/FVC; p < 0.0001); lower percent predictives in FEV1 (p = 0.0178), forced expiratory flow (FEF25–75%; p < 0.0001), FVC (p = 0.0299), and diffusion capacity corrected for hemoglobin (DLCOcorr; p = 0.0079); higher ratio of residual volume and total lung capacity (RV/TLC; p = 0.0193); and higher percent predictives in RV (p = 0.0308) and functional residual capacity (FRC; p = 0.0489). The following percent predictive values declined over time (median follow-up: 8 years): FEF25–75% (p = 0.0064), RV (p = 0.0134), FRC (p = 0.003), FVC (p = 0.0004), TLC (p = 0.0248), and DLCOcorr (p = 0.0077). Also, busulfan use was associated with lower FEV1 (p = 0.026), FVC (p = 0.0194), and DLCOcorr (p = 0.0105). This study underscores the need to monitor risk-adapted long-term lung function and provide early interventions in this vulnerable population, especially for those who received HSCT at an older age or had been administered busulfan.

Background: Staphylococcus aureus is one of the most prevalent organisms isolated from children and adults with cancer. Strains of methicillin resistant S. aureus (MRSA) have emerged in the past decade, that often cause serious infections, in young, otherwise healthy people. Suppurative skin infections and necrotizing pneumonias are some of the diseases most characteristically associated with these new strains. Such MRSA isolates often harbor the Panton-Valentine Leukocidin (PVL) gene, belong to pulsed-field type USA 300, carry the staphylococcal cassette chromosome (SCC) mec IV, and are susceptible to clindamycin. The presence of the PVL gene has been associated with increased virulence and morbidity in these patients. However, the role of these new MRSA strains in causing infections in children and adults with cancer is presently unknown. Studies are needed to determine if the increase in incidence of MRSA infections in the community is paralleled by an increase in MRSA infections in pediatric cancer patients and if infections with these new strains are more virulent in this population. Methods: The present work represents a retrospective study of all children with cancer diagnosed with MRSA infection over an eight year period from January 2000 to December 2007. Medical record review included patient demographics, underlying disease, and antimicrobial susceptibility patterns of MRSA isolates. Genotyping of isolates was performed using PCR for detection of the PVL gene. SCC mec and spa typing was performed on all PVL positive isolates. Logistic regression models were used to study the trend in the increase of MRSA infection over time. Statistical analysis was performed on frequency data between the different categorical variables among the PVL positive and PVL negative MRSA isolates by the Exact Pearson Chi-square test. Results: A total of 98 clinical MRSA isolates were collected from 88 children with cancer from Jan 2000 to Dec 2007. The number of MRSA isolates increased sevenfold from 3 in 2000 to 21 in 2006 (p<0.0001). During the same period there was a significant decrease in the incidence of methicillin-sensitive S. aureus (MSSA) isolates (p<0.0001). Ten of the children had recurrent infection. The increase in MRSA infections was predominantly due to an increase in skin and soft tissue infections (p=0.0004). Children with African American ancestry and inpatients were significantly overrepresented in having MRSA infection as compared to other children with cancer (p<0.0001). Outcome was generally favorable; 33% had fever and only 10 patients (10%) had complications. Resistance to ciprofloxacin, clindamycin, erythromycin, gentamicin and mupirocin was 23%, 20%, 80%, 5%, and 2% respectively. All the isolates were sensitive to trimethoprim-sulfamethoxazole and vancomycin. PVL positive isolates bearing the SCC mec IV element comprised 35 of 98 (36%) of MRSA isolates. 32 of the 35 isolates belonged to the USA 300 type. No child had a recurrent infection with a PVL positive strain. Children infected with PVL positive strains had a significantly higher incidence of skin and soft tissue infections (SSTI, p=0.045), and bacteremia (p=0.045), as compared to children with PVL negative strains. A significantly higher number of the PVL positive isolates were susceptible to clindamycin (p=0.0158) and ciprofloxacin (p=0.0045). Conclusion: This report represents the first description of the changing epidemiology of MRSA infections in children with cancer. The association between PVL positive MRSA infections and bacteremia is a novel finding in this population. PVL positive MRSA infections caused low morbidity and mortality in these immune-suppressed patients. Future studies may determine if patients with colonization from these virulent strains may benefit from preemptive therapy with mupirocin, to eradicate colonization. This approach may reduce the risk of bacteremia in high risk groups such as patients undergoing hematopoietic stem cell transplantation prior to engraftment.

Haploidentical hematopoietic stem cell transplantation (HaploHSCT) from a mismatched family member (MMFM) donor offers an alternative option for patients who lack an HLA-matched donor. The main obstacles to successful haploidentical hematopoietic stem cell transplantation from a mismatched family member donor are delayed immune reconstitution, vulnerability to infections, and severe graft-versus-host disease (GvHD). Method: We designed a reduced-intensity conditioning regimen that excluded total body irradiation and anti-thymocyte globulin. The graft was immunomagnetically depleted of CD3+ T-cells (CD3 negative selection) and contained a large number of both CD34+ and CD34- stem cells and most other immune cells especailly NK cells. This protocol was used to treat 22 pediatric patients with refractory hematologic malignancies. Results and Discussion: After transplantation, 91% of the patients achieved full donor chimerism. They also showed rapid recovery of CD3+ T-cells, T-cell receptor excision circle counts, TCRß repertoire diversity and NK-cells during first four months post-transplantation. The incidence and extent of viremia were limited and no lethal infection was seen. Only 9% of patients had grade 3 acute GvHD, while 27% patients had grade 1 and another 27% had grade 2 acute GvHD. This well-tolerated regimen appears to accelerate immune recovery and shorten the duration of early post-transplant immunodeficiency, thereby reducing susceptibility to viral infections. Rapid T-cell reconstitution, retention of NK-cells in the graft, and induction of low grade GvHD may also enhance the potential anti-cancer immune effect.

We offer an easy-to-use multivariate adaptation of the Lin & Mudholkar (1980) z-test of univariate normality.