Kristy Seidel

Candidemia in Allogeneic Blood and Marrow Transplant Recipients: Evolution of Risk Factors after the Adoption of Prophylactic Fluconazole

The prophylactic use of fluconazole is common in blood and marrow transplant (BMT) recipients. To evaluate how fluconazole has influenced the development of azole resistance and candidemia, weekly mouthwashings were done, and fluconazole susceptibility was determined for 1475 colonizing and invasive isolates obtained from patients undergoing BMT. Of 585 patients, 256 (44%) were colonized with Candida species during the course of BMT. Of these, 136 patients (53%) had at least 1 mouthwashing sample that yielded Candida species other than C. albicans on culture. Only 4.6% of patients developed candidemia. Overall, C. albicans was the most common colonizing isolate, but it caused only 7% of cases of candidemia. About 5% of colonizing C. albicans strains and 100% (2 of 2) invasive C. albicans strains were fluconazole-resistant. Colonization, cytomegalovirus disease, and bacteremia are risk factors for the development of candidemia. The use of prophylactic fluconazole is associated with a low incidence of candidemia and attributable mortality, despite colonization with azole-resistant Candida species in BMT recipients.

Early Adiposity Rebound and the Risk of Adult Obesity

Objective. At 5 to 6 years of age, body fatness normally declines to a minimum, a point called adiposity rebound (AR), before increasing again into adulthood. We determined whether a younger age at AR was associated with an increased risk of adult obesity and whether this risk was independent of fatness at AR and parent obesity. Design. A retrospective cohort study using lifelong height and weight measurements recorded in outpatient medical records. Setting. Group Health Cooperative of Puget Sound (GHC), a health maintenance organization based in Seattle, Washington. Participants. All 390 GHC members (and their parents) born at GHC between January 1, 1965, and January 1, 1971, who had at least one recorded adult height and weight measurement plus two visits with recorded height and weight measurements in each of three age intervals: 1.5 to 4, 4 to 8, and 8 to 16 years. Main Outcome Measures. We calculated the mean body mass index (BMI) of each subject during young adulthood (age 21 to 29 years) and the BMI of the parents when each subject was 1.5 years of age. Adult obesity was defined as a BMI ≥27.8 for males and ≥27.3 for females. Curves were fit to each subjects BMI values between ages 1.5 and 16 years, and the age and BMI at AR were calculated from these curves. Subjects were divided into tertiles of age at AR (early, middle, and late), BMI at AR, and parent BMI (heavy, medium, and lean). Results. The mean age at AR was 5.5 years, and 15% of the cohort was obese in young adulthood. Adult obesity rates were higher in those with early versus late AR (25% vs 5%), those who were heavy versus lean at AR (24% vs 4%), those with heavy versus lean mothers (25% vs 5%), and those with heavy versus lean fathers (21% vs 5%). After adjusting for parent BMI and BMI at AR, the odds ratio for adult obesity associated with early versus late AR was 6.0 (95% CI, 1.3–26.6). Conclusion. An early AR is associated with an increased risk of adult obesity independent of parent obesity and the BMI at AR. Future research should examine the biological and behavioral determinants of AR.

Tumor suppression by p27(kip1) and p21(Cip1) during chemically induced skin carcinogenesis

p27Kip1 and p21Cip1 are cyclin dependent kinase inhibitors which can arrest cell proliferation and p27 is a tumor suppressor gene. To address the mechanism of tumor suppression by p27 and to determine if p21 has a tumor suppressor phenotype, we utilized the two stage skin carcinogenesis model on p27 and p21 knockout mice. In this model, initiation, which involves mutation of H-ras induced by DMBA, can be distinguished from promotion induced by TPA, and progression to carcinoma. The mean number of papillomas did not differ between p27−/− and control littermates, but papilloma growth rate was increased and carcinomas developed earlier. Thus, p27 deficiency did not enhance initiation, but resulted in more rapid clonal expansion of initiated cells during promotion. TPA treatment reduced p27 expression in keratinocytes also supporting a role for p27 during promotion. Tumors from p27−/− mice contained mutant H-ras indicating that p27 deficiency did not substitute for mutant ras and further, that during ras driven tumor growth, p27 is partially antagonistic since its removal led to faster growth. The treated p27−/− mice also developed intestinal adenomas. p21−/− mice did not display a significant increase in tumor numbers, growth rate or progression to carcinomas and these tumors also had mutated H-ras. Carcinomas from p21−/− mice were more poorly differentiated with a high frequency of anaplastic spindle cell carcinomas. Thus p21 deficiency mainly resulted in higher grade undifferentiated tumors.

Long-Term Survival of Individuals with Myelomeningocele

The objectives of this study were to extend survival analysis into adulthood for patients with myelomeningocele (MM) and to compare survival curves for patients born with varying defect severity before and after 1975. We have reviewed existing data for 904 patients with MM seen in a large multidisciplinary children’s clinic over 43 years. Before 1975, a major contributor to decreased survival is death during infancy. The presence of cerebral spinal fluid shunting is a major contributor to increased survival. After 1975, survival to adolescence is similar regardless of shunt status (p = 0.17). For all patients alive at age 16, a significant decrease in survival probability after age 34 years was found for individuals with shunted hydrocephalus compared to those without a shunt (p = 0.03). Although childhood survival for individuals born after 1975 is not related to shunt status, adults with MM and shunted hydrocephalus may be at risk for decreased longevity.

Incidence, risk factors, and mortality from pneumonia developing late after hematopoietic stem cell transplantation

Summary:The incidence, etiology, outcome, and risk factors for developing pneumonia late after hematopoietic stem cell transplantation (SCT) were investigated in 1359 patients transplanted in Seattle. A total of 341 patients (25% of the cohort) developed at least one pneumonic episode. No microbial or tissue diagnosis (ie clinical pneumonia) was established in 197 patients (58% of first pneumonia cases). Among the remaining 144 patients, established etiologies included 33 viral (10%), 31 bacterial (9%), 25 idiopathic pneumonia syndrome (IPS, 7%), 20 multiple organisms (6%), 19 fungal (6%), and 16 Pneumocystis carinii pneumonia (PCP) (5%). The overall cumulative incidence of first pneumonia at 4 years after discharge home was 31%. The cumulative incidences of pneumonia according to donor type at 1 and 4 years after discharge home were 13 and 18% (autologous/syngeneic), 22 and 34% (HLA-matched related), and 26 and 39% (mismatched related/unrelated), respectively. Multivariate analysis of factors associated with development of late pneumonia after allografting were increasing patient age (RR 0.5 for <20 years, 1.2 for >40 years, P=0.009), donor HLA-mismatch (RR 1.6 for unrelated/mismatched related, P=0.01), and chronic graft-versus-host disease (GVHD; RR 1.5, P=0.007). Our data suggest that extension of PCP prophylaxis may be beneficial in high-risk autograft recipients. Further study of long-term anti-infective prophylaxis based on patient risk factors after SCT appear warranted.

A Double-Blind Randomized Trial Comparing Outpatient Parenteral Nutrition With Intravenous Hydration: Effect on Resumption of Oral Intake After Marrow Transplantation

BACKGROUND Outpatient parenteral nutrition (PN) is often given to marrow transplant recipients after high-dose chemoradiotherapy until the resumption of adequate oral intake; however, it may adversely prolong resumption or oral calorie intake by contributing to early satiety. METHODS A double-blind, randomized study compared standard PN (final concentration 25% dextrose, 5% amino acids) with a hydration solution (5% dextrose) during the first 28 days of outpatient treatment. Patients were eligible for the study if they were > or = 2 years of age, < 65 days posttransplant, had < 70% oral caloric intake at hospital discharge, and required < or = 10 U insulin/L PN. Solutions were provided until the patients oral intake met > or = 85% caloric requirements for 3 consecutive days. RESULTS Two hundred fifty-eight marrow transplant recipients (128, PN and 130, hydration solution) were studied. Age, donor type, and diagnoses were similar in the two groups. Time to resumption of > or = 85% oral caloric intake was 6 days sooner in the hydration group than in the PN group (median 10 vs 16 days, respectively; p = .049). When adjusting for sex, age, donor type, total body irradiation, previous oral intake, acute graft-versus-host disease, and prednisone therapy, the hydration group resumed oral intake sooner than the PN group (relative risk = 1.51; 95% confidence interval [CI] 1.04 to 2.19; p = .029). The percentage of weight change from pretransplant values, adjusted for the above covariates and the number of weeks of treatment, indicated that the hydration solution group lost weight (4.63%) compared with the PN group (1.27%) after 4 weeks of therapy (p = .004). Rates of hospital readmissions, relapse of malignancy, and survival did not differ between the two treatment groups. CONCLUSIONS We conclude that outpatient PN delays resumption of oral intake and that its replacement with hydration solution does not result in adverse patient outcome.

A Comparison of a Needle-free Injection System for Local Anesthesia Versus Emla® for Intravenous Catheter Insertion in the Pediatric Patient

Placement of IV catheters is a painful and stressful procedure for children. J-Tip® is a needle-less Food and Drug Administration approved injection system that can be used for delivery of local anesthetic before IV cannulation. In this study, we compared the effectiveness of J-Tip® versus eutectic mixture of local anesthetics (EMLA®) to facilitate IV cannulation and provide adequate analgesia before IV placement. Children 7–19 years of age (n = 116) were randomized to receive 0.25 mL of 1% buffered lidocaine with J-Tip® (n = 57) or 2.5 g of EMLA® (n = 59) before IV cannulation. Measurements of success of cannulation (number of attempts for IV placement) and pain (0–10 visual analog scale) at application of local anesthetic and at cannulation were performed. There was a significant (P = 0.0001) difference in pain ratings during IV cannulation between EMLA® (median = 3) and the J-Tip® (median = 0). Eighty-four percent of patients reported no pain at the time of J-Tip® lidocaine application compared to 61% in the EMLA® group at the time of dressing removal (P = 0.004). We did not find differences in the number of attempts for IV cannulation. J-Tip® application of 1% buffered lidocaine before IV cannulation is not painful and has better anesthetic effectiveness compared with EMLA®.

Inactive disease in polyarticular juvenile idiopathic arthritis: current patterns and associations

OBJECTIVES To describe the achievement of inactive disease (ID) and remission in polyarticular juvenile idiopathic arthritis (JIA) and to measure the associations among patient characteristics, imaging results and these outcomes. METHODS We performed a retrospective cohort study of children with polyarticular JIA diagnosed and treated at Seattle Childrens Hospital between 1 January 2000 and 31 December 2006. Each patients disease status (active disease vs ID) was determined for every clinic visit. Adjusted relative risk estimates were obtained using Mantel-Haenszel methods. RESULTS One hundred and four children were included. Patients were followed up for an average of 30 months. Patients achieved 138 episodes of ID. Fifty-one patients achieved 69 episodes of clinical remission on medication. When duration of active disease was summed over each patients follow-up, patients spent a mean of 66.3% of their follow-up with active disease. Patients with evidence of joint damage on imaging studies obtained within 6 months of their first clinic visit spent a mean of 79% of their follow-up with active disease. Patients without these findings spent a mean of 58.5% of their follow-up with active disease (P < 0.001). Children who were RF(+) and children with early evidence of joint damage tended to have a higher prevalence of active disease during the follow-up period. CONCLUSIONS In this cohort, children with polyarticular JIA spent the majority of their follow-up with active disease. Because children with early radiographic evidence of joint damage and children who were RF(+) tended to have the most active disease, improving outcomes for these subgroups may be an important goal for prospective study.

Bone marrow transplantation for severe aplastic anemia from genotypically HLA-nonidentical relatives : an update of the Seattle experience

This report updates the results of marrow transplantation at the Fred Hutchinson Cancer Research Center for patients with severe aplastic anemia whose donors were HLA-nonidentical relatives. Between 1970 and 1993, 40 patients received transplants for severe aplastic anemia from related donors other than HLA genotypically matched siblings. Nine patients (group 1) were conditioned with cyclophosphamide (Cy) at 50 mg/kg for 4 doses and received marrow from phenotypically HLA-matched relatives. With the exception of one accidental death, all patients are alive and disease free 3-18 years after transplantation. Thirty-one patients received marrow from HLA-mismatched relatives who differed by one or more loci. Fifteen of these patients (group 2) received Cy at 50 mg/kg for 4 doses without total body irradiation (TBI) and none survived. Because of failure to sustain engraftment in 9 of 14 evaluable patients in group 2, the regimen for HLA-mismatched patients was changed in 1984 to include Cy at 60 mg/kg for 2 doses and TBI was added at 1200 cGy to increase immunosuppression (group 3). Sixteen patients in group 3 received marrow grafts after failure to respond to immunosuppressive therapy. Eight of the 16 patients in group 3 remain alive without disease between 1.5 and 11.3 years after transplantation. In conclusion, transplants from phenotypically HLA-identical related donors can be carried after Cy alone and results are comparable to those observed with genotypically HLA-identical siblings. Transplants from related donors mismatched for one or more HLA loci require a more intensive conditioning regimen, for example, one containing TBI, to achieve sustained engraftment.

Scarring, Disfigurement, and Quality of Life in Long-Term Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study

PURPOSE Childhood cancer survivors are at increased risk for adverse outcomes and chronic medical conditions. Treatment-related scarring, disfigurement, and persistent hair loss, in addition to their long-term impact on psychological distress or health-related quality of life (HRQOL), have received little attention. PATIENTS AND METHODS Self-reported scarring/disfigurement and persistent hair loss were examined in 14,358 survivors and 4,023 siblings from the Childhood Cancer Survivor Study. Multivariable models were used to examine associations with demographic and cancer treatment. The impact of disfigurement and hair loss on HRQOL (ie, Medical Outcomes Short Form-36) and emotional distress (ie, Brief Symptom Inventory-18) was examined. RESULTS Survivors reported a significantly higher rate of scarring/disfigurement compared with siblings for head/neck (25.1% v 8.4%), arms/legs (18.2% v 10.2%), and chest/abdomen (38.1% v 9.1%), as well as hair loss (14.0% v 6.3%). In age-, sex-, and race-adjusted models, cranial radiation exposure ≥ 36 Gy increased risk for head/neck disfigurement (relative risk [RR], 2.42; 95% CI, 2.22 to 2.65) and hair loss (RR, 4.24; 95% CI, 3.63 to 4.95). Adjusting for cranial radiation, age, sex, race, education, and marital status, survivor hair loss increased risk of anxiety (RR, 1.60; 95% CI, 1.23 to 2.07), whereas head/neck disfigurement increased risk of depression (RR, 1.19; 95% CI, 1.01 to 1.41). Limitations due to emotional symptoms were associated with head/neck disfigurement (RR, 1.24; 95% CI, 1.10 to 1.41), arm/leg disfigurement (RR, 1.19; 95% CI, 1.05 to 1.35), and hair loss (RR, 1.26; 95% CI, 1.09 to 1.47). CONCLUSION Survivors of childhood cancer are at increased risk for disfigurement and persistent hair loss, which is associated with future emotional distress and reduced quality of life. Future studies are needed to better identify and manage functional outcomes in these patients.