Search

T cells modified to express a chimeric antigen receptor (CAR) targeting CD19 can induce potent and sustained responses in children with relapsed/refractory acute lymphoblastic leukemia (ALL). The durability of remission is related to the length of time the CAR T cells persist. Efforts to understand differences in persistence have focused on the CAR construct, in particular the costimulatory signaling module of the chimeric receptor. We previously reported a robust intent-to-treat product manufacturing success rate and remission induction rate in children and young adults with recurrent/refractory B-ALL using the SCRI-CAR19v1 product, a second-generation CD19-specific CAR with 4-1BB costimulation coexpressed with the EGFRt cell-surface tag (NCT02028455). Following completion of the phase I study, two changes to CAR T-cell manufacturing were introduced: switching the T-cell activation reagent and omitting midculture EGFRt immunomagnetic selection. We tested the modified manufacturing process and resulting product, designated SCRI-CAR19v2, in a cohort of 21 subjects on the phase II arm of the trial. Here, we describe the unanticipated enhancement in product performance resulting in prolonged persistence and B-cell aplasia and improved leukemia-free survival with SCRI-CAR19v2 as compared with SCRI-CAR19v1.

T cells modified to express a chimeric antigen receptor (CAR) targeting CD19 can induce potent and sustained responses in children with relapsed/refractory acute lymphoblastic leukemia (ALL). The durability of remission is related to the length of time the CAR T cells persist. Efforts to understand differences in persistence have focused on the CAR construct, in particular the costimulatory signaling module of the chimeric receptor. We previously reported a robust intent-to-treat product manufacturing success rate and remission induction rate in children and young adults with recurrent/refractory B-ALL using the SCRI-CAR19v1 product, a second-generation CD19-specific CAR with 4-1BB costimulation coexpressed with the EGFRt cell-surface tag (NCT02028455). Following completion of the phase I study, two changes to CAR T-cell manufacturing were introduced: switching the T-cell activation reagent and omitting midculture EGFRt immunomagnetic selection. We tested the modified manufacturing process and resulting product, designated SCRI-CAR19v2, in a cohort of 21 subjects on the phase II arm of the trial. Here, we describe the unanticipated enhancement in product performance resulting in prolonged persistence and B-cell aplasia and improved leukemia-free survival with SCRI-CAR19v2 as compared with SCRI-CAR19v1.

Supplementary Data from Modified Manufacturing Process Modulates CD19CAR T-cell Engraftment Fitness and Leukemia-Free Survival in Pediatric and Young Adult Subjects

Diffuse intrinsic pontine glioma (DIPG) remains a fatal brainstem tumor demanding innovative therapies. As B7-H3 (CD276) is expressed on central nervous system (CNS) tumors, we designed B7-H3–specific chimeric antigen receptor (CAR) T cells, confirmed their preclinical efficacy, and opened BrainChild-03 (NCT04185038), a first-in-human phase I trial administering repeated locoregional B7-H3 CAR T cells to children with recurrent/refractory CNS tumors and DIPG. Here, we report the results of the first three evaluable patients with DIPG (including two who enrolled after progression), who received 40 infusions with no dose-limiting toxicities. One patient had sustained clinical and radiographic improvement through 12 months on study. Patients exhibited correlative evidence of local immune activation and persistent cerebrospinal fluid (CSF) B7-H3 CAR T cells. Targeted mass spectrometry of CSF biospecimens revealed modulation of B7-H3 and critical immune analytes (CD14, CD163, CSF-1, CXCL13, and VCAM-1). Our data suggest the feasibility of repeated intracranial B7-H3 CAR T-cell dosing and that intracranial delivery may induce local immune activation.Significance:This is the first report of repeatedly dosed intracranial B7-H3 CAR T cells for patients with DIPG and includes preliminary tolerability, the detection of CAR T cells in the CSF, CSF cytokine elevations supporting locoregional immune activation, and the feasibility of serial mass spectrometry from both serum and CSF.This article is highlighted in the In This Issue feature, p. 1

Supplementary Data from Intraventricular B7-H3 CAR T Cells for Diffuse Intrinsic Pontine Glioma: Preliminary First-in-Human Bioactivity and Safety

Locoregional delivery of chimeric antigen receptor (CAR) T cells has resulted in objective responses in adults with glioblastoma, but the feasibility and tolerability of this approach is yet to be evaluated for pediatric central nervous system (CNS) tumors. Here we show that engineering of a medium-length CAR spacer enhances the therapeutic efficacy of human erb-b2 receptor tyrosine kinase 2 (HER2)-specific CAR T cells in an orthotopic xenograft medulloblastoma model. We translated these findings into BrainChild-01 ( NCT03500991 ), an ongoing phase 1 clinical trial at Seattle Children’s evaluating repetitive locoregional dosing of these HER2-specific CAR T cells to children and young adults with recurrent/refractory CNS tumors, including diffuse midline glioma. Primary objectives are assessing feasibility, safety and tolerability; secondary objectives include assessing CAR T cell distribution and disease response. In the outpatient setting, patients receive infusions via CNS catheter into either the tumor cavity or the ventricular system. The initial three patients experienced no dose-limiting toxicity and exhibited clinical, as well as correlative laboratory, evidence of local CNS immune activation, including high concentrations of CXCL10 and CCL2 in the cerebrospinal fluid. This interim report supports the feasibility of generating HER2-specific CAR T cells for repeated dosing regimens and suggests that their repeated intra-CNS delivery might be well tolerated and activate a localized immune response in pediatric and young adult patients. In an interim analysis of a phase 1 trial, repeated intracranial infusions of HER2-specific CAR T cells were well tolerated with no observed dose-limiting toxicities in three young adult patients with CNS tumors.

Diffuse intrinsic pontine glioma (DIPG) remains a fatal brainstem tumor demanding innovative therapies. As B7-H3 (CD276) is expressed on central nervous system (CNS) tumors, we designed B7-H3–specific chimeric antigen receptor (CAR) T cells, confirmed their preclinical efficacy, and opened BrainChild-03 (NCT04185038), a first-in-human phase I trial administering repeated locoregional B7-H3 CAR T cells to children with recurrent/refractory CNS tumors and DIPG. Here, we report the results of the first three evaluable patients with DIPG (including two who enrolled after progression), who received 40 infusions with no dose-limiting toxicities. One patient had sustained clinical and radiographic improvement through 12 months on study. Patients exhibited correlative evidence of local immune activation and persistent cerebrospinal fluid (CSF) B7-H3 CAR T cells. Targeted mass spectrometry of CSF biospecimens revealed modulation of B7-H3 and critical immune analytes (CD14, CD163, CSF-1, CXCL13, and VCAM-1). Our data suggest the feasibility of repeated intracranial B7-H3 CAR T-cell dosing and that intracranial delivery may induce local immune activation. Significance: This is the first report of repeatedly dosed intracranial B7-H3 CAR T cells for patients with DIPG and includes preliminary tolerability, the detection of CAR T cells in the CSF, CSF cytokine elevations supporting locoregional immune activation, and the feasibility of serial mass spectrometry from both serum and CSF. This article is highlighted in the In This Issue feature, p. 1

Objective: To assess crowdsourced responses in the evaluation of speech outcomes in children with velopharyngeal dysfunction (VPD). Design: Fifty deidentified speech samples were compiled. Multiple pairwise comparisons obtained by crowdsourcing were used to produce a rank order of speech quality. Ratings of overall and specific speech characteristics were also collected. Twelve speech-language pathologists (SLPs) who specialize in VPD were asked to complete the same tasks. Crowds and experts completed each task on 2 separate occasions at least 1 week apart. Setting: On-line crowdsourcing platform. Participants: Crowdsource raters were anonymous and at least 18 years of age, North American English speakers with self-reported normal hearing. Speech-language pathologists were recruited from multiple cleft/craniofacial teams. Interventions: None. Main Outcome Measure(s): Correlation of repeated assessments and comparison of crowd and SLP assessments. Results: We obtained 6331 lay person assessments that met inclusion criteria via crowdsourcing within 8 hours. The crowds provided reproducible Elo rankings of speech quality, ρ(48) = .89; P Conclusions: Crowdsourcing shows promise as a rapid way to obtain large numbers of speech assessments. Reliability of repeated assessments was acceptable. Large groups of naive raters yield comparable evaluations of overall speech acceptability, intelligibility, and quality, but are not consistent with expert raters for specific speech characteristics such as resonance and nasal air emission.

Background: Outcomes for relapsed osteosarcoma (OS) remain poor and there are no systemic therapies that have been shown to provide a survival benefit. Chimeric Antigen Receptor (CAR) T cell immunotherapy involves the adoptive transfer of T-lymphocytes that have been engineered to recognize tumor-specific antigens, resulting in targeted lysis of malignant cells. Folate receptors (FR) are membrane-bound surface proteins that bind folates with high affinity. FRs are overexpressed in OS and have very limited expression in normal tissue. UB-TT170 (Umoja Biopharma) is a small molecule bispecific “adapter” consisting of folate conjugated to fluorescein (FL). It penetrates tumors in minutes and is retained for long periods of time due to high affinity for the FR, while unbound UB-TT170 rapidly clears from the blood and from FR- tissues. We hypothesize that administration of fixed dosing anti-FL(FITC-E2) CAR T cells followed by escalating doses of UB-TT170 will deliver personalized immunotherapy to OS patients. In addition, this approach offers an attractive safety mechanism since administration of NaFL should reverse CAR T cell reactivity. Methods: We designed a Phase I study for young adult (15-30 yr) patients with recurrent/refractory OS to examine the safety and feasibility of administering autologous, peripheral blood-derived T cells that have been genetically modified to express a 2nd generation FL-specific CAR in combination with intra-subject dose escalation of UB-TT170. The primary objective is to identify a recommended dose escalation sequence of UB-TT170 to move forward in clinical development. A 3+3 design will be used to investigate 3 possible dosing sequences. The trial opened in July 2022. As of January 5, 2023, 5 subjects have enrolled and one subject has been treated on dose regimen 1. T cell products have been successfully manufactured for all enrolled subjects. The trial remains open to enrollment. Clinical trial registration numbers: NCT05312411 Citation Format: Catherine M. Albert, Navin R. Pinto, Mallory Taylor, Ashley Wilson, Stephanie Rawlings-Rhea, Prabha Narayanaswamy, Wenjun Huang, Kristy Seidel, Stephanie Mgebroff, Christopher Brown, Jacob Garcia, Jeffrey Teoh, Rimas J. Orentas, Rebecca A. Gardner, Michael C. Jensen, Julie R. Park. ENLIGHTen-01: a phase 1 study of fluorescein-specific (FITC-E2)-car T cells in combination with folate-fluorescein (UB-TT170) for osteosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT137.

Background: B7-H3 expression on central nervous system (CNS) tumors offers a potential therapeutic target for adoptive cellular therapy. Methods: A 3+3 statistical design was employed to assess the safety of repeated B7-H3 chimeric antigen receptor (CAR) T cells administered into the intracranial ventricular system (ICV) using an intrapatient dose escalation without lymphodepleting chemotherapy in pts 1-26 years of age with recurrent/refractory CNS tumors including (non-pontine) diffuse midline glioma (DMG) (NCT04185038, Arm B). Primary endpoints were feasibility to manufacture sufficient CARs and safety of weekly infusions for 3 weeks of 4-week cycles for 2 cycles. Secondary endpoints were best overall response (BOR) and correlatives of CAR activity. Results: CAR manufacturing was achieved in 20/22 (91%) enrolled pts. Eight pts were inevaluable (rapidly progressive exam precluding initial infusion (n=5), removal from protocol therapy due to progressive disease (n=2), and lack of evaluable disease prior to initial infusion (n=1)). No dose limiting toxicities were observed, identifying the maximally tolerated dose regimen (MTDR) as DR3 (maximum dose: 10 × 107 B7-H3CARs). Subjects received 98 ICV doses (median: 6 doses/patient, range: 3-13). For evaluable patients, the most common adverse events were headache (12/12, 100%), fatigue (9/12, 75%), nausea/vomiting (7/12, 58%), and fever (6/12, 50%). There was no cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS). Imaging analysis is ongoing with current BOR being stable disease. CAR T cells were detected in the CSF in 9/12 evaluable pts (75%). Serial CSF/serum cytokine analysis and mass spectrometry are in process. Conclusion: Repeated ICV administration of B7-H3 CAR T cells is tolerable with circulating CAR T cells detectable in the CSF post infusion. Further investigation is warranted, along with future studies interrogating iterative enhancements such as modifications for enhanced potency and multi-antigen targeting. Citation Format: Nicholas A. Vitanza, Juliane Gust, Rebecca Ronsley, Ashley L. Wilson, Wenjun Huang, Kristy Seidel, Catherine M. Albert, Navin Pinto, Rimas J. Orentas, Rebecca A. Gardner, Michael C. Jensen, Julie R. Park. BrainChild-03: Intraventricular B7-H3 CAR T cells for recurrent/refractory central nervous system tumors and non-pontine diffuse midline glioma in children and young adults [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB121.

Serious chronic medical conditions occur in childhood cancer survivors. We aimed to investigate incidence of and risk factors for end-organ damage resulting in registration on a waiting list for or receiving a solid organ transplantation and 5-year survival following these procedures.The Childhood Cancer Survivor Study (CCSS) is a retrospective cohort of individuals who survived at least 5 years after childhood cancer diagnosed at younger than 21 years of age, between Jan 1, 1970, and Dec 31, 1986, at one of 25 institutions in the USA. We linked data from CCSS participants treated in the USA diagnosed between Jan 1, 1970, and Dec 31, 1986 (without solid organ transplantation before cohort entry) to the Organ Procurement and Transplantation Network-a database of all US organ transplants. Eligible participants had been diagnosed with leukaemia, lymphoma, malignant CNS tumours, neuroblastoma, Wilms' tumours, and bone and soft tissue sarcomas. The two primary endpoints for each type of organ transplant were date of first registration of a transplant candidate on the waiting list for an organ and the date of the first transplant received. We also calculated the cumulative incidence of being placed on a waiting list or receiving a solid organ transplantation, hazard ratios (HRs) for identified risk factors, and 5-year survival following transplantation.Of 13 318 eligible survivors, 100 had 103 solid organ transplantations (50 kidney, 37 heart, nine liver, seven lung) and 67 were registered on a waiting list without receiving a transplant (21 kidney, 25 heart, 15 liver, six lung). At 35 years after cancer diagnosis, the cumulative incidence of transplantation or being on a waiting list was 0·54% (95% CI 0·40-0·67) for kidney transplantation, 0·49% (0·36-0·62) for heart, 0·19% (0·10-0·27) for liver, and 0·10% (0·04-0·16) for lung. Risk factors for kidney transplantation were unilateral nephrectomy (HR 4·2, 95% CI 2·3-7·7), ifosfamide (24·9, 7·4-83·5), total body irradiation (6·9, 2·3-21·1), and mean kidney radiation of greater than 15 Gy (15-20 Gy, 3·6 [1·5-8·5];20 Gy 4·6 [1·1-19·6]); for heart transplantation, anthracycline and mean heart radiation of greater than 20 Gy (dose-dependent, both p0·0001); for liver transplantation, dactinomycin (3·8, 1·3-11·3) and methotrexate (3·3, 1·0-10·2); for lung transplantation, carmustine (12·3, 3·1-48·9) and mean lung radiation of greater than 10 Gy (15·6, 2·6-92·7). 5-year overall survival after solid organ transplantation was 93·5% (95% CI 81·0-97·9) for kidney transplantation, 80·6% (63·6-90·3) for heart, 27·8% (4·4-59·1) for liver, and 34·3% (4·8-68·6) for lung.Solid organ transplantation is uncommon in ageing childhood cancer survivors. Organ-specific exposures were associated with increased solid organ transplantation incidence. Survival outcomes showed that solid organ transplantation should be considered for 5-year childhood cancer survivors with severe end-organ failure.US National Institute of Health, American Lebanese Syrian Associated Charities, US Health Resources and Services Administration.

10011 Background: B7H3 (CD276) has limited expression in normal tissues and high cell-surface expression in pediatric solid malignancies providing rationale for immunologic therapeutic targeting. We present a first-in-human experience of B7H3 chimeric antigen receptor T cells (CAR-T) for children and young adults (CYA) with relapsed or refractory solid tumors (R/RST). Methods: CYA patients with R/RST were enrolled onto a Phase 1 trial (NCT04483778) to examine the safety of autologous T cells genetically modified to express scFV-IgG4hinge-CD28tm-4-1BB-zeta B7H3-specific CAR with the methotrexate resistance/selection cassette DHFRdm and the tracking/suicide construct EGFRt. All patients received lymphodepleting fludarabine and cyclophosphamide prior to infusion of cryopreserved CAR-T at the prescribed dose level. The maximal tolerated dose or biologically effective dose (BED) was determined based upon observed toxicity through day 28 from initial CAR-T infusion and using a 3+3 statistical design. Results: Sixteen subjects (age 11-24, median 17 years) enrolled and received dose level (DL) 1 (0.5 x 106 CAR-T/kg, n = 3) or DL2 (1 x 106 CAR-T cells/kg, n = 6). No dose limiting toxicity was observed following first infusion, most common toxicities were fatigue and cytokine release syndrome (CRS) (n = 2, maximum CTCAE grade 2). Maximum circulating CAR-T expansion on first infusion was 4.98 cells/uL (range 0.23-4.98 cells/uL) with median persistence of 28 days (range 14-90). Best overall response of Stable Disease was observed in 3 of the 9 subjects infused. Given observed expansion and persistence, DL2 was determined to be the BED. A second infusion at DL2 in one subject demonstrated CAR T expansion to 1590 cells/uL (86% of circulating CD3 cells) with CTCAE grade 2 CRS and transient dose limiting CTCAE grade 4 liver enzyme elevation. A partial metabolic response on FDG-PET by PERCIST criteria was observed in this subject at Day 28. Conclusions: B7H3 CAR T cells are safe and demonstrate anti-tumor activity in CYA with R/RST. CAR-T cell expansion and persistence may be necessary to achieve objective responses. STRIvE-02 Arm B will explore dual expression of CD19 CAR with B7H3 CAR, using lymphocytic CD19 expression to drive CAR expansion and persistence. Clinical trial information: NCT04483778.

2541 Background: The epidermal growth factor receptor (EGFR) is a cell surface tyrosine kinase receptor associated with cell proliferation and differentiation. EGFR expression and activating mutations are associated with aggressive neoplastic disease, chemotherapy resistance, and increased metastatic potential. Published data and EGFR immunohistochemistry (IHC) performed on tissue microarrays indicate that 15-40% of pediatric solid tumors (ST) express EGFR. The unique EGFR monoclonal antibody (mAb) 806 selectively binds to an epitope that is conformationally hidden when EGFR is tethered but revealed when tethering is perturbed as occurs with EGFR overexpression, truncation, or through extra-cellular domain missense mutations. Methods: Children and young adults (CYA) with EGFR-expressing recurrent/refractory (R/R) ST were enrolled on a Phase 1 trial to examine the safety and feasibility of administering autologous chimeric antigen receptor (CAR) T cells derived from autologous T cells genetically modified to express a second generation EGFR806-specific scFV-IgG4hinge-CD28tm/cyto-4-1-BB-zeta and EGFRt tracking/suicide contract. All subjects received lymphodepleting chemotherapy with fludarabine and cyclophosphamide prior to the administration of cryopreserved CAR T cells a the prescribed dose level. The biologically effective dose (BED) or maximum tolerated dose was determined based upon observed toxicity through day 28 from initial CAR-T infusion and using a 3+3 statistical design. Results: Eleven subjects (n=10 evaluable, age range 9-25, median 18) were enrolled and received either dose level (DL) 1 (0.5 x 106 CAR-T/kg, n=4) or DL2 (1 x 106 CAR-T cells/kg, n=7). CAR T were manufactured successfully in all subjects. Most common toxicities were fatigue, tumor-related pain and cytokine release syndrome (n=2, maximum CTCAE grade 1). Dose limiting toxicity of CTCAE grade 4 transaminase level and hyperbilirubinemia occurred at DL2 (n=1). Maximum circulating CAR-T expansion was 29.66 cells/uL (range 0.05-29.66 cells/uL) with median persistence of 28 days (range 0-90). Two subjects on DL1 and one subject on DL2 demonstrated mixed response on day 28 and tolerated additional CAR T infusion without dose limiting toxicity. Conclusions: EGFR806 directed CAR-T cells have an acceptable toxicity profile in CYA with R/RST and demonstrate anti-tumor activity in some patients. Additional analyses are ongoing to identify biomarkers of response and toxicity. Clinical trial information: NCT03618381.

Locoregional delivery of chimeric antigen receptor (CAR) T cells has resulted in objective responses in adults with glioblastoma, but the feasibility and tolerability of this approach is yet to be evaluated for pediatric central nervous system (CNS) tumors. Here we show that engineering of a medium-length CAR spacer enhances the therapeutic efficacy of human erb-b2 receptor tyrosine kinase 2 (HER2)-specific CAR T cells in an orthotopic xenograft medulloblastoma model. We translated these findings into BrainChild-01 ( NCT03500991 ), an ongoing phase 1 clinical trial at Seattle Children's evaluating repetitive locoregional dosing of these HER2-specific CAR T cells to children and young adults with recurrent/refractory CNS tumors, including diffuse midline glioma. Primary objectives are assessing feasibility, safety and tolerability; secondary objectives include assessing CAR T cell distribution and disease response. In the outpatient setting, patients receive infusions via CNS catheter into either the tumor cavity or the ventricular system. The initial three patients experienced no dose-limiting toxicity and exhibited clinical, as well as correlative laboratory, evidence of local CNS immune activation, including high concentrations of CXCL10 and CCL2 in the cerebrospinal fluid. This interim report supports the feasibility of generating HER2-specific CAR T cells for repeated dosing regimens and suggests that their repeated intra-CNS delivery might be well tolerated and activate a localized immune response in pediatric and young adult patients.

Background The objective of the current study was to characterize and identify factors associated with perceptions of risk of infertility among adult male survivors of childhood cancer. Methods A total of 1233 adult male survivors from the Childhood Cancer Survivor Study who were without a history of disease recurrence or subsequent malignancy reported their perceptions of their risk of infertility compared with men never diagnosed with cancer. Survivors were a median age of 37.8 years (range, 22.0-58.7 years) and were 28.4 years from their diagnosis (range, 21.4-39.2 years). Multivariable logistic regression evaluated factors associated with perceptions of risk. Results Overall, 35.9% of the survivors (443 of 1233 survivors) reported perceptions of their risk of infertility that were discordant with their actual risk based on previous cancer treatment exposures. Discordant perceptions were equally common among men exposed to gonadotoxic therapies (36.3%; 311 of 857 men) and those with no history of gonadotoxic exposure (35.1%; 132 of 376 men). Survivors who fathered children (odds ratio [OR], 4.14; 95% confidence interval [95% CI], 2.74-6.24), had no survivor-focused health care (OR, 3.07; 95% CI, 1.57-5.99), were nonwhite (OR, 2.28; 95% CI, 1.10-4.75), and were of lower income were more likely to report no increased risk of infertility after gonadotoxic treatment. Perceptions of increased risk of infertility among men with no history of gonadotoxic treatment were predicted by never having fathered a child (OR, 1.88; 95% CI, 1.17-3.03), recent participation in survivor-focused health care (OR, 2.11; 95% CI, 1.01-4.42), and higher educational achievement. Conclusions Many male survivors of childhood cancer are unaware of how their cancer treatments could impact their reproductive health, underscoring the need for all patients to receive education regarding their risk of infertility throughout the continuum of cancer care. Cancer 2018;124:2447-55. © 2018 American Cancer Society.

Background Survivors of childhood central nervous system (CNS) tumors experience high rates of treatment-related neurologic sequelae. Whether survivors continue to be at increased risk for new events as they age is unknown. Methods Adverse neurologic health conditions in 5-year survivors of CNS tumors from the Childhood Cancer Survivor Study (n = 1876) were evaluated longitudinally at a median 23.0 years from diagnosis (range, 5.1-38.9), median age at last evaluation 30.3 years (range, 6.1-56.4). Multivariable regression estimated hazard ratios (HRs) and 95% CIs. Results From 5 to 30 years post diagnosis, cumulative incidence increased for seizures from 27% to 41%, motor impairment 21% to 35%, and hearing loss 9% to 23%. Risks were elevated compared with siblings (eg, seizures HR: 12.7; 95% CI: 9.6-16.7; motor impairment HR: 7.6; 95% CI: 5.8-9.9; hearing loss HR: 18.4; 95% CI: 13.1-25.9). Regional brain doses of radiation therapy were associated with development of new deficits (eg, frontal ≥50 Gy and motor impairment HR: 2.0; 95% CI: 1.2-3.4). Increased risk for motor impairment was also associated with tumor recurrence (HR: 2.6; 95% CI: 1.8-3.8), development of a meningioma (HR: 2.3; 95% CI: 0.9-5.4), and stroke (HR: 14.9; 95% CI: 10.4-21.4). Seizure risk was doubled by recurrence (HR: 2.3; 95% CI: 1.6-3.2), meningioma (HR: 2.6; 95% CI: 1.1-6.5), and stroke (HR: 2.0; 95% CI: 1.1-3.4). Conclusions CNS tumor survivors remain at risk for new-onset adverse neurologic events across their lifespans at a rate greater than siblings. Cranial radiation, stroke, tumor recurrence, and development of meningioma were independently associated with late-onset adverse neurologic sequelae.

Introduction With survival rates higher than 80%, the number of survivors from pediatric cancer continues to increase. Late effects resulting from cancer and cancer therapy are being characterized, but little information exists on sexual health for men who have survived childhood cancer. Aim To assess erectile dysfunction (ED) in men who survived childhood and adolescent cancers and to identify potential risk factors for ED. Methods In total, 1,622 men and 271 eligible brothers in the Childhood Cancer Survivor Study cohort completed the Male Health Questionnaire, which provided information on sexual practices and sexual function. Combined with demographic, cancer, and treatment information from medical record abstraction, results of the Male Health Questionnaire were analyzed using multivariable modeling. The International Index of Erectile Function was used to identify ED in subjects. Main Outcome Measure International Index of Erectile Function. Results Survivors (mean age = 37.4 years, SD = 7.3 years) reported significantly lower sexual activity in the year before the survey than the brothers (mean age = 38.8 years, SD = 8.5 years) without cancer. ED was reported by 12.3% (95% CI = 10.4–14.3) of survivors and 4.2% (95% CI = 2.0–7.9) of brothers. Survivors showed significantly higher relative risk (RR) for ED (RR = 2.63, 95% CI = 1.40–4.97). In addition to older age, survivors who were exposed to higher-dose (≥10 Gy) testicular radiation (RR = 3.55, 95% CI = 1.53–8.24), had surgery on the spinal cord or nerves (RR = 2.87, 95% CI = 1.36–6.05), prostate surgery (RR = 6.56, 95% CI = 3.84–11.20), or pelvic surgery (RR = 2.28, 95% CI = 1.04–4.98) were at higher risk for ED. Conclusion Men who have survived childhood cancer have a greater than 2.6-fold increased risk for ED and certain cancer-specific treatments are associated with increased risk. Attention to sexual health, with its physical and emotional implications, and opportunities for early detection and intervention in these individuals could be important.

Laboratory interpretation of susceptibility data concerning the AmpC-producing Enterobacteriaceae is confusing to clinicians. Typical organisms included in this category are Enterobacter cloacae, Enterobacter aerogenes, Citrobacter freundii, Morganella morganii, and Serratia marcescens. These organisms frequently appear susceptible to extended spectrum cephalosporins by standard in vitro testing, although this is highly contested by treatment failures in cases of invasive infections. The mechanisms of resistance were postulated to be ampC induction or de-repression during therapy. As an alternative to carbapenems, piperacillin-tazobactam has been commonly used for its apparent activities against AmpC producers. In this laboratory study, when cefoxitin was used as an ampC-inducing agent in vitro, piperacillin-tazobactam showed activity in only a limited number of AmpC producers. Most notably, a temporal disc co-diffusion method detected inducible piperacillin- tazobactam resistance in all 20 strains of S. marcescens tested. With more standardized measurement, this method improves our previous Kirby-Bauer disc approximation method for the detection of ampC-mediated inducible resistance.

Acute kidney injury (AKI) is common after hematopoietic cell transplant (HCT). The etiology of AKI is unknown because biopsies are rarely performed. The pathophysiology of injury is inferred from clinical data. Thrombotic microangiopathy (TMA) is often invoked as the cause of renal injury. Patients >2 years old undergoing their first HCT at Fred Hutchinson Cancer Research Center participated in this study. We prospectively measured plasma markers of coagulation activation, (PAI-1 and tPA) and fibrinolyis (D-dimer) weekly in 149 patients during the first 100 days post transplant. Cox proportional hazards modeling was used to determine associations between these markers and AKI (doubling of baseline serum creatinine). Kruskal-Wallis test was used to determine the associations between day 100 urinary albumin to creatinine ratios and these markers. Thirty one percent of patients developed AKI. Though elevations in these markers occurred frequently, neither PAI-1 nor tPA were associated with the development of AKI. D-dimer was associated with a slightly increased risk of AKI (relative risk=1.76; P-value 0.04). None of these markers were associated with micro- or macroalbuminuria at day 100. The lack of an association with AKI suggests that endothelial injury in the form of TMA is not a common cause of AKI early after transplant.

Medulloblastoma is the most common malignant childhood brain tumor, although long-term risks for chronic neurologic health and psychosocial functioning in aging adult survivors are incompletely characterized.The Childhood Cancer Survivor Study (CCSS) includes 380 five-year survivors of medulloblastoma/primitive neuroectodermal tumor (PNET; median age at follow-up: 30 y, interquartile range 24-36) and sibling comparison (n = 4031). Cumulative incidence of neurologic health conditions was reported. Cox regression models provided hazard ratios (HRs) and 95% CIs. Cross-sectional outcomes were assessed using generalized linear models.Compared with siblings, survivors were at increased risk of late-onset hearing loss (HR: 36.0, 95% CI: 23.6-54.9), stroke (HR: 33.9, 95% CI: 17.8-64.7), seizure (HR: 12.8, 95% CI: 9.0-18.1), poor balance (HR: 10.4, 95% CI: 6.7-15.9), tinnitus (HR: 4.8, 95% CI: 3.5-6.8), and cataracts (HR: 31.8, 95% CI: 16.7-60.5). Temporal/frontal lobe radiotherapy of 50 Gy or more increased risk for hearing loss (HR: 1.9, 95% CI: 1.1-1.3), seizure (HR: 2.1, 95% CI: 1.1-3.9), stroke (HR: 3.5, 95% CI: 1.3-9.1), and tinnitus (HR: 2.0, 95% CI: 1.0-3.9). Survivors were less likely than siblings to earn a college degree (relative risk [RR]: 0.49, 95% CI: 0.39-0.60), marry (RR: 0.35, 95% CI: 0.29-0.42), and live independently (RR: 0.58, 95% CI: 0.52-0.66).Adult survivors of childhood medulloblastoma/PNET demonstrate pronounced risk for hearing impairment, stroke, lower educational attainment, and social independence. Interventions to support survivors should be a high priority.

Purpose The development of endocrinopathies in survivors of childhood cancer as they age remains understudied. We characterized endocrine outcomes in aging survivors from the Childhood Cancer Survivor Study on the basis of therapeutic exposures. Patients and Methods We analyzed self-reported conditions in 14,290 5-year survivors from the Childhood Cancer Survivor Study, with a median age 6 years (range, < 1 to 20 years) at diagnosis and 32 years (range, 5 to 58 years) at last follow-up. Identification of high-risk therapeutic exposures was adopted from the Children’s Oncology Group Long-Term Follow-Up Guidelines. Cumulative incidence curves and prevalence estimates quantified and regression models compared risks of primary hypothyroidism, hyperthyroidism, thyroid neoplasms, hypopituitarism, obesity, diabetes mellitus, or gonadal dysfunction between survivors and siblings. Results The cumulative incidence and prevalence of endocrine abnormalities increased across the lifespan of survivors (P < .01 for all). Risk was significantly higher in survivors exposed to high-risk therapies compared with survivors not so exposed for primary hypothyroidism (hazard ratio [HR], 6.6; 95% CI, 5.6 to 7.8), hyperthyroidism (HR, 1.8; 95% CI, 1.2 to 2.8), thyroid nodules (HR, 6.3; 95% CI, 5.2 to 7.5), thyroid cancer (HR, 9.2; 95% CI, 6.2 to 13.7), growth hormone deficiency (HR, 5.3; 95% CI, 4.3 to 6.4), obesity (relative risk, 1.8; 95% CI, 1.7 to 2.0), and diabetes mellitus (relative risk, 1.9; 95% CI, 1.6 to 2.4). Women exposed to high-risk therapies had six-fold increased risk for premature ovarian insufficiency (P < .001), and men demonstrated higher prevalence of testosterone replacement (P < .001) after cyclophosphamide equivalent dose of 20 g/m2 or greater or testicular irradiation with 20 Gy or greater. Survivors demonstrated an increased risk for all thyroid disorders and diabetes mellitus regardless of treatment exposures compared with siblings (P < .001 for all). Conclusion Endocrinopathies in survivors increased substantially over time, underscoring the need for lifelong subspecialty follow-up of those at risk.

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.

Introduction Simulation sessions prepare medical professionals for pediatric emergencies. No validated tools exist to evaluate overall team performance. Our objective was to develop and evaluate the inter-rater reliability and validity of a team performance assessment tool during simulated pediatric resuscitations. Methods We developed the Simulation Team Assessment Tool (STAT) which evaluated 4 domains: basic assessment skills, airway/breathing, circulation, and human factors. Scoring of each element was behaviorally anchored from 0 to 2 points. Two teams of resuscitation experts and two teams of pediatric residents performed the same simulated pediatric resuscitation. Each team was scored by six raters using the STAT. Intraclass correlation coefficients (ICC) were calculated to assess inter-rater reliability. Overall performance and domain scores between expert and resident teams were compared using repeated measures of analysis of variance to assess construct validity. Results ICCs for overall performance were 0.81. Domain ICCs were: basic skills 0.73, airway/breathing skills 0.30, circulation skills 0.76, human factors 0.68. Expert versus resident average scores were: overall performance 84% vs. 66% ( p =0.02), basic skills 73% vs. 55% ( p p =0.25), circulation 90% vs. 69% ( p =0.02), human factors 89% vs. 66% ( p =0.02). Conclusions The STAT's overall performance, basic skills, circulation, and human factors domains had good to excellent inter-rater reliability, discriminating well between expert and resident teams. Similar performance in the airway/breathing domain among all teams magnified the impact of a small number of rater disagreements on the ICC. Additional study is needed to better assess the airway/breathing domain.

Background—Malnutrition is common at diagnosis and during treatment for sarcoma patients. Poor nutritional status is associated with increased risk of complications, particularly infections. We investigated the role of body mass index (BMI) on the incidence of surgical wound complications in patients with localized osteosarcoma treated on the Children's Oncology Group (COG) legacy trial, INT-0133. Procedure—Patients considered in this report had localized osteosarcoma, enrolled on COG trial INT-0133, remained on protocol therapy to have definitive surgery 6–16 weeks after study entry, and had adequate height, weight, and surgical complication data for analysis. By protocol design, definitive surgical resection was planned for 10 weeks after induction chemotherapy. Wound complications within 30 days after definitive surgery were considered post-operative. BMI was calculated at the start of neoadjuvant chemotherapy and expressed as age-and gender-adjusted percentile. The incidence of wound complications was evaluated by logistic regression or Fisher's exact test. Results—A total of 498 patients met criteria for analysis. Low BMI (≤10 th percentile) was seen in 73 (14.7%), middle BMI (11 th –94 th percentile) in 382 (76.7%), and high BMI (≥95 th percentile) in 43 (8.6%) patients. Wound infection or slough was seen in low BMI patients (OR=2.0, p=0.07) although the results did not reach statistical significance. Arterial thrombosis was more common in high BMI patients (OR=9.4, p=0.03). Conclusions—Abnormal BMI at the start of treatment for localized osteosarcoma is associated with increased risk of post-operative wound complications such as arterial thrombosis. Future studies should evaluate whether maintenance of age-appropriate BMI reduces the risk of surgical complications.

The aim of this study was to assess gastroschisis prevalence in Washington (WA) State in relation to putative risk factors. Gastroschisis prevalence was calculated from the WA State birth cohort during 1987-2006 using an administrative database with birth certificate data linked with hospital discharge records and the ICD-9 procedure code 54.71, which specifies gastroschisis repair. Poisson regression analysis was used to evaluate time trends while adjusting for risk factors. Birth year was included as a linear term. Maternal age, smoking, race, residence in urban versus rural area, geographic region (eastern versus western Washington), paternal age, and infant gender were included as categorical factors. Prevalence ratios were adjusted for birth year and all of the preceding factors. Two hundred and eighty-two infants with gastroschisis were identified. In the adjusted analysis, the prevalence ratio for gastroschisis was 1.1 per year (95% CI 1.08-1.13), indicating an average 10% increase per birth year. Teen mothers were at a higher risk compared to mothers≥25 yr old (adjusted rate ratio [aRR] 8.02; 95% CI 5.30-12.13), as were teen fathers (aRR 2.35; 95% CI 1.48-3.74) compared to fathers≥25 years old. Maternal smoking was associated with a higher risk compared to those who were nonsmokers (aRR 1.58; 95% CI 1.19-2.09). Black mothers had a lower risk compared with white mothers. There was no association with geographic classification of mother's residence. Gastroschisis prevalence has increased in WA, particularly in teen mothers and in smokers. This is not explained by a rise in teenage pregnancies or maternal smoking. Further investigation of factors specific to teenage lifestyle is warranted.

The authors conducted an Email survey of their medical staff to explore the attitudes, patterns of recommendation, and communication of pediatric providers about complementary and alternative medicine (CAM) in a large metropolitan children’s hospital. Two thirds of the respondents reported awareness about their patients’ CAM therapy use (65%) and recommended CAM therapy to their patients (67%). Providers who reported personal use of CAM (71%) were more likely to recommend CAM to their patients compared with those who do not (76% vs 45%; P < .05). One half of pediatric providers reported occasional consultation with their patient’s CAM provider, but bidirectional communication was rare (4%). Specific changes in care based on a CAM provider’s recommendations were also unusual (4%). Despite the positive attitudes about and willingness to recommend CAM by pediatric providers, communication between these clinicians and CAM providers may be less than ideal.

Objectives The objective of this study was to determine whether the incidence of emergence agitation (EA) can be reduced by adding an additional, faster onset, non-IV analgesic, intranasal fentanyl or intramuscular (im) ketorolac to rectal acetaminophen.

Summary Background: Graft versus host disease (GVHD) of the gut is thought to delay gastric emptying and so may increase the risk of aspirating retained contents while under anesthesia. Knowing that gastric emptying is delayed in patients with GVHD might lead one to choose to intubate the trachea for all patients with suspected GVHD, who present for diagnostic esophagogastricduodenoscopy (EGD). We are not aware of published data that gives specific guidance as to the need for intubation in the pediatric bone marrow or stem cell transplantation (BMT) population. This review was intended to evaluate the gastric contents (pH and volume) in this group of patients, to provide anesthesiologists with data that would inform their decisions about airway management for these patients. Methods: Retrospective chart review of patients ≤19 years of age undergoing EGD between 2004 and 2006. Gastric content volume and pH were measured in addition to underlying disease state and treatment. We compared BMT patients with suspected GVHD to nontransplant patients with other underlying gastrointestinal conditions. Results: Data were obtained for 77 patients post-BMT undergoing EGD, including 40 patients whose biopsies and endoscopic findings were positive for GVHD, and 37 patients with no demonstrable GVHD. Records of 144 non-BMT patients undergoing EGD within the same study period were also reviewed. Conclusion: Patients in the BMT group overall did not have higher volumes when compared to non-BMT patients. A secondary comparison of BMT patients who were found to have GVHD vs BMT patients without GVHD suggests that gastric content volume may be elevated with GVHD. Patients in the BMT group had statistically significantly higher gastric pH than patients in the non-BMT group. It is possible that the higher gastric volume in the GVHD-positive group could put them at slightly higher risk for aspiration, but the severity of any pneumonitis, should aspiration occur, might be mitigated, by the tendency toward a higher gastric pH in the BMT patients.

Adult studies suggest pain treatment is influenced by patient's race/ ethnicity. The present study aims to evaluate the effect of the patient's race/ethnicity on pain treatment in children.Retrospective cohort study comparing perioperative analgesic administration for tonsillectomy and adenoidectomy (TA) surgery in Latino and Caucasian patients younger than 18 years of age.Ninety-four (94) patients were included (47 Latino, 47 Caucasian), mean age 8.44 yrs (SD 3.45), 43% female. Administration of non-opioid analgesics and intraoperative opioids was similar in both groups. Early post-operative administration of opioid analgesics was significantly different between groups. Latino subjects received 30% less opioid analgesics than Caucasians; median amount in morphine equivalents was 0.05 (0-0.14) vs. 0.07 (0-0.90) mg/kg for Latino and Caucasian patients respectively (p5.02).This study suggests that perioperative pain treatment in children is correlated with the patient's ethnicity. The cause of this difference is unknown and prospective studies are necessary to elucidate the reasons.

OBJECTIVES: We sought to evaluate child, parent and medical provider preferences for chaperones for outpatient encounters and to evaluate the acceptability and frequency of utilization following institution of a chaperone policy. Secondarily, we sought to understand what medical history and examinations teens consider "sensitive." DESIGN: We conducted an observational study 1 month before and 1 month after institution of outpatient clinic chaperone policy. Post clinic questionnaires were used for patients > or =12 years old, parents, and clinicians. A research assistant observed chaperone use. SETTING: Adolescent Medicine, Urology, and Rehabilitation Clinics at a regional, tertiary-care pediatric hospital, in a major metropolitan area were studied. PARTICIPANTS: Convenience sample: 117 clinic patients during control period and 119 after policy implementation. MAIN OUTCOME MEASURES: Preferences for and satisfaction with chaperone use were documented. RESULTS: Although non-parent chaperones were usually declined (99.6%), offers were appreciated. Non-parent chaperone use increased modestly (5.3-18.1%). Most patients preferred not to have non-parent chaperones. This preference was greater among older patients (88%), than early teens (52%). After experiencing sensitive examinations, more young adolescent patients (89%) wished their parent had been present than older patients (38%). Patients' opinions about what constitutes "sensitive" questions and examinations and chaperone preferences varied widely. Providers often did not recognize issues patients and parents considered sensitive questioning (21% agreement), but recognized sensitive physical examinations better (74% agreement). Providers felt chaperones had been a detriment to examination and exams would have gone better without one only 1% of the time. CONCLUSIONS: Although usually declined, offers of chaperones were appreciated and use of non-parent chaperones increased modestly. Offering chaperones for sensitive examinations may remind providers about appropriate, respectful patient encounters. Implications for children's hospitals' patient safety and satisfaction, and institutional staff protection and costs are significant. PRACTICE IMPLICATIONS: Questions and examinations which patients consider sensitive vary widely. Asking patients for their preferences for examination chaperones may reassure them about the appropriateness of examinations, remind staff to conduct respectful examinations and protect providers from accusations of impropriety. Since most chaperone offers are declined, the cost of asking is likely to be minimal. Language: en

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 Children's Hospital between 1 January 2000 and 31 December 2006. Each patient's 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 patient's 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.

Chronic kidney disease (CKD) is common after hematopoietic cell transplantation (HCT). We prospectively measured the urinary albumin:creatinine ratio (ACR) in 142 patients. Total (intact) monomeric albumin was determined by liquid chromatography of untreated urine samples collected weekly to day 100 after HCT. Albuminuria was defined as ACR (mg/g creatinine) > 30; proteinuria, as ACR >300. Cox and logistic regression analyses evaluated ACR as a risk factor for clinical events. The prevalence of albuminuria was 37% at baseline, 64% at day 100, and 50% at 1 year. Proteinuria occurred in 4% of patients at baseline, in 15% at day 100, and in 4% at 1 year. Characteristics associated with albuminuria include age, sex, donor type, hypertension, and sinusoidal obstruction syndrome (SOS). Albuminuria was associated with an increased risk of acute graft-versus-host disease (aGVHD) and bacteremia, but not acute kidney injury (AKI). Albuminuria at day 100 was associated with CKD at 1 year (odds ratio = 4.0; 95% confidence interval [CI] = 1.1 to 14.6). Nonrelapse mortality (NRM) risk was elevated (hazard ratio = 6.8; 95% CI = 1.1 to 41.5) in patients with overt proteinuria at day 100. Albuminuria occurs frequently after HCT and is correlated with aGVHD, bacteremia, hypertension, and progression of renal disease. Proteinuria at day 100 is associated with an 6-fold increased risk of NRM by 1 year after HCT.

This study assessed HIV attitudes among pregnant women attending antenatal clinics in the Namakkal district of Tamilnadu, India, as well as HIV knowledge before and after group counseling sessions. Two hundred thirteen women (97%) attending five antenatal clinics in July 2004 accepted HIV counseling and testing and completed precounseling and postcounseling questionnaires. Although the majority of women had heard of HIV, precounseling knowledge was low (mean precounseling score; 6.9/18, SD: 4.53), with scores correlating with the women's educational level and the number of sources from which they had received information about HIV. Posttest scores increased by 21%, however, understanding of modalities to prevent HIV infection remained poor. Group counseling sessions achieve small gains in HIV knowledge, but there is a continued need for ongoing and multifaceted HIV education in rural India.

The material properties of the anterior cruciate ligament (ACL) in female rats with normal estrous cycles were compared to those regulated by oral contraceptive steroids. Forty female Sprague–Dawley rats were divided into two groups: an experimental group received daily ethinylestradiol and levonorgestrel in a dosing model designed to simulate a typical oral contraception regime in humans, while a control group received daily oral placebo. After eight cycles, six rats from each group underwent daily phlebotomy to measure serum estradiol and progesterone levels over the course of a single 5-day estrous cycle. Significant differences between groups were found for the area under the curve of blood progesterone levels versus time over the length of the estrous cycle (P = 0.02). After 12 cycles, the rats were euthanized and one femur-ACL-tibia complex from each animal was dynamically loaded to failure. The ACLs from the rats in the experimental group had significantly decreased average and tangent stiffness, (P = 0.002 and 0.0001, respectively), and significantly increased elongation (P = 0.002) and total energy absorbed (P = 0.03), or greater toughness than controls. In rats, it appears that the administration of reproductive hormones designed to simulate typical oral contraception in humans alters the mechanical properties of the rat ACL.

OBJECTIVE. Gastroesophageal reflux disease is extremely common in the pediatric population, and antireflux procedures are performed with increasing frequency. The objective of this study was to determine whether pediatric antireflux procedures are associated with a decreased rate of reflux-related hospitalizations.METHODS. A study was conducted of pediatric patients who were undergoing antireflux procedures using data that were derived from the Washington State Comprehensive Hospital Abstract Reporting System and Vital Records. Patients were identified by a search of all records (1987–2001) for procedure codes that pertained to antireflux procedures in patients who were younger than 19 years. The number of hospitalizations for and rates of reflux-related events per patient-year before and after an antireflux procedure was calculated, and factors that were associated with higher antireflux procedure rates were examined.RESULTS. A total of 1142 patients underwent antireflux procedures. The rate of reflux-related events declined sharply with age both before and after an antireflux procedure. The cohort was divided into 3 groups on the basis of age at first antireflux procedure (CONCLUSIONS. The rate of reflux-related events was lower after an antireflux operation for children who underwent an antireflux procedure before age 4. Older children, however, were hospitalized at equal rates before and after an antireflux procedure, and older children with developmental delay were hospitalized at greater rates after an antireflux procedure. These findings highlight the need to clarify the subjective and objective indications for antireflux procedures in infants and children.

To observe the effects of right carotid artery ligation and variations in extracorporeal life support (ECLS) flow on regional cerebral oxygenation index (rSO2i) measured using near infrared spectroscopy.Prospective observational study.Tertiary children's hospital.Eleven neonatal and pediatric patients requiring veno-arterial ECLS support between June 2000 and March 2003.Near infrared spectroscopy probe placement on left and right frontal regions of patients undergoing ECLS, before vessel cannulation or within 24 hrs of initiation of ECLS.Regional cerebral oxygenation was measured every minute for 72 hrs or until the patient was decannulated. The effect of cannulation on rSO2i from each hemisphere of the brain and the relationship between ECLS flow and rSO2i during ECLS support and "trialing off" periods were determined. Ligation of the right carotid artery resulted in a 12-25% decrease in rSO2i from baseline in the right frontal region for a duration ranging from 17 to 45 mins before returning toward baseline. No substantial change in the left frontal region rSO2i was detected during cannulation. Following this depression in rSO2i on the right, there was a transient increase above baseline in rSO2i observed in both hemispheres on initiating ECLS. No correlation between ECLS flow and rSO2i was found over the 72-hr period. Periods of "trialing off" ECLS were not related to any change in rSO2i in either hemisphere.This study demonstrated no relationship between ECLS flow and rSO2i changes during the 72-hr observation period. A brief period of cerebral oxygen desaturation of the right frontal region at the time of right carotid ligation was seen in all three study patients examined during cannulation, followed by an increased rSO2i with initiation of ECLS flow. Near infrared spectroscopy measurement may offer an important adjunct for neurologic monitoring of ECLS patients.

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.

Identify the incidence and risk factors for development of acute, severe central nervous system (CNS) complications of pediatric extracorporeal life support (ECLS).Retrospective review of Extracorporeal Life Support Organization (ELSO) registry database.Pediatric intensive care units of 115 tertiary centers internationally.Pediatric patients, 1 month to 18 yrs of age, who had ECLS between the years 1981-2002.Data concerning 4,942 patients who underwent one run of ECLS were analyzed. Six hundred thirty-six patients (12.9%) developed acute, severe CNS complications. Patients who required ECLS during extracorporeal cardiopulmonary resuscitation (n = 161; 3.3%) were more likely to develop CNS complications (n = 42; 26.1%) than patients who did not have extracorporeal cardiopulmonary resuscitation (p.001; odds ratio [OR], 2.48; 95% confidence interval [CI], 1.73-3.57). Stepwise logistic regression analysis of therapies patients received before initiation of ECLS showed that the use of a left ventricular assist device (p = .001; OR, 3.45; 95% CI, 1.64-7.22), bicarbonate (p.001; OR, 1.61; 95% CI, 1.26-2.05), and vasopressor/inotropic medications (p = .035; OR, 1.22; 95% CI, 1.01-1.48) were significant independent predictors of development of CNS complications. Among patients who had pulmonary failure as an indication for ECLS, the CNS complication rate was significantly higher for those treated with venoarterial ECLS than those who had venovenous ECLS (13.5% vs. 5.7%; p.001; OR, 0.43; 95% CI, 0.34-0.67). Multiple logistic regression analysis of the complications other than CNS complications associated with the use of ECLS showed that pH7.20, creatinine concentration3.0 mg/dL, use of inotropes, presence of myocardial stun, and requirement of cardiopulmonary resuscitation during ECLS independently predicted development of CNS complications.Patients who have metabolic acidosis, a bicarbonate or inotrope/vasopressor requirement, cardiopulmonary resuscitation, or a left ventricular assist device before initiation of ECLS are at greater risk for development of CNS complications. After initiation of ECLS, patients who develop renal failure or metabolic acidosis or undergo venoarterial ECLS should be closely monitored for development of CNS complications.

Background: Chronic hepatitis C is often a mild disease in children, but whether this is related to younger age or shorter duration of infection is unclear. Histologic severity has been shown to correlate with duration of infection regardless of age. Objectives: We compared histologic findings in children and adults with chronic hepatitis C while controlling for sex, duration of infection, hepatitis C virus (HCV)-RNA level, and genotype. Methods: Twenty-one children and 52 adults whose infection was less than 20 years in duration and who had undergone a liver biopsy were included. Two blinded liver pathologists reviewed the liver biopsies and scored inflammatory activity and fibrosis using the modified Knodell scoring system. Results: The groups were the same with respect to HCV-RNA level (P = 0.8), and genotype (P = 0.6) but differed in duration of disease (P = 0.01) and sex composition (P = 0.005). Covariate analysis showed no influence of genotype, duration of infection, or HCV-RNA level on outcome. In controlling for sex, children had significantly milder liver disease and alanine aminotransferase (ALT) elevations. Conclusions: With equal duration of infection, HCV-RNA level, and genotype, children have lower serum ALT levels and less severe liver disease than adults infected with HCV.

The quantification of human immunodeficiency virus type 1 (HIV-1) by an assay measuring heat-dissociated (HD) p24 antigen (Ag) in specimens of whole blood and plasma stored on filter paper, and of plasma stored in tubes, was compared to HIV-1 RNA plasma levels determined by real-time reverse transcription (RT)-PCR. The stability of p24 Ag on filter paper under conditions simulating specimen transport was also evaluated. The HD p24 Ag in both plasma and whole-blood specimens stored on filter paper correlated with plasma HIV-1 RNA levels (Spearman rank ρ = 0.74 [ P < 0.0001] and ρ = 0.56 [ P = 0.0001], respectively). The sensitivity of the HD p24 Ag assay was similar when plasma and whole blood on filter paper were contrasted to the real-time RT-PCR assay (80% versus 82.5% and 78.6% versus 83.3%, respectively). However, while the specificity of the HD p24 Ag assay of plasma on filter paper was 100%, the specificity was diminished in whole-blood specimens. The storage of specimens on filter paper for 2 weeks at 37°C, 24°C, or 0°C did not alter the detection or quantification of HD p24 Ag. These results suggest that transport and storage of plasma on filter paper and quantification of HD p24 Ag may be a reliable method for HIV-1 load monitoring.

Continuous renal replacement therapy (CRRT) is used to treat renal failure in children. Despite widespread use of the technique, little research has evaluated how variations in dose of replacement fluid or degree of fluid overload at initiation relate to outcomes. We conducted a retrospective review of patients treated with convective CRRT at our institution, using a multivariable Cox regression model. Children with high fluid overload (>10%) at CRRT initiation were at 3.02 times greater risk of mortality than those with low or no fluid overload [95% confidence interval (CI) 1.50–6.10, P =0.002]. The hazard ratio for death in children treated with high-dose convective clearance was not statistically significant. Our data support previous findings that volume overload in excess of 10% is strongly correlated with poor outcome. We favor early institution of CRRT, before excessive fluid overload occurs. In contrast to findings in adults, we find no advantage to higher rates of convective clearance. Given the risks and increased complexity associated with high-volume hemofiltration, we recommend further study prior to widespread adoption of high-level convection in children treated with continuous veno-venous hemofiltration.

Interventions such as heparin-coated circuits, epsilon-aminocaproic acid, and reduced shed blood reinfusion have shown mixed results when applied individually for limiting hemostatic activation during cardiopulmonary bypass (CPB). We compared coagulation and fibrinolytic activation during conventional CPB (control) (CTRL) using noncoated circuits, no antifibrinolytics, and open cardiotomy with a combined strategy (HAC) that used heparin-coated circuits, epsilon-aminocaproic acid, and closed cardiotomy. Blood samples were drawn before, during, and after CPB for primary coronary bypass grafting surgery from 9 CTRL patients and 10 HAC patients. Thrombin-antithrombin complex and fibrinopeptide A levels (markers of thrombin and fibrin generation) were reduced in the HAC versus CTRL group after 30 min of CPB (P0.05). Average tissue plasminogen activator (tPA) levels were significantly lower in the HAC group by 30 min on CPB (P0.05), resulting in preservation of plasminogen activator inhibitor (PAI)-1 during CPB (P0.05). D-Dimer, a measure of intravascular fibrin formation and removal, was reduced in the HAC group during and after CPB (P0.005). Overall, the combined strategy was associated with a reduction in CPB-induced increases in markers of thrombin generation, fibrin formation, tPA release, and fibrin degradation and better preservation of PAI-1.A combined approach during cardiopulmonary bypass (CPB) that uses heparin-coated circuits, epsilon-aminocaproic acid, and limited reinfusion of shed pericardial blood is associated with reduced activation of the coagulation and fibrinolytic systems that typically occurs during conventional CPB.

The child with posterior plagiocephaly may have positional molding or unilateral lambdoid synostosis. Molding responds to conservative treatment, lambdoid synostosis requires surgical reconstruction. CT is diagnostic, but uses ionizing radiation, may need sedation, and the incidence of lambdoid fusion is only 2–3%. The purpose of this prospective study was to evaluate ultrasound as a screening test of lambdoid sutural patency using CT as the reference standard. In total, 41 children having head CT examinations were enrolled over 6 months. Of those, 29 were referred for abnormal head shape and suspected synostosis, of whom two had lambdoid fusion; 12 were referred for indications not related to head shape and found to have a normal study. Ultrasound scanning and interpretation of the lambdoid sutures was performed blinded to the CT reference standard. The lambdoid suture was read as patent or fused if a hypoechoic gap could or could not be seen between the hyperechoic calvarial bones, respectively. The mean sensitivity and specificity of ultrasound in distinguishing a patent from fused lambdoid suture by three blinded pediatric radiologists was 100% and 89%, respectively. Sonography of the lambdoid sutures shows excellent preliminary promise as a screening test of lambdoid sutural patency.

Objectives Assessment of ventricular volume change is critical and can be difficult in the child with suspected shunt failure. Objective techniques described to measure ventricular volumes have used limited anatomic sampling or have been computationally intensive. Phantoms used to evaluate these techniques have used static volumes. The purpose of this study was to construct a computed tomography (CT) phantom to simulate changing ventricular volumes and to evaluate a new program to measure volumes. Methods The phantom is 5 Foley catheters embedded in gelatin. The balloons were filled and then scanned at 15-mL increments from 0-300 mL. The program measures the voxels of specified density within a larger volume created by applying a region of interest to a stacked volume. Calculated volumes and percent changes were compared with actual volumes and percent changes. Results Calculated volumes were consistently 7%-9% (mean: -7.8%) less than actual injected volumes across the entire 0- to 300-mL range. For true changes between -50% and +50%, all calculated changes were within +/-2.5% points of true percent change; for true changes between +50% and +100%, all calculated changes were within +/-5% points of true percent change. Conclusions A dynamic CT phantom simulating changing ventricular volumes can be constructed from readily available materials. A new volumetric program accurately measures ventricular volumes and percent change from baseline across a wide range of volumes.

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 for20 years, 1.2 for40 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.

10559 Background: Childhood cancer therapy is associated with late onset, organ-specific impairment. However, the prevalence of and outcomes after solid organ transplant (SOT) in childhood cancer survivors (CCS) are unknown. Methods: Data on U.S-based participants in the Childhood Cancer Survivor Study were linked with the Organ Procurement and Transplantation Network. Cumulative incidence of transplant (CIT) 35 years after cancer diagnosis, multivariable Cox regression models for hazard ratios (HR), Kaplan-Meier (KM) survival and corresponding 95% confidence intervals (CI) were estimated. Results: Among 13,318 survivors, median follow-up age 39 years (interquartile range, IQR 33-46), and median time since cancer diagnosis 31 years (IQR 28-36 years), 100 CCS had SOT after study entry with characteristics and outcomes provided (table). Conclusions: Organ-specific radiation and chemotherapy exposure increase the risk for SOT after childhood cancer. Five-year survival rates after renal and cardiac SOT are favorable. [Table: see text]

The purpose of this study was to assess the prevalence of male infertility and treatment-related risk factors in childhood cancer survivors.Within the Childhood Cancer Survivor Study, 1,622 survivors and 274 siblings completed the Male Health Questionnaire. The analysis was restricted to survivors (938/1,622; 57.8 %) and siblings (174/274; 63.5 %) who tried to become pregnant. Relative risks (RR) and 95 % confidence intervals (CI) for the prevalence of self-reported infertility were calculated using generalized linear models for demographic variables and treatment-related factors to account for correlation among survivors and siblings of the same family. All statistical tests were two-sided.Among those who provided self-report data, the prevalence of infertility was 46.0 % in survivors versus 17.5 % in siblings (RR = 2.64, 95 % CI 1.88-3.70, p 0.001). Of survivors who met the definition for infertility, 37 % had reported at least one pregnancy with a female partner that resulted in a live birth. In a multivariable analysis, risk factors for infertility included an alkylating agent dose (AAD) score ≥3 (RR = 2.13, 95 % CI 1.69-2.68 for AAD ≥3 versus AAD3), surgical excision of any organ of the genital tract (RR = 1.63, 95 % CI 1.20-2.21), testicular radiation ≥4 Gy (RR = 1.99, 95 % CI 1.52-2.61), and exposure to bleomycin (RR = 1.55, 95 % CI 1.20-2.01).Many survivors who experience infertility father their own children, suggesting episodes of both fertility and infertility. This and the novel association of infertility with bleomycin warrant further investigation.Though infertility is common, male survivors reporting infertility often father their own children. Bleomycin may pose some fertility risk.

Acquisition of nevirapine (NVP)–resistant human immunodeficiency virus type 1 (HIV-1) by breast-feeding infants after receipt of single-dose NVP to prevent mother-to-child transmission is not well defined. A prospective observational study of 307 infants evaluated the rate of breast milk transmission of NVP-resistant HIV and the concentrations of mutants over time. NVP resistance was detected in 9 of 24 infants (37.5%; 95% confidence interval, 18.8%–59.4%) infected via breast milk. Eight had a pure mutant HIV population at the time infection was first detected, and majority mutant populations persisted in all 6 infants with follow-up specimens. Infection of breast-feeding infants with NVP-resistant HIV resulted in mutants persisting as the dominant virus, which may indefinitely compromise treatment with NVP-based antiretroviral regimens.

A retrospective study was performed to determine risk factors for the development of de novo chronic graft-versus-host disease (GVHD) in patients given marrow grafts from HLA-identical sibling donors (85%), HLA-nonidentical family members (3%), or HLA-matched unrelated donors (12%) and for postgrafting immunosuppression with methotrexate and cyclosporine. We also examined the impact of chronic GVHD on survival and identified patients at low risk for chronic GVHD in whom immunosuppression might be stopped safely early after transplantation. Among 489 patients with either grade 0 or I acute GVHD, 33% developed chronic GVHD. Overall survival was 70%, and relapse-free survival was 63% at 8 years. Risk factors for chronic GVHD were found to include donor buffy coat infusions among patients given transplants for aplastic anemia (relative risk [RR] = 2.9, P = .05), patient-donor sex/parity combination (likelihood ratio test, P < .001), grade I acute GVHD (RR = 1.6, P = .003), and active cytomegalovirus infection (RR = 1.5, P = .05) before day 60. Among 45 patients aged

Two randomized, placebo-controlled trials previously showed that fluconazole (400 mg/d) administered prophylactically decreases the incidence of candidiasis in blood and marrow transplant (BMT) recipients. However, there exists conflicting data regarding the optimal duration of fluconazole administration, specifically whether prophylaxis through acute graft-versus-host disease (GVHD) results in improved survival in allograft recipients. Reported here are the results of long-term follow-up and a detailed analysis of invasive candidiasis and candidiasis-related death in 300 patients who received fluconazole (400 mg/d) or placebo for 75 days after BMT at the Fred Hutchinson Cancer Research Center. Patients in both treatment arms were compared for survival, causes of death, and the incidence of invasive fungal infections early (less than 110 days) and late (more than 110 days) after BMT. After 8 years of follow-up, survival is significantly better in fluconazole recipients compared with placebo recipients (68 of 152 vs 41 of 148,P = .0001). The overall incidence of invasive candidiasis was increased in patients who received placebo compared with fluconazole (30 of 148 vs 4 of 152, P