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The post-transplant course of pediatric kidney transplant recipients is marked by a myriad of challenges, encompassing medical complications, recurrent hospitalizations, physical and dietary restrictions, and mental health concerns such as depression, anxiety, and post-traumatic stress disorder. Moreover, pediatric recipients are at risk of neurodevelopmental impairment, which may result in neurocognitive deficits and pose significant psychosocial obstacles. Addressing these multifaceted demands necessitates a multidisciplinary approach to pediatric kidney transplant care. However, the existing literature on the effective implementation of such a model remains scarce. This review examines the psychosocial and neurodevelopmental challenges faced by pediatric kidney transplant recipients and their families, discussing their impact on long-term transplant outcomes. Furthermore, it provides insights into risk assessment strategies and potential interventions within a multidisciplinary framework, aiming to enhance patient care and optimize post-transplant outcomes., (© 2024. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Background: Heart transplant recipients frequently require kidney transplantation for concomitant advanced chronic kidney disease. Data on simultaneous (heart and kidney transplants performed simultaneously) versus sequential (heart transplant performed before kidney) heart-kidney transplants in children are limited. Herein, we compare kidney transplant outcomes between the two groups., Method: We used the Scientific Registry of Transplant Recipients to identify all pediatric (age <21 years) heart transplant recipients who also received a kidney transplant within 10 years of the heart transplant. We divided the study cohort into simultaneous heart-kidney and sequential heart-kidney recipients. We compared patient and death-censored graft survival using the Cox regression, adjusting for age at kidney transplant, sex, race, pre-transplant dialysis, donor type, and prior kidney transplant. We evaluated delayed graft function (defined as dialysis within the first week posttransplant) using logistic regression., Results: Our analysis cohort included 165 recipients (86 simultaneous and 79 sequential). The incidence of delayed graft function was higher in simultaneous recipients (22.4 vs. 7.7%, p=0.017), but the difference lost statistical significance on multivariable analysis. We found no difference in patient survival (aHR 0.97; 95% CI 0.39, 2.41; p=0.95) after kidney transplant but higher death-censored kidney graft survival in sequential heart-kidney recipients compared with simultaneous heart-kidney recipients (aHR 4.26; 95% CI 1.21, 14.9; p=0.02)., Conclusion: Sequential heart-kidney transplants are associated with higher death-censored kidney allograft survival in children compared with simultaneous heart-kidney transplants., (© 2024. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Background: Norovirus is the most common cause of viral gastroenteritis. Studies in adult kidney recipients have documented significant morbidity associated with norovirus infection, but there are few studies in pediatric recipients., Methods: Multicenter retrospective cohort study of pediatric kidney transplant recipients with norovirus, confirmed by stool PCR, between January 1, 2008, and December 31, 2018. Outcomes of interest included duration of diarrhea, incidence of chronic diarrhea, management strategies, and graft function., Results: Forty pediatric kidney transplant recipients from four centers were identified for inclusion. Median age at transplant was 5.4 years (IQR 2.2-11.2 years), and median time post-transplant was 1.9 years (IQR 0.8-3.8 years). Median diarrheal duration was 16 days (IQR 6.0-41.5 days); 15 patients (43%) had acute diarrhea, 8 (23%) had persistent, and 12 (30%) had chronic diarrhea. Twenty-one (53%) patients developed acute kidney injury. Thirty-five (88%) patients required supplemental fluids, 8 (20%) patients underwent immunosuppression reduction for a median of 22 days, 5 (13%) were treated with nitazoxanide, and 5 (13%) received oral immunoglobulin. Acute rejection was diagnosed in 3 (8%) patients within 6 months of norovirus diagnosis. We observed no sustained decline in eGFR at 12 months after diarrhea resolution (median eGFR difference: 2.8 mL/min/1.73 m 2 [IQR: -17.1, 7.4]). Of the patients in the cohort, two lost their graft at 6.8 and 30.0 months after the onset of diarrhea., Conclusion: Norovirus is associated with significant morbidity in pediatric kidney transplant recipients. Various treatment interventions are being employed for norovirus infection. Larger studies, both observational and interventional, are needed to determine the optimal treatment., (© 2024 The Author(s). Pediatric Transplantation published by Wiley Periodicals LLC.)

Background: We evaluated the effects of kidney failure etiology, dialysis, and sociodemographic factors on the subdomains of intellectual functioning in pediatric kidney transplant candidates., Methods: This retrospective study included 78 pediatric kidney transplant candidates who completed a Wechsler Intelligence Scale assessment during pre-transplant neuropsychological evaluation between 1/1/2010 and 10/31/2022. Linear regression models were employed to examine the effects of kidney failure etiology, dialysis status, neighborhood area deprivation, and race on subdomains of intellectual functioning., Results: The mean scores of various intellectual functioning domains in pediatric kidney transplant candidates were significantly lower than in the general population (ps <0.001). After adjusting for covariates, patients with congenital anomalies of the kidney and urinary tract had significantly lower processing speed (M=85; 95% CI: 79-91) compared to patients with nephrotic syndrome (M=99; 95% CI: 90-107) and other etiologies (M=84; 95% CI: 78-90) (p=0.003). Patients living in high-level deprivation neighborhoods showed lower working memory performance (M=84, 95% CI: 77-91) than patients living in median-level (M=91, 95% CI: 87-95) and low-level (M=98, 95% CI: 92-104) neighborhood area deprivation (p=0.03). Patients from marginalized racial groups demonstrated lower verbal skills (M=80, 95% CI: 74-87) than White patients (M=92, 95% CI: 88-97) (p=0.02). Additionally, patients receiving dialysis showed higher reasoning skills (M=98, 95% CI: 90-104) than patients without dialysis (M= 90, 95% CI: 86-95) (p=0.04)., Conclusions: Neurocognitive development in pediatric kidney transplant candidates is associated with medical and sociodemographic factors. Strategies to monitor, treat, and accommodate neurocognitive concerns need to be considered to optimize long-term medical and social outcomes., Competing Interests: Declarations The authors did not receive financial support from any organization for the study design, data collection, interpretation of the data, writing of the report, or the decision to submit the paper for publication. Data analyses were performed by Michael Evans who is supported by the National Institutes of Health’s National Center for Advancing Translational Sciences (UL1TR002494). Finola E. Kane-Grade’s graduate education is supported by a National Science Foundation Graduate Research Fellowship (2237827). The content is solely the responsibility of the authors and does not represent the official views of the National Institutes of Health’s National Center for Advancing Translational Sciences or the National Science Foundation. The other authors have no relevant financial or non-financial interests to disclose.

Background: Infants and toddlers with kidney failure are susceptible to neurodevelopmental delays due to medical comorbidities and rapid brain development in early childhood. However, research on the neuropsychological development of this patient population has been limited over the past 10 years., Methods: We performed a retrospective study to evaluate the neurodevelopmental functioning of infants/toddlers with kidney failure who completed the Bayley Scales of Infant and Toddler Development (3rd and 4th Edition) as part of a pretransplant evaluation between 2010 and 2022 (n = 23; M age  = 18 months, SD = 8.53; 16 males) using t-tests, linear model, and Pearson correlations., Results: Mean Bayley scores of participants were below normative means for cognition (M = 86.74, 95% CI = 80.53-92.94, p < 0.001), language (M = 79.20, 95% CI = 73.32-85.08, p < 0.001), and motor (M = 78.00, 95% CI = 70.15-85.85, p < 0.001) domains. After adjusting for prematurity and epilepsy, patients on dialysis had significantly lower cognitive (78.7 vs. 93.8; p = 0.001) and motor scores (67.1 vs. 85.5; p = 0.01) compared to no dialysis. Pretransplant cognitive scores were positively correlated with posttransplant Full-Scale IQ (r(8) = 0.65 p = 0.04), verbal comprehension (r(8) = 0.75 p = 0.02), and fluid reasoning (r(7) = 0.68 p = 0.045). Similarly, pretransplant language scores were positively correlated with posttransplant Full-Scale IQ (r(7) = 0.74 p = 0.03) and verbal comprehension (r(7) = 0.73 p = 0.03). Of the 16 participants who reached age > 5 years during the study period, seven were diagnosed with a neurodevelopmental disorder, including three with autism spectrum disorder., Conclusions: Infants and toddlers with kidney failure are at risk of developmental delays and later neurodevelopmental disorders. Dialysis is associated with cognitive and motor delays independent of prematurity and epilepsy., (© 2024. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Introduction: Acute kidney injury (AKI) defined by changes in serum creatinine (SCr), or oliguria is associated with increased morbidity and mortality in children who are critically ill. We derived and validated a clinical cutoff value for urine neutrophil gelatinase-associated lipocalin (NGAL), in a prospective multicenter study of children who were critically ill. We report the clinical performance of urine NGAL (uNGAL) to aid in pediatric AKI risk assessment., Methods: Eligible subjects were aged ≥ 90 days to < 22 years, admitted to an intensive care unit (ICU), and had 1 or more of the following: mechanical ventilation, vasoactive medication administration, solid organ or bone marrow transplantation, or hypotension within 24-hours of admission. uNGAL was assessed within 24-hours of admission. The primary outcome was SCr-based stage 2/3 AKI presence at 48- to 72-hours., Results: Twenty-five (12.3%) derivation study patients had stage 2/3 AKI at 48- to 72-hours. uNGAL concentration of 125 ng/ml was the optimal cutoff. Forty-seven (9.1%) validation study patients had stage 2/3 AKI at 48- to 72-hours. The area under the curve of a receiver operator characteristics curve (AUC-ROC) for uNGAL performance was 0.83 (95% confidence interval [CI]: 0.77-0.90). Performance characteristics were sensitivity 72.3% (95% CI: 57.4%-84.4%), specificity 86.3% (95% CI: 82.8%-89.3%), positive predictive value 34.7% (95% CI: 28.5%-41.5%), and negative predictive value 96.9% (95% CI: 95.1%-98.0%)., Conclusion: These prospective, pediatric, multicenter studies demonstrate that uNGAL in the first 24-hours performs very well to predict Kidney Disease Improving Global Outcomes (KDIGO) stage 2/3 AKI at 48- to 72-hours into an ICU course. We suggest that a uNGAL cut point of 125 ng/ml can aid in the risk assessment for stage 2/3 AKI persistence or development., (© 2024 International Society of Nephrology. Published by Elsevier Inc.)

Purpose: To investigate the molecular characteristics of and potential for precision medicine in KRAS wildtype pancreatic ductal adenocarcinoma (PDAC)., Patients and Methods: We investigated 27 patients with KRAS WT PDAC at our institution. Clinical data were obtained via chart review. Tumor specimens for each subject were interrogated for somatic single nucleotide variants, insertion and deletions, and copy number variants by DNA sequencing. Gene fusions were detected from RNA-seq. A patient-derived organoid (PDO) was developed from a patient with a MET translocation and expanded ex vivo to predict therapeutic sensitivity prior to enrollment in a phase 2 clinical trial., Results: Transcriptomic analysis showed our cohort may be stratified by the relative gene expression of the KRAS signaling cascade. The PDO derived from our patient harboring a TFG-MET rearrangement was found to have in vitro sensitivity to the multi-tyrosine kinase inhibitor crizotinib. The patient was enrolled in the phase 2 SPARTA clinical trial and received monotherapy with vebrelitinib, a c-MET inhibitor, and achieved a partial and durable response., Conclusions: KRAS WT PDAC is molecularly distinct from KRAS MUT and enriched with potentially actionable genetic variants. In our study, transcriptomic profiling revealed that the KRAS signaling cascade may play a key role in KRAS WT PDAC. Our report of a KRAS WT PDAC patient with TFG-MET rearrangement who responded to a cMET inhibitor further supports the pursuit of precision oncology in this sub-population. Identification of targetable mutations, perhaps through approaches like RNA-seq, can help enable precision-driven approaches to select optimal treatment based on tumor characteristics.

Background: There are scant data on the effect of rituximab on EBV DNA levels and prevention of post-transplant lymphoproliferative disorder (PTLD) in pediatric kidney transplant recipients with EBV DNAemia., Methods: Kidney transplant recipients with EBV DNAemia treated with rituximab to prevent PTLD between 7/1999 and 7/2019 at five pediatric centers were included. Those with confirmed PTLD at the onset of rituximab were excluded. Primary outcomes included percentage change in EBV DNAemia and occurrence of PTLD post rituximab., Results: Twenty-six pediatric kidney transplant recipients were included. Median age at transplant was 4 years (IQR 2.1-10.3). EBV DNA load monitoring by qPCR was performed at 1-3 month intervals. EBV DNAemia onset occurred at a median of 73 days post-transplant (IQR 52-307), followed by DNAemia peak at a median of 268 days (IQR 112-536). Rituximab was administered at a median of 9 days post peak (IQR 0-118). Rituximab regimens varied; median dose 375 mg/m 2 (IQR 375-439) weekly for 1-4 doses per course. Following rituximab, EBV DNA load decreased to <10% of baseline at 120 days in 20/26 patients; however, only 30% achieved complete resolution at last follow-up (median 2094 days post-transplant [IQR 1538-3463]). Two (7%) developed PTLD at 915 and 1713 days post rituximab. All recipients had functioning grafts. One death occurred in a child with PTLD following remission due to unrelated reasons., Conclusions: In the largest pediatric kidney transplant recipient case series with EBV DNAemia given rituximab to prevent PTLD, rituximab achieved a short-term reduction in DNA load; however, recurrent DNAemia is common., (© 2024 Wiley Periodicals LLC.)

Background: Coronavirus disease of 2019 (COVID-19) has disproportionately affected adults with kidney disease. Data regarding outcomes among children with kidney disease are limited. The North American Pediatric Renal Trials Collaborative Studies Registry (NAPRTCS) has followed children with chronic kidney disease (CKD) since 1987 at 87 participating centers. This study aimed to evaluate the impact of COVID-19 among participants enrolled in the three arms of the registry: CKD, dialysis, and transplant., Methods: This was a retrospective cohort study of COVID-19 among participants in the NAPRTCS CKD, dialysis, and transplant registries from 2020 to 2022. Where appropriate, t-tests, chi-square analyses, and univariate logistic regression were used to evaluate the data., Results: The cohort included 1505 NAPRTCS participants with recent data entry; 260 (17%) had documented COVID-19. Infections occurred in all three registry arms, namely, 10% (n = 29) in CKD, 11% (n = 67) in dialysis, and 26% (n = 164) in transplant. The majority of participants (75%) were symptomatic. Hospitalizations occurred in 17% (n = 5) of participants with CKD, 27% (n = 18) maintenance dialysis participants, and 26% (n = 43) of transplant participants. Fourteen percent (n = 4) of CKD participants and 10% (n = 17) of transplant participants developed acute kidney injury (AKI), and a total of eight participants (one CKD, seven transplant) required dialysis initiation. Among transplant participants with moderate to severe illness, 40-43% developed AKI and 29-40% required acute dialysis. There were no reported deaths., Conclusions: COVID-19 was documented in 17% of active NAPRTCS participants. While there was no documented mortality, the majority of participants were symptomatic, and a quarter required hospitalization., (© 2023. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

In pediatric kidney failure, native kidneys may pose a risk to successful transplant outcomes. The indications and timing of native nephrectomy represent a controversial management decision. A lack of high-quality, outcomes-based data has prevented development of evidence-based guidelines for intervention. In this article, we review the published literature on medical indications for native nephrectomy and current knowledge gaps. In addition, we provide a surgical perspective regarding timing and approach., (© 2023. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Background: Early in the history of kidney transplantation, short-term graft survival was low. Yet some have had excellent long-term survival. Herein, we describe characteristics of pediatric recipients with > 40 years of graft survival currently alive with a functioning first graft., Methods: We reviewed all pediatric (age < 18 years) kidney transplants performed at the University of Minnesota between January 1, 1970, and December 31, 1979 (n = 148), to identify all recipients currently alive with a functioning first graft. Data are presented as medians with interquartile ranges (IQR) and proportions., Results: We identified 10 recipients with > 40-year graft survival (median follow-up: 45.0 years (IQR: 43.1, 48.1)). The median age at transplant was 13.8 years (IQR: 5.1, 16.3). All recipients were white; half were male. Of the 10, 4 had glomerulonephritis, 2 had congenital anomalies of the kidney and the urinary tract, 2 had congenital nephrotic syndrome, 1 had Alport syndrome, and 1 had cystic kidney disease as kidney failure cause. Nine patients received a living-related donor transplant, and 1 patient received a deceased-donor transplant. The median estimated glomerular filtration rate at 20 years post-transplant was 79.9 (IQR: 72.3, 98.4); at 30 years, 67.7 (IQR: 63.2, 91.8); and at 40 years, 80.3 ml/min/1.73 m 2 (IQR: 73.7, 86.0). None developed rejection, 5 developed hypertension, 2 developed dyslipidemia, 1 developed diabetes, and 7 patients developed malignancy (4 skin cancer, 2 breast cancer, and 1 post-transplant lymphoproliferative disease)., Conclusion: Pediatric kidney transplant recipients may achieve > 4 decades of graft survival. Cancer is a common complication warranting vigilant screening., (© 2023. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Posttransplant anemia (PTA) is a common complication of pediatric kidney transplantation, with a prevalence ranging from 22 to 85%. PTA is categorized as early (within 6 months posttransplant) and late (>6 months posttransplant). Early PTA is typically associated with surgical blood losses and iron deficiency. Late PTA primarily results from graft dysfunction; however, iron deficiency, drug toxicity, and posttransplant inflammation also play a role. PTA is more severe compared with the anemia in glomerular-filtration-rate matched patients with native chronic kidney disease. Treatment of PTA is directed toward the underlying cause. Erythropoiesis stimulating agents (ESA) are effective; however, their use is limited in the transplant setting. Timely diagnosis and treatment of PTA are vital to prevent long-term adverse outcomes in pediatric transplant recipients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kouri, Balani and Kizilbash.)

Purpose: Our previous work demonstrated that 3,4-dihydroxy-6-[18F]-fluoro-L-phenylalanine ( 18 F-DOPA) positron emission tomography (PET) is sensitive and specific for identifying regions of high density and biologically aggressive glioblastoma. The purpose of this prospective phase 2 study was to determine the safety and efficacy of biologic-guided, dose-escalated radiation therapy (DERT) using 18 F-DOPA PET in patients with glioblastoma., Methods and Materials: Patients with newly diagnosed, histologically confirmed glioblastoma aged ≥18 years without contraindications to 18 F-DOPA were eligible. Target volumes included 51, 60, and 76 Gy in 30 fractions with a simultaneous integrated boost, and concurrent and adjuvant temozolomide for 6 months. 18 F-DOPA PET imaging was used to guide DERT. The study was designed to detect a true progression-free survival (PFS) at 6 months (PFS6) rate ≥72.5% in O6-methylguanine methyltransferase (MGMT) unmethylated patients (DE-Un), with an overall significance level (alpha) of 0.20 and a power of 80%. Kaplan-Meier analysis was performed for PFS and overall survival (OS). Historical controls (HCs) included 139 patients (82 unmethylated) treated on prospective clinical trials or with standard RT at our institution. Toxicities were evaluated with Common Terminology Criteria for Adverse Events v4.0., Results: Between January 2014 and December 2018, 75 evaluable patients were enrolled (39 DE-Un, 24 methylated [DE-Mth], and 12 indeterminate). PFS6 for DE-Un was 79.5% (95% confidence interval, 63.1%-90.1%). Median PFS was longer for DE-Un patients compared with historical controls (8.7 months vs 6.6 months; P = .017). OS was similarly longer, but the difference was not significant (16.0 vs 13.5 months; P = .13). OS was significantly improved for DE-Mth patients compared with HC-Mth (35.5 vs 23.3 months; P = .049) despite nonsignificant improvement in PFS (10.7 vs 9.0 months; P = .26). Grade 3 central nervous system necrosis occurred in 13% of patients, but treatment with bevacizumab improved symptoms in all cases., Conclusions: 18 F-DOPA PET-guided DERT appears to be safe, and it significantly improves PFS in MGMT unmethylated glioblastoma. OS is significantly improved in MGMT methylated patients. Further investigation of 18 F-DOPA PET biologic guided DERT for glioblastoma is warranted., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction : Recent discoveries in the molecular makeup of gliomas, the relationship of certain molecular drivers, and the patient's response to therapy and overall prognosis have resulted in a paradigm shift and redefined our understanding of glioma and revealed potential vulnerabilities within this recalcitrant and lethal disease. Areas covered : We summarize the current classification of malignant glioma in the context of the historical background, current data-driven treatment strategies, and recent discoveries of the mechanisms of pathogenesis of this disease which recapitulates the developing brain. We describe the relationship to common genetic alterations found in glioma, and possible avenues to exploit these newly revealed mechanisms. Expert opinion : Improved understanding of the molecular underpinnings of this disease has been directly translated into treatment decisions and an improved ability to counsel patients regarding their prognosis. We are beginning to see the first glimmer of a return on the investment in regard to immunotherapy in malignant glioma, with further anticipated successful exploitations of the unique pathophysiology of glioma.

Objective: Asthma poses an increased risk for serious pneumococcal disease, but little is known about the influence of asthma status on the 23-valent serotype-specific pneumococcal antibody response. We examined differences in antibody titers between pre- and post-vaccination with 23-valent pneumococcal polysaccharide vaccine (PPSV-23) in relation to asthma status. Methods: Asthma status was retrospectively ascertained by the Predetermined Asthma Criteria in an existing vaccine cohort through comprehensive medical record review. Twenty-three serotype-specific pneumococcal antibody titers measured at baseline and 4-6 weeks post-vaccination were analyzed. Vaccine responses to PPSV-23 were calculated from pre- to post-vaccine titers for each of the serotypes. Results: Of the 64 eligible and enrolled subjects, 18 (28%) had asthma. Controls (i.e., subjects without asthma) demonstrated a statistically significant fold change response compared to their baseline for all serotypes, while those with asthma did not mount a significant response to serotypes 7F, 22F, and 23F. The overall vaccine response as measured by fold change over baseline was lower in subjects with asthma than controls. Conclusions: Poorer humoral immune responses to PPSV-23 as measured by fold change were more likely to be observed in subjects with asthma compared to controls. We recommend the consideration of asthma status when interpreting vaccine response for immune competence workup through larger studies. Further studies are warranted to replicate these findings.

Antibody-mediated rejection leads to allograft loss after kidney transplantation. Bortezomib has been used in adults for the reversal of antibody-mediated rejection; however, pediatric data are limited. This retrospective study was conducted in collaboration with the Midwest Pediatric Nephrology Consortium. Pediatric kidney transplant recipients who received bortezomib for biopsy-proven antibody-mediated rejection between 2008 and 2015 were included. The objective was to characterize the use of bortezomib in pediatric kidney transplant recipients. Thirty-three patients received bortezomib for antibody-mediated rejection at nine pediatric kidney transplant centers. Ninety percent of patients received intravenous immunoglobulin, 78% received plasmapheresis, and 78% received rituximab. After a median follow-up of 15 months, 65% of patients had a functioning graft. The estimated glomerular filtration rate improved or stabilized in 61% and 36% of patients at 3 and 12 months post-bortezomib, respectively. The estimated glomerular filtration rate at diagnosis significantly predicted estimated glomerular filtration rate at 12 months after adjusting for chronic histologic changes (P .001). Fifty-six percent of patients showed an at least 25% reduction in the mean fluorescence intensity of the immune-dominant donor-specific antibody, 1-3 months after the first dose of bortezomib. Non-life-threatening side effects were documented in 21 of 33 patients. Pediatric kidney transplant recipients tolerated bortezomib without life-threatening side effects. Bortezomib may stabilize estimated glomerular filtration rate for 3-6 months in pediatric kidney transplant recipients with antibody-mediated rejection., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

PARP inhibition can enhance the efficacy of temozolomide and prolong survival in orthotopic glioblastoma (GBM) xenografts. The aim of this study was to evaluate the combination of the PARP inhibitor rucaparib with temozolomide and to correlate pharmacokinetic and pharmacodynamic studies with efficacy in patient-derived GBM xenograft models. The combination of rucaparib with temozolomide was highly effective in vitro in short-term explant cultures derived from GBM12, and, similarly, the combination of rucaparib and temozolomide (dosed for 5 days every 28 days for 3 cycles) significantly prolonged the time to tumor regrowth by 40% in heterotopic xenografts. In contrast, the addition of rucaparib had no impact on the efficacy of temozolomide in GBM12 or GBM39 orthotopic models. Using Madin-Darby canine kidney (MDCK) II cells stably expressing murine BCRP1 or human MDR1, cell accumulation studies demonstrated that rucaparib is transported by both transporters. Consistent with the influence of these efflux pumps on central nervous system drug distribution, Mdr1a/b(-/-)Bcrp1(-/-) knockout mice had a significantly higher brain to plasma ratio for rucaparib (1.61 ± 0.25) than wild-type mice (0.11 ± 0.08). A pharmacokinetic and pharmacodynamic evaluation after a single dose confirmed limited accumulation of rucaparib in the brain is associated with substantial residual PARP enzymatic activity. Similarly, matrix-assisted laser desorption/ionization mass spectrometric imaging demonstrated significantly enhanced accumulation of drug in flank tumor compared with normal brain or orthotopic tumors. Collectively, these results suggest that limited drug delivery into brain tumors may significantly limit the efficacy of rucaparib combined with temozolomide in GBM., (©2015 American Association for Cancer Research.)

Objective: To determine the frequency of initial misclassification of diabetes mellitus (DM) in children and to compare the presenting features of DM1, DM2, and the misclassified cases., Results: A total of 206 patients fulfilled the inclusion criteria. Of them, 74.75% had DM1 and 25.25% had DM2. Ten percent of studied patients had a subsequent change in classification. The mean HbA1c of the DM2 patients, who were initially misclassified, was 13.35% (SD = 1.96). The mean HbA1c of DM2 patients with correct initial classification was 8.83% (SD = 3.01). Diabetes ketoacidosis (DKA) was seen in 59.44% of DM1 and 23.91% of DM2 patients. Of the DM2 patients who were initially misclassified, 58.82% had presented in DKA as opposed to only 6.45% of patients who were correctly classified., Conclusion: The initial classification of DM frequently requires revision (10% in this study). The misclassification is highest among DM2 patients who initially present with higher HbA1c and DKA.