Frontal theta reveals further information about neural valence-dependent processing of augmented feedback in extensive motor practice-A secondary analysis.

Supplementing an earlier analysis of event-related potentials in extensive motor learning (Margraf et al., 2022a, 2022b), frontal theta-band activity (4-8 Hz) was scrutinized. Thirty-seven participants learned a sequential arm movement with 192 trials in each of five practice sessions. Feedback, based on a performance adaptive bandwidth, was given after every trial. Electroencephalogram (EEG) was recorded in the first and last practice sessions. The degree of motor automatization was tested under dual-task conditions in a pre-test-post-test design. Quantitative error information was transported in both feedback conditions (positive and negative). Frontal theta activity was discussed as a general signal that cognitive control is needed and, therefore, was expected to be higher after negative feedback. Extensive motor practice promotes automatization, and therefore, decreased frontal theta activity was expected in the later practice. Further, it was expected that frontal theta was predictive for subsequent behavioural adaptations and the amount of motor automatization. As the results show, induced frontal theta power was higher after negative feedback and decreased after five sessions of practice. Moreover, induced theta activity was predictive for error correction and, therefore, an indicator of whether the recruited cognitive resources successfully induced behavioural adaptations. It remains to be solved why these effects, which fit well with the theoretical assumptions, were only revealed by the induced part of frontal theta activity. Further, the amount of theta activity during practice was not predictive for the degree of motor automatization. It seems that there might be a dissociation between attentional resources associated with feedback processing and attentional resources associated with motor control.

Pleuropulmonary Blastoma: A Single-center Case Series of 6 Patients.

Pleuropulmonary blastoma (PPB) is a rare malignancy of childhood which when left untreated often shows pathologic progression resulting in a more aggressive neoplasm with an increasingly poor prognosis. Because of this it is important to diagnose and initiate treatment early. However, early stage PPB can appear as a cystic lung lesion on imaging and can be easily misdiagnosed given the rarity of the malignancy. Moreover, current therapeutic guidelines for these lesions are not well established, making treatment decisions and management difficult for clinicians. DICER1 mutations are known to be present in a majority of PPBs with or without a germline mutation and may be part of a familial tumor predisposition syndrome. The clinical, pathologic, and genetic data of 6 patients are summarized here. Two patients with type I PPB and 4 patients with type II PPB underwent surgical and chemotherapeutic treatment and all are alive and without recurrence 1 to 13 years after treatment. With increasing awareness of PPB, it is important for clinicians to consider this malignant entity in the evaluation and treatment of patients presenting with a cystic lung abnormality, especially in cases with a history strongly suggestive of a DICER1 mutation.

Genomic analysis of diffuse pediatric low-grade gliomas identifies recurrent oncogenic truncating rearrangements in the transcription factor MYBL1.

Pediatric low-grade gliomas (PLGGs) are among the most common solid tumors in children but, apart from BRAF kinase mutations or duplications in specific subclasses, few genetic driver events are known. Diffuse PLGGs comprise a set of uncommon subtypes that exhibit invasive growth and are therefore especially challenging clinically. We performed high-resolution copy-number analysis on 44 formalin-fixed, paraffin-embedded diffuse PLGGs to identify recurrent alterations. Diffuse PLGGs exhibited fewer such alterations than adult low-grade gliomas, but we identified several significantly recurrent events. The most significant event, 8q13.1 gain, was observed in 28% of diffuse astrocytoma grade IIs and resulted in partial duplication of the transcription factor MYBL1 with truncation of its C-terminal negative-regulatory domain. A similar recurrent deletion-truncation breakpoint was identified in two angiocentric gliomas in the related gene v-myb avian myeloblastosis viral oncogene homolog (MYB) on 6q23.3. Whole-genome sequencing of a MYBL1-rearranged diffuse astrocytoma grade II demonstrated MYBL1 tandem duplication and few other events. Truncated MYBL1 transcripts identified in this tumor induced anchorage-independent growth in 3T3 cells and tumor formation in nude mice. Truncated transcripts were also expressed in two additional tumors with MYBL1 partial duplication. Our results define clinically relevant molecular subclasses of diffuse PLGGs and highlight a potential role for the MYB family in the biology of low-grade gliomas.

Mutation in the type IB bone morphogenetic protein receptor Alk6b impairs germ-cell differentiation and causes germ-cell tumors in zebrafish.

Germ-cell tumors (GCTs), which arise from pluripotent embryonic germ cells, exhibit a wide range of histologic differentiation states with varying clinical behaviors. Although testicular GCT is the most common cancer of young men, the genes controlling the development and differentiation of GCTs remain largely unknown. Through a forward genetic screen, we previously identified a zebrafish mutant line, tgct, which develops spontaneous GCTs consisting of undifferentiated germ cells [Neumann JC, et al. (2009) Zebrafish 6:319-327]. Using positional cloning we have identified an inactivating mutation in alk6b, a type IB bone morphogenetic protein (BMP) receptor, as the cause of the zebrafish GCT phenotype. Alk6b is expressed in spermatogonia and early oocytes, and alk6b mutant gonads display impaired BMP signal transduction, altered expression of BMP target genes, and abnormal germ-cell differentiation. We find a similar absence of BMP signaling in undifferentiated human GCTs, such as seminomas and embryonal carcinoma, but not in normal testis or in differentiated GCTs. These results indicate a germ-cell-autonomous role for BMP signal transduction in germ-cell differentiation, and highlight the importance of the BMP pathway in human GCTs.

Novel FOXF1 mutations in sporadic and familial cases of alveolar capillary dysplasia with misaligned pulmonary veins imply a role for its DNA binding domain.

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare and lethal developmental disorder of the lung defined by a constellation of characteristic histopathological features. Nonpulmonary anomalies involving organs of gastrointestinal, cardiovascular, and genitourinary systems have been identified in approximately 80% of patients with ACD/MPV. We have collected DNA and pathological samples from more than 90 infants with ACD/MPV and their family members. Since the publication of our initial report of four point mutations and 10 deletions, we have identified an additional 38 novel nonsynonymous mutations of FOXF1 (nine nonsense, seven frameshift, one inframe deletion, 20 missense, and one no stop). This report represents an up to date list of all known FOXF1 mutations to the best of our knowledge. Majority of the cases are sporadic. We report four familial cases of which three show maternal inheritance, consistent with paternal imprinting of the gene. Twenty five mutations (60%) are located within the putative DNA-binding domain, indicating its plausible role in FOXF1 function. Five mutations map to the second exon. We identified two additional genic and eight genomic deletions upstream to FOXF1. These results corroborate and extend our previous observations and further establish involvement of FOXF1 in ACD/MPV and lung organogenesis.

Common pediatric cerebellar tumors: correlation between cell densities and apparent diffusion coefficient metrics.

PURPOSE: To test whether there is correlation between cell densities and apparent diffusion coefficient (ADC) metrics of common pediatric cerebellar tumors. MATERIALS AND METHODS: This study was reviewed for issues of patient safety and confidentiality and was approved by the Institutional Review Board of the University of Texas Southwestern Medical Center and was compliant with HIPAA. The need for informed consent was waived. Ninety-five patients who had preoperative magnetic resonance imaging and surgical pathologic findings available between January 2003 and June 2011 were included. There were 37 pilocytic astrocytomas, 34 medulloblastomas (23 classic, eight desmoplastic-nodular, two large cell, one anaplastic), 17 ependymomas (13 World Health Organization [WHO] grade II, four WHO grade III), and seven atypical teratoid rhabdoid tumors. ADCs of solid tumor components and normal cerebellum were measured. Tumor-to-normal brain ADC ratios (hereafter, ADC ratio) were calculated. The medulloblastomas and ependymomas were subcategorized according to the latest WHO classification, and tumor cellularity was calculated. Correlation was sought between cell densities and mean tumor ADCs, minimum tumor ADCs, and ADC ratio. RESULTS: When all tumors were considered together, negative correlation was found between cellularity and mean tumor ADCs (ρ = -0.737, P < .05) and minimum tumor ADCs (ρ = -0.736, P < .05) of common pediatric cerebellar tumors. There was no correlation between cellularity and ADC ratio. Negative correlation was found between cellularity and minimum tumor ADC in atypical teratoid rhabdoid tumors (ρ = -0.786, P < .05). In atypical teratoid rhabdoid tumors, no correlation was found between cellularity and mean tumor ADC and ADC ratio. There was no correlation between the ADC metrics and cellularity of the pilocytic astrocytomas, medulloblastomas, and ependymomas. CONCLUSION: Negative correlation was found between cellularity and ADC metrics of common pediatric cerebellar tumors. Although ADC metrics are useful in the preoperative diagnosis of common pediatric cerebellar tumors and this utility is generally attributed to differences in cellularity of tumors, tumor cellularity may not be the sole determinant of the differences in diffusivity.

Management of intratonsillar abscess in children.

BACKGROUND: The aim of this study was to assess outcomes of medical and surgical treatment of intratonsillar abscess in children. METHODS: The medical charts of children with intratonsillar abscess were reviewed to obtain information on history and physical examination, imaging, management, and follow-up assessment. RESULTS: Eleven children (six male, five female; age range, 4-18 years) were identified. The common complaints included sore throat, fever, and odynophagia. Asymmetric tonsil hypertrophy was present in nine patients and erythema of tonsils in all patients. Peritonsillar fullness was present in three patients. One patient needed emergency intubation due to respiratory compromise. Computed tomography indicated unilateral intratonsillar abscess in nine patients, bilateral intratonsillar abscess in one, and unilateral phlegmon in one. Inflammatory changes were observed in the parapharyngeal space in all patients, retropharyngeal space in one, and pyriform sinus and aryepiglottic folds in two. Antibiotic treatment included clindamycin in seven patients, ampicillin/sulbactam in one, and clindamycin plus ceftriaxone in three. The patients with respiratory compromise underwent surgery prior to antibiotic treatment. Patients with isolated intratonsillar abscess or phlegmon had resolution of their symptoms with i.v. antibiotic treatment. Patients with combination of intratonsillar and peritonsillar abscess required incision and drainage of peritonsillar abscess. CONCLUSIONS: Clinically stable children with intratonsillar abscess or phlegmon respond to i.v. antibiotic therapy. Surgical drainage can accomplish clinical resolution in the presence of a combination of intra- and peri-tonsillar abscess, airway compromise, or unresponsiveness to medical treatment.

Valence-dependent neural correlates of augmented feedback processing in extensive motor sequence learning - Part II: Predictive value of event-related potentials for behavioral adaptation and learning.

To examine the neural processing of valence-dependent augmented feedback, 38 students learned a sequential arm movement task with 192 trials in each of five practice sessions. The degree of motor automatization was tested under dual-task-conditions. Electroencephalogram (EEG) was recorded in the first and last practice session. This study is an additional analysis of the data from Margraf et al. [Margraf, L., Krause, D., & Weigelt, M. (this issue). Valence-dependent neural correlates of augmented feedback processing in extensive motor sequence learning - Part I: Practice-related changes of feedback processing.]. While Part I focused on changes in neural feedback processing after extensive motor practice, Part II examines coherences between neural feedback processing and short-term behavioral adaptations, as well as different dimensions of long-term learning (i.e., accuracy, consistency, and automaticity). It was found that more negative amplitudes of the feedback-related-negativity (FRN) after negative feedback were predictive for goal-independent changes of behavior in the early practice phase, whereas more positive amplitudes of the late fronto-central positivity (LFCP) after negative feedback were predictive for goal-directed behavioral adaptations (error reduction), independent from the practice phase. Unexpectedly, more positive amplitudes of the P300 after positive feedback were also predictive for goal-directed behavioral adaptations. Concerning long-term learning and motor automatization, a positive correlation was found for the reduction of dual-task costs (DTC) and LFCP-amplitudes after positive feedback in the early practice.

Valence-dependent Neural Correlates of Augmented Feedback Processing in Extensive Motor Sequence Learning - Part I: Practice-related Changes of Feedback Processing.

Several event-related potentials (ERPs) are associated with the processing of valence-dependent augmented feedback during the practice of motor tasks. In this study, 38 students learned a sequential arm-movement-task with 192 trials in each of five practice sessions (960 practice trials in total), to examine practice-related changes in neural feedback processing. Electroencephalogram (EEG) was recorded in the first and last practice session. An adaptive bandwidth for movement accuracy led to equal amounts of positive and negative feedback. A frontal located negative deflection in the time window of the feedback-related negativity (FRN) was more negative for negative feedback and might reflect reward prediction errors in reinforcement learning. This negativity increased after extensive practice, which might indicate that smaller errors are harder to identify in the later phase. The late fronto-central positivity (LFCP) was more positive for negative feedback and is assumed to be associated with supervised learning and behavioral adaptations based on feedback with higher complexity. No practice-related changes of the LFCP were observed, which suggests that complex feedback is processed independent from the practice phase. The P300 displayed a more positive activation for positive feedback, which might be interpreted as the higher significance of positive feedback for the updating of internal models in this setting. A valence-independent increase of the P300 amplitude after practice might reflect an improved ability to update the internal representation based on feedback information. These results demonstrate that valence-dependent neural feedback processing changes with extensive practice of a novel motor task. Dissociating changes in latencies of different components support the assumption that they are related to distinct mechanisms of feedback-dependent learning.

Multidisciplinary Multiagent Treatment of Complex Lymphatic Anomalies with Severe Bone Disease: A Single-Site Experience.

Background: Complex lymphatic anomalies (CLA) are a group of conditions that pose diagnostic and therapeutic challenges due to their rarity and overlapping clinical findings. This case series describes the complex pathology and novel combination therapies of three patients diagnosed with various types of CLA. Methods and Results: A retrospective review of medical records was performed for three patients treated for CLA between 2011 and 2019. Diagnostics, imaging, treatment, and follow-up were reviewed in the electronic medical record and combined with the literature review within the analysis. One patient had involvement of her skull base and ear canals, diagnosed after ear canal abnormalities were detected on computed tomography following meningitis. The second patient had involvement of her posterior ribs and T7-T12 vertebral bodies, with thoracic instability requiring a back brace. The third patient had involvement of his left lower extremity and hemipelvis, necessitating a left above the knee amputation. Case 1 progressed on sirolimus and pamidronate but responded to zoledronic acid (ZA). She developed flares of coagulopathy and cellulitis that required reinforcement with vincristine and steroid pulses. Similarly, case 2 progressed on sirolimus and ZA alone, but achieved stable disease with added vincristine. Upon further disease progression, stabilization was obtained by the reinforcement of ZA. Case 3 required a combination of surgery as well as medical management with sirolimus and pamidronate. All three patients now have stable disease. Conclusion: This case series depicts a multidisciplinary and multiagent approach to the management of CLA with severe bony involvement using sirolimus, bisphosphonates, vincristine, and steroids.

mTORC1 activation in childhood ependymoma and response to sirolimus.

Recurrent ependymomas are considered rarely responsive to chemotherapy and often have a dismal prognosis after tumor progression. Below is a brief report of a 6 year old child with a multiply progressive ependymoma whose tumor had a near complete response to sirolimus that was durable for 18 months. Immunohistochemistry for phosphorylated S6, which has been reported to be associated with tumor sensitivity to mTORC1 inhibitors, was positive in this patient's tumor.

Conformal Radiation Therapy for Pediatric Patients with Low-Grade Glioma: Results from the Children's Oncology Group Phase 2 Study ACNS0221.

PURPOSE: To determine the rate of marginal relapse, progression-free survival (PFS), and overall survival (OS) in patients with pediatric low-grade glioma (PLGG) treated with conformal radiation therapy (CRT) with a clinical target volume (CTV) margin of 5 mm in the Children's Oncology Group trial ACNS0221. METHODS AND MATERIALS: Patients aged 3 to 21 years with unresectable progressive, recurrent, or residual PLGG were eligible for this study. Patients younger than 10 years were required to have received at least 1 chemotherapy course. Patients with neurofibromatosis type I were not eligible. All patients underwent magnetic resonance imaging-based planning and received 54 Gy CRT in 30 fractions with a 5-mm CTV margin. RESULTS: Of 85 eligible patients (median age, 13.6 years) treated between March 2006 and December 2010, 14 were younger than 10 years and 36 received prior chemotherapy. Sixty-six had pilocytic astrocytoma, 15 had other histologic subtypes, and 4 had unbiopsied chiasmatic lesions. Events included 23 relapses (19 central, 4 distant, and no marginal) and 7 deaths. At a median follow-up of 5.15 years, 5-year PFS was 71% ± 6% and OS was 93% ± 4%. Male sex (P = .068) and large tumor size (P = .050) trended toward significance for association with decreased PFS. Age, histology, tumor location, time between diagnosis and study entry, and MIB-1 status were not associated with PFS. OS was negatively associated with male sex (P = .064), non-pilocytic astrocytoma histology (P = .010), and large tumor size (P = .0089). CONCLUSIONS: For patients with PLGG, CRT with a CTV margin of 5 mm yields an acceptable PFS and does not lead to a high rate of marginal relapse.

Study of the MIB-1 labeling index as a predictor of tumor progression in pilocytic astrocytomas in children and adolescents.

PURPOSE: The pilocytic astrocytoma (PA) is the most common childhood brain tumor. This report examines the MIB-1 labeling index (LI) as a predictor of progression-free survival (PFS) among childhood PAs. PATIENTS AND METHODS: Consecutive PAs were examined to determine whether the MIB-1 LI was associated with tumor progression. Other variables evaluated included tumor location, use of adjuvant therapy, extent of resection, and age at diagnosis. RESULTS: One hundred forty-one children were identified (mean +/- SD age, 7.6 +/- 4.7 years; range, 0.43 to 18.56 years); 118 children had adequate tissue for MIB-1 immunohistochemistry. The 5-year PFS was 61.25%. By log-rank analysis, an MIB-1 LI of more than 2.0 was associated with shortened PFS (P =.035). Patients with PAs who underwent complete surgical resection, had tumors located in the cerebellum, and were treated with surgery only also had more prolonged PFS (P =.001 for all). Tumors in the optic pathways were associated with a shorter PFS (P =.001). Restricting the evaluation of MIB-1 LI to only incompletely resected tumors revealed an insignificant trend of MIB-1 LI of more than 2.0 having a shortened PFS. Multivariate analysis demonstrated completely resected tumors and tumors located in the cerebellum as less likely to progress (P =.001 and.019, respectively). CONCLUSION: Children with PAs with an MIB-1 LI of more than 2.0 have a shortened PFS. PAs that are completely resected and are located in the cerebellum have a prolonged PFS. This initial study suggests that the MIB-1 LI identifies a more aggressive subset of PAs. Further work should focus on elucidating features of pilocytic astocytomas that will identify prospectively children at risk for progression.

Pediatric oligodendrogliomas: a study of molecular alterations on 1p and 19q using fluorescence in situ hybridization.

Oligodendrogliomas (OGs) are rare in children and have not been well characterized from a molecular viewpoint. In adults, losses on chromosomes 1p and/or 19q are common in "oligodendroglial" neoplasms and are highly associated with chemosensitivity and greater length of survival, especially in the anaplastic category. We have analyzed the 1p/19q status of pediatric OGs and compared it with similar alterations in adult OGs. Paraffin sections from 26 pediatric OGs (21 WHO Grade II OGs: 2 anaplastic oligodendrogliomas [AOGs]: and 3 mixed oligo-astrocytomas [MOA]) were retrieved. Fluorescence in situ hybridization (FISH) was performed using probes spanning the 1p32 and 19q13 regions. In tumors from children 0 to 9 years of age (n = 15), none had any deletions on 1p or 19q, but 2 had polysomies for 1p and/or 19q. All are alive and 4 have had recurrences. In tumors from children > 9 years, losses were identified on chromosomes 1p (5/11; 45%) and/or 19q (3/11; 27%), but to a much lesser extent than that observed in adult OGs. Tumors from 6 older patients also had polysomies for 1p and/or 19q. Although the majority of the older children are alive, 4 had recurrences. Curiously, 2 of the older children with AOGs had combined losses and polysomies on 1p and 19q, but responded poorly to treatment and died within a year. We conclude that alterations on 1p or 19q are infrequent in pediatric compared to adult OGs and are virtually absent in OGs presenting in the first decade of life. Compared to adults therefore, different genetic pathways are likely involved in the pathogenesis of most pediatric OGs. Genomic screening on a larger series is clearly indicated to delineate the unique molecular characteristics of these rare pediatric tumors.

Placental histopathology of congenital syphilis.

OBJECTIVE: To evaluate the contribution of placental histopathology to the diagnosis of congenital syphilis. METHODS: From January 1, 1986, through December 31, 1998, all pregnant women presenting to a large, urban Dallas County labor and delivery unit with untreated syphilis at delivery and who had placental evaluation performed were identified. Women were clinically staged, and the infants were evaluated for congenital syphilis using a standard protocol. Each placenta was evaluated by two independent pathologists. Histologic characteristics of the placenta related to congenital syphilis in live-born and stillborn infants were then analyzed. RESULTS: Sixty-seven women met the study criteria: 33 (49%) stillborn and 18 (27%) live-born infants with congenital syphilis, 15 (22%) uninfected live-born infants, and one uninfected stillborn fetus diagnosed by current criteria. There were no differences between the groups with regard to demographic characteristics, prenatal care, or stage of syphilis. Stillborn infants were more likely to deliver preterm (P <.001). Controlling for gestational age, histopathology revealed necrotizing funisitis, villous enlargement, and acute villitis associated with congenital syphilis. Erythroblastosis was more common in stillborn infants with congenital syphilis than all live-born infants (odds ratio 16, 95% confidence interval 1, 370). The addition of histologic evaluation to conventional diagnostic evaluations improved the detection rate for congenital syphilis from 67% to 89% in live-born infants, and 91% to 97% in stillborn infants. CONCLUSION: Our results show that histopathologic examination of the placenta is a valuable adjunct to the contemporary diagnostic criteria used to diagnose congenital syphilis.

Hepatic mesenchymal hamartoma with translocation involving chromosome band 19q13.4: a recurrent abnormality.

We report a case of mesenchymal hamartoma of the liver in an 8-month-old male child, in which the cytogenetic analysis revealed a balanced translocation, t(11;19)(q13;q13.4). This is the fifth description of a cytogenetic abnormality in mesenchymal hamartoma and is similar to the four cases reported previously in that one of the breakpoints involved chromosome band 19q13.4.

Intracerebral schwannomas: a rare disease with varying natural history.

Although intracerebral schwannomas are typically regarded as benign intracranial tumors, malignancy and recurrence have been reported among patients harboring such neoplasms. The available literature consists of case reports and small series that present variable characteristics distinguishing these unusual lesions. Little advancement has been made to further the understanding and management of these tumors. The authors present 3 cases from their institution that highlight the difference between typical benign intracerebral schwannomas and histopathological variants that may portend more aggressive behavior. Also provided is a review of the literature in the hope of gaining a better understanding of these rare tumors.

DNA fragmentation simulation method (FSM) and fragment size matching improve aCGH performance of FFPE tissues.

Whole-genome copy number analysis platforms, such as array comparative genomic hybridization (aCGH) and single nucleotide polymorphism (SNP) arrays, are transformative research discovery tools. In cancer, the identification of genomic aberrations with these approaches has generated important diagnostic and prognostic markers, and critical therapeutic targets. While robust for basic research studies, reliable whole-genome copy number analysis has been unsuccessful in routine clinical practice due to a number of technical limitations. Most important, aCGH results have been suboptimal because of the poor integrity of DNA derived from formalin-fixed paraffin-embedded (FFPE) tissues. Using self-hybridizations of a single DNA sample we observed that aCGH performance is significantly improved by accurate DNA size determination and the matching of test and reference DNA samples so that both possess similar fragment sizes. Based on this observation, we developed a novel DNA fragmentation simulation method (FSM) that allows customized tailoring of the fragment sizes of test and reference samples, thereby lowering array failure rates. To validate our methods, we combined FSM with Universal Linkage System (ULS) labeling to study a cohort of 200 tumor samples using Agilent 1 M feature arrays. Results from FFPE samples were equivalent to results from fresh samples and those available through the glioblastoma Cancer Genome Atlas (TCGA). This study demonstrates that rigorous control of DNA fragment size improves aCGH performance. This methodological advance will permit the routine analysis of FFPE tumor samples for clinical trials and in daily clinical practice.

Proliferative and metabolic markers in incompletely excised pediatric pilocytic astrocytomas--an assessment of 3 new variables in predicting clinical outcome.

Although pilocytic astrocytoma (PA) is the most common brain tumor diagnosed in children, few prognostic variables have been delineated that stratify the risk of clinical progression in patients with this tumor. In this study, the MIB-1 labeling index was compared with 2 other immunohistochemical markers of cell proliferation, phospho-histone H3 (PHH3) and mini-chromosomal maintenance protein 2 (MCM2) in 80 incompletely resected PAs to see which was best able to identify patients at risk for tumor progression. 0(6)-Methylguanine-DNA methyltransferase (MGMT) protein expression, which has been predictive of progression-free survival (PFS) in high-grade gliomas in children, was also evaluated in these cases. The mean follow-up period was 7.81 ± 3.9 years, and 42.8% of tumors have shown progression at the time of censoring. A MIB-1 labeling index ≥2.0 was associated with shortened PFS as a grouped variable by log-ranked analysis (P = .03) and by Cox regression analysis as a continuous variable (P = .007). None of the other potential biomarkers was significantly predictive of PFS. Although the amount of MCM2 staining correlated with the MIB-1 labeling index (P < .001), MCM2 reactivity was not independently associated with outcome. We conclude that MIB-1 labeling remains the best predictor of PFS in pediatric PAs.

Wilms tumor in a child with L-2-hydroxyglutaric aciduria.

We report a male infant with L-2-hydroxyglutaric aciduria and Wilms tumor. L-2-hydroxyglutaric aciduria is a rare, autosomal-recessive, inborn error of metabolism characterized by a variable degree of progressive encephalopathy. Of the fewer than 100 cases reported in the literature, at least 9 patients have developed tumors of the central nervous system. To our knowledge, the present case is the 1st example of an extracranial tumor associated with L-2-hydroxyglutaric aciduria. This observation potentially widens the tumor spectrum in this metabolic disorder and may lead to further insight into the relationship between L-2-hydroxyglutaric acid and cellular transformation.