John S. Myseros

Recurrent somatic mutations in ACVR1 in pediatric midline high-grade astrocytoma

Pediatric midline high-grade astrocytomas (mHGAs) are incurable with few treatment targets identified. Most tumors harbor mutations encoding p.Lys27Met in histone H3 variants. In 40 treatment-naive mHGAs, 39 analyzed by whole-exome sequencing, we find additional somatic mutations specific to tumor location. Gain-of-function mutations in ACVR1 occur in tumors of the pons in conjunction with histone H3.1 p.Lys27Met substitution, whereas FGFR1 mutations or fusions occur in thalamic tumors associated with histone H3.3 p.Lys27Met substitution. Hyperactivation of the bone morphogenetic protein (BMP)-ACVR1 developmental pathway in mHGAs harboring ACVR1 mutations led to increased levels of phosphorylated SMAD1, SMAD5 and SMAD8 and upregulation of BMP downstream early-response genes in tumor cells. Global DNA methylation profiles were significantly associated with the p.Lys27Met alteration, regardless of the mutant histone H3 variant and irrespective of tumor location, supporting the role of this substitution in driving the epigenetic phenotype. This work considerably expands the number of potential treatment targets and further justifies pretreatment biopsy in pediatric mHGA as a means to orient therapeutic efforts in this disease.

Long-term outcomes of primary craniofacial reconstruction for craniosynostosis: a 12-year experience.

Background: The purpose of this study was to critically assess long-term outcomes after open reconstruction of craniosynostosis within the recent decade. Methods: The authors performed a retrospective, institutional review board–approved review of open repair for craniosynostosis between 1997 and 2009. Surgical factors, complications, and long-term outcomes were assessed. Pearson chi-square, Fishers exact, and Kaplan-Meier analyses were performed. Results: Of 212 patients, 72 underwent primary extended synostectomy and 140 had traditional open craniofacial repair. Mean follow-up was 36.3 months (range, 0.5 to 138 months). Indications included sagittal (n = 96), metopic (n = 40), unicoronal (n = 33), bicoronal (n = 24), multisutural (n = 15), bilambdoidal (n = 3), and unilambdoidal (n = 1) synostoses; 8.5 percent of patients were syndromic. Surgical reconstruction was performed at a mean age of 11.3 months (range, 0.2 to 117.8 months), including nonsyndromic patients at an average age of 10.6 months and syndromic patients at age 19.3 months. There were no deaths. A 3.3 percent complication rate included two cerebral contusions, two hematomas, one cerebrospinal fluid leak, one infection, and one wound breakdown. Patients were categorized as 89.2 percent Whitaker class I/II and 10.8 percent Whitaker class III/IV. Major and total reoperation rates were 9.0 percent and 10.8 percent, respectively. Higher total reoperation rate and Whitaker class III/IV distribution significantly correlated with syndromic diagnosis, bicoronal synostosis, and surgical age younger than 6 months. Conclusions: In this experience of contemporary open craniosynostosis surgery, rates of morbidity, mortality, and reoperation were low. These results support the merits of surgical delay, targeting an age of 6 months or older, and may serve as a more accurate metric of comparison to current minimally invasive techniques for craniosynostosis repair.

CNS germ cell tumor (CNSGCT) of childhood: Presentation and delayed diagnosis

Objective: To describe the relationship between symptomatology and time to diagnosis of an institutional series of patients with CNS germ cell tumor (CNSGCT) over a 16-year period. Methods: Thirty consecutive patients newly diagnosed with CNSGCT (mean age 10.9 years; range 6 to 17 years; 70% boys) were evaluated at our institution between 1990 and 2006. Results: Duration of symptoms prior to diagnosis ranged from 5 days to 3 years (mean 8.4 months). Tumor location included pineal (14), suprasellar (8), pineal/suprasellar (3), pineal/thalamic (4), and basal ganglionic/thalamic (3). Five patients had disseminated disease at the time of diagnosis. Features including headache, nausea, vomiting, and visual changes led to earlier diagnosis. Symptoms including movement disorders, enuresis, anorexia, and psychiatric complaints delayed diagnosis in 9 of 30 patients, diagnosed 7 months to 3 years (mean 22.3 months) from symptom onset. In 7 of 9 patients with delayed diagnosis, enuresis was present. Seventeen of 30 patients had signs of endocrine dysfunction at presentation that included diabetes insipidus (4), hypothyroidism (8), and growth hormone deficiency (4). Ophthalmologic findings of decreased visual acuity, visual field deficits, or ocular abnormalities were present in 13 patients. Duration of symptoms did not correlate with tumor subtype or event-free survival. In three patients with basal ganglionic/temporal lobe, thalamic, or pineal/suprasellar signal abnormalities on MRI, neuroradiographic diagnosis was difficult. Conclusions: Diagnosis of CNS germ cell tumor is often delayed, and presentation may include movement disorders or mimic psychiatric disease. MRI interpretation can be challenging and may require serum/CSF markers and biopsy for diagnosis.

ACR Appropriateness Criteria® on Suspected Physical Abuse—Child

The appropriate imaging for pediatric patients being evaluated for suspected physical abuse depends on the age of the child, the presence of neurologic signs and symptoms, evidence of thoracic or abdominopelvic injuries, and whether the injuries are discrepant with the clinical history. The clinical presentations reviewed consider these factors and provide evidence-based consensus recommendations by the ACR Appropriateness Criteria(®) Expert Panel on Pediatric Imaging.

Spatial heterogeneity in medulloblastoma

Spatial heterogeneity of transcriptional and genetic markers between physically isolated biopsies of a single tumor poses major barriers to the identification of biomarkers and the development of targeted therapies that will be effective against the entire tumor. We analyzed the spatial heterogeneity of multiregional biopsies from 35 patients, using a combination of transcriptomic and genomic profiles. Medulloblastomas (MBs), but not high-grade gliomas (HGGs), demonstrated spatially homogeneous transcriptomes, which allowed for accurate subgrouping of tumors from a single biopsy. Conversely, somatic mutations that affect genes suitable for targeted therapeutics demonstrated high levels of spatial heterogeneity in MB, malignant glioma, and renal cell carcinoma (RCC). Actionable targets found in a single MB biopsy were seldom clonal across the entire tumor, which brings the efficacy of monotherapies against a single target into question. Clinical trials of targeted therapies for MB should first ensure the spatially ubiquitous nature of the target mutation.

Unreliability of intraoperative estimated blood loss in extended sagittal synostectomies

OBJECT Intraoperative blood loss represents a significant concern during open repair of craniosynostosis, and its reliable measurement remains a serious challenge. In this study of extended sagittal synostectomies, the authors analyzed the relationship between estimated blood loss (EBL) and calculated blood loss (CBL), and investigated predictors of hemodynamic outcomes. METHODS The authors reviewed outcomes in infants with sagittal synostosis who underwent primary extended synostectomies (the so-called Pi procedure) between 1997 and 2009. Patient demographic data, operating time, and mean arterial pressures (MAPs) were recorded. Serial MAPs were averaged for a MAP(mean). The EBL was based on anesthesia records, and the CBL on pre- and postoperative hemoglobin values in concert with transfusion volumes. Factors associated with EBL, CBL, red blood cell transfusion (RBCT), and hospital length of stay (LOS) were investigated. Hemodynamic outcomes were reported as percent estimated blood volume (% EBV), and relationships were analyzed using simple and multiple linear and logistic regression models. A p value < 0.05 was considered significant. RESULTS Seventy-one infants with sagittal synostosis underwent primary extended synostectomies at a mean age and weight of 4.9 months and 7.3 kg, respectively. The average operating time was 1.4 hours, and intraoperative MAP was 54.6 mm Hg (21.3% lower than preoperative baseline). There was no association between mean EBL (12.7% EBV) and mean CBL (23.6% EBV) (r = 0.059, p = 0.63). The EBL inversely correlated with the patients age (r = -0.07) and weight (r = -0.11) at surgery (p < 0.05 in both instances). With regard to intraoperative factors, EBL positively trended with operating time (r = 0.26, p = 0.09) and CBL inversely trended with MAP(mean) (r = -0.04, p = 0.10), although these relationships were only borderline significant. Intraoperative RBCT, which was required in 59.1% of patients, positively correlated with EBL (r = 1.55, p < 0.001), yet negatively trended with CBL (r = -0.40, p = 0.01). Undertransfusion was significantly more common than overtransfusion (40.8% vs 22.5%, p = 0.02, respectively). The mean hospital LOS was 2.3 days and was not significantly associated with patient demographic characteristics, intraoperative factors, blood loss, RBCT, or total fluid requirements. CONCLUSIONS In extended synostectomies for sagittal synostosis, EBL and CBL demonstrated a decided lack of correlation with one another. Intraoperative blood transfusion positively correlated with EBL, but inversely correlated with CBL, with a significantly higher proportion of patients undertransfused than overtransfused. These findings highlight the need for reliable, real-time monitoring of intraoperative blood loss to provide improved guidance for blood and fluid resuscitation.

Germinoma: Unusual Imaging and Pathological Characteristics. Report of Two Cases.

Primary germ cell neoplasms of the central nervous system typically develop as midline mass lesions during the first three decades of life. The authors present two cases with atypical clinicopathological features that stimulate discussion on the diagnosis and management of these tumors. The first patient was an 11-year-old boy of Japanese-American heritage who presented with a 6-month-long history of cognitive decline, difficulty swallowing, unsteady gait, and intermittent right-sided posturing. The initial magnetic resonance (MR) image of the brain displayed a mildly increased T2 signal in the cerebral peduncles, putamen, and globus pallidus bilaterally. Follow-up MR images showed an increase in the T2 signal abnormality in the left basal ganglia. The second patient was a 10-year-old Caucasian boy who presented with diabetes insipidus and subsequently displayed progressive fatigue, involuntary eye and mouth movements, and obsessive-compulsive behavior. An MR image demonstrated signs of mineral deposition and foci of increased T2 signal in both basal ganglia. Follow-up MR images demonstrated a progressive increase in the T2 signal (which was then located within the mesial temporal lobe). A biopsy performed on the left thalamic lesion in the first patient revealed a germinoma. The patient was treated with chemotherapy and died 2 years later. The second patient underwent a lumbar puncture, which demonstrated an elevated level of beta-human chorionic gonadotropin. Despite the lack of a mass on MR images in this child, the need for a tissue diagnosis prompted the authors to perform an anterior temporal lobectomy. The diagnosis of diffuse germinoma was confirmed, and the patient was treated with adjunctive chemotherapy. Although uncommon, germ cell tumors can present outside the midline and exhibit a multifocal growth pattern.

The influence of lesion volume, perilesion resection volume, and completeness of resection on seizure outcome after resective epilepsy surgery for cortical dysplasia in children.

OBJECT Focal cortical dysplasia (FCD) is one of the most common causes of intractable epilepsy leading to surgery in children. The predictors of seizure freedom after surgical management for FCD are still unclear. The objective of this study was to perform a volumetric analysis of factors shown on the preresection and postresection brain MRI scans of patients who had undergone resective epilepsy surgery for cortical dysplasia and to determine the influence of these factors on seizure outcome. METHODS The authors reviewed the medical records and brain images of 43 consecutive patients with focal MRI-documented abnormalities and a pathological diagnosis of FCD who had undergone surgical treatment for refractory epilepsy. Preoperative lesion volume and postoperative resection volume were calculated by manual segmentation using OsiriX PRO software. RESULTS Forty-three patients underwent first-time surgery for resection of an FCD. The age range of these patients at the time of surgery ranged from 2 months to 21.8 years (mean age 7.3 years). The median duration of follow-up was 20 months. The mean age at onset was 31.6 months (range 1 day to 168 months). Complete resection of the area of an FCD, as adjudged from the postoperative brain MR images, was significantly associated with seizure control (p = 0.0005). The odds of having good seizure control among those who underwent complete resection were about 6 times higher than those among the patients who did not undergo complete resection. Seizure control was not significantly associated with lesion volume (p = 0.46) or perilesion resection volume (p = 0.86). CONCLUSIONS The completeness of FCD resection in children is a significant predictor of seizure freedom. Neither lesion volume nor the further resection of perilesional tissue is predictive of seizure freedom.

Blood loss estimation during fronto-orbital advancement: implications for blood transfusion practice and hospital length of stay.

Background Reliable measurement of intraoperative blood loss remains a serious challenge during correction of craniosynostosis. This study analyzed the relationship between estimated blood loss (EBL) and calculated blood loss (CBL) in fronto-orbital advancement and its implications on blood transfusion practice and hospital length of stay (LOS). Methods The authors reviewed infants who underwent primary fronto-orbital advancement for craniosynostosis (1997–2009). Estimated blood loss was based on anesthesia records and CBL by preoperative/postoperative hemoglobin. Perioperative red blood cell transfusion (RCT) and hospital LOS were recorded. Results Ninety infants were included. Mean EBL was 42.2% of estimated blood volume (% EBV), and CBL was 39.3% EBV, without significant difference (P = 0.23). Bland-Altman analysis revealed that EBL was greater than CBL at lower levels of blood loss (⩽47.0% EBV) and less than CBL at higher levels (>47.0% EBV). Mean intraoperative RCT was 45.8% EBV; overtransfusion was more frequent at lower levels of bleeding, and undertransfusion at higher levels. Postoperative RCT occurred more frequently with greater blood loss. Mean LOS was 3.7 days, increasing with CBL (hazard ratio of discharge, HRdischarge = 0.988, P < 0.01), postoperative RCT (HRdischarge = 0.96, P < 0.05), total RCT (HRdischarge = 0.991, P < 0.05), and total intraoperative fluid (HRdischarge = 0.999, P < 0.05). Conclusions Estimated blood loss is a less accurate marker for CBL at the extremes of blood loss during fronto-orbital advancement. The tendency to overestimate blood loss with less intravascular volume loss can result in unnecessary transfusion, whereas underestimation with greater actual blood loss can lead to delay in resuscitation and longer hospitalization.

Pediatric Incidental Brain Tumors: a Growing Treatment Dilemma

OBJECT Rising numbers of MRI studies performed during evaluations for pediatric disorders have contributed to a significant increase in the number of incidentally found brain tumors. Currently, there is very little literature on the nature of and the preferred treatment for these incidental brain tumors. In this paper the authors review their experience diagnosing and treating these lesions in children as well as the current literature on this topic. METHODS Records from 2 centers were reviewed for incidentally found brain tumors, treatment approaches, and outcomes for both surgical and nonsurgical cohorts. RESULTS Forty-seven children (30 males and 17 females) with a mean age of 8.6 years were found to have incidental brain lesions suspected to be neoplasms. Twenty-five underwent surgery and 22 were observed. Two children in the observation group required surgery at a later stage. Tumor pathology in 24 patients was benign. Only 3 patients had high-grade tumors. All nonsurgically treated lesions were presumed to be low-grade tumors and were followed up for 25 ± 20 months. CONCLUSIONS The discovery of incidental brain tumors on MRI in children poses an increasing challenge. Additional studies are needed to determine the significance as well as the optimal management strategies in this situation.