A Comparison of Intracranial Volume Growth in Normal Children and Patients With Metopic Craniosynostosis.

BACKGROUND: The impact of metopic craniosynostosis on intracranial volume (ICV) and ICV growth is unclear. In addition, the relationship between head circumference (HC) and ICV in these patients is not previously described. METHODS: A retrospective review of 72 patients with metopic craniosynostosis was performed. The ICVs were calculated from manually segmented preoperative computed tomography scans. Magnetic resonance imaging data for 270 healthy children were available. The ICVs were calculated in FreeSurfer.First, a growth curve for metopic patients was generated and a logarithmic best-fit curve was calculated. Second, the impact of metopic craniosynostosis on ICV relative to healthy controls was assessed using multivariate linear regression. Third, the growth curves for metopic patients and healthy children were compared.Pearson's correlation was used to measure the association between HC and ICV. RESULTS: Mean metopic ICV was significantly lower than normal ICV within the first 3 to 6 months (674.9 versus 813.2 cm; P = 0.002), 6 to 9 months (646.6 versus 903.9 cm; P = 0.005), and 9 to 12 months of life (848.0 versus 956.6 cm; P = 0.038). There was no difference in ICV after 12 months of age (P = 0.916).The ICV growth in patients with metopic craniosynostosis is defined by a significantly different growth curve than in normal children (P = 0.005).The ICV and HC were highly correlated across a broad range of ICVs and patient age (r = 0.98, P < 0.001). CONCLUSION: Patients with metopic craniosynostosis have significantly reduced ICVs compared to healthy children, yet greater than normal ICV growth, which allows them to achieve normal volumes by 1 year of age. The HC is a reliable metric for ICV in these patients.

Can Head Circumference Be Used as a Proxy for Intracranial Volume in Patients With Craniosynostosis?

BACKGROUND: Calculation of intracranial volume from neuroimaging can be complex and time consuming. In the adult population, there is evidence suggesting that owing to its strong correlation, head circumference (HC) may be used as a surrogate for intracranial volume (ICV). We were interested in studying the correlation between HC and ICV in patients with craniosynostosis. METHODS: After institutional review board approval, a retrospective review was performed on patients with craniosynostosis. GE Healthcare AdW 4.3 volume assessment software was used to calculate ICV and HC based on preoperative computed tomographic scans. Pearson correlation was used to estimate correlation coefficients between ICV and HC for this patient population, with 0 to 0.3 considered a weak correlation, 0.4 to 0.6 considered a moderate correlation, 0.7 to 1 considered a strong correlation, and P < 0.05 was considered statistically significant. RESULTS: A total of 196 craniosynostosis patients were included in this study. There were 121 male and 75 female patients. Seventy-nine patients had metopic, 45 had coronal, 64 had sagittal, and 8 had lambdoid synostosis. Mean age was 8.2 months. Mean HC and ICV were 42.9 cm and 829 cm, respectively. Overall, there was a strong correlation between HC and ICV (r = 0.81). Patients were further categorized by craniosynostosis type. Very strong correlation was obtained for patients with coronal (0.89), metopic (0.98), and lambdoid craniosynostosis (0.97). Strong correlation was obtained for patients with sagittal synostosis (0.73). When categorized by sex, a stronger correlation was obtained for female patients (0.84) compared with male patients (0.80). Statistical significance was reached for all reported correlations. CONCLUSION: Our preliminary data suggest that a very strong correlation exists between HC and ICV for male and female patients with all types of craniosynostosis, making HC a useful surrogate for ICV in this patient population.

Description of Mexican Cleft Surgeons' Experience With Foreign Surgical Volunteer Missions in Mexico.

BACKGROUND AND PURPOSE: Mexican cleft surgeons provide multidisciplinary comprehensive cleft lip and palate care to children in Mexico. Many Mexican cleft surgeons have extensive experience with foreign, visiting surgeons. The purpose of this study was to characterize Mexican cleft surgeons' domestic and volunteer practice and to learn more about Mexican cleft surgeons' experience with visiting surgeons. METHODS: A cross-sectional validated e-mail survey tool was sent to Mexican cleft surgeons through 2 Mexican plastic surgery societies and the Asociación Mexicana de Labio y Paladar Hendido y Anomalías Craneofaciales, the national cleft palate society that includes plastic and maxillofacial surgeons who specialize in cleft surgery. We utilized validated survey methodology, including neutral fact-based questions and repeated e-mails to survey nonresponders to maximize validity of statistical data; response rate was 30.6% (n = 81). RESULTS: Mexican cleft surgeons performed, on average, 37.7 primary palate repairs per year with an overall complication rate of 2.5%; 34.6% (n = 28) of respondents had direct experience with patients operated on by visiting surgeons; 53.6% of these respondents performed corrective surgery because of complications from visiting surgeons. Respondents rated 48% of the functional outcomes of visiting surgeons as "acceptable," whereas 43% rated aesthetic outcomes of visiting surgeons as "poor"; 73.3% of respondents were never paid for the corrective surgeries they performed. Thirty-three percent of Mexican cleft surgeons believe that there is a role for educational collaboration with visiting surgeons. CONCLUSIONS: Mexican cleft surgeons have a high volume of primary cleft palate repairs in their domestic practice with good outcomes. Visiting surgeons may play an important role in Mexican cleft care through educational collaborations that complement the strengths of Mexican cleft surgeons.

Carfilzomib-associated pulmonary arterial hypertension in multiple myeloma.

Drug-induced pulmonary arterial hypertension (PAH) is constantly evolving as new drugs are developed. Carfilzomib is a recently approved therapy for relapsed and refractory multiple myeloma. While it has been associated with cardiovascular adverse events, such as ischemic heart disease and heart failure, PAH has not been a well-described side effect. We present two patients who developed PAH associated with initiation of carfilzomib. They both initially presented with severe dyspnea, had elevated right ventricular systolic pressure on transthoracic echocardiography and ultimately underwent right heart catheterization. With discontinuation of carfilzomib, both patients had improvement in hemodynamics. However, one patient required initiation of PAH-targeted therapies and has had worsening right ventricular function again despite permanent discontinuation of carfilzomib. It is important to recognize the association between carfilzomib and PAH. Echocardiography can be an important initial screening tool. PAH from carfilzomib therapy may be reversible, especially if diagnosed early; however, extended follow-up is essential.

Developmental phosphoproteomics identifies the kinase CK2 as a driver of Hedgehog signaling and a therapeutic target in medulloblastoma.

A major limitation of targeted cancer therapy is the rapid emergence of drug resistance, which often arises through mutations at or downstream of the drug target or through intrinsic resistance of subpopulations of tumor cells. Medulloblastoma (MB), the most common pediatric brain tumor, is no exception, and MBs that are driven by sonic hedgehog (SHH) signaling are particularly aggressive and drug-resistant. To find new drug targets and therapeutics for MB that may be less susceptible to common resistance mechanisms, we used a developmental phosphoproteomics approach in murine granule neuron precursors (GNPs), the developmental cell of origin of MB. The protein kinase CK2 emerged as a driver of hundreds of phosphorylation events during the proliferative, MB-like stage of GNP growth, including the phosphorylation of three of the eight proteins commonly amplified in MB. CK2 was critical to the stabilization and activity of the transcription factor GLI2, a late downstream effector in SHH signaling. CK2 inhibitors decreased the viability of primary SHH-type MB patient cells in culture and blocked the growth of murine MB tumors that were resistant to currently available Hh inhibitors, thereby extending the survival of tumor-bearing mice. Because of structural interactions, one CK2 inhibitor (CX-4945) inhibited both wild-type and mutant CK2, indicating that this drug may avoid at least one common mode of acquired resistance. These findings suggest that CK2 inhibitors may be effective for treating patients with MB and show how phosphoproteomics may be used to gain insight into developmental biology and pathology.