Long-Term Outcome of Time-Staged Gamma Knife Radiosurgery for Large Arteriovenous Malformations.

BACKGROUND: Treatment for large (> 10 mL) arteriovenous malformations (AVMs) remains highly challenging. This study evaluated long-term effect of time-staged gamma knife radiosurgery (GKS) for large AVMs. METHODS: For patients with large AVMs treated by time-staged GKS over 10 years, time-staged GKS was repeated every three years targeting the entire nidus if total obliteration was not achieved. Obliteration rate and post-GKS complications were assessed based on 10 mL volume interval of AVMs. Prognostic factors for these outcomes were evaluated using Cox regression analysis. RESULTS: Ninety-six patients were analyzed. For AVMs in the 10-20 mL subgroup, a dose ≥ 13.5Gy yielded higher obliteration rate in the first GKS. In the 20-30 mL subgroup, a second GKS significantly boosted obliteration. AVMs > 30 mL did not achieve any obliteration with the first GKS. Among 35 (36.4%) cases lost to follow-up, 7 (7.2%) were lost due to GKS complications. Kaplan-Meier analysis showed that each subgroup needed different time for achieving 50% favorable obliteration outcome rate: 3.5, 6.5, and 8.2 years for 10-20 mL, 20-30 mL, and > 30 mL subgroup, respectively. Total obliteration rate calculated by intention-to-treat method: 73%, 51.7%, 35.7%, respectively, 61.5% overall. Post-GKS hemorrhage and chronic encapsulated expanding hematoma (CEEH) occurred in 13.5% and 8.3% of cases, respectively. Two patients died. Dose and volume were significant prognostic factors for obliteration. Initial AVM volume was a significant prognostic factor of post-GKS hemorrhage and CEEH. CONCLUSION: Time-staged GKS for large AVMs less than 30 mL has highly favorable long-term outcome and a tolerable complication rate.

Long-Term Outcomes of Gamma Knife Radiosurgery for Cerebral Cavernous Malformations: 10 Years and Beyond.

BACKGROUND: We aimed to evaluate long-term outcomes of gamma knife radiosurgery (GKS) for cerebral cavernous malformations (CCMs). METHODS: Among the 233 CCM patients who underwent GKS, 79 adult patients (96 lesions) followed for over 10 years were included and analyzed retrospectively. Annual hemorrhage rate (AHR) was analyzed the entire cohort of 233 patients and the subset of 79 enrolled patients by dividing lesions into overall CCM lesions and brainstem lesions. AHR, neurologic outcome, adverse radiation effect (ARE), and changes of lesions in magnetic resonance imaging (MRI) were compared before and after GKS. Cox-regression analysis was performed to identify risk factors for hemorrhage following GKS. RESULTS: Mean follow-up duration of 79 enrolled patients was 14 years (range, 10-23 years). The AHR of all CCMs for entire cohort at each time point was 17.8% (pre-GKS), 5.9% (≤ 2 years post-GKS), 1.8% (≤ 10 years post-GKS). The AHR of all CCM for 79 enrolled patients was 21.4% (pre-GKS), 3.8% (2 years post-GKS), 1.4% (10 years post-GKS), and 2.3% (> 10 years post-GKS). The AHR of brainstem cavernous malformation (CM) for entire cohort at each time point was 22.4% (pre-GKS), 10.1% (≤ 2 years post-GKS), 3.2% (≤ 10 years post-GKS). The AHR of brainstem CM for 79 enrolled patients was 27.2% (pre-GKS), 5.8% (2 years post-GKS), 3.4% (10 years post-GKS), and 3.5% (> 10 years post-GKS). Out of the 79 enrolled patients, 35 presented with focal neurologic deficits at the initial clinical visit. Among these patients, 74.3% showed recovery at the last follow-up. Symptomatic ARE occurred in five (6.4%) patients. No mortality occurred. Most lesions were decreased in size at the last follow-up MRI. Previous hemorrhage history (hazard ratio [HR], 8.38; 95% confidence interval [CI], 1.07-65.88; P = 0.043), and brainstem location (HR, 3.10; 95% CI, 1.26-7.64; P = 0.014) were significant risk factors for hemorrhage event. CONCLUSION: GKS for CCM showed favorable long-term outcomes. GKS should be considered for CCM, especially when it has a previous hemorrhage history and brainstem location.

Long-Term Outcome of Unilateral Acoustic Neuromas With or Without Hearing Loss: Over 10 Years and Beyond After Gamma Knife Radiosurgery.

BACKGROUND: Since the long-term outcomes of 162 patients who underwent gamma knife radiosurgery (GKS) as an initial or adjuvant treatment for acoustic neuromas (ANs) with unilateral hearing loss were first reported in 1998, there has been no report of a comprehensive analysis of what has changed in GKS practice. METHODS: We performed a retrospective study of the long-term outcomes of 106 patients with unilateral sporadic ANs who underwent GKS as an initial treatment. The mean patient age was 50 years, and the mean initial tumor volume was 3.68 cm3 (range, 0.10-23.30 cm3). The median marginal tumor dose was 12.5 Gy (range, 8.0-15.0 Gy) and the median follow-up duration was 153 months (range, 120-216 months). RESULTS: The tumor volume increased in 11 patients (10.4%), remained stationary in 27 (25.5%), and decreased in 68 patients (64.2%). The actuarial 3, 5, 10, and 15-year tumor control rates were 95.3 ± 2.1%, 94.3 ± 2.2%, 87.7 ± 3.2%, and 86.6 ± 3.3%, respectively. The 10-year actuarial tumor control rate was significantly lower in the patients with tumor volumes of ≥ 8 cm3 (P = 0.010). The rate of maintaining the same Gardner-Robertson scale grade was 28.6%, and that of serviceable hearing was 46.4%. The rates of newly developed facial and trigeminal neuropathy were 2.8% and 4.7%, respectively. The patients who received marginal doses of less than 12 Gy revealed higher tumor control failure rates (P = 0.129) and newly occurred facial or trigeminal neuropathy rates (P = 0.040 and 0.313, respectively). CONCLUSION: GKS as an initial treatment for ANs could be helpful in terms of tumor control, the preservation of serviceable hearing, and the prevention of cranial neuropathy. It is recommended to perform GKS as soon as possible not only for tumor control in unilateral ANs with hearing loss but also for hearing preservation in those without hearing loss.

Intracranial juvenile xanthogranuloma in an infant.

Juvenile xanthogranuloma (JXG) is a type of non-Langerhans cell histiocytosis that most commonly manifests as a solitary cutaneous lesion of the head and neck in children. Intracranial JXG is extremely rare. Although it is widely known that JXG skin lesions gradually disappear over time without treatment, treatment guidelines for intracranial JXG have not been established. It is very difficult to predict whether an intracranial lesion is JXG with only a pre-operative imaging work-up without pathologic confirmation. We report a case of the youngest, a 3-month-old male infant with an intracranial extra-axial mass with rapid growth for 2 months. Additionally, we suggest characteristic MRI findings for intracranial extra-axial JXG of a low T2 signal and a kidney bean shape.

Identification of novel therapeutic target genes in acquired lapatinib-resistant breast cancer by integrative meta-analysis.

Acquired resistance to lapatinib is a highly problematic clinical barrier that has to be overcome for a successful cancer treatment. Despite efforts to determine the mechanisms underlying acquired lapatinib resistance (ALR), no definitive genetic factors have been reported to be solely responsible for the acquired resistance in breast cancer. Therefore, we performed a cross-platform meta-analysis of three publically available microarray datasets related to breast cancer with ALR, using the R-based RankProd package. From the meta-analysis, we were able to identify a total of 990 differentially expressed genes (DEGs, 406 upregulated, 584 downregulated) that are potentially associated with ALR. Gene ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of the DEGs showed that "response to organic substance" and "p53 signaling pathway" may be largely involved in ALR process. Of these, many of the top 50 upregulated and downregulated DEGs were found in oncogenesis of various tumors and cancers. For the top 50 DEGs, we constructed the gene coexpression and protein-protein interaction networks from a huge database of well-known molecular interactions. By integrative analysis of two systemic networks, we condensed the total number of DEGs to six common genes (LGALS1, PRSS23, PTRF, FHL2, TOB1, and SOCS2). Furthermore, these genes were confirmed in functional module eigens obtained from the weighted gene correlation network analysis of total DEGs in the microarray datasets ("GSE16179" and "GSE52707"). Our integrative meta-analysis could provide a comprehensive perspective into complex mechanisms underlying ALR in breast cancer and a theoretical support for further chemotherapeutic studies.

Clinical Significance of Intracranial Aneurysms in Adult Moyamoya Disease.

OBJECTIVE: We present the relationship between an aneurysm in adult moyamoya disease (MMD) patients and a future stroke event. METHODS: One hundred forty-seven aneurysms were found in 118 adult MMD patients. To find risk factors for future hemorrhagic and ischemic stroke, Kaplan-Meier and Cox-regression analyses were performed on clinical and radiologic factors. In addition to the anatomical classification method based on the circle of Willis, aneurysms occurring in the collateral pathway were analyzed by reflecting the hemodynamic changes in MMD. RESULTS: The initial clinical presentations are divided into ischemia (n = 53, 44.9%), hemorrhage (n = 51, 43.2%), and asymptomatic (n = 14, 11.9%). The mean size of the aneurysms was 2.9 ± 1.67 mm. Thirty-four aneurysms were treated with coil (n = 24) and glue embolization (n = 10). One hundred thirteen aneurysms were conservatively managed. All of aneurysms did not cause recurrent hemorrhagic strokes by aneurysm rupture. The mean follow-up period duration was 78.3 ± 58.9 months. The overall estimated rate of hemorrhage was 10.5%/hemisphere at 5 years and 18.2%/hemisphere at 10 years after the initial angiography. The overall estimated rate of infarction was 2.8%/hemisphere at 5 years and 4.5%/hemisphere at 10 years after the initial angiography. A Cox regression analysis revealed that a collateral pathway aneurysm is a significant risk factor for hemorrhagic stroke (P = 0.045, hazard ratio = 2.366). However, less hemorrhaging occurred in MMD patients with hypertension (P = 0.018, hazard ratio = 0.364). CONCLUSIONS: The presence of a collateral pathway aneurysm appears to reflect the hemodynamic stress exerted on the cerebral hemispheres of MMD patients, suggesting an increased risk of future hemorrhagic strokes.

Topological network analysis of differentially expressed genes in cancer cells with acquired gefitinib resistance.

BACKGROUND/AIM: Despite great effort to elucidate the process of acquired gefitinib resistance (AGR) in order to develop successful chemotherapy, the precise mechanisms and genetic factors of such resistance have yet to be elucidated. MATERIALS AND METHODS: We performed a cross-platform meta-analysis of three publically available microarray datasets related to cancer with AGR. For the top 100 differentially expressed genes (DEGs), we clustered functional modules of hub genes in a gene co-expression network and a protein-protein interaction network. We conducted a weighted correlation network analysis of total DEGs in microarray dataset GSE 34228. The identified DEGs were functionally enriched by Gene Ontology (GO) function and KEGG pathway. RESULTS: We identified a total of 1,033 DEGs (510 up-regulated, 523 down-regulated, and 109 novel genes). Among the top 100 up- or down-regulated DEGs, many genes were found in different types of cancers and tumors. Through integrative analysis of two systemic networks, we selected six hub DEGs (Pre-B-cell leukemia homeobox1, Transient receptor potential cation channel subfamily C member 1, AXL receptor tyrosine kinase, S100 calcium binding protein A9, S100 calcium binding protein A8, and Nucleotide-binding oligomerization domain containing 2) associated with calcium homeostasis and signaling, apoptosis, transcriptional regulation, or chemoresistance. We confirmed a correlation of expression of these genes in the microarray dataset. CONCLUSION: Our study may lead to comprehensive insights into the complex mechanism of AGR and to novel gene expression signatures useful for further clinical studies.