BACKGROUND: Up to 15% of all patients with brain metastases have no clearly detected primary site despite intensive evaluation, and this incidence has decreased with the use of improved imaging technology. Radiosurgery has been evaluated as one of the treatment modality for patients with limited brain metastases. In this study, we evaluated the effectiveness of radiosurgery for brain metastases from unknown primary tumors. METHODS: We retrospectively evaluated 540 patients who underwent gamma knife radiosurgery (GKRS) for brain metastases radiologically diagnosed between August 1992 and September 2007 in our institution. First, the brain metastases were grouped into metachronous, synchronous, and precocious presentations according to the timing of diagnosis of the brain metastases. Then, synchronous and precocious brain metastases were further grouped into 1) unknown primary; 2) delayed known primary; and 3) synchronous metastases according to the timing of diagnosis of the primary origin. We analyzed the survival time and time to new brain metastasis in each group. RESULTS: Of the 540 patients, 29 (5.4%) presented precocious or synchronous metastases (34 GKRS procedures for 174 lesions). The primary tumor was not found even after intensive and repeated systemic evaluation in 10 patients (unknown primary, 34.5%); found after 8 months in 3 patients (delayed known primary, 1.2%); and diagnosed at the same time as the brain metastases in 16 patients (synchronous metastasis, 55.2%). No statistically significant differences in survival time and time to new brain metastasis were found among the three groups. CONCLUSION: Identification of a primary tumor before GKRS did not affect the patient outcomes. If other possible differential diagnoses were completely excluded, early GKRS can be an effective treatment option for brain metastases from unknown primary tumor.
Brain* ; Diagnosis ; Diagnosis, Differential ; Humans ; Incidence ; Neoplasm Metastasis* ; Neoplasms, Unknown Primary ; Radiosurgery* ; Retrospective Studies

BACKGROUND: The predominant treatment modality for meningioma is surgical resection. However, gamma knife radiosurgery is also an important treatment modality for meningioma that is small or cannot be completely removed because of its location. In this study, we evaluated the effectiveness and long-term results of radiosurgical treatment for meningioma in our institution. METHODS: We studied 628 patients (130 men and 498 women) who underwent gamma knife radiosurgery for intracranial meningioma, which is radiologically diagnosed, from Jan 2008 to Nov 2012. We included patients with single lesion meningioma, and followed up after 6 months with imaging, and then at 24 months with a clinical examination. Patients with high-grade meningioma or multiple meningiomas were excluded. We analyzed each of the factors associated with progression free survival. The median patient's age was 56.8 years. Maximal dosage was 27.8 Gy and marginal dosage was 13.9 Gy. RESULTS: The overall tumor control rate was 95%. Twenty-eight patients (4.4%) showed evidence of tumor recurrence. Ninety-eight patients (15%) developed peritumoral edema (PTE) after gamma-knife surgery; two of them (2%) underwent surgical resections due to PTE. Nine patients had craniotomy and tumor removal after gamma knife surgery. CONCLUSION: Gamma knife surgery for intracranial meningioma has proven to be a safe and effective treatment tool with successful long-term outcomes. Gamma knife radiosurgery can be especially effective in cases of remnant meningioma after surgical resection or where PTE is not present.
Craniotomy ; Disease-Free Survival ; Edema ; Humans ; Male ; Meningioma* ; Radiosurgery* ; Recurrence

OBJECTIVE: Although metastasis of hepatocellular carcinoma to the brain is uncommon, it is associated with a very high mortality rate and most patients usually expire within 1 year after brain metastasis. The aim of this study is to identify the effectiveness of the active interventions such as gamma knife radiosurgery or surgical intervention for these patients. METHODS: We retrospectively reviewed the medical records and imaging data of 59 patients with metastatic brain tumors from hepatocellular carcinoma from May 2004 to September 2012. The study included patients with available clinical and radiological data who had been diagnosed with metastatic hepatocellular carcinoma of the brain, confirmed by magnetic resonance imaging. The overall survival time was analyzed and compared according to each risk factor. RESULTS: The mean age at diagnosis of metastatic brain tumor was 52.2 years (14-77). The mean follow-up duration was 13.3 weeks (0.1-117.6). Overall median survival was 4.3 weeks (95% confidence interval, 2.2-6.4). The results from an analysis of clinical factors related to survival revealed that treatment modalities were significantly related to the patient's survival (log rank, p=0.006). Twenty patients (32.8%) experienced tumor bleeding, and the survival time of the patients with tumor bleeding tended to be shorter, although the result was not statistically significant (log rank, p=0.058). Hepatic reserve, by Child-Pugh classification, was grade A in 38 patients (64.4%), grade B in 16 patients (27.1%), and grade C in 5 patients (8.5%), and was significantly related to the patient's survival (log rank, p=0.000). CONCLUSION: Although patients with metastatic brain tumors from hepatocellular carcinoma showed poor survival, active intervention including surgical resection or gamma knife radiosurgery may result in better survival, especially if patients have preserved liver function.
Brain Neoplasms* ; Brain* ; Carcinoma, Hepatocellular* ; Classification ; Diagnosis ; Follow-Up Studies ; Hemorrhage ; Humans ; Liver ; Magnetic Resonance Imaging ; Medical Records ; Mortality ; Neoplasm Metastasis ; Radiosurgery* ; Retrospective Studies ; Risk Factors

Temporal fossa hollowing can represent a serious cosmetic concern to patients after post-traumatic surgery, oncological resection, or surgical dissection for obtaining access to the temporal area. Various methods have been described to augment temporal fossa hollowing, such as use of autogenous bone and cartilage implants, high-density polyethylene implants, and dermal fat grafts. We report a case of 22-year-old man with temporal fossa hollowing after post-traumatic surgery, including temporal muscle resection, whose defect was augmented by using titanium mesh even though long after cranioplasty.
Cartilage ; Humans ; Methods ; Polyethylene ; Temporal Muscle* ; Titanium* ; Transplants ; Young Adult

Temporal fossa hollowing can represent a serious cosmetic concern to patients after post-traumatic surgery, oncological resection, or surgical dissection for obtaining access to the temporal area. Various methods have been described to augment temporal fossa hollowing, such as use of autogenous bone and cartilage implants, high-density polyethylene implants, and dermal fat grafts. We report a case of 22-year-old man with temporal fossa hollowing after post-traumatic surgery, including temporal muscle resection, whose defect was augmented by using titanium mesh even though long after cranioplasty.
Cartilage ; Humans ; Methods ; Polyethylene ; Temporal Muscle* ; Titanium* ; Transplants ; Young Adult

OBJECTIVE: Angiopoietin-1 (Ang1) is a potent angiogenic factor that can increase synovial angiogenesis and also enhance osteoblast maturation and bone formation. However, its role in rheumatoid arthritis (RA) has not been well documented. Thus, we investigated roles of Ang1 in collagen-induced arthritis (CIA). METHODS: A recombinant adenovirus carrying the gene that encodes either cartilage oligomeric matrix protein (AdCOMP)-Ang1 (a modified form of Ang1) or LacZ (AdLacZ) was injected intravenously into CIA mice. Clinical, radiological, histopathological, and immunofluorescent analyses were performed. Serum levels of receptor activators of nuclear factor kappaB ligand (RANKL) and osteoprotegerin (OPG) and expression of osteoblast maturation genes were analyzed. RESULTS: AdCOMP-Ang1-injected mice developed more severe inflammation than the AdLacZ-injected mice. However, there were no significant differences in cartilage damage and bone erosion. More PECAM-1-positive blood vessels were seen in the synovium of the AdCOMP-Ang1-injected mice than in those injected with AdLacZ. Interestingly, a lower number of TRAP-positive osteoclasts were observed in AdCOMP-Ang1-injected CIA mice than in the AdLacZ group when comparing sections obtained from joints showing similar synovial proliferation. The serum OPG/RANKL ratio and expression of osteoblast maturation genes, such as runt-related transcription factor 2, bone sialoprotein, type 1 collagen, osteopontin, and osterix, were significantly upregulated in the AdCOMP-Ang1 group. CONCLUSION: COMP-Ang1 facilitates arthritis onset and increases synovial inflammation, but enhances osteoblast maturation, which in turn inhibits osteoclastogenesis by increasing the OPG/RANKL ratio in CIA. Our results suggest that careful investigation is necessary to delineate the possible therapeutic use of COMP-Ang1 as an adjunctive agent, in combination with anti-inflammatory therapies, for the prevention of bone destruction in RA.
Adenoviridae ; Angiogenesis Inducing Agents ; Angiopoietin-1 ; Animals ; Arthritis ; Arthritis, Experimental ; Arthritis, Rheumatoid ; Blood Vessels ; Cartilage ; Collagen Type I ; Extracellular Matrix Proteins ; Glycoproteins ; Inflammation ; Integrin-Binding Sialoprotein ; Joints ; Lifting ; Mice ; Osteoblasts ; Osteoclasts ; Osteogenesis ; Osteopontin ; Osteoprotegerin ; Synovial Membrane ; Transcription Factors

BACKGROUND: Epithelial tumor cells with a CD44(+)/CD24(-/low) immunoprofile may have the ability to cause breast cancer. We studied these cells and their clinicopathological significance. METHODS: The clinicopathologic findings of 100 invasive ductal carcinoma (IDC) cases and 45 ductal carcinoma in situ (DCIS) cases were reviewed. CD44(+)/CD24(-/low) tumor cells were identified by immunohistochemistry, and their clinicopathological implications in IDC and DCIS were analyzed. RESULTS: IDC with a high prevalence of CD44(+)/CD24(-/low) tumor cells was significantly associated with larger mass, higher grade, estrogen receptor (ER) negativity, and tumor cells with a higher frequency of metastasis. The proportion of CD44(+)/CD24(-/low) tumor cells in IDC, and its DCIS components was not significantly different, whereas the proportion of CD44(+)/CD24(-/low) tumor cells was higher in DCIS than in the DCIS component of IDC (p < 0.001). CONCLUSIONS: IDC with a high prevalence of CD44(+)/CD24(-/low) tumor cells might correlate with aggressive features, such as ER and higher grades. Moreover, the proportion of CD44(+)/CD24(-/low) tumor cells in the DCIS components of IDC and DCIS might harbor different biology, which may lead to differences in cancer progression and early carcinogenesis.
Antigens, CD24 ; Antigens, CD44 ; Biology ; Breast ; Breast Neoplasms ; Carcinoma, Ductal ; Carcinoma, Intraductal, Noninfiltrating ; Estrogens ; Immunohistochemistry ; Neoplasm Metastasis ; Neoplastic Stem Cells ; Prevalence

BACKGROUND: Embryonic lethal abnormal vision (ELAV)-like protein HuR is known to stabilize mRNA through binding AU-rich elements in the 3'-untranslated region. Recent studies show that HuR expression is associated with the expression of several genes including cyclooxygenase-2 (COX-2). HuR exists predominantly in the nucleus, but cytoplasmic translocation of HuR is thought to be more important for its activity. COX-2 is a well-known enzyme that promotes tumor growth. METHODS: To evaluate the correlation of HuR and COX-2 expression, we analyzed expression of HuR and COX-2 in 91 cases of breast cancer using immunohistochemistry. RESULTS: Nuclear and cytoplasmic expression of HuR was seen in 76 (83.5%) and 19 (20.9%) of 91 cases respectively. COX-2 immunoreactivity was seen in 54 (59.4%) cases. Cytoplasmic HuR expression showed significant correlation with COX-2 expression (p=0.001). Nuclear HuR showed no correlation with COX-2 expression or other clinicopathological parameters. COX-2 expression is significantly associated with tumor grade (p=0.028). COX-2 (p=0.092) and cytoplasmic (p=0.569) and nuclear HuR (p=0.247) expression showed no correlation with survival. CONCLUSIONS: These results suggest that cytoplasmic HuR expression is associated with COX-2 expression in breast cancer and cytoplasmic location of HuR might contribute to the stabilization of COX-2 mRNA.
Breast Neoplasms

Reactive oxygen species (ROS) play a crucial role in acute lung injury. Tissue inflammation, the increased vascular permeability, and plasma exudation are cardinal features of acute lung injury. Angiopoietin-1 (Ang1) has potential therapeutic applications in preventing vascular leakage and also has beneficial effects in several inflammatory disorders. Recently developed COMP-Ang1 is more potent than native Ang1 in phosphorylating tyrosine kinase with immunoglobulin and EGF homology domain 2 receptor in endothelial cells. However, there are no data on effects and related molecular mechanisms of COMP- Ang1 on ROS-induced acute lung injury. We used hydrogen peroxide (H2O2)-inhaled mice to evaluate the effect of COMP-Ang1 on pulmonary inflammation, bronchial hyper-responsiveness, and vascular leakage in acute lung injury. The results have revealed that VEGF expression, the levels of IL-4, TNF-alpha, IL-1 beta, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 in lungs, the levels of hypoxia-inducible factor-1alpha (HIF-1 alpha) and NF-kappa B in nuclear protein extracts, phosphorylation of Akt, and vascular permeability were increased after inhalation of H2O2 and that the administration of COMP-Ang1 markedly reduced airway hyper-responsiveness, pulmonary inflammation, plasma extravasation, and the increases of cytokines, adhesion molecules, and VEGF in lungs treated with H2O2. We have also found that the activation of HIF-1a and NF-kappa B and the increase of phosphoinositide 3-kinase activity in lung tissues after H2O2 inhalation were decreased by the administration of COMP-Ang1. These results suggest that COMP-Ang1 ameliorates ROS-induced acute lung injury through attenuating vascular leakage and modulating inflammatory mediators.
Acute Lung Injury/chemically induced/complications/*drug therapy/metabolism ; Administration, Inhalation ; Airway Resistance/drug effects ; Animals ; Bronchial Hyperreactivity/drug therapy/etiology ; Bronchoalveolar Lavage Fluid ; Capillary Permeability/*drug effects ; Cytokines/antagonists & inhibitors ; Female ; Hydrogen Peroxide/adverse effects ; Hypoxia-Inducible Factor 1, alpha Subunit/antagonists & inhibitors ; Intercellular Adhesion Molecule-1/metabolism ; Mice ; Mice, Inbred BALB C ; NF-kappa B/antagonists & inhibitors ; Pneumonia/*drug therapy/etiology ; Recombinant Fusion Proteins/*administration & dosage ; Vascular Cell Adhesion Molecule-1/metabolism

Inflammation of the asthmatic airway is usually accompanied by increased vascular permeability and plasma exudation. Angiopoietin-1 (Ang1) has potential therapeutic applications in preventing vascular leakage. Recently, we developed a soluble, stable, and potent Ang1 variant, COMP-Ang1. COMP-Ang1 is more potent than native Ang1 in phosphorylating the tyrosine kinase with immunoglobulin and epidermal growth factor homology domain 2 receptor in lung endothelial cells. We have used a mouse model for allergic airway disease to determine effects of COMP-Ang1 on allergen-induced bronchial inflammation and airway hyper-responsiveness. These mice develop the following typical pathophysiological features of allergic airway disease in the lungs: increased numbers of inflammatory cells of the airways, airway hyper-responsiveness, increased levels of Th2 cell cytokines (IL-4, IL-5, and IL-13), adhesion molecules (intercellular adhesion molecule-1 and vascular cell adhesion molecule-1), and chemokines (eotaxin and RANTES), and increased vascular permeability. Intravenous administration of COMP-Ang1 reduced bronchial inflammation and airway hyper-responsiveness. In addition, the increased plasma extravasation in allergic airway disease was significantly reduced by the administration of COMP-Ang1. These results suggest that COMP-Ang1 attenuates airway inflammation and hyper-responsiveness, prevents vascular leakage, and may be used as a therapeutic agent in allergic airway disease.
Allergens/immunology ; Angiopoietin-1/genetics/pharmacology/*therapeutic use ; Animals ; Asthma/*prevention & control ; Bronchial Hyperreactivity/physiopathology/prevention & control ; Chemokines/metabolism ; Inflammation/pathology/*prevention & control ; Mice ; Mice, Inbred C57BL ; Recombinant Fusion Proteins/*therapeutic use