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1.  Fractionated Gamma Knife Radiosurgery for Benign Perioptic Tumors: Outcomes of 38 Patients in a Single Institute 
Background
This study was performed to evaluate the efficacy and safety of fractionated Gamma Knife radiosurgery (GKRS) for perioptic lesions.
Methods
Thirty-eight patients with perioptic tumors were treated at our institute from May 2004 to December 2008. All patients had a lesion in close contact with the optic apparatus. Twenty-four of these patients had undergone surgical resection before fractionated GKRS. Radiation was delivered in four sessions with 12 hours intervals between sessions. The mean target volume was 3,851 mm3 and the median cumulative marginal dose was 20 Gy. The median follow-up was 38.2 months. Visual acuity and visual fields were analyzed according to visual impairment score using the German Ophthalmological Society guidelines.
Results
Tumor control was achieved in 35 (94.6%) of the 37 patients with available follow-up images. Progressive tumor growth was observed in two craniopharyngioma patients (5.4%). Favorable visual outcomes in the postoperative period were achieved in 94.7% of cases (36/38). Sixteen patients showed visual function after fractionated GKRS, twenty cases were stationary, and two patients showed visual function deterioration after GKRS.
Conclusion
GKRS is a safe and effective alternative to either surgery or fractionated radiotherapy for selected benign lesions that are adjacent to the optic apparatus.
doi:10.14791/btrt.2014.2.2.56
PMCID: PMC4231616  PMID: 25408926
Gamma Knife radiosurgery; Fractionated radiosurgery; Stereotactic radiosurgery; Tumor control; Visual outcome
2.  Prognosis of hepatocellular carcinoma expressing cytokeratin 19: Comparison with other liver cancers 
AIM: To investigate whether expressing biliary phenotype predicted poor outcome after the surgical treatment in primary liver cancers.
METHODS: Out of 204 patients that underwent liver resection due to hepatocellular carcinoma (HCC), liver specimens of 70 patients with HCC were evaluated for biliary components by cytokeratin (CK) 19 immunostain (CK19- HCC and CK19+ HCC). CK19 positivity was defined as membranous and/or cytoplasmic expression in ≥ 5% of tumor cells with moderate or strong intensity. Patients with other primary liver cancers, such as combined HCC and cholangiocarcinoma (cHCC-CC), intrahepatic cholangiocarcinoma (ICC) who received curative liver resection, were also included in the study. Clinical characteristics of CK19- HCC and CK19+ HCC patients, including survival outcome after curative liver resection, were compared with that of cHCC-CC and ICC patients.
RESULTS: The overall survival (OS) rate of CK19- HCC (n = 49) after the curative surgical treatment was 90.7%, and 80.4% at 1 and 5 years after the resection. OS rate of CK19+ HCC (n = 21) was 74.3%, 28.9% and OS rate of cHCC-CC (n = 22) was 66.7%, 32.2% at 1 and 5 years after the surgery. For ICC (n = 19), 1 and 5-year-OS rate was 50.2% and 14.3% after the curative resection. The OS rates of CK19+ HCC and cHCC-CC were significantly lower than that of CK19- HCC, but higher than the OS rate of ICC (P = 0.000). There was no statistically significant difference in OS rate between CK19+ HCC and cHCC-CC. The disease free survival (DFS) rate of CK19- HCC was 72.0% and 54.5% at 1 and 3 years after the surgical treatment. DFS rate of CK19+ HCC was 53.3%, 34.3% and DFS rate of cHCC-CC was 51.5%, 39.2% at 1 and 3 years after the resection. For ICC, 1 and 3-year-DFS rate was 28.0% and 14.0% after the curative resection. DFS rate of CK19- HCC was significantly higher than that of ICC (P = 0.017), but marginally higher than DFS rate of either CK19+ HCC or cHCC-CC (P = 0.097, P = 0.089, respectively). Predictors of outcome after the surgery of primary liver cancer were pathology of the resected mass, existence of microvascular invasion and accompanying satellite nodule.
CONCLUSION: Primary liver cancers with biliary components tended to show poorer surgical outcome. This suggested that immuno-phenotype of liver cancers was as important as their morphological classification.
doi:10.3748/wjg.v18.i34.4751
PMCID: PMC3442214  PMID: 23002345
Cytokeratin 19; Hepatocellular carcinoma; Intrahepatic cholangiocarcinoma; Liver cancers; Hepatectomy
3.  Regional Diversity of Hepatitis C Virus Prevalence: Seeking for Culture Specific Mode of Transmission 
Gut and Liver  2014;8(4):337-338.
doi:10.5009/gnl.2014.8.4.337
PMCID: PMC4113051  PMID: 25071897
4.  Gamma Knife Radiosurgery for Brain Metastases from Breast Cancer 
Objective
The authors conducted a retrospective cohort study to determine prognostic factors and treatment outcomes of brain metastases (BM) from breast cancer (BC) after Gamma Knife radiosurgery (GKS).
Methods
Pathologic and clinical features, and outcomes were analyzed in a cohort of 62 patients with BM from BC treated by GKS. The Kaplan-Meier method, the log-rank test, and Cox's proportional hazards model were used to assess prognostic factors.
Results
Median survival after GKS was 73.0 weeks (95% confidence interval, 46.0-100.1). HER2+ [hazard ratio (HR) 0.441; p=0.045], Karnofsky performance scale (KPS) ≥70 (RR 0.416; p=0.050) and systemic chemotherapy after GKS (RR 0.282; p=0.001) were found to be a favorable prognostic factor of overall survival. Actuarial local control (LC) rate were 89.5±4.5% and 70.5±6.9% at 6 and 12 months after GKS, respectively. No prognostic factors were found to affect LC rate. Uni- and multivariate analysis revealed that the distant control (DC) rate was higher in patients with; a small number (≤3) of metastasis (HR 0.300; p=0.045), no known extracranial metastasis (p=0.013, log-rank test), or the HER2+ subtype (HR 0.267; p=0.027). Additional whole brain radiation therapy and metastasis volume were not found to be significantly associated with LC, DC, or overall survival.
Conclusion
The treatment outcomes of patients with newly diagnosed BM from BC treated with GKS could be affected primarily by intrinsic subtype, KPS, and systemic chemotherapy. Therapeutic strategy and prognosis scoring system should be individualized based on considerations of intrinsic subtype in addition to traditionally known parameters related to stereotactic radiosurgery.
doi:10.3340/jkns.2013.54.5.399
PMCID: PMC3873352  PMID: 24379946
Brain metastasis; Breast cancer; Gamma Knife radiosurgery; Intrinsic subtype; Treatment outcomes
5.  Survival outcome of patients with spontaneously ruptured hepatocellular carcinoma treated surgically or by transarterial embolization 
AIM: To evaluate clinical outcomes of patients that underwent surgery, transarterial embolization (TAE), or supportive care for spontaneously ruptured hepatocellular carcinoma (HCC).
METHODS: A consecutive 54 patients who diagnosed as spontaneously ruptured HCC at our institution between 2003 and 2012 were retrospectively enrolled. HCC was diagnosed based on the diagnostic guidelines issued by the 2005 American Association for the Study of Liver Diseases. HCC rupture was defined as disruption of the peritumoral liver capsule with enhanced fluid collection in the perihepatic area adjacent to the HCC by dynamic liver computed tomography, and when abdominal paracentesis showed an ascitic red blood cell count of > 50000 mm3/mL in bloody fluid.
RESULTS: Of the 54 patients, 6 (11.1%) underwent surgery, 25 (46.3%) TAE, and 23 (42.6%) supportive care. The 2-, 4- and 6-mo cumulative survival rates at 2, 4 and 6 mo were significantly higher in the surgery (60%, 60% and 60%) or TAE (36%, 20% and 20%) groups than in the supportive care group (8.7%, 0% and 0%), respectively (each, P < 0.01), and tended to be higher in the surgical group than in the TAE group. Multivariate analysis showed that serum bilirubin (HR = 1.09, P < 0.01), creatinine (HR = 1.46, P = 0.04), and vasopressor requirement (HR = 2.37, P = 0.02) were significantly associated with post-treatment mortality, whereas surgery (HR = 0.41, P < 0.01), and TAE (HR = 0.13, P = 0.01) were inversely associated with post-treatment mortality.
CONCLUSION: Post-treatment survival after surgery or TAE was found to be better than after supportive care, and surgery tended to provide better survival benefit than TAE.
doi:10.3748/wjg.v19.i28.4537
PMCID: PMC3725379  PMID: 23901230
Ruptured hepatocellular carcinoma; Surgery; Transarterial embolization
6.  Esophageal mucosal metastasis from adenocarcinoma of the distal stomach 
Dissemination of gastric cancer may usually occur by direct spread through the perigastric tissues to adjacent organ, lymphatic spread, and hematogenous spread. We report a rare case of gastric cancer with mucosal metastastic lesion on the upper esophagus that was diagnosed by endoscopy and endosonography. A biopsy of the esophageal mass was performed and the pathologic findings with immunohistochemical stain for Mucin-5AC are proved to be identical to that of gastric adenocarcinoma, suggesting metastasis from main lesion of the gastric cancer. The lesion could not be explained by lymphatic or hematogenous spread, and its metastasis mechanism is considered to be different from previous studies. We suggest that the gastroesophageal reflux of cancer cells could be one of the possible metastatic pathways for metastasis of esophagus from an adenocarcinoma of the stomach.
doi:10.3748/wjg.v19.i23.3699
PMCID: PMC3691037  PMID: 23801875
Stomach cancer; Neoplasm metastasis; Esophagus
7.  Complete remission of advanced hepatocellular carcinoma by sorafenib: A case report 
Hepatocellular carcinoma (HCC) is the fifth most common malignant disease worldwide, and curative treatment remains difficult because the majority of cases are diagnosed in the advanced stage. Sorafenib is the only known effective systemic treatment, but patients rarely achieve complete remission (CR). A 66-year-old man with a history of alcoholic liver cirrhosis with a diagnosis of advanced HCC, was initially treated with transarterial chemoembolization on four occasions. However, the disease progressed with portal vein thrombosis. Therefore, sorafenib was started, and 4 mo later, the patient achieved CR. The treatment was continued for 12 mo, and CR was maintained up to 4 mo after sorafenib discontinuation.
doi:10.4251/wjgo.v5.i2.38
PMCID: PMC3613770  PMID: 23556056
Hepatocellular carcinoma; Sorafenib; Portal vein thrombosis; Complete remission
8.  Cerebellar Liponeurocytoma with an Unusually Aggressive Histopathology : Case Report and Review of the Literature 
We report a rare case of cerebellar liponeurocytoma with an unusually aggressive histopathology. A 49-year-old man presented with a four-month history of headache, vertigo, and progressive swaying gait. Magnetic resonance imaging showed a 3×3.5 cm sized relatively well-demarcated round mass lesion in the fourth ventricle, characterized by high signal intensity on T2-weighted images. Postcontrast images revealed strong enhancement of the solid portion and the cyst wall. The patient underwent suboccipital craniectomy and tumor removal. The pathologic diagnosis was cerebellar liponeurocytoma. Adjuvant radiotherapy was offered due to concerns related to the high proliferative index (Ki-67, 13.68%) of the tumor. At the last routine postoperative follow-up visit (12 months), the patient complained of no specific symptom and there was no evidence of tumor recurrence. However, long-term follow-up and the analysis of similar cases are necessary because of the low number of reports and the short follow-up of cases.
doi:10.3340/jkns.2012.52.3.250
PMCID: PMC3483329  PMID: 23115671
Liponeurocytoma; Ki-67 index; Radiotherapy
9.  Giant choledocholithiasis treated by mechanical lithotripsy using a gastric bezoar basket 
Mechanical lithotripsy (ML) is usually considered as a standard treatment option for large bile duct stones. However, it is impossible to retrieve oversized stones because the conventional lithotripsy basket may not be able to grasp the stone. However, there is no established endoscopic extraction method for such giant stone removal. We describe a case of successful extraction of a 4-cm large stone using a gastric bezoar basket. A 78-year-old woman had suffered from upper abdominal pain for 20 d. Contrast-enhanced computed tomogram revealed a 4-cm single stone in the distal common bile duct (CBD). Endoscopic stone retraction was decided upon and endoscopic papillary balloon dilation was performed using a large balloon. An attempt to capture the stone using a standard lithotripsy basket failed due to the large stone size. Subsequently, we used a gastric bezoar basket to successfully capture the stone. The stone was fragmented into small pieces and extracted. The stone was completely removed after two sessions of endoscopic retrograde cholangiopancreatography; each of which took 30 min. No complications occurred during or after the procedure. The patient was fully recovered and discharged on day 11 of hospitalization. ML using a gastric bezoar basket is a safe and effective retrieval method in select cases, and is considered as an alternative nonoperative option for the management of difficult CBD stones.
doi:10.3748/wjg.v18.i25.3327
PMCID: PMC3391773  PMID: 22783060
Giant choledocholithiasis; Mechanical lithotripsy; Bezoar basket; Common bile duct stone; Endoscopic papillary balloon dilatation
10.  Omega-3 polyunsaturated fatty acid and ursodeoxycholic acid have an additive effect in attenuating diet-induced nonalcoholic steatohepatitis in mice 
Nonalcoholic steatohepatitis (NASH) can progress into liver cirrhosis; however, no definite treatment is available. Omega-3 polyunsaturated fatty acid (omega-3) has been reported to alleviate experimental NASH, although its beneficial effect was not evident when tested clinically. Thus, this study aimed to investigate the additive effect of omega-3 and ursodeoxycholic acid (UDCA) on diet-induced NASH in mice. C57BL/6 mice were given a high-fat diet (HFD) for 24 weeks, at which point the mice were divided into three groups and fed HFD alone, HFD with omega-3 or HFD with omega-3 in combination with UDCA for another 24 weeks. Feeding mice an HFD and administering omega-3 improved histologically assessed liver fibrosis, and UDCA in combination with omega-3 further attenuated this disease. The assessment of collagen α1(I) expression agreed with the histological evaluation. Omega-3 in combination with UDCA resulted in a significant attenuation of inflammation whereas administering omega-3 alone failed to improve histologically assessed liver inflammation. Quantitative analysis of tumor necrosis factor α showed an additive effect of omega-3 and UDCA on liver inflammation. HFD-induced hepatic triglyceride accumulation was attenuated by omega-3 and adding UDCA accentuated this effect. In accordance with this result, the expression of sterol regulatory binding protein-1c decreased after omega-3 administration and adding UDCA further diminished SREBP-1c expression. The expression of inducible nitric oxide synthase (iNOS), which may reflect oxidative stress-induced tissue damage, was suppressed by omega-3 administration and adding UDCA further attenuated iNOS expression. These results demonstrated an additive effect of omega-3 and UDCA for alleviating fibrosis, inflammation and steatosis in diet-induced NASH.
doi:10.1038/emm.2014.90
PMCID: PMC4274398  PMID: 25523099
11.  Silymarin suppresses hepatic stellate cell activation in a dietary rat model of non-alcoholic steatohepatitis: Analysis of isolated hepatic stellate cells 
Non-alcoholic steatohepatitis (NASH) is characterized by hepatocellular injury and initial fibrosis severity has been suggested as an important prognostic factor of NASH. Silymarin was reported to improve carbon tetrachloride-induced liver fibrosis and reduce the activation of hepatic stellate cells (HSC). We investigated whether silymarin could suppress the activation of HSCs in NASH induced by methionine- and choline-deficient (MCD) diet fed to insulin-resistant rats. NASH was induced by feeding MCD diet to obese diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Non-diabetic Long-Evans Tokushima Otsuka (LETO) rats were fed with standard chow and served as the control. OLETF rats were fed on either standard laboratory chow, or MCD diet or MCD diet mixed with silymarin. Histological analysis of the liver showed improved non-alcoholic fatty liver disease (NAFLD) activity score in silymarin-fed MCD-induced NASH. Silymarin reduced the activation of HSCs, evaluated by counting α-smooth muscle actin (SMA)-positive cells and measuring α-SMA mRNA expression in the liver lysates as well as in HSCs isolated from the experimental animals. Although silymarin decreased α1-procollagen mRNA expression in isolated HSCs, the anti-fibrogenic effect of silymarin was not prominent so as to show significant difference under histological analysis. Silymarin increased the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and decreased tumor necrosis factor (TNF)-α mRNA expression in the liver. Our study suggested that the possible protective effect of silymarin in diet induced NASH by suppressing the activation of HSCs and disturbing the role of the inflammatory cytokine TNF-α.
doi:10.3892/ijmm.2012.1029
PMCID: PMC3573753  PMID: 22710359
non-alcoholic steatohepatitis; methionine- and choline-deficient diet; insulin resistance; hepatic stellate cell; silymarin
12.  Glioblastoma Following Radiosurgery for Meningioma 
We report a patient who underwent gamma knife radiosurgery to treat recurrent meningioma after microsurgery and thereafter developed secondary malignancy adjacent to the original tumor. A 47-year-old woman had underwent resection of the olfactory groove meningioma. Then radiosurgery was done three times over 4 year period for the recurrent tumor. After 58 months from the initial radiosurgery, she presented with headache and progressive mental dullness. Huge tumor in bifrontal location was revealed in MRI. Subsequent operation and pathological examination confirmed diagnosis of glioblastoma. This case fits the criteria of radiation-induced tumor and the clinical implication of the issue is discussed.
doi:10.3340/jkns.2012.51.2.98
PMCID: PMC3322216  PMID: 22500202
Glioblastoma; Radiosurgery
13.  Malignant Ascites after Subduroperitoneal Shunt in a Patient with Leptomeningeal Metastasis 
Leptomeningeal metastasis is a devastating complication of advanced stage cancer. It is frequently accompanied by hydrocephalus and intracranial hypertension that must be treated by ventriculoperitoneal shunts. However, there are actual risks of peritoneal seeding or accumulation of malignant ascites after the cerebrospinal fluid diversion procedure, though it has not been reported. Here, we present the case of a patient with non-small cell lung cancer with leptomeningeal metastasis in whom malignant ascites developed after a subduroperitoneal shunt.
doi:10.3340/jkns.2011.50.4.385
PMCID: PMC3243845  PMID: 22200024
Leptomeningeal metastasis; Malignant ascites; Ventriculoperitoneal shunt
14.  Does the bile duct angulation affect recurrence of choledocholithiasis? 
AIM: To investigate whether bile duct angulation and T-tube choledochostomy influence the recurrence of choledocholithiasis.
METHODS: We conducted a retrospective study inclu-ding 259 patients who underwent endoscopic sphincterotomy and cholecystectomy for choledocholithiasis between 2000 and 2007. The imaginary line was drawn along the center of the bile duct and each internal angle was measured at the two angulation sites of the bile duct respectively. The values of both angles were added together. We then tested our hypothesis by examining whether T-tube choledochostomy was performed and stone recurrence occurred by reviewing each subject’s medical records.
RESULTS: The overall recurrence rate was 9.3% (24 of 259 patients). The mean value of sums of angles in the recurrence group was 268.3° ± 29.6°, while that in the non-recurrence group was 314.8° ± 19.9° (P < 0.05). Recurrence rate of the T-tube group was 15.9% (17 of 107), while that of the non T-tube group was 4.6% (7 of 152) (P < 0.05). Mean value of sums of angles after T-tube drainage was 262.5° ± 24.6° and that before T-tube drainage was 298.0° ± 23.9° in 22 patients (P < 0.05).
CONCLUSION: The bile duct angulation and T-tube choledochostomy may be risk factors of recurrence of bile duct stones.
doi:10.3748/wjg.v17.i36.4118
PMCID: PMC3203364  PMID: 22039327
Choledocholithiasis; Common bile duct; Cholecystectomy; Recurrence; Endoscopic retrograde cholangio pancreatography
15.  The Role of Radiosurgery in Patients with Brain Metastasis from Small Cell Lung Carcinoma 
Objective
The purpose of this retrospective study was to evaluate the outcome of gamma knife radiosurgery (GKRS) and/or whole brain radiation therapy (WBRT) for the treatment of small cell lung carcinoma (SCLC) metastasis to the brain.
Methods
From 2000 to 2010, 50 patients underwent GKRS for metastatic brain lesions originating from SCLC. Among these patients, 11 received prophylactic cranial irradiation (PCI) before the development of metastatic lesions (PCI group), and GKRS was performed as an initial treatment for newly diagnosed lesions in 12 patients who had not received PCI (primary GKRS group). In addition, GKRS was performed as a salvage treatment for progressive lesions after WBRT in 27 patients (salvage GKRS group). The medical records and imaging data of all patients were retrospectively analyzed.
Results
The overall survival of the 50 patients was 20.8 months (range 1-53) after the diagnosis of primary tumor and 12.0 months (range 1-47) after the development of cerebral metastasis. Median survival after GKRS was 4.8 months (range 1-15) in the PCI group, 4.6 months (range 0-18) in the primary GKRS group, and 7.6 months (range 0-33) in the salvage GKRS group. Further treatment for progressive lesions after GKRS was necessary in 15 patients, after a mean interval of 3.8 months. Causes of death were systemic organ failure in 15 patients, deterioration of neurological state in 13 patients, and unknown or combined causes in 16 patients. The local control rate of the lesions treated with GKRS was 76.4% (decreased in 13 patients and stable in 16 patients at the final imaging follow-up (mean 5.60 months).
Conclusion
GKRS is an effective local treatment for brain metastasis from SCLC both as an initial treatment for newly diagnosed lesions after PCI and as a salvage treatment for recurrent or progressive lesions. However, the survival benefit is not significant because most patients die of systemic multi-organ failure with a short life expectancy.
doi:10.3340/jkns.2011.50.2.99
PMCID: PMC3206286  PMID: 22053227
Small cell lung carcinoma; Radiosurgery; Gamma knife; Metastasis
16.  Development of De Novo Cavernous Hemangioma after Radiosurgery for Cavernous Hemangioma 
We report a rare case of cavernous hemangioma (CH) which developed in adjacent location to a preexisting CH after gamma knife radiosurgery (GKRS). A 36-year-old woman underwent GKRS for a CH in the left lentiform nucleus. Three-and-half years after radiosurgery, MRI revealed a new CH in the left caudate nucleus. Surgical excision of the new lesion was performed. The pathological examination confirmed the diagnosis of CH. In radiosurgery for CH, it should be noted that a new CH may develop, which is likely to result from the interaction between radiation and predisposing factors of the patient.
doi:10.3340/jkns.2010.48.6.532
PMCID: PMC3053549  PMID: 21430981
Cavernous hemangioma; Cavernous angioma; Gamma knife; Radiosurgery; Radiation-induced tumor
17.  The effect of sorafenib on hepatic stellate cells: implication of its effect on tumor microenvironment 
The Korean Journal of Hepatology  2010;16(4):418-419.
doi:10.3350/kjhep.2010.16.4.418
PMCID: PMC3304606
Sorafenib; Hepatocellular carcinoma; Stellate cell
18.  Clinical Features and Treatment Outcome of Chordoid Meningiomas in a Single Institute 
Objective
Meningioma is the second most common primary central nervous system neoplasm. In contrast, chordoid meningioma is rare; due to the paucity of cases, little is known about its clinical features or treatment outcomes. The objectives of this study were to describe the clinical characteristics and outcomes for patients with chordoid meningioma.
Methods
In total, 16 patients, with newly diagnosed chordoid meningioma who underwent surgical excision between 1999 and 2012 were included. We retrospectively evaluated the medical records, radiological findings, and pathological findings. The median follow-up period was 56.5 (range, 3-170) months. The MIB-1 labeling index ranged from 1 to 26.60% (median, 5.04).
Results
Simpson grade I, II, and III resections were performed in four, nine, and three patients, respectively. The overall recurrence rate was 37.5%. Overall progression-free survival (PFS) after resection was 94.7 months (95% CI=62.9-126.6). Of the 4 patients with Simpson grade I resection, recurrence occurred in one patient. Among the Simpson grade II and III resection groups, eight patients underwent adjuvant radiation therapy and they showed significantly longer PFS (121 months, 95% CI=82.1-159.9) than the patients who underwent surgery alone (40.5 months, 95% CI=9.6-71.3) by the log-rank test (p<0.05).
Conclusion
Chordoid meningiomas are difficult to manage and have a high rate of recurrence. Complete resection of the tumor is a key determinant of better outcomes. Adjuvant radiation therapy is recommended, eparticulary when Simpson grade I resection was not achieved.
doi:10.3340/jkns.2014.56.3.194
PMCID: PMC4217054  PMID: 25368760
Chordoid meningioma; MIB-1 labeling index; Adjuvant radiation therapy
19.  Disseminated Hemangioblastomatosis of the Central Nervous System without von Hippel-Lindau Disease: A Case Report 
Journal of Korean Medical Science  2009;24(4):755-759.
We report a very rare case of hemangioblastomatosis that developed after surgical removal of a solitary cerebellar hemangioblastoma (HB). A 51-yr-old man presented with back pain 10 yr after undergoing surgery for cerebellar HB. Magnetic resonance imaging showed numerous mass lesions along the entire neuraxis accompanied by prominent leptomeningeal enhancement. Genomic DNA analysis showed no mutation in the von Hippel-Lindau (VHL) genes. A surgical specimen obtained from a lesion in the cauda equina showed pathological findings identical to those of the cerebellar HB that had been resected 10 yr earlier. External beam radiation therapy and radiosurgery were subsequently performed; however, the patient succumbed one year after receiving the diagnosis of hemangioblastomatosis. The reduction of tumor cell spillage during surgery and regular long-term follow-up are recommended for patients with HBs.
doi:10.3346/jkms.2009.24.4.755
PMCID: PMC2719216  PMID: 19654966
Hemangioblastoma; von Hippel-Lindau Disease; Central Nervous System
20.  Translational Validation of Personalized Treatment Strategy Based on Genetic Characteristics of Glioblastoma 
PLoS ONE  2014;9(8):e103327.
Glioblastoma (GBM) heterogeneity in the genomic and phenotypic properties has potentiated personalized approach against specific therapeutic targets of each GBM patient. The Cancer Genome Atlas (TCGA) Research Network has been established the comprehensive genomic abnormalities of GBM, which sub-classified GBMs into 4 different molecular subtypes. The molecular subtypes could be utilized to develop personalized treatment strategy for each subtype. We applied a classifying method, NTP (Nearest Template Prediction) method to determine molecular subtype of each GBM patient and corresponding orthotopic xenograft animal model. The models were derived from GBM cells dissociated from patient's surgical sample. Specific drug candidates for each subtype were selected using an integrated pharmacological network database (PharmDB), which link drugs with subtype specific genes. Treatment effects of the drug candidates were determined by in vitro limiting dilution assay using patient-derived GBM cells primarily cultured from orthotopic xenograft tumors. The consistent identification of molecular subtype by the NTP method was validated using TCGA database. When subtypes were determined by the NTP method, orthotopic xenograft animal models faithfully maintained the molecular subtypes of parental tumors. Subtype specific drugs not only showed significant inhibition effects on the in vitro clonogenicity of patient-derived GBM cells but also synergistically reversed temozolomide resistance of MGMT-unmethylated patient-derived GBM cells. However, inhibitory effects on the clonogenicity were not totally subtype-specific. Personalized treatment approach based on genetic characteristics of each GBM could make better treatment outcomes of GBMs, although more sophisticated classifying techniques and subtype specific drugs need to be further elucidated.
doi:10.1371/journal.pone.0103327
PMCID: PMC4118874  PMID: 25084005
21.  Gamma Knife Radiosurgery for Ten or More Brain Metastases 
Objective
This study was performed to assess the efficacy of GKS in patients with ten or more brain metastases.
Methods
From Aug 2002 to Dec 2007, twenty-six patients (13 men and 13 women) with ten or more cerebral metastatic lesions underwent GKS. The mean age was 55 years (32-80). All patients had Karnofsky performance status (KPS) score of 70 or better. According to recursive partitioning analysis (RPA) classification, 3 patients belonged to class I and 23 to class II. The location of primary tumor was lung (21), breast (3) and unknown (2). The mean number of the lesions per patient was 16.6 (10-37). The mean cumulated volume was 10.9 cc (1.0-42.2). The median marginal dose was 15 Gy (9-23). Overall survival and the prognostic factors for the survival were retrospectively analyzed by using Kaplan Meier method and univariate analysis.
Results
Overall median survival from GKS was 34 weeks (8-199). Local control was possible for 79.5% of the lesions and control of all the lesions was possible in at least 14 patients (53.8%) until 6 months after GKS. New lesions appeared in 7 (26.9%) patients during the same period. At the last follow-up, 18 patients died; 6 (33.3%) from systemic causes, 10 (55.6%) from neurological causes, and 2 (11.1%) from unknown causes. Synchronous onset in non-small cell lung cancer (p=0.007), high KPS score (≥80, p=0.029), and controlled primary disease (p=0.020) were favorable prognostic factors in univariate analysis.
Conclusion
In carefully selected patients, GKS may be a treatment option for ten or more brain metastases.
doi:10.3340/jkns.2008.44.6.358
PMCID: PMC2615138  PMID: 19137079
Multiple; Brain metastases; Gamma knife radiosurgery; Prognostic factor
22.  Preliminary Report of Multisession Gamma Knife Radiosurgery for Benign Perioptic Lesions: Visual Outcome in 22 Patients 
Objective
Radiosurgery may be contraindicated for lesions adjacent to the optic pathways because of the substantial risk of visual complication. Multisession radiosurgery has been tried as a compromise between single session radiosurgery and fractionated radiotherapy. The purpose of this study is to evaluate the outcomes of multisession gamma knife radiosurgery (GKRS) in 22 patients with perioptic lesions of benign pathology.
Methods
In all 22 cases, the lesions were within 1 mm of the optic apparatus and were therefore not considered suitable for single session radiosurgery. Radiation was delivered in 3 to 4 fractions with a median cumulated marginal dose of 20 Gy (range, 15-20 Gy).
Results
During a mean follow-up of 29 months (range, 14-44 months), tumor control was achieved in 21 patients. Visual function improved in 7 patients, remained unchanged in 14 patients, and deteriorated in 1 patient with tumor progression. No other complication was observed.
Conclusion
This preliminary result supports the idea that multisession GKRS may be an effective and safe alternative for treatment in perioptic lesions that are unsuitable for single session radiosurgery.
doi:10.3340/jkns.2008.44.2.67
PMCID: PMC2588338  PMID: 19096695
Multisession radiosurgery; Gamma knife; Visual complication
23.  Retrospective Analysis on 76 Cases of Cerebral Arteriovenous Malformations Treated by Gamma Knife Radiosurgery 
Objective
Outcome of gamma knife radiosurgery (GKS) in the consecutive 100 cases with cerebral arteriovenous malformations (AVMs) was analyzed.
Methods
Data from initial 100 patients treated with GKS in the authors' institute were reviewed retrospectively. Spetzler-Martin grade at diagnosis were I in 18 patients, II in 27, III in 36, IV in 11, and V in 8. Thirty-five patients had experienced previous bleeding, 27 patients presented with seizure, and 31 patients presented with headache. The mean volume of the lesion was 4.3 cm3 (0.1-29.3 cm3). The median radiation dose delivered to the margin was 20.0 Gy (13-32 Gy). Mean follow-up period was 37.5 months (5-63 months).
Results
Angiographic follow-up was performed in 48 patients at least 2 years after GKS. Sixteen patients were lost in follow up following 2 years from GKS. Twenty-eight of 48 patients (58%) showed complete obliteration and 20 patients (42%) showed partial obliteration. Seven patients presented with post-GKS hemorrhage. Adverse radiation effect (ARE) was observed at follow-up MRI in 25 of 76 patients, and it was symptomatic in 5 patients. Complete obliteration was confirmed in 24 of 31 (77%) patients with volume less than 4 cm3, meanwhile only 4 of 17 (24%) patients with volume of 4 cm3 or more showed complete obliteration. Complete obliteration rate was 67% with 20 Gy or higher marginal dose, 63% with 15-20 Gy, and 17% with less than 15 Gy.
Conclusion
GKS can provide high rates of obliteration with acceptable risk of morbidity in a subgroup of small AVMs. However, overall outcome in whole spectrum of AVMs, in which large proportion of cases have unfavorable characteristics for radiosurgery, is much worse. More effective therapeutic strategy needs to be developed for large AVMs that are difficult to be managed with current available treatment modalities.
doi:10.3340/jkns.2008.43.6.265
PMCID: PMC2588252  PMID: 19096630
Gamma knife radiosurgery; Arteriovenous malformation; Outcome
24.  Progression of diet induced nonalcoholic steatohepatitis is accompanied by increased expression of kruppel-like-factor 10 in mice 
Background
Kruppel-like-factor (KLF) 10 is identified as transforming growth factor (TGF) β inducible early gene and is reported to suppress lipogenic genes. Although previous studies report that TGFβ plays an important role in progression of nonalcoholic steatohepatitis (NASH) by regulating liver fibrosis, the association of KLF10 and NASH has never been explored. Thus we evaluated expressions and changes of KLF10 in diet induced NASH and in NASH which was alleviated by ursodeoxycholic acid (UDCA). We also assessed KLF10 in quiescent and activated hepatic stellate cells (HSCs).
Methods
C57BL/6 mice were given high fat, sucrose diet (HFSD) at least for 12 weeks up to 48 weeks and sacrificed at 12, 24 and 48 weeks thereafter. In other groups, either standard diet (SD) or HFSD was given for 24 weeks at which point mice fed with HFSD were divided into two groups, and were given either UDCA in combination with HFSD or vehicle with HFSD. Mice under SD were given vehicle. HSCs were isolated from C57BL/6 mice in order to evaluated KLF10 expression in activated HSCs.
Results
The mice were found to acquire liver steatosis and inflammation starting from week 12 of HFSD feeding, although significant liver fibrosis was noticed by week 24. Increased TGFβ and collagen α1(I) (Col1α(I)) expression was also apparent from week 24. However, expression of KLF10 mRNA started to increase from week 12, earlier than TGFβ gene. Up-regulation of KLF10 was accompanied by suppressed carbohydrate response element-binding protein (ChREBP) that is known to be protective against insulin resistance. The mice fed with HFSD and UDCA had decreased Colα(I) mRNA that was coincided with reduced TGFβ and KLF10 expression. Expression of ChREBP was also recovered by UDCA administration. Enhanced KLF10 was noticed in activated HSCs when quiescent cell showed minimal expression.
Conclusions
Our study demonstrated that KLF10 expression was significantly increased in diet induced NASH and collagen producing activated HSCs. We also noticed that this up-regulation of KLF10 was accompanied by increased TGFβ signaling genes and suppressed ChREBP expression. These observations suggest possible association of KLF10 and NASH progression.
doi:10.1186/1479-5876-12-186
PMCID: PMC4086692  PMID: 24986741
25.  Prognosis of Non-Small Cell Lung Cancer with Synchronous Brain Metastases Treated with Gamma Knife Radiosurgery 
Journal of Korean Medical Science  2006;21(3):527-532.
The clinical outcome and prognostic factors of patients with synchronous brain metastases from non-small cell lung cancer (NSCLC) who were treated with gamma knife radiosurgery (GKS) were analyzed. A total of 35 patients with NSCLC underwent GKS as an initial treatment for metastatic brain lesions of synchronous onset. The period of survival and various prognostic factors such as age, gender, performance status, multiplicity of the brain lesions, intracranial tumor volume, and extent of the primary tumor were analyzed. The overall median survival time for this series was 12 months (range 0.75 to 43 months) from the diagnosis. Of the 21 patients who were no longer alive at the conclusion of this study, only 7 (33.3%) died of neurological causes. Multivariate analysis of these data revealed that N stage, whole-brain radiotherapy (WBRT), and chemotherapy were significant predictors for survival (p<0.05). Survival of patients with NSCLC and synchronous brain metastases is mainly dependent upon the progression of the systemic disease, provided that the cerebral lesions are treated adequately with local treatment modalities including radiosurgery. Application of radiosurgery as an initial treatment option and aggressive local and systemic modalities to control extracranial disease may improve survival.
doi:10.3346/jkms.2006.21.3.527
PMCID: PMC2729962  PMID: 16778400
Carcinoma, Non-Small-Cell Lung; Neoplasm Metastasis; Radiosurgery

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