Supramaximal Resection for Glioblastoma: Redefining the Extent of Resection Criteria and Its Impact on Survival

Glioblastomas (GBMs) are the most common and aggressive primary brain tumors, and despite advances in treatment, prognosis remains poor. The extent of resection has been widely recognized as a key factor affecting survival outcomes in GBM patients. The surgical principle of “maximal safe resection” has been widely applied to balance tumor removal and neurological function preservation. Historically, T1-contrast enhanced (T1CE) extent of resection has been the focus of research; however, the “supramaximal resection” concept has emerged, advocating for even greater tumor resection while maintaining neurological function. Recent studies have demonstrated potential survival benefits associated with resection beyond T1CE extent in GBMs. This review explores the developing consensus and newly established criteria for “supramaximal resection” in GBMs, with a focus on T2-extent of resection. Systematic reviews and meta-analyses on supramaximal resection are summarized, and the Response Assessment in Neuro-Oncology (RANO) resect group classification for extent of resection is introduced. The evolving understanding of the role of supramaximal resection in GBMs may lead to improved patient outcomes and more objective criteria for evaluating the extent of tumor resection.

The efficacy of EGFR-tyrosine kinase inhibitor in non-small cell lung cancer patients with synchronous brain metastasis: a real-world study

Background/Aims@#The optimal treatment (Tx) for epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) patients with brain metastasis (BM) remains to be determined. @*Methods@#A retrospective review was conducted on 77 NSCLC patients with synchronous BM who underwent first-line EGFR-tyrosine kinase inhibitor (TKI) Tx. The outcomes of patients were analyzed according to the clinicopathological characteristics including local Tx modalities. @*Results@#Fifty-nine patients underwent local Tx for BM (gamma knife surgery [GKS], 37; whole brain radiotherapy [WBRT], 18; others, four) concurrently or sequentially with EGFR-TKI. Patients treated with TKI alone showed significantly lower incidence of central nervous system (CNS) symptoms. The median progression-free survival (PFS) and overall survival (OS) after the initiation of EGFR-TKI for all patients were 9 and 19 months, respectively. In 60 patients with follow-up brain imaging, the median time to CNS progression was 15 months. Patients with EGFR exon 19 deletion had a significantly longer median OS than those with other mutations including L858R (23 months vs. 17 months). Other clinical characteristics, including CNS symptoms, number of BM, and the use of local Tx were not associated with OS, as well as PFS. In terms of the local optimal Tx modality, no difference was found between GKS and WBRT in the OS and PFS. @*Conclusions@#This study suggests that EGFR-TKI may result in a favorable outcome in NSCLC patients with synchronous BM, especially in deletion 19 mutant, regardless of the extent of BM lesions or local Tx modalities. Patients with asymptomatic BM can be treated with EGFR-TKI and careful surveillance.

Influence of Concurrent and Adjuvant Temozolomide on Health-Related Quality of Life of Patients with Grade III Gliomas: A Secondary Analysis of a Randomized Clinical Trial (KNOG-1101 Study) / Journal of the Korean Cancer Association, 대한암학회지

Purpose@#The KNOG-1101 study showed improved 2-year PFS with temozolomide during and after radiotherapy compared to radiotherapy alone for patients with anaplastic gliomas. This trial investigates the effect of concurrent and adjuvant temozolomide on health-related quality of life (HRQoL). @*Materials and Methods@#In this randomized, open-label, phase II trial, 90 patients with World Health Organization grade III glioma were enrolled across multiple centers in South Korea between March 2012 to February 2015 and followed up through 2017. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire 30 (EORTC QLQ-C30) and 20-item EORTC QLQ-Brain Neoplasm (QLQ-BN20) were used to compare HRQoL between patients assigned to concurrent chemoradiotherapy with temozolomide followed by 6 cycles of adjuvant temozolomide (arm A) and radiotherapy (RT) alone (arm B). @*Results@#Of the 90 patients in the study, 84 patients (93.3%) completed the baseline HRQoL questionnaire. Emotional functioning, fatigue, nausea and vomiting, dyspnea, constipation, appetite loss, diarrhea, seizures, itchy skin, drowsiness, hair loss, and bladder control were not affected by the addition of temozolomide. All other items did not differ significantly between arm A and arm B throughout treatment. Global health status particularly stayed consistent at the end of adjuvant temozolomide (p=0.47) and at the end of RT (p=0.33). @*Conclusion@#The addition of concurrent and adjuvant temozolomide did not show negative influence on HRQoL with improvement of progression-free survival for patients with anaplastic gliomas. The absence of systematic and clinically relevant changes in HRQoL suggests that an overall long-term net clinical benefit exists for concurrent and adjuvant temozolomide.

Concurrent and Adjuvant Temozolomide for Newly Diagnosed Grade IIIGliomas without 1p/19q Co-deletion: A Randomized, Open-Label,Phase 2 Study (KNOG-1101 Study) / Journal of the Korean Cancer Association, 대한암학회지

Purpose@#We investigated the efficacy of temozolomide during and after radiotherapy in Korean adultswith anaplastic gliomas without 1p/19q co-deletion. @*Materials and Methods@#This was a randomized, open-label, phase 2 study and notably the first multicenter trial forKorean grade III glioma patients. Eligible patients were aged 18 years or older and hadnewly diagnosed non-co-deleted anaplastic glioma with an Eastern Cooperative OncologyGroup performance status of 0-2. Patients were randomized 1:1 to receive radiotherapyalone (60 Gy in 30 fractions of 2 Gy) (control group, n=44) or to receive radiotherapy withconcurrent temozolomide (75 mg/m2/day) followed by adjuvant temozolomide (150-200mg/m2/day for 5 days during six 28-day cycles) (treatment group, n=40). The primary endpointwas 2-year progression-free survival (PFS). Seventy patients (83.3%) were availablefor the analysis of the isocitrate dehydrogenase 1 gene (IDH1) mutation status. @*Results@#The two-year PFS was 42.2% in the treatment group and 37.2% in the control group. Overallsurvival (OS) did not reach to significant difference between the groups. In multivariableanalysis, age was a significant risk factor for PFS (hazard ratio [HR], 2.08; 95% confidenceinterval [CI], 1.04 to 4.16). The IDH1mutation was the only significant prognostic factor forPFS (HR, 0.28; 95% CI, 0.13 to 0.59) and OS (HR, 0.19; 95% CI, 0.07 to 0.50). Adverseevents over grade 3 were seen in 16 patients (40.0%) in the treatment group and werereversible. @*Conclusion@#Concurrent and adjuvant temozolomide in Korean adults with newly diagnosed nonco-deleted anaplastic gliomas showed improved 2-year PFS. The survival benefit of this regimenneeds further analysis with long-term follow-up at least more than 10 years.

The Korean Society for Neuro-Oncology (KSNO) Guideline for Glioblastomas: Version 2018.01

BACKGROUND: There has been no practical guidelines for the management of patients with central nervous system (CNS) tumors in Korea for many years. Thus, the Korean Society for Neuro-Oncology (KSNO), a multidisciplinary academic society, started to prepare guidelines for CNS tumors from February 2018. METHODS: The Working Group was composed of 35 multidisciplinary medical experts in Korea. References were identified through searches of PubMed, MEDLINE, EMBASE, and Cochrane CENTRAL using specific and sensitive keywords as well as combinations of keywords. RESULTS: First, the maximal safe resection if feasible is recommended. After the diagnosis of a glioblastoma with neurosurgical intervention, patients aged ≤70 years with good performance should be treated by concurrent chemoradiotherapy with temozolomide followed by adjuvant temozolomide chemotherapy (Stupp's protocol) or standard brain radiotherapy alone. However, those with poor performance should be treated by hypofractionated brain radiotherapy (preferred)±concurrent or adjuvant temozolomide, temozolomide alone (Level III), or supportive treatment. Alternatively, patients aged >70 years with good performance should be treated by hypofractionated brain radiotherapy+concurrent and adjuvant temozolomide or Stupp's protocol or hypofractionated brain radiotherapy alone, while those with poor performance should be treated by hypofractionated brain radiotherapy alone or temozolomide chemotherapy if the patient has methylated MGMT gene promoter (Level III), or supportive treatment. CONCLUSION: The KSNO's guideline recommends that glioblastomas should be treated by maximal safe resection, if feasible, followed by radiotherapy and/or chemotherapy according to the individual comprehensive condition of the patient.

The Korean Society for Neuro-Oncology (KSNO) Guideline for WHO Grade III Cerebral Gliomas in Adults: Version 2019.01

BACKGROUND: There was no practical guideline for the management of patients with central nervous system tumor in Korea in the past. Thus, the Korean Society for Neuro-Oncology (KSNO), a multidisciplinary academic society, developed the guideline for glioblastoma successfully and published it in Brain Tumor Research and Treatment, the official journal of KSNO, in April 2019. Recently, the KSNO guideline for World Health Organization (WHO) grade III cerebral glioma in adults has been established. METHODS: The Working Group was composed of 35 multidisciplinary medical experts in Korea. References were identified by searches in PubMed, MEDLINE, EMBASE, and Cochrane CENTRAL databases using specific and sensitive keywords as well as combinations of keywords. Scope of the disease was confined to cerebral anaplastic astrocytoma and oligodendroglioma in adults. RESULTS: Whenever radiological feature suggests high grade glioma, maximal safe resection if feasible is globally recommended. After molecular and histological examinations, patients with anaplastic astrocytoma, isocitrate dehydrogenase (IDH)-mutant should be primary treated by standard brain radiotherapy and adjuvant temozolomide chemotherapy whereas those with anaplastic astrocytoma, NOS, and anaplastic astrocytoma, IDH-wildtype should be treated following the protocol for glioblastomas. In terms of anaplastic oligodendroglioma, IDH-mutant and 1p19q-codeletion, and anaplastic oligodendroglioma, NOS should be primary treated by standard brain radiotherapy and neoadjuvant or adjuvant PCV (procarbazine, lomustine, and vincristine) combination chemotherapy. CONCLUSION: The KSNO's guideline recommends that WHO grade III cerebral glioma of adults should be treated by maximal safe resection if feasible, followed by radiotherapy and/or chemotherapy according to molecular and histological features of tumors.

The Korean Society for Neuro-Oncology (KSNO) Guideline for WHO Grade II Cerebral Gliomas in Adults: Version 2019.01

BACKGROUND: There was no practical guideline for the management of patients with central nervous system tumor in Korea for many years. Thus, the Korean Society for Neuro-Oncology (KSNO), a multidisciplinary academic society, has developed the guideline for glioblastoma. Subsequently, the KSNO guideline for World Health Organization (WHO) grade II cerebral glioma in adults is established. METHODS: The Working Group was composed of 35 multidisciplinary medical experts in Korea. References were identified by searching PubMed, MEDLINE, EMBASE, and Cochrane CENTRAL databases using specific and sensitive keywords as well as combinations of keywords regarding diffuse astrocytoma and oligodendroglioma of brain in adults. RESULTS: Whenever radiological feature suggests lower grade glioma, the maximal safe resection if feasible is recommended globally. After molecular and histological examinations, patients with diffuse astrocytoma, isocitrate dehydrogenase (IDH)-wildtype without molecular feature of glioblastoma should be primarily treated by standard brain radiotherapy and adjuvant temozolomide chemotherapy (Level III) while those with molecular feature of glioblastoma should be treated following the protocol for glioblastomas. In terms of patients with diffuse astrocytoma, IDH-mutant and oligodendroglioma (IDH-mutant and 1p19q codeletion), standard brain radiotherapy and adjuvant PCV (procarbazine+lomustine+vincristine) combination chemotherapy should be considered primarily for the high-risk group while observation with regular follow up should be considered for the low-risk group. CONCLUSION: The KSNO's guideline recommends that WHO grade II gliomas should be treated by maximal safe resection, if feasible, followed by radiotherapy and/or chemotherapy according to molecular and histological features of tumors and clinical characteristics of patients.

Procarbazine and CCNU Chemotherapy for Recurrent Glioblastoma with MGMT Promoter Methylation

BACKGROUND: While procarbazine, CCNU (lomustine), and vincristine (PCV) has been an alternative chemotherapy option for malignant gliomas, it is worth investigating whether the combination of only procarbazine and CCNU is comparable because vincristine adds toxicity with uncertain benefit. The purpose of this study was to evaluate the feasibility of procarbazine and CCNU chemotherapy for recurrent glioblastoma multiforme (GBM) with O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation. METHODS: Eight patients with recurrent GBM following concurrent chemoradiotherapy and temozolomide (TMZ) adjuvant therapy were enrolled in this trial; they received no other chemotherapeutic agents or target therapy. They received CCNU (75 mg/m²) on day 1 and procarbazine (60 mg/m²) through days 11 and 24 every 4 weeks. The median cycle of CCNU and procarbazine was 3.5 (range: 2–6). RESULTS: One patient achieved stable disease. The median progression-free survival (PFS) with procarbazine and CCNU chemotherapy was eight weeks (range: 5–73), and the PFS rates were 25% and 12.5% at 16 and 30 weeks, respectively. The median overall survival (OS) from the initial diagnosis to death was 40 months, and the median OS from the administration of procarbazine and CCNU chemotherapy to death was 9.7 months (95% confidence interval: 6.7–12.7). Serious adverse events were found at six visits, and two cases were considered to be grade 3 toxicities. CONCLUSION: The efficacy of procarbazine and CCNU chemotherapy is not satisfactory. This study suggests the need to develop other treatment strategies for recurrent and TMZ-refractory GBM. Trial registry at ClinicalTrials.gov, NCT017337346.

Underexpression of HOXA11 Is Associated with Treatment Resistance and Poor Prognosis in Glioblastoma / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Homeobox (HOX) genes are essential developmental regulators that should normally be in the silenced state in an adult brain. The aberrant expression of HOX genes has been associated with the prognosis of many cancer types, including glioblastoma (GBM). This study examined the identity and role of HOX genes affecting GBM prognosis and treatment resistance. MATERIALS AND METHODS: The full series of HOX genes of five pairs of initial and recurrent human GBM samples were screened by microarray analysis to determine the most plausible candidate responsible for GBM prognosis. Another 20 newly diagnosed GBM samples were used for prognostic validation. In vitro experiments were performed to confirm the role of HOX in treatment resistance. Mediators involved in HOX gene regulation were searched using differentially expressed gene analysis, gene set enrichment tests, and network analysis. RESULTS: The underexpression of HOXA11 was identified as a consistent signature for a poor prognosis among the HOX genes. The overall survival of the GBM patients indicated a significantly favorable prognosis in patients with high HOXA11 expression (31±15.3 months) compared to the prognoses in thosewith low HOXA11 expression (18±7.3 months, p=0.03). When HOXA11 was suppressed in the GBM cell lines, the anticancer effect of radiotherapy and/or temozolomide declined. In addition, five candidate mediators (TGFBR2, CRIM1, TXNIP, DPYSL2, and CRMP1) that may confer an oncologic effect after HOXA11 suppression were identified. CONCLUSION: The treatment resistance induced by the underexpression of HOXA11 can contribute to a poor prognosis in GBM. Further investigation will be needed to confirm the value of HOXA11 as a potential target for overcoming the treatment resistance by developing chemo- or radiosensitizers.

Neurological Change after Gamma Knife Radiosurgery for Brain Metastases Involving the Motor Cortex

BACKGROUND: Although Gamma Knife radiosurgery (GKRS) can provide beneficial therapeutic effects for patients with brain metastases, lesions involving the eloquent areas carry a higher risk of neurologic deterioration after treatment, compared to those located in the non-eloquent areas. We aimed to investigate neurological change of the patients with brain metastases involving the motor cortex (MC) and the relevant factors related to neurological deterioration after GKRS. METHODS: We retrospectively reviewed clinical, radiological and dosimetry data of 51 patients who underwent GKRS for 60 brain metastases involving the MC. Prior to GKRS, motor deficits existed in 26 patients (50.9%). The mean target volume was 3.2 cc (range 0.001–14.1) at the time of GKRS, and the mean prescription dose was 18.6 Gy (range 12–24 Gy). RESULTS: The actuarial median survival time from GKRS was 19.2±5.0 months. The calculated local tumor control rates at 6 and 12 months after GKRS were 89.7% and 77.4%, respectively. During the median clinical follow-up duration of 12.3±2.6 months (range 1–54 months), 18 patients (35.3%) experienced new or worsened neurologic deficits with a median onset time of 2.5±0.5 months (range 0.3–9.7 months) after GKRS. Among various factors, prescription dose (>20 Gy) was a significant factor for the new or worsened neurologic deficits in univariate (p=0.027) and multivariate (p=0.034) analysis. The managements of 18 patients were steroid medication (n=10), boost radiation therapy (n=5), and surgery (n=3), and neurological improvement was achieved in 9 (50.0%). CONCLUSION: In our series, prescription dose (>20 Gy) was significantly related to neurological deterioration after GKRS for brain metastases involving the MC. Therefore, we suggest that careful dose adjustment would be required for lesions involving the MC to avoid neurological deterioration requiring additional treatment in the patients with limited life expectancy.

Continuous Renal Replacement Therapy for Acute Renal Failure in Patients with Traumatic Brain Injury / 대한신경손상학회지

OBJECTIVE: The purpose of this study was to investigate the impact of continuous renal replacement therapy (CRRT) on survival and relevant factors in patients who underwent CRRT after traumatic brain injury (TBI). METHODS: We retrospectively reviewed the laboratory, clinical, and radiological data of 29 patients who underwent CRRT among 1,190 TBI patients treated at our institution between April 2011 and June 2015. There were 20 men and 9 women, and the mean age was 60.2 years. The mean initial Glasgow Coma Scale score was 9.2, and the mean injury severity score was 24. Kaplan-Meier method and Cox regression were used for analysis of survival and relevant factors. RESULTS: The actuarial median survival time of the 29 patients was 163 days (range, 3-317). Among the above 29 patients, 22 died with a median survival time of 8 days (range, 3-55). The causes of death were TBI-related in 8, sepsis due to pneumonia or acute respiratory distress syndrome (ARDS) in 4, and multi-organ failure in 10. Among the various factors, urine quantity of more than 500 mL for 24-hours before receiving CRRT was a significant and favorable factor for survival in the multivariate analysis (p=0.026). CONCLUSION: According to our results, we suggest that early intervention with CRRT may be beneficial in the treatment of TBI patients with impending acute renal failure (ARF). To define the therapeutic advantages of early CRRT in the TBI patients with ARF, a well-designed and controlled study with more cases is required.

Clinical Experience of Glioma Surgery Using "Tailed Bullet": Overcoming the Limitations of Conventional Neuro-Navigation Guided Surgery

PURPOSE: Although conventional neuro-navigation is a useful tool for image-guided glioma surgery, there are some limitations, such as brain shift. We introduced our methods using an identifiable marker, a "tailed bullet", to overcome the limitation of conventional neuro-navigation. A tailed bullet is an identifiable tumor location marker that determines the extent of a resection and we have introduced our technique and reviewed the clinical results. MATERIALS AND METHODS: We have developed and used "tailed bullets" for brain tumor surgery. They were inserted into the brain parenchyma or the tumor itself to help identify the margin of tumor. We retrospectively reviewed surgically resected glioma cases using "tailed bullet". Total 110 gliomas included in this study and it contains WHO grade 2, 3, and 4 glioma was 14, 36, and 60 cases, respectively. RESULTS: Gross total resection (GTR) was achieved in 71 patients (64.5%), subtotal resection in 36 patients (32.7%), and partial resection in 3 patients (2.7%). The overall survival (OS) duration of grade 3 and 4 gliomas were 20.9 (range, 1.2-82.4) and 13.6 months (range, 1.4-173.4), respectively. Extent of resection (GTR), younger age, and higher initial Karnofsky Performance Status (KPS) score were related to longer OS for grade-4 gliomas. There was no significant adverse event directly related to the use of tailed bullets. CONCLUSION: Considering the limitations of conventional neuro-navigation methods, the tailed bullets could be helpful during glioma resection. We believe this simple method is an easily accessible technique and overcomes the limitation of the brain shift from the conventional neuro-navigation. Further studies are needed to verify the clinical benefits of using tailed bullets.

Incidence of Post-Traumatic Stress Disorder after a Mild Traumatic Brain Injury: Preliminary Investigation Using the Brief Neuropsychological Screening Test

OBJECTIVE: Post-traumatic stress disorder (PTSD) is a group of diseases that are observed in patients who had experienced a serious trauma or accident. However, some experienced it even after only a mild traumatic brain injury (TBI), and they are easily ignored due to the relatively favorable course of mild TBI. Herein, the authors investigated the incidence of PTSD in mild TBI using brief neuropsychological screening test (PTSD checklist, PCL). METHODS: This study was conducted on patients with mild TBI (Glasgow coma scale > or =13) who were admitted from January 2012 to December 2012. As for PCL, it was done on patients who showed no difficulties in communication upon admission and agreed to participate in this study. By using sum of PCL, the patients were divided into high-risk group and low-risk group. PTSD was diagnosed as the three major symptoms of PTSD according to the Diagnostic and Statistical Manual of Mental Disorders, fourth-edifion. RESULTS: A total of 314 TBI patients were admitted and 71 of them met the criteria and were included in this study. The mean age was 52.9 years-old (range: 15-94). The mean PCL score was 28.8 (range: 17-68), and 10 patients were classified as high-risk group. During follow-up, 2 patients (2.7%) of high risk group, were confirmed as PTSD and there was no patient who was suspected of PTSD in the low-risk group (p=0.017). CONCLUSION: PTSD is observed 2.8% in mild TBI. Although PTSD after mild TBI is rare, PCL could be considered as a useful tool for screening of PTSD after mild TBI.

Outcomes of Ultra-Early Decompressive Craniectomy after Severe Traumatic Brain Injury-Treatment Outcomes after Severe TBI / 대한신경손상학회지

OBJECTIVE: The beneficial effect of decompressive craniectomy in the treatment of severe traumatic brain injury (TBI) is controversial, but there is no debate that decompression should be performed before irreversible neurological deficit occurs. The aim of our study was to assess the value of ultra-early decompressive craniectomy in patients with severe TBI. METHODS: Total of 127 patients who underwent decompressive craniectomy from January 2007 to December 2013 was included in this study. Among them, 60 patients had underwent ultra-early (within 4 hours from injury) emergent operation for relief of increased intracranial pressure. Initial Glasgow coma scale, brain computed tomography (CT) scan features by Marshall CT classification, and time interval between injury and craniectomy were evaluated retrospectively. Clinical outcome was evaluated, using the modified Rankin score. RESULTS: The outcomes of ultra-early decompressive craniectomy group were not better than those in the comparison group (p=0.809). The overall mortality rate was 68.5% (87 patients). Six of all patients (4.7%) showed good outcomes, and 34 patients (26.8%) remained in a severely disabled or vegetative state. Forty of sixty patients (66.7%) had died, and two patients (3.3%) showed good outcomes at last follow-up. CONCLUSION: Ultra-early decompressive craniectomy for intracranial hypertension did not improve patient outcome when compared with "early or late" decompressive craniectomy for managing severe TBI.

The Effectiveness Evaluation of Helicopter Ambulance Transport among Neurotrauma Patients in Korea

OBJECTIVE: Helicopter ambulance transport (HAT) is a highly resource-intensive facility that is a well-established part of the trauma transport system in many developed countries. Here, we review the benefit of HAT for neurosurgical patients in Korea. METHODS: This retrospective study followed neurotrauma patients who were transferred by HAT to a single emergency trauma center over a period of 2 years. The clinical benefits of HAT were measured according to the necessity of emergency surgical intervention and the differences in the time taken to transport patients by ground ambulance transport (GAT) and HAT. RESULTS: Ninety-nine patients were transferred to a single university hospital using HAT, of whom 32 were taken to the neurosurgery department. Of these 32 patients, 10 (31.3%) needed neurosurgical intervention, 14 (43.8%) needed non-neurosurgical intervention, 3 (9.4%) required both, and 11 (34.4%) did not require any intervention. The transfer time was faster using HAT than the estimated time needed for GAT, although for a relatively close distance (<50 km) without ground obstacles (mountain or sea) HAT did not improve transfer time. The cost comparison showed that HAT was more expensive than GAT (3,292,000 vs. 84,000 KRW, p<0.001). CONCLUSION: In this Korean-based study, we found that HAT has a clinical benefit for neurotrauma cases involving a transfer from a distant site or an isolated area. A more precise triage for using HAT should be considered to prevent overuse of this expensive transport method.

Retrovirus-mediated transduction of a cytosine deaminase gene preserves the stemness of mesenchymal stem cells

Human mesenchymal stem cells (MSCs) have emerged as attractive cellular vehicles to deliver therapeutic genes for ex-vivo therapy of diverse diseases; this is, in part, because they have the capability to migrate into tumor or lesion sites. Previously, we showed that MSCs could be utilized to deliver a bacterial cytosine deaminase (CD) suicide gene to brain tumors. Here we assessed whether transduction with a retroviral vector encoding CD gene altered the stem cell property of MSCs. MSCs were transduced at passage 1 and cultivated up to passage 11. We found that proliferation and differentiation potentials, chromosomal stability and surface antigenicity of MSCs were not altered by retroviral transduction. The results indicate that retroviral vectors can be safely utilized for delivery of suicide genes to MSCs for ex-vivo therapy. We also found that a single retroviral transduction was sufficient for sustainable expression up to passage 10. The persistent expression of the transduced gene indicates that transduced MSCs provide a tractable and manageable approach for potential use in allogeneic transplantation.

Pituitary Apoplexy Mimicking Meningitis

Pituitary apoplexy is a rare but life-threatening disorder. Clinical presentation of this condition includes severe headaches, impaired consciousness, fever, visual disturbance, and variable ocular paresis. The clinical presentation of meningeal irritation is very rare. Nonetheless, if present and associated with fever, pituitary apoplexy may be misdiagnosed as a meningitis. We experienced a case of pituitary apoplexy masquerading as a meningitis. A 42-year-old man presented with meningitis associated symptoms and initial imaging studies did not show evidence of intra-lesional hemorrhage in the pituitary mass. However, a follow-up imaging after neurological deterioration revealed pituitary apoplexy. Hereby, we report our case with a review of literatures.

Temozolomide Salvage Chemotherapy for Recurrent Anaplastic Oligodendroglioma and Oligo-Astrocytoma

OBJECTIVE: To evaluate the efficacy of temozolomide (TMZ) chemotherapy for recurrent anaplastic oligodendroglioma (AO) and anaplastic oligoastrocytoma (AOA). METHODS: A multi-center retrospective trial enrolled seventy-two patients with histologically proven AO/AOA who underwent TMZ chemotherapy for their recurrent tumors from 2006 to 2010. TMZ was administered orally (150 to 200 mg/m2/day) for 5 days per 28 days until unacceptable toxicity occurred or tumor progression was observed. RESULTS: TMZ chemotherapy cycles administered was median 5.3 (range, 1-41). The objective response rate was 24% including 8 cases (11%) of complete response and another 23 patients (32%) were remained as stable disease. Severe side effects (> or =grade 3) occurred only in 9 patients (13%). Progression-free survival (PFS) of all patients was a median 8.0 months (95% confidence interval, 6.0-10.0). The time to recurrence of a year or after was a favorable prognostic factor for PFS (p<0.05). Overall survival (OS) was apparently differed by the patient's histology, as AOA patients survived a median OS of 18.0 months while AO patients did not reach median OS at median follow-up of 11.5 months (range 2.7-65 months). Good performance status of Eastern Cooperative Oncology Group 0 and 1 showed prolonged OS (p<0.01). CONCLUSION: For recurrent AO/AOA after surgery followed by radiation therapy, TMZ could be recommended as a salvage therapy at the estimated efficacy equal to procarbazine, lomustine, and vincristine (PCV) chemotherapy at first relapse. For patients previously treated with PCV, TMZ is a favorable therapeutic option as 2nd line salvage chemotherapy with an acceptable toxicity rate.

Radiation-Induced Intratumoral Necrosis and Peritumoral Edema after Gamma Knife Radiosurgery for Intracranial Meningiomas

OBJECTIVE: To study the clinical significance and relevant factors of radiation-induced intratumoral necrosis (RIN) and peritumoral edema (PTE) after Gamma knife radiosurgery (GKRS) for intracranial meningiomas. METHODS: We retrospectively analyzed the data of 64 patients who underwent GKRS for intracranial meningioma. The mean lesion volume was 4.9 cc (range, 0.3-20), and the mean prescription dose of 13.4 Gy (range, 11-18) was delivered to the mean 49.9% (range, 45-50) isodose line. RIN was defined as newly developed or enlarged intratumoral necrosis after GKRS. RESULTS: RIN and new development or aggravation of PTE were observed in 21 (32.8%) and 18 (28.1%) cases of meningioma, respectively during the median follow-up duration of 19.9+/-1.0 months. Among various factors, maximum dose (>25 Gy) and target volume (>4.5 cc) were significantly related to RIN, and RIN and maximum dose (>24 Gy) were significantly related to the development or aggravation of PTE. In 21 meningiomas with development of RIN after GKRS, there was no significant change of the tumor volume itself between the times of GKRS and RIN. However, the PTE volume increased significantly compared to that at the time of GKRS (p=0.013). The median interval to RIN after GKRS was 6.5+/-0.4 months and the median interval to new or aggravated PTE was 7.0+/-0.7 months. CONCLUSION: A close observation is required for meningiomas treated with a maximum dose >24 Gy and showing RIN after GKRS, since following or accompanying PTE may deteriorate neurological conditions especially when the location involves adjacent critical structures.

Use of Continuous Venovenous Hemodiafiltration to Enhance the Elimination of Serum Pentobarbital before Diagnosis of Brain Death / 대한이식학회지

Continuous venovenous hemodiafiltration (CVVHDF) was used to eliminate pentobarbital from the blood of a 30-year-old potentially brain dead male patient with traumatic intracranial hemorrhage after a motorcycle accident. The Acute Physiology and Chronic Health Evaluation (APACHE) II score of hospital day 1 was 24, but by day 8 it was 36, when the patient was considered to be brain dead. To control seizures and reduce intracranial pressure, pentobarbital had been administered in a continuous flow (2,880 mg/day for 5 days). Coma can be induced by pentobarbital at a serum level of 1~5 mg/dL. However, drug intoxication should be excluded from a brain death evaluation; therefore, the patient was not given any drug for approximately 88 hrs after ceasing pentobarbital in order for serum level to dip below 0.5 mg/dL (which is the hypnotic level). At 48 hours from CVVHDF, the pentobarbital level was close to the hypnotic level (0.1~0.5 mg/dL). Before stopping, the serum level of pentobarbital was 3.89 mg/dL and between 48 and 72 hours from CVVHDF, 4 cycles of pentobarbital half-life elimination (0.24 mg/dL) could be measured. Therefore, we suggest that in case of potential brain dead patients who have been administered pentobarbital, CVVHDF can enhance the elimination of pentobarbital from the circulatory system and shorten the waiting time for a brain death evaluation.