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In our translational research, an immunotherapeutic, ADCTA-G, has been developed to emphasize autologous tumor antigens, DC antigen processing/presentation, enhanced tumor immunogenicity and CTL induction. Two clinical trials, Phase I/II [2003-2005Taiwan DOH/MA 0910072504] and phase II [2005–2016 NIH {"type":"clinical-trial","attrs":{"text":"NCT02772094","term_id":"NCT02772094"}}NCT02772094], “Dendritic Cell(DC)-Based Tumor Vaccine Adjuvant Immunotherapy of Human Glioblastoma Multiforme”, respectively enrolled 17 and 42 WHO Grade-IV glioblastomas. Every patient received peripheral blood apheresis for PBMNCs. Monocytes were used for derivation of 3-7x108 phagocytic dendritic cells (iDC). Autologous glioma cells grown out of surgical tumor specimen were irradiated and co-cultivated 1 to 2:1 with iDC to make a ADCTA-G lot. After surgical tumor de-bulking, 10 vaccinations were given, each with 2-5x107 mature DC from the ADCTA lot, in a [4x biweekly and 6x monthly] scheduled s.c. injection in both axillar regions. The follow-up period has been 15 years. Primary endpoint is the overall survival (OS); phenotypes of tumor infiltrating T cells and tumor IDH mutation were also analyzed for long-term survivors. The ADCTA-G inoculations were tolerated well, and curtailed the grade-3/4 lymphopenia adverse effect of the temozolomide CCRT. The median OS is 22.9 months for the total 59 grade IV patients in the two trials. The median OS is 21.8 months for the 44 newly diagnosed patients and 28.1 months for the 15 recurrent patients; the difference is insignificant statistically. In this study, vaccinations were initiated early in the recurrent GBM patients while the newly diagnosed GBM patients had to wait till after external radiation therapy, leading to a comparable OS benefit of the ADCTA vaccination. Also, we demonstrated in vitro the earlier vaccinations in the recurrent decrease CD133+ tumor stem-like cells. In addition, the CD8(+) cells were susceptible to ionizing radiation. A phase 3 open-labelled randomized study will be initiated to improve the survival of this aggressive malignancy.

BACKGROUND: Primary central nervous system lymphoma (PCNSL) is an uncommon disease. Conventional treatment has consisted of either whole-brain radiotherapy (WBRT) or methotrexate (MTX)-based combined modality therapy combining chemotherapy and cranial irradiation. The addition of chemotherapy to cranial RT has significantly improved survival outcomes. However, delayed treatment-related cognitive sequelae have emerged as a significant debilitating complication of combined modality treatment in PCNSL patients, especially when effective treatment can result in disease control and greater survival. Furthermore, the specific contribution of the disease per se and various treatment modalities to cognitive impairment remains unclear because it is difficult to differentiate the individual neurotoxic effects of combined modalities when each can lead to cognitive dysfunctions respectively. METHODS: A prospective observational cohort study with longitudinal assessments of neurobehavioral functions, neuroimaging, and activities of daily living in newly-diagnosed PCNSL patients was undertaken at our institute. Neurobehavioral outcomes were integrated into this prospective study and a battery of neuropsychological measures was used to evaluate neurocognitive functions (NCFs). The battery is composed of ten standardized NCF tests, representing four domains sensitive to disease and treatment effects (executive function, attention, verbal memory, psychomotor speed), and activities of daily living. RESULTS: Totally 15 patients with newly-diagnosed PCNSL including two cases with primary intraocular lymphoma were consecutively enrolled from February 2014 to January 2018. Comparing the differences in NCF scores between the baseline and post-treatment intervals, neurobehavioral outcomes consistently remained improving or in almost every domain evaluated in this study. Specifically, the scores of executive functions based on Paced Auditory Serial Addition Test (PACT) significantly improved between the baseline and post-chemoradiation assessment (Wilcoxon rank sum test, p = 0.016). CONCLUSIONS: Under the multidisciplinary treatment guidelines implemented at our institute, both improving neurobehavioral outcomes and maintaining oncological outcomes can be achieved.

Many molecules and signaling pathways involved in neural development play a role in neurodegenerative diseases and brain tumor progression. Peroxisome proliferator-activated receptor (PPAR) proteins regulate the differentiation of tissues and the progression of many diseases. However, the role of these proteins in neural development is unclear.We examined the function of Pparα in the neural development of zebrafish. Two duplicate paralogs for mammalian PPARA/Ppara, namely pparaa and pparab, are present in the zebrafish genome. Both pparaa and pparab are expressed in the developing central nervous system in zebrafish embryos. Inhibiting the function of Pparα by using either the PPARα/Pparα antagonist GW6471 or pparaa or pparab truncated constructs produced identical phenotypes, which were sufficient to reduce the proliferation of neuronal and glial precursor cells without affecting the formation of neural progenitors.We demonstrated that both Pparαa and Pparαb proteins are essential regulators of the proliferation of neuronal and glial precursors. This study provides a better understanding of the functions of PPARα/Pparα in neural development and further expands our knowledge of the potential role of PPARα/Pparα in neurological disorders and brain tumors. Developmental Dynamics 247:1264-1275, 2018. © 2018 Wiley Periodicals, Inc.

Background: Migraine attack has been associated with magnesium deficiency. Previous studies investigating the effect of intravenous and oral magnesium on acute migraine attacks and the prevention of migraine have produced equivocal findings. Objective: To evaluate the effects of intravenous magnesium on acute migraine attacks and oral magnesium supplements on migraine prophylaxis. Study Design: A meta-analysis of randomized controlled trials (RCTs). Setting: Electronic databases, namely EMBASE, PubMed, the Wanfang Data Chinese Database, and the China Knowledge Resource Integrated Database were searched from inception to February 24, 2015. Methods: This review was conducted according to the guidelines of the PRISMA. Only RCTs evaluating the effects of intravenous or oral magnesium on migraine compared with a control group were included. Results: A total of 21 studies were included. Of which, 11 studies investigated the effects of intravenous magnesium on acute migraine (948 participants) and 10 examined the effects of oral magnesium on migraine prophylaxis (789 participants). Intravenous magnesium significantly relieved acute migraine within 15 – 45 minutes, 120 minutes, and 24 hours after the initial infusion (Odd ratios [ORs] = 0.23, 0.20, and 0.25, respectively). Oral magnesium significantly alleviated the frequency and intensity of migraine (ORs = 0.20 and 0.27). Limitations: Some of the included studies did not adopt adequate randomization methods. Conclusions: Intravenous magnesium reduces acute migraine attacks within 15 – 45 minutes, 120 minuts, and 24 hours after the initial infusion and oral magnesium alleviates the frequency and intensity of migraine. Intravenous and oral magnesium should be adapted as parts of multimodal approach to reduce migraine. Key words: Magnesium, migraine, meta-analysis

Nasopharyngeal carcinoma (NPC) is an Epstein Barr virus (EBV)-related malignancy in which the tumor microenvironment plays a pivotal role in tumor progression. Here, we developed two patient-derived xenograft (PDX) mouse lines from engrafted NPC metastatic tumors. Positive staining for EBV-encoded small RNAs confirmed that these tumors harbored EBV, and gene expression profile analyses further showed that the PDX was highly similar to the primary parent tumor. In vivo drug screening using the PDX system demonstrated that gemcitabine had the best antitumor effect among the tested drugs. The donor of this PDX also showed excellent responsiveness to gemcitabine treatment. The combination of gemcitabine and valproic acid exerted synergistic antitumor effects. Further addition of ganciclovir to this two-drug combination regimen enhanced cytolytic viral activation, yielding the best antitumor response among tested regimens. Treatment with this three-drug combination regimen decreased plasma EBV-DNA load, tumor viral concentration, and the number of viable tumor cells to a greater extent than the two-drug gemcitabine and valproic acid combination. These results highlight the value of PDX models in the development of EBV-targeted strategies to treat NPC.

PARK14 patients with homozygous (D331Y) PLA2G6 mutation display motor deficits of pure early-onset Parkinson's disease (PD). The aim of this study is to investigate the pathogenic mechanism of mutant (D331Y) PLA2G6-induced PD. We generated knockin (KI) mouse model of PARK14 harboring homozygous (D331Y) PLA2G6 mutation. Then, we investigated neuropathological and neurological phenotypes of PLA2G6D331Y/D331Y KI mice and molecular pathogenic mechanisms of (D331Y) PLA2G6-induced degeneration of substantia nigra (SN) dopaminergic neurons. Six-or nine-month-old PLA2G6D331Y/D331Y KI mice displayed early-onset cell death of SNpc dopaminergic neurons. Lewy body pathology was found in the SN of PLA2G6D331Y/D331Y mice. Six-or nine-month-old PLA2G6D331Y/D331Y KI mice exhibited early-onset parkinsonism phenotypes. Disrupted cristae of mitochondria were found in SNpc dopaminergic neurons of PLA2G6D331Y/D331Y mice. PLA2G6D331Y/D331Y mice displayed mitochondrial dysfunction and upregulated ROS production, which may lead to activation of apoptotic cascade. Upregulated protein levels of Grp78, IRE1, PERK, and CHOP, which are involved in activation of ER stress, were found in the SN of PLA2G6D331Y/D331Y mice. Protein expression of mitophagic proteins, including parkin and BNIP3, was downregulated in the SN of PLA2G6D331Y/D331Y mice, suggesting that (D331Y) PLA2G6 mutation causes mitophagy dysfunction. In the SN of PLA2G6D331Y/D331Y mice, mRNA levels of eight genes that are involved in neuroprotection/neurogenesis were decreased, while mRNA levels of two genes that promote apoptotic death were increased. Our results suggest that PARK14 (D331Y) PLA2G6 mutation causes degeneration of SNpc dopaminergic neurons by causing mitochondrial dysfunction, elevated ER stress, mitophagy impairment, and transcriptional abnormality.

Objectives: Although topiramate is a relatively safe and effective for seizure control, there is a need to compare the anti-epileptic effects either in monotherapy or as the first add-on therapy for epilepsy. This study was a multicenter, randomized, open-label, parallel-group trial involving neurosurgical patients. Materials and methods: We enrolled 55 patients and assigned them to either the monotherapy group or the add-on therapy group with a slow titration schedule. Patients were evaluated for eight weeks. Results: At the end of this study, the seizure-free response rate, seizure response rate (seizure control ≥ 50%), and seizure frequency improved compared to the baseline values (45.6% to 80%, 80% to 83.6% and 2.53/month to 0.971/month, respectively); However, in patients without tumors, the seizure frequency decreased significantly, indicating reduced efficacy in this subgroup. Although adverse events were mostly minor, eight patients withdrew because of them. Overall, the rate of improvement as assessed by patients was 87.0% and 92.9% in the monotherapy and add-on therapy groups. Conclusions: Seizure control is crucial in neurosurgical patients. In this study, monotherapy as well as add-on therapy showed similar anti-epileptic efficacy, implying that topiramate monotherapy alone maybe sufficient for treatment of epilepsy.

Many studies have shown that mitochondrial aldehyde dehydrogenase 2 (ALDH2) functions as a cellular protector against oxidative stress by detoxification of cytotoxic aldehydes. Within dopaminergic neurons, dopamine is metabolized by monoamine oxidase to yield 3,4-dihydroxyphenylacetaldehyde (DOPAL) then converts to a less toxic acid product by ALDH. The highly toxic and reactive DOPAL has been hypothesized to contribute to the selective neurodegeneration in Parkinson's disease (PD). In this study, we investigated the neuroprotective mechanism and therapeutic effect of ALDH2 in rotenone models for parkinsonism. Overexpression of wild-type ALDH2 gene, but not the enzymatically deficient mutant ALDH2*2 (E504K), reduced rotenone-induced cell death. Application of a potent activator of ALDH2, Alda-1, was effective in protecting against rotenone-induced apoptotic cell death in both SH-SY5Y cells and primary cultured substantia nigra (SN) dopaminergic neurons. In addition, intraperitoneal administration of Alda-1 significantly reduced rotenone- or MPTP-induced death of SN tyrosine hydroxylase (TH)-positive dopaminergic neurons. The attenuation of rotenone-induced apoptosis by Alda-1 resulted from decreasing ROS accumulation, reversal of mitochondrial membrane potential depolarization, and inhibition of activation of proteins related to mitochondrial apoptotic pathway. The present study demonstrates that ALDH2 plays a crucial role in maintaining normal mitochondrial function to protect against neurotoxicity and that Alda-1 is effective in ameliorating mitochondrial dysfunction and inhibiting mitochondria-mediated apoptotic pathway. These results indicate that ALDH2 activation could be a neuroprotective therapy for PD.

Glioblastoma multiforme (GBM) is the most prevalent and high malignant primary brain tumors, and contains a small cohort of self-renewing, tumorigenic glioblastoma stem cells (GSCs) that contribute to tumor relapse and therapeutic resistance. GSCs are typically recognized by the expression of cell surface marker, CD133, encoded from prominin-1 (PROM1) gene. Recent studies have indicated CD133+ cancer stem-like cells are enriched after the treatment of ionizing radiation (IR). To investigate the effect of cytotoxic TILs to glioblastoma cells experienced irradiation, we used post-vaccination TILs treat with glioblastoma cells derived from patient’s tissue specimens without experienced and experienced irradiation respectively. The effect of cytotoxic TILs was not evident in glioblastoma cells experienced IR until 120 hours later. To further investigate whether immune cytokines have cytotoxicity in CD133+ glioblastoma cells, we observed that TNF-α and IFN-γ have the cytotoxic effects in CD133+ glioblastoma cells, implicating the reason why the cytotoxic of CD8+ TILs were delayed to 120 hours. These data provide the framework for understanding the radioresistance in glioblastoma cells that can be used to develop an efficient vaccine.

Background The prognosis and recurrence rate after resection of an anterior skull base lesion via transciliary supraorbital keyhole craniotomy depend on residual tumor volume. The extent to which pathology and size of tumor influence the resection rate using this approach is unknown. Methods Sixty-two patients underwent a total of 64 operations using the supraorbital keyhole approach in this retrospective study. Meningioma was the most common tumor, followed by pituitary adenoma and craniopharyngioma. Age, sex, tumor volume, operative duration, blood loss, and complication rates were evaluated. Pre- and postoperative residual tumor volumes were measured using OsiriX software (medical image viewer system) based on magnetic resonance imaging. A 15-mL cut value divided the subjects into large versus small meningioma groups. Results The average resection rate for meningiomas was 95.2% compared with 83.9% for craniopharyngiomas and 53.2% for pituitary adenomas. The major complication rate (primarily blindness and hemiplegia) was 4.48% in all tumors. No operative-related deaths occurred. There were no surgical revisions to traditional large craniotomies. No significant differences in age, sex, postoperative volumes, resection rates, or recurrence rates were noted between small and large meningioma groups. However, longer operative times and hospital stays, and greater blood loss occurred in the large meningioma group. Conclusions Transciliary keyhole craniotomy is a safe and effective approach for anterior skull base tumors, especially meningiomas. Excellent resection results were achieved even in cases of large meningiomas. Although longer operative times, longer hospital stays, and greater blood loss occurred in larger compared with smaller meningioma cases, recurrence rates were similar.

Hexanucleotide repeat expansions in the C9orf72 gene are a common genetic cause of familial and sporadic amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, the function of C9orf72 in neural development and the pathogenic mechanism underlying neurodegeneration are unknown. We found that disrupting C9orf72 expression by using C9orf72 constructs that lack the complete DENN domain result in reduced GTPase activity in zebrafish embryos, demonstrating the indispensability of the complete DENN domain. This effect was phenocopied by knocking down endogenous C9orf72 expression by using morpholinos. C9orf72-deficient zebrafish embryos exhibited impaired axonogenesis and motility defects. The C9orf72 deficiency upregulated the expression of tp53 and caused neuronal apoptosis. Knockdown Tp53 in the C9orf72-deficient embryos rescued only the apoptotic phenotype but not the phenotype with axonal and motility defects. The C9orf72 deficiency also induced ccng1 (encodes Cyclin G1) mRNA expression, and injection of a dominant-negative Cyclin G1 construct rescued the axonal impairment, apoptosis, and motility defects in the C9orf72-deficient embryos. Our results revealed the GTPase activity of C9orf72 and demonstrated that Cyclin G1 is an essential downstream mediator for C9orf72 in neural development and motility. Furthermore, downregulating Cyclin G1 was sufficient to rescue all the defects caused by C9orf72 deficiency. In summary, we revealed a novel regulatory mechanism underlying the role of C9orf72 in neurological and motility defects. This result facilitates understanding the function of the C9orf72 gene in the developing nervous system and provides a potential mechanism underlying the pathogenesis of ALS-FTD.

OBJECTIVECranioplasty is a relatively simple and less invasive intervention, but it is associated with a high incidence of postoperative seizures. The incidence of, and the risk factors for, such seizures and the effect of prophylactic antiepileptic drugs (AEDs) have not been well studied. The authors’ aim was to evaluate the risk factors that predispose patients to postcranioplasty seizures and to examine the role of seizure prophylaxis in cranioplasty.METHODSThe records of patients who had undergone cranioplasty at the authors’ medical center between 2009 and 2014 with at last 2 years of follow-up were retrospectively reviewed. Demographic and clinical characteristics, the occurrence of postoperative seizures, and postoperative complications were analyzed.RESULTSAmong the 583 patients eligible for inclusion in the study, 247 had preexisting seizures or used AEDs before the cranioplasty and 336 had no seizures prior to cranioplasty. Of these 336 patients, 89 (26.5%) had new-onset seizures following cranioplasty. Prophylactic AEDs were administered to 56 patients for 1 week after cranioplasty. No early seizures occurred in these patients, and this finding was statistically significant (p = 0.012). Liver cirrhosis, intraoperative blood loss, and shunt-dependent hydrocephalus were risk factors for postcranioplasty seizures in the multivariable analysis.CONCLUSIONSCranioplasty is associated with a high incidence of postoperative seizures. The prophylactic use of AEDs can reduce the occurrence of early seizures.

To determine the systemic impact of intravitreal injection of bevacizumab (IVB), an anti-vascular endothelium growth factor antibody, in newborn rabbits.We used four groups of rabbits. Group 1 rabbits received a single injection of IVB starting from the age of 6 weeks. Group 2 rabbits received a single injection of balanced salt solution (BSS, 0.025 ml) and served as controls for group 1. Group 3 rabbits received two consecutive injections of IVB at the ages of 6 and 10 weeks. Group 4 rabbits received two consecutive injections of BSS at the ages of 6 and 10 weeks and served as controls for group 3. During the experiment, a complete blood count (CBC), clinical biochemistry, weight gain, food intake, body temperature, blood pressure, pulse, and mortality were measured in the animals. Two months after IVB injection, the animals were sacrificed, and histology of the major organs was checked. Immunohistochemistry was assessed to explore the neurons in the central nervous system (CNS).We found there were no morphological or functional changes in the eyes following IVB injection. Furthermore, there were no differences in CBC, biochemistry, or other measured parameters among the four groups of animals. We checked the histology of the major organs and neurons in the CNS and they did not reveal significant differences among the four groups of animals.Conclusively, IVB of either one or two injections (0.625 mg) in newborn rabbit eyes is well tolerated and does not cause noticeable systemic organ pathology.

Objective Diseases of the pancreas, especially pancreatitis, have been implicated as possible risk factors for psychiatric illnesses, such as depression and anxiety disorder. This nested case-control study aimed to investigate the association between diseases of the pancreas and completed suicide in a psychiatric population-based study. Methods The case group comprised 6568 completed suicides (ICD-9: E950-E959, E980-989) patients from the national mortality database between January 1, 2002 and December 1, 2010. These cases were compared with 6568 gender-, age-, residence-, and insurance premium-matched controls. Both suicide and non-suicide study patients were drawn from a group with previous psychiatric diagnoses. The risk of suicide among patients with diseases of the pancreas was analyzed using a conditional logistic regression model that controlled for alcohol-related disorder, drug dependence, schizophrenia, depressive disorder, bipolar disorder, anxiety disorder, Charlson comorbidity score, and outpatient visits. Results Disease of the pancreas was an independent risk factor for psychiatric patients who had completed suicide when adjusted for clinical and other comorbid factors. Among these covariates, alcohol-related disorders partially mediate the suicide risk among patients with disease of the pancreas, and mental disorders may not mediate this suicide risk. Conclusions Diseases of the pancreas were associated with increased risk of completed suicide after controlling for potential confounding factors.

OBJECTIVEBurr hole craniostomy is an effective and simple procedure for treating chronic subdural hematoma (CSDH). However, the surgical outcomes and recurrence of CSDH in patients with liver cirrhosis (LC) remain unknown.METHODSA nationwide population-based cohort study was retrospectively conducted using data from the Taiwan National Health Insurance Research Database. The study included 29,163 patients who underwent first-time craniostomy for CSDH removal between January 1, 2001, and December 31, 2013. In total, 1223 patients with LC and 2446 matched non-LC control patients were eligible for analysis. All-cause mortality, surgical complications, repeat craniostomy, extended craniotomy, and long-term medical costs were analyzed.RESULTSThe in-hospital mortality rate (8.7% vs 3.1% for patients with LC and non-LC patients, respectively), frequency of hospital admission, length of ICU stay, number of blood transfusions, and medical expenditures of patients with LC who underwent craniostomy for CSDH were considerably higher than those of non-LC control patients. Patients with LC tended to require an extended craniotomy to remove subdural hematomas in the hospital or during long-term follow-up. The surgical outcome worsened with an increase in the severity of LC.CONCLUSIONSEven for simple procedures following minor head trauma, LC remains a serious comorbidity with a poor prognosis.

Multiple epigenetic factors play a critical role in cell proliferation and differentiation. However, their function in embryogenesis, especially in neural development, is currently unclear. The Trithorax group (TrxG) homolog KMT2A (MLL1) is an important epigenetic regulator during development and has an especially well-defined role in hematopoiesis. Translocation and aberrant expression of KMT2A is often observed in many tumors, indicating its proto-oncogenic character. Here, we show that Kmt2a was essential for neural development in zebrafish embryos. Disrupting the expression of Kmt2a using morpholino antisense oligonucleotides and a dominant-negative variant resulted in neurogenic phenotypes, including downregulated proliferation of neural progenitors, premature differentiation of neurons, and impaired gliogenesis. This study therefore revealed a novel function of Kmt2a in cell proliferation and differentiation, providing further insight into the function of TrxG proteins in neural development and brain tumors. © 2014 Wiley Periodicals, Inc. Develop Neurobiol 75: 452–462, 2015

Primitive neuro-ectodermal tumors (PNET) are rare malignant brain tumors, mostly undifferentiated, that tend to spread through the cerebrospinal fluid (CSF). Extra-pineal supratentorial PNET in adults are very rare. Published guidelines for adult PNET were not available until 2011, and at our institute surgeons and oncologists did not have consensus on imaging evaluation or treatment protocols between 1994 to 2008. Twenty-two consecutive adult patients with extra-pineal supratentorial PNET from this period were reviewed in this retrospective study. Their clinical profiles and radiologic images were evaluated. A pathological review based on the 2007 World Health Organization criteria was also conducted. Prognostic factors were analyzed. The 1 and 3 year overall survival rates were 64% and 32% for adult extra-pineal supratentorial PNET, respectively. Limited by the small number of tumors in this series, we suggest that negative prognostic factors are multiplicity at onset, initial CSF seeding, and tumor differentiation. Although age of onset, extent of resection, radiation and chemotherapy were assumed to be good prognostic factors, the analysis did not reveal strong significance for overall survival with univariate and multivariate analysis. We believe more detailed investigations on the genetic/molecular basis of supratentorial PNET and their clinical outcomes are warranted.

Objective Primary malignant brain tumors are relatively uncommon, and their incidence and survival rates have seldom been reported. Patients and methods We identified all patients with malignant brain tumors in Taiwan between 1997 and 2012 using the National Health Insurance database. We estimated the stratified incidence of malignant brain tumors by age and sex. We estimated the median 1-, 2-, and 5-year survival, taking comorbidities into account. Trends for incidence and survival were analyzed using Joinpoint regression. The incidence in different geographic areas was also evaluated. Results A total of 7746 men and 5846 women were identified. The incidence of malignant brain tumor was 3.34 (95% CI, 3.09–3.59) per 100,000 person-years in 1997 and 3.82 (95% CI, 3.56–4.08) per 100,000 person-years in 2012. The average annual percentage change (APC) of the standardized incidence over this period was 0.1 (95% CI, −1.9 to 2.2), suggesting a relatively stable incidence. However, the incidence significantly decreased between 1999 and 2012, with an APC of −1.8 [95% CI, −2.5 to −1.0]. One- and 5-year survival was 53.8% (50.0%–57.5%) and 27.5% (24.1%–30.9%) in 1997 and 67.6% (64.3%–70.7%) and 32.8% (29.6%–35.9%) in 2012. The average APC was 1.1 (95% CI, 0.7–1.5) for 1-year survival and 0.2 (95% CI, −1.0–1.4) for 5-year survival. The trend of improvement in the survival rate was seen for short-term but not long-term survival, especially in the group with more comorbidities. Conclusions A slightly decreased trend in incidence of primary malignant brain tumors was observed in Taiwanese general population since 1999. Over the past 15 years, the short-term survival of malignant brain tumors has improved, especially in adults.

Decompressive craniectomy has been considered the most attractive option for surgical treatment of malignant middle cerebral artery (MCA) infarction. We retrospectively reviewed the clinical and radiological records of 78 patients with malignant MCA infarction who underwent decompressive craniectomy with dura augmentation over a 6-year period. Twenty-six patients had undergone additional anterior temporal resection during decompressive craniectomy. The overall mortality at 30 days after surgery was 25.6% while the mortality rate at 6 months after surgery was 30.8%. At 6 months after surgery, 30.8% of the patients were considered to have good outcomes, while 69.2% had a poor outcome (16.7% suffered from severe disability, 21.8% remained in a vegetative state, and 30.8% died). Ipsilateral surgery was performed on 48 patients with infarction on the dominant side and on 30 patients with lesions on the non-dominant side. No significant difference was noted between these two groups at the 30-day mortality rate. Although no patient with an infarction on the dominant side recovered effective verbal ability during the 6 months of follow-up, there was no significant difference between the two groups in clinical outcome at 6 months after surgery. The 30-day survival rate in the 26 patients who underwent additional anterior temporal lobectomy was significantly higher (84.6%) than that in patients who underwent decompressive craniectomy and duroplasty only (69.2%) (p

The co-primary aims are: 1) to compare the risk of fracture between adults with bipolar disorder and those without bipolar disorder; and 2) to assess whether lithium, anticonvulsants and antipsychotics reduce risk of fracture among individuals with bipolar disorder.The analysis herein is a population-based retrospective cohort study, utilizing the National Health Insurance (NHI) medical claims data collected between 1997 and 2013 in Taiwan. We identified 3705 cases with incident diagnoses of bipolar disorder during study period and 37,050 matched controls without bipolar diagnoses. Incident diagnosis of fracture was operationalized as any bone fracture after the diagnosis of bipolar disorder or after the matched index date for controls.Bipolar patients had significantly higher risk of facture when compared to matched controls (17.6% versus 11.7%, respectively p0.001). The hazard ratio (HR) was 1.33 (95% confidence interval [CI]＝1.23-1.48, p0.001) after adjusting for covariates. Persons with bipolar disorder and a prior history of psychiatric hospitalization were had higher risk for bone fracture than those without prior history of psychiatric hospitalization when compared to match controls. Higher cumulative dose of antipsychotics or mood stabilizers did not increase the risk of fracture.The diagnoses of bipolar disorder were not confirmed with structured clinical interview. Drug adherence, exact exposure dosage, smoking, lifestyle, nutrition and exercise habits were unable to be assessed in our dataset.Bipolar disorder is associated with increased risk of fracture, and higher cumulative dose of mood stabilizers and antipsychotics did not further increase the risk of fracture.

Atypical and malignant meningiomas are rare. Our aim was to examine the treatment outcomes following surgical resection, and analyze associations between clinical characteristics and overall survival (OS) or relapse free survival (RFS). 102 patients with atypical or malignant meningiomas underwent microsurgical resection between June 2001 and November 2009 were analyzed retrospectively. We compared demographics, clinical characteristics, treatment, and complications. The five-year and ten-year overall survival rates were 93.5% and 83.4%, respectively. Three factors significantly reduced OS: Malignant meningiomas (p

Object Liver cirrhosis was identified as an independent predictor of poor outcomes in patients suffering trauma and in those undergoing major surgeries. The aim of this study was to report the authors' experiences treating patients with cirrhosis who undergo brain surgeries. Methods Between 2004 and 2009, 121 consecutive patients with cirrhosis underwent 144 brain procedures. Patients were categorized as Child-Turcotte-Pugh (referred to as “Child”) Class A, B, or C. The patient profiles, including the severity of cirrhosis, reason for surgery, complications, and prognosis factors, were analyzed. Results In this retrospective study, the overall surgical complication rate for patients with cirrhosis was 52.1% and the mortality rate was 24.3%. For patients with acute traumatic brain injury (TBI), the complication, rebleeding, and mortality rates reached 84.4%, 68.8%, and 37.5%, respectively. Surgery for TBI was a significant risk factor for postoperative complications (p = 0.0002) and postoperative hemorrhage (p < 0.0001). Otherwise, according to the Child classification, the complication rate increased in a stepwise fashion from 38.7% to 60% to 84.2%, the rebleeding rate from 29.3% to 48.0% to 63.2%, and the mortality rate from 5.3% to 38% to 63.2% for Child A, B, and C, respectively. The Child classification was associated with higher risk of complications—Child B vs A OR 2.84 (95% CI 1.28–6.29), Child C vs A OR 5.39 (95% CI 1.32–22.02). It was also associated with risk of death—Child C vs A OR 30.43 (95% CI 7.71–120.02), Child B vs A OR 10.88 (95% CI 3.42–34.63). Conclusions Liver cirrhosis is a poor comorbidity factor for brain surgery. The authors' results suggest that the Child classification used independently is a poor prognostic factor; in addition, grave outcomes were observed in patients with TBI.

Although accumulating evidence has confirmed the important roles of thyroid hormone (T(3)) and its receptors (TRs) in tumor progression, the specific functions of TRs in carcinogenesis remain unclear. In the present study, tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) was directly upregulated by T(3) in TR-overexpressing hepatoma cell lines. TRAIL is an apoptotic inducer, but it can nonetheless trigger non-apoptotic signals favoring tumorigenesis in apoptosis-resistant cancer cells. We found that TR-overexpressing hepatoma cells treated with T(3) were apoptosis resistant, even when TRAIL was upregulated. This apoptotic resistance may be attributable to simultaneous upregulation of Bcl-xL by T(3), because (1) knockdown of T(3)-induced Bcl-xL expression suppressed T(3)-mediated protection against apoptosis, and (2) overexpression of Bcl-xL further protected hepatoma cells from TRAIL-induced apoptotic death, consequently leading to TRAIL-promoted metastasis of hepatoma cells. Moreover, T(3)-enhanced metastasis in vivo was repressed by the treatment of TRAIL-blocking antibody. Notably, TRAIL was highly expressed in a subset of hepatocellular carcinoma (HCC) patients, and this high-level expression was significantly correlated with that of TRs in these HCC tissues. Together, our findings provide evidence for the existence of a novel mechanistic link between increased TR and TRAIL levels in HCC. Thus, TRs induce TRAIL expression, and TRAIL thus synthesized acts in concert with simultaneously synthesized Bcl-xL to promote metastasis, but not apoptosis.

Oculomotor nerve palsy is a relatively rare symptom in pituitary adenoma compared to visual compromise or endocrine deficiency. The causes and recovery remain unclear. A total of 23 patients with pituitary adenomas presenting with oculomotor nerve palsy were reviewed. Patients were treated immediately with glucocorticoid therapy. Elective pure-endoscopic transsphenoidal surgery was used for decompression and histopathological confirmation. The clinical differences of patients with apoplectic (hemorrhage or infarction) (20 patients) and non-apoplectic tumors (three patients) were compared. In the apoplectic group, hemorrhage was noted in 13 patients and infarction in seven. Most patients presented with ptosis, followed by limited gaze and diplopia. In the long-term follow-up, the overall complete recovery rate was 19/23 (82.6%): 18/20 in the apoplectic group (90%), and one in three patients in the non-apoplectic group (33%). The median recovery time was 9 days after surgical decompression; and early treatment resulted in early recovery (p = 0.03). Patients with pupil-sparing pituitary adenoma recovered more rapidly than those with pupil involvement (p = 0.012). Patients with minor symptoms recovered earlier than patients with complete palsy (p = 0.003). MRI revealed that the tumor had invaded the interclinoid ligament region in all patients. We conclude that oculomotor nerve palsy usually occurs in patients with apoplectic adenomas, especially those with hemorrhage. Early treatment, pupil-sparing, and minor oculomotor symptoms are factors indicating a good recovery. Endoscopic transsphenoidal surgical decompression achieved good results in this study.

Previous clinical trials of dendritic cell (DC)-based immunotherapy in patients with glioblastoma multiforme (GBM) have reported induction of systemic immune responses and prolonged survival. From 2003 to 2005, we performed a clinical trial in which patients with malignant glioma underwent surgery for maximal cytoreduction followed by a 6-month 10-injection course of autologous DC-tumor vaccine therapy, each injection containing 1-6×10(7) DC. Of the 17 treated patients (16 with World Health Organization grade IV and one with grade III glioma), eight (47.1%) had an initial transient elevation in aspartate aminotransferase (AST)/alanine aminotransferase (ALT). Vaccination caused some tumor shrinkage and increased concentration of tumor-infiltrating CD8(+) lymphocytes. Median survival and 5-year survival were 525 days and 18.8%, respectively, for 16 patients with grade IV glioma (381 days and 12.5% for eight newly diagnosed; 966 days and 25% for eight relapsed patients) compared to 380 days and 0% for 63 historical control patients. We concluded that autologous DC-tumor immunotherapy benefits patients with malignant glioma but may cause transient but reversible elevation of serum AST/ALT levels.

In 1995 a government-supported Universal National Health care system was implemented in Taiwan, which in 2008 was available to 98% of the population. This system offers affordable, rapid medical attention. A multi-center retrospective study was conducted to assess the prognosis of malignant glioma patients under this system. In 2005 and 2006, patients at 14 independent neuro-oncology centers with newly diagnosed malignant glioma were enrolled. The patient profile, pathology, treatment modalities, and prognosis were collected by questionnaire at each center. The Taiwan Neuro-Oncology Society was responsible for the data analysis. The overall median survival period, 1-year survival rate, and 2-year survival rate for patients with World Health Organization grade III glioma were 33.8 months, 81.4%, and 58.2%, respectively, and 15 months, 57.3%, and 33.9% in patients with grade IV glioma. The median survival period, 1-year survival rate, and 2-year-survival rate in patients receiving temozolomide adjuvant therapy was 36 months, 84.2%, and 61.8%, respectively, for patients with grade III glioma and 19.8 months, 73.1%, and 43.7%, for patients with grade IV glioma. The universal health care system in Taiwan offers a comparable prognosis with an affordable premium relative to other large series in developed countries.

[Purpose] In clinical trial of autologous dendritic cell/autologous tumor cell antigens (ADCTA) adjuvant immunotherapy of glioblastoma multiforme (GBM), we studied if and how GBM CD133(+) stem-like initiator cells are susceptible to immune cytotoxic eradication [Methods] Tumor-infiltrating T lymphocytes (TILs) were isolated from GBM patients after the ADCTA vaccination and tested for their effects on CD133(+) and CD133(-) glioma cells separated from the same patients. [Results] TILs isolated from GBM patients after ADCTA vaccination were cytotoxic to both CD133(+) and CD133(-) autologous glioma cells. However, the cell lysis was detectable in CD133(-) in 4 hours but did not occur until more than 18 hours later in the CD133(+) cancer stem-like initiator cells. Surprisingly, we found that, upon exposure to the TILs, the GBM tumor cells showed phenotype shift from CD133(+) to CD133 (-). Similar CD133(+) to CD133(-) phenotype shift was also observed by exposure to culture condition medium of the TILs. The responsible factors secreted by the TILs that caused the phenotype shift was determined to be INFγ and TNFα. [Conclusion] ADCTA vaccination in GBM patients would generate TILs that are not only specifically cytotoxic to autologous CD133(-) glioma cells but also secret INFγ and TNFα etc to induce phenotypic shift of the resistant CD133(+) stem-like GBM to susceptible CD133(-) glioma cells. Citation Format: Yin-Cheng Huang, Kuo-Chen Wei, Chen-Nen Chang, Wen K. Yang. Cytotoxic effects of tumor-specific T lymphocytes on autologous cancer initiator stem-like glioblastoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3124.

The aim of this study was to investigate the efficacy of linear accelerator (LINAC)-based radiosurgery in the treatment of acoustic neuromas. In this retrospective study, we enrolled 75 patients with non-neurofibromatosis type 2 acoustic neuromas who were followed-up for more than 5 years. The 75 patients were divided into 3 groups: patients with a newly diagnosed tumor; those with a residual tumor; and those with a recurrent tumor. The average follow-up period was 97.8 months. The overall tumor progression-free rate was 92%, and corresponding rates among those with newly diagnosed tumors was 100%, residual tumors was 84.4%, and recurrent tumors was 92.8% (p = 0.028). Lesion localization using CT scans correlated with a higher tendency for tumor progression than lesion localization using CT–MRI fusion images (15.6% versus 2.4%, respectively). Residual tumors treated with radiosurgery have a higher progression rate, and careful lesion localization using CT–MRI image fusion is required.

Chen CP, Wong AM, Hsu C-C, Tsai W-C, Chang C-N, Lin S-C, Huang Y-C, Chang C-H, Tang SF. Ultrasound as a screening tool for proceeding with caudal epidural injections. Objective To study the anatomical structure of the sacral hiatus using ultrasound. Based on the sonographic images of the sacral hiatus, the feasibility of caudal epidural injection can then be assessed. Design Case-controlled study. Setting Rehabilitation outpatient clinic in a tertiary medical center. Participants Patients (N=47; 20 women, 27 men) with low back pain and sciatica who were to receive caudal epidural injection treatments were recruited into this study. Interventions Sonographic images of the sacral hiatus were obtained from all the patients. An ultrasound machine capable of examining musculoskeletal tissues with real-time linear-array ultrasound transducer was used to measure the distance between the anterior wall and posterior wall of the sacral hiatus (diameter of the sacral hiatus) and the distance between bilateral cornua. Main Outcome Measures Diameter of the sacral canal and distance between bilateral cornua measured in millimeters. Results The mean diameter of the sacral canal was measured to be 5.3±2.0mm in our recruited patients. The mean distance between bilateral cornua was measured to be 9.7±1.9mm. Caudal epidural injections failed in 7 patients. In these 7 patients, 4 had very small diameter of the sacral canal (1.6, 1.2, 1.4, and 1.5mm). In 1 man, sonographic images revealed a closed sacral hiatus (no sacral canal diameter can be measured). Two patients revealed flow of fresh blood into the syringe while checking for the escape of cerebrospinal fluid after the needles were inserted into the sacral canal. For safety reasons, steroid injections were not performed in these 2 patients. Conclusions Ultrasound may be used as an effective screening tool for caudal epidural injections. Anatomic variations of the sacral hiatus can be clearly observed using ultrasound. Sonographic images indicating a closed sacral canal and sacral diameters ranging from 1.2 to 1.6mm may suggest a higher failure rate in caudal epidural injection.

Background Primary central nervous system lymphomas (PCNSLs) are relatively rare brain tumors. Accurate diagnosis is usually made by surgical biopsy. In addition to surgical biopsy and decompression, treatment options include high-dose methotrexate and chemotherapy, radiation therapy, and stem cell therapy. Because of the rarity of this disease, guidelines for PCNSL diagnosis and treatment usually are formed from a large series of experiences. Methods We retrospectively reviewed 79 patients in our tertiary referral center during a 13-year period. All patients with PCNSL underwent surgical or bone marrow biopsy procedures, and diagnoses were confirmed by hematologists or neuropathologists. At the time of diagnosis, 44 patients presented with a single lesion. Human immunodeficiency virus was confirmed positive in 1 patient. The standard therapy protocol included high-dose methotrexate (intravenous and intrathecal) and chemotherapy with cytosine arabinoside, followed by external irradiation of the brain. Results Significant prognostic factors in these patients were low serum lactate dehydrogenase levels and radiation therapy. Multiplicity of lesions at time of diagnosis did not imply a worse outcome, and surgical resection and debulking did not show a significant survival benefit. Conclusions PCNSL has a poor prognosis. Further clinical trials and diagnostic tools are needed to reveal the complexity of this disease.

The incidence and associated mortality of major intraoperative rupture (MIOR) in intracranial aneurysm surgery is diverse. One possible reason is that many studies failed to consider and properly adjust the factor of surgical experience in the context. We conducted this study to clarify the role of surgical experience on MIOR and associated outcome. 538 consecutive intracranial aneurysm surgeries performed on 501 patients were enrolled in this study. Various potential predictors of MIOR were evaluated with stratified analysis and multivariate logistic regression. The impact of surgical experience and MIOR on outcome was further studied in a logistic regression model with adjustment of each other. The outcome was evaluated using the Glasgow Outcome Scale one year after the surgery. Surgical experience and preoperative Glasgow Coma Scale (GCS) were identified as independent predictors of MIOR. Experienced neurovascular surgeons encountered fewer cases of MIOR compared to novice neurosurgeons (MIOR, 18/225, 8.0% vs. 50/313, 16.0%, P = 0.009). Inexperience and MIOR were both associated with a worse outcome. Compared to experienced neurovascular surgeons, inexperienced neurosurgeons had a 1.90-fold risk of poor outcome. On the other hand, MIOR resulted in a 3.21-fold risk of unfavorable outcome compared to those without it. Those MIOR cases managed by experienced neurovascular surgeons had a better prognosis compared with those managed by inexperienced neurosurgeons (poor outcome, 4/18, 22% vs. 30/50, 60%, P = 0.013).

Case report.Tertiary referral center hospital in Taiwan.To report a case of spinal Rosai-Dorfman disease (RDD) presenting with paraparesis and also preceding by relapsing uveitis for 6 months. A thoracic laminectomy was performed to remove the solid mass. The pathological diagnosis reveals infiltrating histiocytes, emperipolesis and positivity for S-100. There is no recurrence 1 year later with MR imaging.The relapsing idiopathic uveitis may be a prodrome for this unusual disease, because RDD is associated closely to defective immunogical response. Early and accurate diagnosis of CNS RDD may reverse the neurologic deficits by early decompression.

Transplantation of neural stem cells (NSCs) and the mobilization of endogenous neural precursors in the adult brain have been proposed as therapies for a wide range of central nervous system disorders, including neurodegenerative disease (eg, Parkinson's disease), demyelinating disorders (eg, multiple sclerosis), stroke, and trauma. Although there is great hope for the success of such therapies, the clinical development of NSC-based therapies is still in its infancy. A greater understanding of how to control the proliferation, migration, differentiation, and survival of NSCs and their progeny is critical for the development of cell replacement therapies. NSCs are partially regulated by the specialized microenvironment--or "niche"--in which these cells reside. The adult rodent brain retains NSCs in two separate niches that continually generate new neurons: the subventricular zone (SVZ) of the lateral ventricle and the dentate gyrus subgranular zone (SGZ) of the hippocampus. Similar niches may be found in the human brain. In tis article, the authors briefly review their current understanding of the SVZ and SGZ niches. Lessons learned from these niches may allow one to manipulate NSCs better in culture for therapeutic transplantation and possibly even to mobilize endogenous precursors to repair diseased or injured brain.

In day care for a driver, continuous ECG (electrocardiogram) monitoring is required because symptoms of cardiac arrhythmia and hypoxia can occur unexpectedly. To enhance care service and quality for a driver, this study proposed a real-time ECG monitoring system of transmitting ECG signals to Android mobile phones or tablets through Bluetooth transmission in vehicles. These signals are then uploaded to a cloud database, enabling healthcare physicians and nurses to instantly monitor and access ECG data.

Background The annual hemorrhage rate of intracranial cavernous malformation (CM) is reported to range from 0.23% to 1.1%. Because of the low hemorrhage rate, operating on a deep symptomatic lesion with or without hemorrhage is considered controversial. For the prevention of hemorrhage, radiosurgery is an alternative method, targeting smaller lesions and delivering higher doses of radiation. Linear accelerator (LINAC) radiosurgery, aside from the gamma knife (GK), is not often discussed in the treatment of CM. Patients and methods From 1995 to 2005, 30 patients presenting with hemorrhage or seizures, aged 14–79 years (mean 24.0 years) with single (27 patients) or multiple (three patients) CMs received LINAC radiosurgery at our institute. Six patients received LINAC radiosurgery following craniotomy for residual lesions revealed by the follow-up MRI. The temporal lobe was the most common site for CM in this series ( n =8), followed by the brain stem ( n =7). Thirty patients received 34 radiosurgery treatments with peripheral doses ranging from 800cGy to 2200cGy. The mean follow-up time was 59.9 months (range 1–122 months). Results One patient re-bled post-radiosurgery (0.67% in 149.75 observation-years). Two patients had asymptomatic post-LINAC edema (6.7%). Those three patients were symptom-free during the follow-up period. Conclusion We suggest that LINAC radiosurgery is a relatively safe technique for treating deep or residual CM, although the actual effectiveness for CM obliteration is not known.

monly includes cognitive changes, headache, cranial nerve deficit, motor deficit and seizure. Treatment includes radiotherapy and chemotherapy, which may be administrated either systemically or intrathecally. The patient with solitary intracranial plasmacytoma should undergo systemic evaluation, including bone marrow examination, skeletal survey and bone scan to exclude multiple myeloma. In one study, multiple myeloma was diagnosed in four of eight patients, who initially presented with intracranial plasmacytoma. 3 In this study, the strongest predictor of diagnosis of multiple myeloma from a single known plasmacytoma was cranial base involvement Plasmacytoma can involve either the dura or the parenchyma; or occasionally both.

Corpus callosum involvement is associated with poorer survival in high grade glioma (HGG), but the prognostic value in low grade glioma (LGG) is unclear. To determine the prognostic impact of corpus callosum involvement on progression free survival (PFS) and overall survival (OS) in HGG and LGG, the records of 233 glioma patients treated from 2008 to 2011 were retrospectively reviewed. Preoperative magnetic resonance (MR) images were used to identify corpus callosum involvement. Age, sex, preoperative Karnofsky performance scale, postoperative Eastern Cooperative Oncology Group (ECOG) score and extent of resection (EOR) were evaluated with respect to PFS and OS. The incidence of corpus callosum involvement was similar among HGG (14 %) and LGG (14.5 %). Univariate analysis revealed that PFS and OS were significantly shorter in both WHO grade II and grade IV glioma with corpus callosum involvement (both, p

Multiple epigenetic factors play a critical role in cell proliferation and differentiation. However, their function in embryogenesis, especially in neural development, is currently unclear. The Trithorax group (TrxG) homolog KMT2A (MLL1) is an important epigenetic regulator during development and has an especially well-defined role in hematopoiesis. Translocation and aberrant expression of KMT2A is often observed in many tumors, indicating its proto-oncogenic character. Here, we show that Kmt2a was essential for neural development in zebrafish embryos. Disrupting the expression of Kmt2a using morpholino antisense oligonucleotides and a dominant-negative variant resulted in neurogenic phenotypes, including downregulated proliferation of neural progenitors, premature differentiation of neurons, and impaired gliogenesis. This study therefore revealed a novel function of Kmt2a in cell proliferation and differentiation, providing further insight into the function of TrxG proteins in neural development and brain tumors.

We report the case of a 15-year-old girl with amenorrhea and a several-week history of headache. After the diagnosis of membranous obstruction of the foramen of Magendie suggested by MRI, suboccipital craniotomy for removal of the membrane was carried out. The patient made an excellent postoperative recovery, and postoperative phase-contrast MRI demonstrated patent cerebrospinal fluid (CSF) pathways at the level of the foramina of Magendie and Luschka. We believe that this case is of interest because of the unequivocal evidence on MRI studies of the occlusion of the foramen of Magendie preoperatively, and because of the dramatic postoperative MRI findings demonstrating the effectiveness of the surgical procedure both in terms of ventricular size and CSF flow characterization.

Anterior cervical disectomy and fusion (ACDF) is a highly effective and safe method for spinal cord and cervical root decompression. However, vocal cord paralysis (VCP) remains an important cause of postoperative morbidity. The true incidence and recovery course of postoperative VCP is still uncertain. This study is a report on VCP after ACDF to evaluate the incidence, recovery course, and possible risk factors.From 2004 to 2008, 1,895 consecutive patients underwent ACDF in our hospital and were followed up for at least 3 years. All surgeons were well trained and used a right-sided exposure. Prolonged VCP, where patients suffered from postoperative VCP lasting more than 3 months, was recorded and analyzed.In this retrospective study, 9 of the 1,895 patients (0.47%) documented prolonged VCP lasting over 3 months. Six of the nine patients had total recovery within 9 months. Only three patients (0.16%) still had symptoms even after 3 years postoperatively. All symptoms of VCP, except hoarseness, could be improved. After matching with 36 non-VCP patients, no differences with regard to longer operative or anesthesia time, shorter neck, obesity, and prevertebral edema. All cases of prolonged course of postoperative VCP occurred in patients who underwent exposure at the C67 level.In our study, only 0.47% documented prolonged postoperative VCP, while most patients recovered within 9 months. However, if symptoms last longer, there could be almost permanent VCP (0.16%). In our study, choking and dysphagia subsided mostly within 6 months, but hoarseness remained. The exposure of the C67 level obviously was a risk factor for postoperative VCP.

Background: Arteriovenous malformation (AVM) is one of the cerebrovascular diseases that bear a high risk of hemorrhage. The treatment modalities include microsurgical resection, endovascular embolization, stereotactic radiosurgery, or combinations that vary widely. Several large series have been reported, while data from Asian populations were few. The aim of this study was to examine the efficacy of linear accelerator stereotactic radiosurgery (LINAC SRS) for the treatment of intracranial AVMs, to evaluate the hemorrhage rate and to analyze associated factors. Methods: One hundred and sixteen patients with AVM were treated with LINAC SRS in a single institute between September 1994 and May 2005 and were retrospectively evaluated. The demographics of patients, clinical characteristics of AVM, the treatment modalities, and the parameters of the LINAC SRS were analyzed. Delayed toxicity and hemorrhage rate after treatment were also evaluated. The AVM obliteration and bleed rates were calculated using the Kaplan-Meier method and Cox regression analyses. Results: The efficacy rate with total obliteration after treatment was 81.9% (95 of 116 patients). The median interval to achieve total obliteration was 49 months. Microsurgical resection combined with SRS for residual AVMs achieved better obliteration rates compared to SRS alone (statistically significant, p = 0.001), while no significant difference was found between the embolization group and the group with no prior treatment (p = 0.895). The Spetzler-Martin grade of AVM is a relative factor of obliteration, higher grades resulting in a worse outcome (p = 0.009). Obliteration was significantly influenced by AVM volume in univariate analysis (p = 0.034), and volume 3 contributed to improved obliteration (p = 0.01). There was no statistically significant difference in the hemorrhagic rate and the complication rate between ruptured and unruptured AVMs, while the unruptured group had a higher obliteration rate (p = 0.024). The annual hemorrhage rate after LINAC SRS treatment was 1.9%. The bleeding rate was 3.3% in the first year after radiosurgery, 2.1% in the second year, 1.9% between the second and fifth year, and 1.5% between the fifth and tenth year. Patients with hemorrhagic events before radiosurgery appeared to have a higher rebleeding risk during the latency period. Twenty-three patients (19.8%) had late adverse effects with regard to posttreatment radiological follow-up, but only 1 (0.8%) had newly developed neurological deficits. Conclusion: LINAC SRS achieved a high obliteration rate and reduced the risk of hemorrhage effectively in ruptured and unruptured intracranial AVMs. Prior microsurgical resection provided better outcome, while embolization showed no benefit. Adverse effects after treatment are acceptable and require long-term follow-up.

This clinical study was conducted to evaluate factors affecting outcome in the cases following major intraoperative rupture (MIOR) of the intracranial aneurysms.Thirty cases with MIOR in a series of 467 surgeries for ruptured aneurysms were enrolled in this study. Clinical parameters, including: age, Hunt-Hess grading, Fisher grading, aneurysm size, aneurysm contour, operative timing, aneurysm location, and rupture timing were studied and compared with the prognosis in this particular cohort. The outcome was evaluated using the Glasgow Outcome Scale at least 3 months after surgery. Severe disability, vegetative survival, and death were classified as poor outcome.Among the 30 cases with MIOR, 11 resulted in poor outcomes (36.7%). Age was an important prognostic factor in this cohort. Those patients with poor outcome after MIOR were significantly older than those with good outcome (mean age: 64.6 vs 51.4 years, P=0.006). In this study, a trend toward poor outcome was observed in cases with MIOR on internal carotid artery aneurysms (8/14, 57.1% vs 2/9, 22.2% and 1/6, 16.7% on middle cerebral artery and anterior communicating artery aneurysms, P=0.197, after adjustment for age factor). There was a higher incidence of a poor outcome when MIOR occurred during clip application (5/6, 83.3% vs 1/5, 20.0% and 5/19, 26.3% when MIOR happened during brain retraction and aneurysm dissection, P=0.041 after adjustment with the factor of age).Although a larger sample population is required for a more conclusive result, MIOR occuring in older age, during clip application, or on an internal carotid artery aneurysm possibly has the trend to bear a worse outcome in the cohort of patients with MIOR during aneurysm surgery.

The combination of chemo-thermal therapy is the best strategy to ablate tumors, but how to heat deep tumor tissues effectively without side-damage is a challenge. Here, a systemically delivered nanocarrier is designed with multiple advantages, including superior heat absorption, highly efficient hyperthermia, high drug capacity, specific targeting ability, and molecular imaging, to achieve both high antitumor efficacy and effective amplification of hyperthermia with minimal side effects.

Nasopharyngeal carcinoma (NPC) was an Epstein Barr virus (EBV)-related malignancy and tumor microenvironment had a pivotal role in tumor progression. Paucity of good NPC animal models hindered the research in this field. Recently, patient-derived xenograft (PDX) had been shown to be a good preclinical model for drug screening and cancer related research. We had developed two PDX mice lines from engrafting NPC metastatic tumors. Positive EBV-encoded small RNAs staining confirmed these tumors harboring EBV. Further gene expression profile analysis showed higher similarity of PDX to primary parent tumor than NPC cell line xenograft. In vivo drug screening in the PDX system demonstrated gemcitabine had the best antitumor effect among the tested drugs. In this PDX corresponding patient also showed excellent response to gemcitabine treatment. Combination of gemcitabine and valproic acid had synergistic antitumor effect. Further adding ganciclovir in this two combined regimen enhancing cytolytic viral activation had the best antitumor response among the tested regimens. This three combined regimen treated group had lower plasma EBV-DNA load and tumor viral concentration and less viable tumor cells than gemcitabine + valproic acid group. These promising results would open a new era for EBV-targeting therapy in NPC treatment. Citation Format: Cheng-Lung Hsu, Yung-Chia Kuo, Yenlin Huang, Yin-Cheng Huang, Kar-Wai Lui, Kai-Ping Chang, Tung-Liang Lin, Hsien-Chi Fan, An-Chi Lin, Chia-Hsun Hsieh, Li-Yu Lee, Hung-Ming Wang, Hsin-Pai Li, Angel Chao, Yu-Sun Chang. Application of patient-derived xenograft model in nasopharyngeal carcinoma research. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 626.