Chun Chung Chen

Adjuvant Immunotherapy with Whole-Cell Lysate Dendritic Cells Vaccine for Glioblastoma Multiforme: A Phase II Clinical Trial

BACKGROUND This study sought to evaluate effectiveness of autologous dendritic cell vaccine (immunotherapy) for glioblastoma multiforme (GBM). METHODS Patients 14 to 70 years of age with newly diagnosed GBM and Karnofsky Performance Scale (KPS) score >70 who were receiving initial treatment were enrolled and were randomized into 2 groups during the 5-year study period. Eighteen patients underwent conventional treatment (surgery, radiotherapy, and chemotherapy) and received adjuvant autologous dendritic cell vaccine, and 16 patients (control group) underwent conventional treatment only. Administration of the vaccine was begun within 1 to 2 months postoperatively, with 10 inoculations given over 6 months. Outcome measures were overall survival (OS); progression-free survival (PFS); 1-, 2-, and 3-year survival rates, and quality of life (QoL). RESULTS Follow-up time ranged from 14 to 56 months (median, 33 months). The 1-, 2-, and 3-year survival rates were 88.9%, 44.4%, and 16.7% for the vaccine group, respectively, and 75.0%, 18.8%, and 0%, respectively, for the control group, (P = 0.299, 0.0035, 0.0014, respectively). The median OS for the vaccine group was 31.9 months and for the control group was 15.0 months (P < 0.002). The median progression-free survival (PFS) for the vaccine group was 8.5 months, and 8.0 months for the control group (P = 0.075). The surviving fraction was significantly higher in the vaccine group based on Kaplan-Meier analysis. CONCLUSIONS Adjuvant immunotherapy with whole-cell lysate dendritic cell vaccine may improve short-term survival. It seems to be safe, and its long-term effectiveness is worthy of further investigation.

Targeting cancer stem cells for treatment of glioblastoma multiforme

Cancer stem cells (CSCs) in glioblastoma multiforme (GBM) are radioresistant and chemoresistant, which eventually results in tumor recurrence. Targeting CSCs for treatment is the most crucial issue. There are five methods for targeting the CSCs of GBM. One is to develop a new chemotherapeutic agent specific to CSCs. A second is to use a radiosensitizer to enhance the radiotherapy effect on CSCs. A third is to use immune cells to attack the CSCs. In a fourth method, an agent is used to promote CSCs to differentiate into normal cells. Finally, ongoing gene therapy may be helpful. New therapeutic agents for targeting a signal pathway, such as epidermal growth factor (EGF) and vascular epidermal growth factor (VEGF) or protein kinase inhibitors, have been used for GBM but for CSCs the effects still require further evaluation. Nonsteroidal anti-inflammatory drugs (NSAIDs) such as cyclooxygenase-2 (Cox-2) inhibitors have proven to be effective for increasing radiation sensitivity of CSCs in culture. Autologous dendritic cells (DCs) are one of the promising immunotherapeutic agents in clinical trials and may provide another innovative method for eradication of CSCs. Bone-morphogenetic protein 4 (BMP4) is an agent used to induce CSCs to differentiate into normal glial cells. Research on gene therapy by viral vector is also being carried out in clinical trials. Targeting CSCs by eliminating the GBM tumor may provide an innovative way to reduce tumor recurrence by providing a synergistic effect with conventional treatment. The combination of conventional surgery, chemotherapy, and radiotherapy with stem cell-orientated therapy may provide a new promising treatment for reducing GBM recurrence and improving the survival rate.

Outcome of and prognostic factors for decompressive hemicraniectomy in malignant middle cerebral artery infarction

Decompressive hemicraniectomy as an appropriate treatment for malignant middle cerebral artery (MCA) infarction is still a controversial issue. This study aimed to determine the survival rate and functional outcome, and factors associated with these, in patients with malignant MCA infarction. From January 2000 to December 2003, 60 patients with malignant MCA infarction were treated in our hospital. All patients in the study underwent a large ipsilateral craniectomy and duroplasty for decompression. The infarction territory was evaluated by either diffusion weighted magnetic resonance imaging or computed tomography. Clinical neurological presentation was evaluated using the Glasgow Coma Scale. Functional outcome was evaluated using the Barthel index (BI) and the Glasgow Outcome Scale (GOS) at follow-up 12 months later. Thirty-day mortality was 20% (12 patients) and 12-month mortality was 26.6%. The factors associated with higher mortality were age>or=60 years, involvement of more than one vascular territory, presence of signs indicating clinical herniation before surgery, and treatment more than 24 hours after ictus. The mean GOS score was 3.3+/-1.7. The mean Barthel index was 65.1+/-40.1. Twenty-nine (65.9%) patients had a favourable outcome (BI>or=60). The factors associated with favourable outcome were age<60 years and treatment within 24 hours of ictus, before clinical signs of herniation were noted. Decompressive hemicraniectomy should be performed in patients younger than 60 years within 24 hours of ictus before clinical signs of herniation develop. Age, timing of surgery and clinical signs of herniation are prognostic factors for mortality and functional outcome.

A new Modified Intracerebral Hemorrhage score for treatment decisions in basal ganglia hemorrhage--a randomized trial.

Objectives:To develop a Modified Intracerebral Hemorrhage (MICH) score to determine optimal cut-offs for conservative treatment vs surgical intervention for basal ganglia hemorrhage and to predict outcomes. Design:Prospective randomized trial. Setting:A 1,720-bed medical center affiliated with a university. Patients:In all, 226 patients with basal ganglia hemorrhage who presented at our hospital from 2001–2005. Interventions:Group A (n = 113) underwent endoscopic surgery; group B (n = 113) underwent conservative treatment. Score differences on the Glasgow Outcome Scale and 1-yr Barthel Index were analyzed by chi-square test and Student’s t-tests. Cut-offs for MICH scoring were evaluated using receiver operating characteristic curves for calculating the Youden Index. The treatment odds ratio was analyzed by univariate, multivariate, and multiple logistic regressions. Measurements and Main Results:The optimal cut-off point for mortality was a MICH score ≥3 in which the Youden Index is 0.66 (sensitivity, 76.3%; specificity, 89.8%; area under the receiver operating characteristic curve, 0.897). The positive and negative predictive values were 81.8% and 86.3%, respectively. The treatment odds ratio for surgical treatment was 6.87 (95% confidence interval, 3.13–14.5) at MICH scores ≥3. The best cut-off for good functional outcomes (Glasgow Outcome Scale ≥4 or Barthel index ≥55) was MICH ≥2. Conservative treatment achieved a better mean Barthel Index at MICH = 0 or 1 than surgical treatment, p < .01. At MICH scores = 3 or 4, 6-month mortality for conservative treatment was higher than for surgical treatment, p < .01 and p = .04, respectively. At MICH scores of 5, all patients died. Conclusions:MICH scoring provides a simple, reliable system for treatment decisions regarding basal ganglia hemorrhage and may accurately predict functional outcomes. Conservative treatment is recommended for basal ganglia ICH patients with low MICH scores (0, 1) to preserve neurologic function. Surgery is recommended for patients with a midlevel MICH score to obtain better functional outcomes (MICH = 2) and to reduce mortality (MICH = 3 or 4). At MICH scores = 5, there are no indications for surgery.

Endoscopic Surgery for Intraventricular Hemorrhage (IVH) Caused by Thalamic Hemorrhage: Comparisons of Endoscopic Surgery and External Ventricular Drainage (EVD) Surgery

BACKGROUND Intraventricular hemorrhage (IVH) caused by thalamic hemorrhage has high mortality and morbidity. The aim of this study was to investigate the efficacy and the results of endoscopic surgery for the evacuation of IVH caused by thalamic hemorrhage compared with that of external ventricular drainage (EVD) surgery. METHODS From January 2006 to December 2008, 48 patients with IVH caused by thalamic hemorrhage were enrolled and treated in our department. Patients with IVH caused by thalamic hemorrhage who also resulted in acute hydrocephalus were indicated for surgery; the patients who were included were randomly divided into an EVD group and an endoscopic surgery group. The clinical evaluation data included the Glasgow Coma Scale, length of intensive care unit (ICU) stay, age, intracerebral hemorrhage volume, and severity of IVH. Outcome was measured using the 30-day and 90-day mortality rate, ventriculoperitoneal (VP) shunt dependent rate, and Glasgow Outcome Scale after three months. RESULTS The clinical features of the 24 patients in each group showed no significant differences in age or Glasgow Coma Scale assessment on admission. There was also no significant difference in intracerebral hemorrhage volume or Graeb score between the endoscopic group and the EVD group. The length of ICU stay was 11 ± 5 days in the endoscopic surgery group and 18 ± 7 days in the EVD group. The endoscopic surgery group had a shorter ICU stay (P = 0.04) compared with the EVD group. The 30-day and 90-day mortality rates were 12.5% and 20.8% in the endoscopic surgery group and 12.5% and 16.6% in the EVD group, respectively. The mean Glasgow Outcome Scale score was 3.08 ± 1.38 in the endoscopic surgery group and 3.33 ± 1.40 in the EVD group. Outcome significantly correlated with initial consciousness level; the severity of IVH did not influence the outcome in all of the cases. There was no significant difference in mortality rate or outcome between the endoscopic group and the EVD group. The VP shunt rates were 47.62% in the endoscopic surgery group and 90.48% in the EVD group. Endoscopic surgery group had a significant lower VP shunt rate (P = 0.002; odds rate = 9.8) compared with the EVD group. CONCLUSIONS Endoscopic surgery was found to have significantly lower shunt-dependent hydrocephalus, and the ICU stay was shorter compared with EVD surgery. This can decrease the need for permanent VP shunts in patients with IVH caused by thalamic hemorrhage.

A stainless steel sheath for endoscopic surgery and its application in surgical evacuation of putaminal haemorrhage

A stainless steel tube was used as an endoscope sheath in combination with a working channel endoscope to evacuate hypertensive putaminal intracerebral haematoma (ICH). A frontal entry point ipsilateral to the haematoma was selected for insertion of the sheath. From January to June 2004, seven patients with putaminal ICH underwent endoscopic surgery in our hospital. There were no surgical complications. Haematoma evacuation rates were greater than 90% (median of 93%). Six patients (87%) regained consciousness within one week. Six patients, including four who had no residual disability and two who had moderate disability, were able to function independently. One patient remained in a persistent vegetative state at clinical follow-up after 6 months. Use of a stainless steel endoscopic sheath combined with working channel endoscopy via a frontal approach facilitates evacuation of putaminal ICH.

Cerebrolysin enhances cognitive recovery of mild traumatic brain injury patients: double-blind, placebo-controlled, randomized study.

Abstract In adults, mild traumatic brain injury (MTBI) frequently results in impairments of cognitive functions which would lead to psychological consequences in the future. Cerebrolysin is a nootropic drug, and can significantly improve cognitive function in patients with Alzheimers disease and stroke. The purpose of this study was to investigate how Cerebrolysin therapy enhances cognitive recovery for mild traumatic brain injury patients using a double-blinded, placebo-controlled, randomized phase II pilot study. Patients having head injury within 24 h sent to our hospital were screened and recruited if patients were alert and conscious, and had intracranial contusion haemorrhage. From July 2009 to June 2010, totally, thirty-two patients were recruited in the double-blinded, placebo-controlled, and randomized study. Patients were randomized to receive Cerebrolysin (Group A, once daily intravenous infusion of 30 mL Cerebrolysin over a 60-min period for 5 days) or placebo (Group B, same dosage and administration of normal saline as Group A). The primary outcome measures were differences of cognitive function including Mini-Mental Status Examination (MMSE), and Cognitive Abilities Screening Instrument (CASI) scores between baseline and week 1, between baseline and week 4, and between baseline and week 12. Thirty-two patients completed the trial. For Group A, the CASI score difference between baseline and week 12 was 21.0 ± 20.4, a significantly greater change than that of Group B (7.6 ± 12.1) (p = 0.0461). Besides, drawing function (one of the domains of CASI; p = 0.0066) on week 4 and both drawing function (p = 0.0472) and long-term memory (one of the domains of CASI; p = 0.0256) on week 12were also found to be significantly improved in the patients receiving Cerebrolysin treatment. Our results suggest that Cerebrolysin improves the cognitive function of the MTBI in patients at 3rd month after injury, especially for long-term memory and drawing function.

Applying Cerebral Hypothermia and Brain Oxygen Monitoring in Treating Severe Traumatic Brain Injury

BACKGROUND Severe traumatic brain injury (TBI) was to be one of the major health problems encountered in modern medicine and had an incalculable socioeconomic impact. The initial cerebral damage after acute brain injury is often exacerbated by postischemic hyperthermia and worsens the outcome. Hypothermia is one of the current therapies designed to combat this deleterious effect. The brain tissue oxygen (P(ti)o(2))-guided cerebral perfusion pressure (CPP) management was successfully reduced because of cerebral hypoxic episodes following TBI. MATERIALS AND METHODS Forty-five patients with severe TBI whose Glasgow Coma Scale (GCS) score ranged between 4 and 8 during September 2006 and August 2007 were enrolled in China Medical University Hospital, Taichung, Taiwan. One patient with a GCS score of 3 was excluded for poor outcome. These patients were randomized into three groups. Group A (16 patients) was intracranial pressure/cerebral perfusion pressure (ICP/CPP)-guided management only, Group B (15 patients) was ICP/CPP guided with mild hypothermia, and Group C (14 patients) was combined mild hypothermia and P(ti)o(2) guided with CPP management on patients with severe TBI. All patients were treated with ICP/CPP management (ICP <20 mm Hg, CPP >60 mm Hg). However, the group with P(ti)o(2) monitoring was required to raise the P(ti)o(2) above 20 mm Hg. Length of intensive care unit stay, ICP, P(ti)o(2), Glasgow Outcome Scale (GOS) score, mortality, and complications were analyzed. RESULTS The ICP values progressively increased in the first 3 days but showed smaller changes in hypothermia groups (Groups B and C) and were significantly lower than those of the normothermia group (Group A) at the same time point. We also found out that the averaged ICP were significantly related to days and the daily variations [measured as (daily observation - daily group mean)(2)] of ICP were shown to the significantly different among three treatment groups after the third posttraumatic day. The values of P(ti)o(2) in Group C tended to rise when the ICP decreased were also observed. A favorable outcome is divided by the result of GOS scores. The percentage of favorable neurologic outcome was 50% in the normothermia group, 60% in the hypothermia-only group, and 71.4% in the P(ti)o(2) group, with statistical significance. The percentage of mortality was 12.5% in the normothermia group, 6.7% in the hypothermia-only group, and 8.5% in the P(ti)o(2) group, without statistical significance in three groups. Complications included pulmonary infections, peptic ulcer, and leukocytopenia (43.8% in the normothermia group, 55.6% in the hypothermia-only group, and 50% in the P(ti)o(2) group). CONCLUSIONS Therapeutic mild hypothermia combined with P(ti)o(2)-guided CPP/ICP management allows reducing elevated ICP before 24 hours after injury, and daily variations of ICP were shown to be significantly different among the three treatment groups after the third posttraumatic day. It means that the hypothermia groups may reduce the ICP earlier and inhibit the elicitation of acute inflammation after cerebral contusion. Our data also provided evidence that early treatment that lowers P(ti)o(2) may improve the outcome and seems the best medical treatment method in these three groups. We concluded that therapeutic mild hypothermia combined with P(ti)o(2)-guided CPP/ICP management provides beneficial effects when treating TBI, and a multicenter randomized trial needs to be undertaken.

Glasgow Coma Scale and hematoma volume as criteria for treatment of putaminal and thalamic intracerebral hemorrhage

BACKGROUND The decision to administer conservative or surgical treatment for putaminal and thalamic ICH is still a controversial issue. This study was undertaken to examine the decision-making criteria for these 2 treatments. METHODS In a retrospective study, case records of 400 patients with spontaneous putaminal and thalamic hemorrhage who underwent conservative treatment (n = 201) and surgical treatment (n = 199) over the past 5 years were examined. Conservative treatment included hypertonic solution treatment and hypertension control. Surgical treatments included endoscopic surgery, craniotomy, and stereotactic aspiration. Preoperative GCS score and ICH volume were the major evaluating factors, and comparison of the 30-day mortality rate and 6-month BI score was used for outcome evaluation. RESULTS In patients with a GCS score of 13 to 15, there was no difference in mortality between conservative and surgical treatments. At a GCS score of 9 to 12 and ICH volume of less than 30 mL, the mortality rate with surgical treatment (10.5%) was lower than that with conservative treatment (20.0%, P < .05). At a GCS score of 3 to 8 and ICH volume of at least 30 mL, surgical treatment was for life saving. Mortality rates were lower for conservative treatment than for surgical treatment when the GCS score was 3 to 12 and ICH volume less than 30 mL. Endoscopic surgery had a better functional outcome compared with craniotomy and stereotactic aspiration when the GCS score was at least 9 (P < .001 and P < .02, respectively). Those in conservative treatment received a better BI score than those in surgical treatment did when the ICH volume was less than 40 mL (P < .001). CONCLUSIONS Intracerebral hemorrhage volume is probably more important than GCS score in determining treatment. Our nonrandomized data could be interpreted to show that conservative treatment is suggested at GCS score of at least 13 or when ICH volume is less than 30 mL, regardless of GCS score. Surgical treatment could be recommended at GCS score of less than 12 with ICH volume of at least 30 mL for life saving. Endoscopic surgery may improve the functional outcomes because it is less invasive and effectively removes the ICH at GCS score of at least 9.

Limbic leukotomy for intractable major affective disorders: A 7-year follow-up study using nine comprehensive psychiatric test evaluations

Surgical treatment of psychiatric disease can be effective for some patients with severe, intractable disorders. However, few long-term studies using comprehensive psychiatric test evaluation of patients who have undergone surgery have been carried out. Stereotactic limbic leukotomy (subcaudate tractotomy and cingulotomy) was performed via radiofrequency thermocoagulation on 16 patients with intractable major affective disorders (bipolar). Patients were followed for 7 years, and nine complete psychiatric test evaluations were conducted before and after the procedure. Clinical outcomes were evaluated using the Current Global Psychiatric-Social Status Scale (CGPSS). In the 7-year follow-up, mean scores on the Hamilton Depression Rating Scale and the Beck Depression Inventory declined significantly from 42+/-5.76 to 20+/-11.98 (p<0.01) and from 32+/-9.13 to 19 +/- 14.29 (p<0.05), respectively. Also, mean scores on the Hamilton Anxiety Rating Scale and Negative Symptom Scale declined significantly from 104+/-53.62 to 57+/-36.41 (p<0.01) and from 57+/-15.38 to 33+/-18.8 (p<0.05), respectively. There were no statistical differences before and after surgery for Youngs Mania Rating Scale, p>0.1. Using the CGPSS, 68.8% of patients had a marked response (CGPSS of >or=3), 18.9% of patients had a possible response (CGPSS of 2), and 12.6% did not improve or became worse (CGPSS of 0 or 1). There was no surgical mortality and only three patients experienced temporary minor complications. Based on these nine comprehensive psychiatric test evaluations, limbic leukotomy is an effective procedure for long-term treatment of severe, intractable major affective disorders, with no significant side effects. The results of the psychiatric tests carried out during the 7 years of follow-up were constant and stable. The current findings demonstrate that depression, anxiety, and negative symptoms are significantly reduced by limbic leukotomy, but mania and active symptoms are not. Surgical intervention remains an important therapeutic option for the treatment of major affective disorders, and is probably underused.